PTSD

Posttraumatic stress disorder (PTSD) is a chronic and disabling psychiatric disorder. The lifetime prevalence among American adults is 6.8%.¹ Management of PTSD includes treating distressing symptoms, reducing avoidant behaviors, treating comorbid conditions (eg, depression, substance use disorders, or mood dysregulation), and improving adaptive functioning, which includes restoring a psychological sense of safety and trust. PTSD can be treated using evidence-based psychotherapies, pharmacotherapy, or a combination of both modalities. For adults, evidence-based treatment guidelines recommend the use of cognitive-behavioral therapy, cognitive processing therapy, cognitive therapy, and prolonged exposure therapy.² These guidelines also recommend (with some reservations) the use of brief eclectic psychotherapy, eye movement desensitization and reprocessing, and narrative exposure therapy.² Although the evidence base for the use of medications is not as strong as that for the psychotherapies listed above, the guidelines recommend the use of fluoxetine, paroxetine, sertraline, and venlafaxine.²

Currently available treatments for PTSD have significant limitations. For example, trauma-focused psychotherapies can have significant rates of nonresponse, partial response, or treatment dropout.^3,4 Additionally, such therapies are not widely accessible. As for pharmacotherapy, very few available options are supported by evidence, and the efficacy of these options is limited, as shown by the reports that only 60% of patients with PTSD show a response to selective serotonin reuptake inhibitors (SSRIs), and only 20% to 30% achieve complete remission.⁵ Additionally, it may take months for patients to achieve an acceptable level of improvement with medications. As a result, a substantial proportion of patients who seek treatment continue to remain symptomatic, with impaired levels of functioning. This lack of progress in PTSD treatment has been labeled as a national crisis, calling for an urgent need to find effective pharmacologic treatments for PTSD.⁶

In this article, we review 8 randomized controlled trials (RCTs) of treatments for PTSD published within the last 5 years (Table^7-14).

1. Feder A, Costi S, Rutter SB, et al. A randomized controlled trial of repeated ketamine administration for chronic posttraumatic stress disorder. Am J Psychiatry. 2021;178(2):193-202

Feder et al had previously found a significant and quick decrease in PTSD symptoms after a single dose of IV ketamine had. This is the first RCT to examine the effectiveness and safety of repeated IV ketamine infusions for the treatment of persistent PTSD.⁷ 

Study design

• This randomized, double-blind, parallel-arm controlled trial treated 30 individuals with chronic PTSD with 6 infusions of either ketamine (0.5 mg/kg) or midazolam (0.045 mg/kg) over 2 consecutive weeks. 
• Participants were individuals age 18 to 70 with a primary diagnosis of chronic PTSD according to the DSM-5 criteria and determined by The Structure Clinical Interview for DSM-5, with a score ≥30 on the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5).  
• Any severe or unstable medical condition, active suicidal or homicidal ideation, lifetime history of psychotic or bipolar disorder, current anorexia nervosa or bulimia, alcohol or substance use disorder within 3 months of screening, history of recreational ketamine or phencyclidine use on more than 1 occasion or any use in the previous 2 years, and ongoing treatment with a long-acting benzodiazepine or opioid medication were all considered exclusion criteria. Individuals who took short-acting benzodiazepines had their morning doses held on infusion days. Marijuana or cannabis derivatives were allowed. 
• The primary outcome measure was a change in PTSD symptom severity as measured with CAPS-5. This was administered before the first infusion and weekly thereafter. The Impact of Event Scale-Revised, the Montgomery–Åsberg Depression Rating Scale, and adverse effect measurements were used as secondary outcome measures. 
• Treatment response was defined as ≥30% symptom improvement 2 weeks after the first infusion as assessed with CAPS-5. 
• Individuals who responded to treatment were followed naturalistically weekly for up to 4 weeks and then monthly until loss of responder status, or up to 6 months if there was no loss of response. 

Outcomes

• At the second week, the mean CAPS-5 total score in the ketamine group was 11.88 points (SE = 3.96) lower than in the midazolam group (d = 1.13; 95% CI, 0.36 to 1.91).  
• In the ketamine group, 67% of patients responded to therapy, compared to 20% in the midazolam group.  
• Following the 2-week course of infusions, the median period until loss of response among ketamine responders was 27.5 days.  
• Ketamine infusions showed good tolerability and safety. There were no clinically significant adverse effects. 

Continue to: Conclusions/limitations

• Repeated ketamine infusions are effective in reducing symptom severity in individuals with chronic PTSD. 
• Limitations to this study include the exclusion of individuals with comorbid bipolar disorder, current alcohol or substance use disorder, or suicidal ideations, the small sample size, and a higher rate of transient dissociative symptoms in the ketamine group. 
• Future studies could evaluate the efficacy of repeated ketamine infusions in individuals with treatment-resistant PTSD. Also, further studies are required to assess the efficacy of novel interventions to prevent relapse and evaluate the efficacy, safety, and tolerability of periodic IV ketamine use as maintenance.  
• Additional research might determine whether pairing psychotherapy with ketamine administration can lessen the risk of recurrence for PTSD patients after stopping ketamine infusions. 

2. Rauch SAM, Kim HM, Powell C, et al. Efficacy of prolonged exposure therapy, sertraline hydrochloride, and their combination among combat veterans with posttraumatic stress disorder: a randomized clinical trial. JAMA Psychiatry. 2019;76(2):117-126

Clinical practice recommendations for PTSD have identified trauma-focused psychotherapies and SSRIs as very effective treatments. The few studies that have compared trauma-focused psychotherapy to SSRIs or to a combination of treatments are not generalizable, have significant limitations, or are primarily concerned with refractory disorders or augmentation techniques. This study evaluated the efficacy of prolonged exposure therapy (PE) plus placebo, PE plus sertraline, and sertraline plus enhanced medication management in the treatment of PTSD.⁸ 

Study design

• This randomized, 4-site, 24-week clinical trial divided participants into 3 subgroups: PE plus placebo, PE plus sertraline, and sertraline plus enhanced medication management. 
• Participants were veterans or service members of the Iraq and/or Afghanistan wars with combat-related PTSD and significant impairment as indicated by a CAPS score ≥50 for at least 3 months. The DSM-IV-TR version of CAPS was used because the DSM-5 version was not available at the time of the study.
• Individuals who had a current, imminent risk of suicide; active psychosis; alcohol or substance dependence in the past 8 weeks; inability to attend weekly appointments for the treatment period; prior intolerance to or failure of an adequate trial of PE or sertraline; medical illness likely to result in hospitalization or contraindication to study treatment; serious cognitive impairment; mild traumatic brain injury; or concurrent use of antidepressants, antipsychotics, benzodiazepines, prazosin, or sleep agents were excluded. 
• Participants completed up to thirteen 90-minute sessions of PE. 
• The sertraline dosage was titrated during a 10-week period and continued until Week 24. Dosages were adjusted between 50 and 200 mg/d, with the last dose increase at Week 10. 
• The primary outcome measure was symptom severity of PTSD in the past month as determined by CAPS score at Week 24.
• The secondary outcome was self-reported symptoms of PTSD (PTSD checklist [PCL] Specific Stressor Version), clinically meaningful change (reduction of ≥20 points or score ≤35 on CAPS), response (reduction of ≥50% in CAPS score), and remission (CAPS score ≤35). 

Outcomes

• At Week 24, 149 participants completed the study; 207 were included in the intent-to-treat analysis. 
• PTSD symptoms significantly decreased over 24 weeks, according to a modified intent-to-treat analysis utilizing a mixed model of repeated measurements; nevertheless, slopes were similar across therapy groups. 

Continue to: Conclusions/limitations

• Although the severity of PTSD symptoms decreased in all 3 subgroups, there was no difference in PTSD symptom severity or change in symptoms at Week 24 among all 3 subgroups.  
• The main limitation of this study was the inclusion of only combat veterans. 
• Further research should focus on enhancing treatment retention and should include administering sustained exposure therapy at brief intervals. 

3. Lehrner A, Hildebrandt T, Bierer LM, et al. A randomized, double-blind, placebo-controlled trial of hydrocortisone augmentation of prolonged exposure for PTSD in US combat veterans. Behav Res Ther. 2021;144:103924

First-line therapy for PTSD includes cognitive-behavioral therapies such as PE. However, because many people still have major adverse effects after receiving medication, improving treatment efficacy is a concern. Glucocorticoids promote extinction learning, and alterations in glucocorticoid signaling pathways have been associated with PTSD. Lehrner et al previously showed that adding hydrocortisone (HCORT) to PE therapy increased patients’ glucocorticoid sensitivity at baseline, improved treatment retention, and resulted in greater treatment improvements. This study evaluated HCORT in conjunction with PE for combat veterans with PTSD following deployment to Iraq and Afghanistan.⁹ 

Study design

• This randomized, double-blind, placebo-controlled trial administered HCORT 30 mg oral or placebo to 96 combat veterans 30 minutes before PE sessions.  
• Participants were veterans previously deployed to Afghanistan or Iraq with deployment-related PTSD >6 months with a minimum CAPS score of 60. They were unmedicated or on a stable psychotropic regimen for ≥4 weeks. 
• Exclusion criteria included a lifetime history of a primary psychotic disorder (bipolar I disorder or obsessive-compulsive disorder), medical or mental health condition other than PTSD that required immediate clinical attention, moderate to severe traumatic brain injury (TBI), substance abuse or dependence within the past 3 months, medical illness that contraindicated ingestion of hydrocortisone, acute suicide risk, and pregnancy or intent to become pregnant. 
• The primary outcome measures included PTSD severity as assessed with CAPS. 
• Secondary outcome measures included self-reported PTSD symptoms as assessed with the Posttraumatic Diagnostic Scale (PDS) and depression as assessed with the Beck Depression Inventory-II (BDI). These scales were administered pretreatment, posttreatment, and at 3-months follow-up. 

Outcomes

• Out of 96 veterans enrolled, 60 were randomized and 52 completed the treatment.  
• Five participants were considered recovered early and completed <12 sessions.
• Of those who completed treatment, 50 completed the 1-week posttreatment evaluations and 49 completed the 3-month follow-up evaluation.
• There was no difference in the proportion of dropouts (13.33%) across the conditions.
• HCORT failed to significantly improve either secondary outcomes or PTSD symptoms, according to an intent-to-treat analysis.
• However, exploratory analyses revealed that veterans with recent post-concussive symptoms and moderate TBI exposure saw a larger decrease in hyperarousal symptoms after PE therapy with HCORT augmentation.  
• The reduction in avoidance symptoms with HCORT augmentation was also larger in veterans with higher baseline glucocorticoid sensitivity. 

Continue to: Conclusions/limitations

Conclusions/limitations 

• HCORT does not improve PTSD symptoms as assessed with the CAPS and PDS, or depression as assessed with the BDI. 
• The main limitation of this study is generalizability. 
• Further studies are needed to determine whether PE with HCORT could benefit veterans with indicators of enhanced glucocorticoid sensitivity, mild TBI, or postconcussive syndrome. 

4. Inslicht SS, Niles AN, Metzler TJ, et al. Randomized controlled experimental study of hydrocortisone and D-cycloserine effects on fear extinction in PTSD. Neuropsychopharmacology. 2022;47(11):1945-1952

PE, one of the most well-researched therapies for PTSD, is based on fear extinction. Exploring pharmacotherapies that improve fear extinction learning and their potential as supplements to PE is gaining increased attention. Such pharmacotherapies aim to improve the clinical impact of PE on the extent and persistence of symptom reduction. This study evaluated the effects of HCORT and D-cycloserine (DCS), a partial agonist of the N-methyl-D-aspartate (NMDA) receptor, on the learning and consolidation of fear extinction in patients with PTSD.¹⁰ 

Study design

• This double-blind, placebo-controlled, 3-group experimental design evaluated 90 individuals with PTSD who underwent fear conditioning with stimuli that was paired (CS+) or unpaired (CS−) with shock. 
• Participants were veterans and civilians age 18 to 65 recruited from VA outpatient and community clinics and internet advertisements who met the criteria for PTSD or subsyndromal PTSD (according to DSM-IV criteria) for at least 3 months. 
• Exclusion criteria included schizophrenia, bipolar disorder, substance abuse or dependence, alcohol dependence, previous moderate or severe head injury, seizure or neurological disorder, current infectious illness, systemic illness affecting CNS function, or other conditions known to affect psychophysiological responses. Excluded medications were antipsychotics, mood stabilizers, alpha- and beta-adrenergics, benzodiazepines, anticonvulsants, antihypertensives, sympathomimetics, anticholinergics, and steroids.  
• Extinction learning took place 72 hours after extinction, and extinction retention was evaluated 1 week later. Placebo, HCORT 25 mg, or DCS 50 mg was given 1 hour before extinction learning. 
• Clinical measures included PTSD diagnosis and symptom levels as determined by interview using CAPS and skin conduction response. 

Outcomes

• The mean shock level, mean pre-stimulus skin conductance level (SCL) during habituation, and mean SC orienting response during the habituation phase did not differ between groups and were not associated with differential fear conditioning. Therefore, variations in shock level preference, resting SCL, or SC orienting response magnitude are unlikely to account for differences between groups during extinction learning and retention.
• During extinction learning, the DCS and HCORT groups showed a reduced differential CS+/CS− skin conductance response (SCR) compared to placebo. 
• One week later, during the retention testing, there was a nonsignificant trend toward a smaller differential CS+/CS− SCR in the DCS group compared to placebo. HCORT and DCS administered as a single dosage facilitated fear extinction learning in individuals with PTSD symptoms. 

Continue to: Conclusions/limitations

Conclusions/limitations 

• In traumatized people with PTSD symptoms, a single dosage of HCORT or DCS enhanced the learning of fear extinction compared to placebo. A nonsignificant trend toward better extinction retention in the DCS group but not the HCORT group was also visible. 
• These results imply that glucocorticoids and NMDA agonists have the potential to promote extinction learning in PTSD. 
• Limitations include a lack of measures of glucocorticoid receptor sensitivity or FKBP5. 
• Further studies could evaluate these findings with the addition of blood biomarker measures such as glucocorticoid receptor sensitivity or FKBP5.  

5. Mitchell JM, Bogenschutz M, Lilienstein A, et al. MDMA-assisted therapy for severe PTSD: a randomized, double-blind, placebo-controlled phase 3 study. Nat Med. 2021;27(6):1025-1033. doi:10.1038/s41591-021-01336-3

Poor PTSD treatment results are associated with numerous comorbid conditions, such as dissociation, depression, alcohol and substance use disorders, childhood trauma, and suicidal ideation, which frequently leads to treatment resistance. Therefore, it is crucial to find a treatment that works for individuals with PTSD who also have comorbid conditions. In animal models, 3,4-methylenedioxymethamphetamine (MDMA), an empathogen/entactogen with stimulant properties, has been shown to enhance fear memory extinction and modulate fear memory reconsolidation. This study evaluated the efficacy and safety of MDMA-assisted therapy for treating patients with severe PTSD, including those with common comorbidities.¹¹ 

Study design

• This randomized, double-blind, placebo-controlled, multi-site, phase 3 clinical trial evaluated individuals randomized to receive manualized therapy with MDMA or with placebo, combined with 3 preparatory and 9 integrative therapy sessions.  
• Participants were 90 individuals (46 randomized to MDMA and 44 to placebo) with PTSD with a symptom duration ≥6 months and CAPS-5 total severity score ≥35 at baseline. 
• Exclusion criteria included primary psychotic disorder, bipolar I disorder, eating disorders with active purging, major depressive disorder with psychotic features, dissociative identity disorder, personality disorders, current alcohol and substance use disorders, lactation or pregnancy, and any condition that could make receiving a sympathomimetic medication dangerous due to hypertension or tachycardia, including uncontrolled hypertension, history of arrhythmia, or marked baseline prolongation of QT and/or QTc interval. 
• Three 8-hour experimental sessions of either therapy with MDMA assistance or therapy with a placebo control were given during the treatment period, and they were spaced approximately 4 weeks apart. 
• In each session, participants received placebo or a single divided dose of MDMA 80 to 180 mg. 
• At baseline and 2 months after the last experimental sessions, PTSD symptoms were measured with CAPS-5, and functional impairment was measured with Sheehan Disability Scale (SDS). 
• The primary outcome measure was CAPS-5 total severity score at 18 weeks compared to baseline for MDMA-assisted therapy vs placebo-assisted therapy. 
• The secondary outcome measure was clinician-rated functional impairment using the mean difference in SDS total scores from baseline to 18 weeks for MDMA-assisted therapy vs placebo-assisted therapy. 

Outcomes

• MDMA was found to induce significant and robust attenuation in CAPS-5 score compared to placebo. 
• The mean change in CAPS-5 score in completers was –24.4 in the MDMA group and –13.9 in the placebo group. 
• MDMA significantly decreased the SDS total score. 
• MDMA did not induce suicidality, misuse, or QT prolongation. 

Continue to: Conclusions/limitations

• MDMA-assisted therapy is significantly more effective than manualized therapy with placebo in treating patients with severe PTSD, and it is also safe and well-tolerated, even in individuals with comorbidities. 
• No major safety issues were associated with MDMA-assisted treatment. 
• MDMA-assisted therapy should be promptly assessed for clinical usage because it has the potential to significantly transform the way PTSD is treated. 
• Limitations of this study include a smaller sample size (due to the COVID-19 pandemic); lack of ethnic and racial diversity; short duration; safety data were collected by site therapist, which limited the blinding; and the blinding of participants was difficult due to the subjective effects of MDMA, which could have resulted in expectation effects. 

6. Bonn-Miller MO, Sisley S, Riggs P, et al. The short-term impact of 3 smoked cannabis preparations versus placebo on PTSD symptoms: a randomized cross-over clinical trial. PLoS One. 2021;16(3):e0246990

Sertraline and paroxetine are the only FDA-approved medications for treating PTSD. Some evidence suggests cannabis may provide a therapeutic benefit for PTSD.¹⁵ This study examined the effects of 3 different preparations of cannabis for treating PTSD symptoms.¹²  

Study design

• This double-blind, randomized, placebo-controlled, crossover trial used 3 active treatment groups of cannabis: high delta-9-tetrahydrocannabinol (THC)/low cannabidiol (CBD), high CBD/low THC, and high THC/high CBD (THC+CBD). A low THC/low CBD preparation was used as a placebo. “High” content contained 9% to 15% concentration by weight of the respective cannabinoid, and “low” content contained <2% concentration by weight.  
• Inclusion criteria included being a US military veteran, meeting DSM-5 PTSD criteria for ≥6 months, having moderate symptom severity (CAPS-5 score ≥25), abstaining from cannabis 2 weeks prior to study and agreeing not to use any non-study cannabis during the trial, and being stable on medications/therapy prior to the study.  
• Exclusion criteria included women who were pregnant/nursing/child-bearing age and not taking an effective means of birth control; current/past serious mental illness, including psychotic and personality disorders; having a first-degree relative with a psychotic or bipolar disorder; having a high suicide risk based on Columbia-Suicide Severity Rating Scale; meeting DSM-5 criteria for moderate-severe cannabis use disorder; screening positive for illicit substances; or having significant medical disease.  
• Participants in Stage 1 (n = 80) were randomized to 1 of the 3 active treatments or placebo for 3 weeks. After a 2-week washout, participants in Stage 2 (n = 74) were randomized to receive for 3 weeks 1 of the 3 active treatments they had not previously received.
• During each stage, participants had ad libitum use for a maximum of 1.8 g/d. 
• The primary outcome was change in PTSD symptom severity by the end of Stage 1 as assessed with CAPS-5.
• Secondary outcomes included the PTSD Checklist for DSM-5 (PCL-5), the general depression subscale and anxiety subscale from the self-report Inventory of Depression and Anxiety Symptoms (IDAS), the Inventory of Psychosocial Functioning, and the Insomnia Severity Index. 

Outcomes

• Six participants did not continue to Stage 2. Three participants did not finish Stage 2 due to adverse effects, and 7 did not complete outcome measurements. The overall attrition rate was 16.3%. 
• There was no significant difference in total grams of smoked cannabis or placebo between the 4 treatment groups in Stage 1 at the end of 3 weeks. In Stage 2, there was a significant difference, with the THC+CBD group using more cannabis compared to the other 2 groups. 
• Each of the 4 groups had significant reductions in total CAPS-5 scores at the end of Stage 1, and there was no significant difference in CAPS-5 severity scores between the 4 groups.
• In Stage 1, PCL-5 scores were not significantly different between treatment groups from baseline to the end of stage. There was a significant difference in Stage 2 between the high CBD and THC+CBD groups, with the combined group reporting greater improvement of symptoms. 
• In Stage 2, the THC+CBD group reported greater reductions in pre/post IDAS social anxiety scores and IDAS general depression scores, and the high THC group reported greater reductions in pre/post IDAS social anxiety scores. 
• In Stage 1, 37 of 60 participants in the active groups reported at least 1 adverse event, and 45 of the 74 Stage 2 participants reported at least 1 adverse event. The most common adverse events were cough, throat irritation, and anxiety. Participants in the Stage 1 high THC group had a significant increase in reported withdrawal symptoms after 1 week of stopping use.  

Continue to: Conclusions/limitations

• This first randomized, placebo-control trial of cannabis in US veterans did not show a significant difference among treatment groups, including placebo, on the primary outcome of CAPS-5 score. All 4 groups had significant reductions in symptom severity on CAPS-5 and showed good tolerability.
• Prior beliefs about the effects of cannabis may have played a role in the reduction of PTSD symptoms in the placebo group.
• Many participants (n =34) were positive for THC during the screening process, so previous cannabis use/chronicity of cannabis use may have contributed.
• One limitation was that participants assigned to the Stage 1 high THC group had Cannabis Use Disorders Identification Test scores (which assesses cannabis use disorder risk) about 2 times greater than participants in other conditions.
• Another limitation was that total cannabis use was lower than expected, as participants in Stage 1 used 8.2 g to 14.6 g over 3 weeks, though they had access to up to 37.8 g. 
• There was no placebo in Stage 2.
• Future studies should look at longer treatment periods with more participants.

7. Youngstedt SD, Kline CE, Reynolds AM, et al. Bright light treatment of combat-related PTSD: a randomized controlled trial. Milit Med. 2022;187(3-4):e435-e444

Bright light therapy is an inexpensive treatment approach that may affect serotonergic pathways.¹⁶ This study examined bright light therapy for reducing PTSD symptoms and examined if improvement of PTSD is related to a shift in circadian rhythm.¹³  

Study design

• Veterans with combat-related PTSD had to have been stable on treatment for at least 8 weeks or to have not received any other PTSD treatments prior to the study.
• Participants were randomized to active treatment of 30 minutes daily 10,000 lux ultraviolet-filtered white light while sitting within 18 inches (n = 34) or a control condition of 30 minutes daily inactivated negative ion generator (n = 35) for 4 weeks.
• Inclusion criteria included a CAPS score ≥30.
•  Exclusion criteria included high suicidality, high probability of alcohol/substance abuse in the past 3 months, bipolar disorder/mania/schizophrenia/psychosis, ophthalmologic deformities, shift work in past 2 months or travel across time zones in past 2 weeks, head trauma, high outdoor light exposure, history of winter depression, history of seizures, or myocardial infarction/stroke/cancer within 3 years.
• Primary outcomes were improvement on CAPS and Clinical Global Impressions-Improvement scale (CGI-IM) score at Week 4.
• Wrist actigraphy recordings measured sleep.
• Other measurements included the Hamilton Depression Rating Scale (HAM-D), Hamilton atypical symptoms (HAM-AS), PCL-Military (PCL-M), Pittsburg Sleep Quality Index (PSQI), BDI, Spielberger State-Trait Anxiety Inventory (STAI Form Y-2), Beck Suicide Scale, and Systematic Assessment for Treatment Emergent Effects questionnaire.

Outcomes

• There was a significant decrease in CAPS score in participants who received bright light therapy compared to controls. Treatment response (defined as ≥33% reduction in score) was significantly greater in the bright light (44%) vs control (8.6%) group. No participants achieved remission. 
• There was a significant improvement in CGI-IM scores in the bright light group, but no significant difference in participants who were judged to improve “much” or “very much.”
• PCL-M scores did not change significantly between groups, although a significantly greater proportion of participants had treatment response in the bright light group (33%) vs control (6%).
• There were no significant changes in HAM-D, HAM-AS, STAI, BDI, actigraphic estimates of sleep, or PSQI scores. 
• Bright light therapy resulted in phase advancement while control treatment had phase delay. 
• There were no significant differences in adverse effects. 

Continue to: Conclusions/limitations

• Bright light therapy may be a treatment option or adjunct for combat-related PTSD as seen by improvement on CAPS and CGI scores, as well as a greater treatment response seen on CAPS and PCL-5 scores in the bright light group.  
• There was no significant difference for other measures, including depression, anxiety, and sleep.  
• Limitations include excluding patients with a wide variety of medical or psychiatric comorbidities, as well as limited long-term follow up data.  
• Other limitations include not knowing the precise amount of time participants stayed in front of the light device and loss of some actigraphic data (data from only 49 of 69 participants).  

8. Peterson AL, Mintz J, Moring JC, et al. In-office, in-home, and telehealth cognitive processing therapy for posttraumatic stress disorder in veterans: a randomized clinical trial. BMC Psychiatry. 2022;22(1):41 doi:10.1186/s12888-022-03699-4

Cognitive processing therapy (CPT), a type of trauma-focused psychotherapy, is an effective treatment for PTSD in the military population.^17,18 However, patients may not be able to or want to participate in such therapy due to barriers such as difficulty arranging transportation, being homebound due to injury, concerns about COVID-19, stigma, familial obligations, and job constraints. This study looked at if CPT delivered face-to-face at the patient’s home or via telehealth in home would be effective and increase accessibility.¹⁴  

Study design

• Participants (n = 120) were active-duty military and veterans who met DSM-5 criteria for PTSD. They were randomized to receive CPT in the office, in their home, or via telehealth. Participants could choose not to partake in 1 modality but were then randomized to 1 of the other 2. 
• Exclusion criteria included suicide/homicide risk needing intervention, items/situations pertaining to danger (ie, aggressive pet or unsafe neighborhood), significant alcohol/substance use, active psychosis, and impaired cognitive functioning. 
• The primary outcome measurement was change in PCL-5 and CAPS-5 score over 6 months. The BDI-II was used to assess depressive symptoms.  
• Secondary outcomes included the Reliable Change Index (defined as “an improvement of 10 or more points that was sustained at all subsequent assessments”) on the PCL-5 and remission on the CAPS-5.
• CPT was delivered in 60-minute sessions twice a week for 6 weeks. Participants who did not have electronic resources were loaned a telehealth apparatus. 

Outcomes

• Overall, 57% of participants opted out of 1 modality, which resulted in fewer participants being placed into the in-home arm (n = 32). Most participants chose not to do in-home treatments (54%), followed by in-office (29%), and telehealth (17%). 
• There was a significant posttreatment improvement in PCL-5 scores in all treatment arms, with improvement greater with in-home (d = 2.1) and telehealth (d = 2.0) vs in-office (d=1.3). The in-home and telehealth scores were significantly improved compared to in-office, and the difference between in-home and telehealth PCL-5 scores was minimal.
• At 6 months posttreatment, the differences between the 3 treatment groups on PCL-5 score were negligible. 
• CAPS-5 scores were significantly improved in all treatment arms, with improvement largest with in-home treatment; however, the differences between the groups were not significant.  
• BDI-II scores improved in all modalities but were larger in the in-home (d = 1.2) and telehealth (d = 1.1) arms than the in-office arm (d = 0.52). 
• Therapist time commitment was greater for the in-home and in-office arms (2 hours/session) than the telehealth arm (1 hour/session). This difference was due to commuting time for the patient or therapist.
• The dropout rate was not statistically significant between the groups.
• Adverse events did not significantly differ per group. The most commonly reported ones included nightmares, sleep difficulty, depression, anxiety, and irritability.

Conclusions/limitations

• Patients undergoing CPT had significant improvement in PTSD symptoms, with posttreatment PCL-5 improvement approximately twice as large in those who received the in-home and telehealth modalities vs in-office treatment. 
• The group differences were not seen on CAPS-5 scores at posttreatment, or PCL-5 or CAPS-5 scores at 6 months posttreatment.  
• In-home CPT was declined the most, which suggests that in-home distractions or the stigma of a mental health clinician being in their home played a role in patients’ decision-making. However, in-home CPT produced the greatest amount of improvement in PTSD symptoms. The authors concluded that in-home therapy should be reserved for those who are homebound or have travel limitations.  
• This study shows evidence that telehealth may be a good modality for CPT, as seen by improvement in PTSD symptoms and good acceptability and retention. 
• Limitations include more patients opting out of in-home CPT, and reimbursement for travel may not be available in the real-world setting.  

Posttraumatic stress disorder (PTSD) is a chronic and disabling psychiatric disorder. The lifetime prevalence among American adults is 6.8%.¹ Management of PTSD includes treating distressing symptoms, reducing avoidant behaviors, treating comorbid conditions (eg, depression, substance use disorders, or mood dysregulation), and improving adaptive functioning, which includes restoring a psychological sense of safety and trust. PTSD can be treated using evidence-based psychotherapies, pharmacotherapy, or a combination of both modalities. For adults, evidence-based treatment guidelines recommend the use of cognitive-behavioral therapy, cognitive processing therapy, cognitive therapy, and prolonged exposure therapy.² These guidelines also recommend (with some reservations) the use of brief eclectic psychotherapy, eye movement desensitization and reprocessing, and narrative exposure therapy.² Although the evidence base for the use of medications is not as strong as that for the psychotherapies listed above, the guidelines recommend the use of fluoxetine, paroxetine, sertraline, and venlafaxine.²

Currently available treatments for PTSD have significant limitations. For example, trauma-focused psychotherapies can have significant rates of nonresponse, partial response, or treatment dropout.^3,4 Additionally, such therapies are not widely accessible. As for pharmacotherapy, very few available options are supported by evidence, and the efficacy of these options is limited, as shown by the reports that only 60% of patients with PTSD show a response to selective serotonin reuptake inhibitors (SSRIs), and only 20% to 30% achieve complete remission.⁵ Additionally, it may take months for patients to achieve an acceptable level of improvement with medications. As a result, a substantial proportion of patients who seek treatment continue to remain symptomatic, with impaired levels of functioning. This lack of progress in PTSD treatment has been labeled as a national crisis, calling for an urgent need to find effective pharmacologic treatments for PTSD.⁶

In this article, we review 8 randomized controlled trials (RCTs) of treatments for PTSD published within the last 5 years (Table^7-14).

1. Feder A, Costi S, Rutter SB, et al. A randomized controlled trial of repeated ketamine administration for chronic posttraumatic stress disorder. Am J Psychiatry. 2021;178(2):193-202

Feder et al had previously found a significant and quick decrease in PTSD symptoms after a single dose of IV ketamine had. This is the first RCT to examine the effectiveness and safety of repeated IV ketamine infusions for the treatment of persistent PTSD.⁷ 

Study design

• This randomized, double-blind, parallel-arm controlled trial treated 30 individuals with chronic PTSD with 6 infusions of either ketamine (0.5 mg/kg) or midazolam (0.045 mg/kg) over 2 consecutive weeks. 
• Participants were individuals age 18 to 70 with a primary diagnosis of chronic PTSD according to the DSM-5 criteria and determined by The Structure Clinical Interview for DSM-5, with a score ≥30 on the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5).  
• Any severe or unstable medical condition, active suicidal or homicidal ideation, lifetime history of psychotic or bipolar disorder, current anorexia nervosa or bulimia, alcohol or substance use disorder within 3 months of screening, history of recreational ketamine or phencyclidine use on more than 1 occasion or any use in the previous 2 years, and ongoing treatment with a long-acting benzodiazepine or opioid medication were all considered exclusion criteria. Individuals who took short-acting benzodiazepines had their morning doses held on infusion days. Marijuana or cannabis derivatives were allowed. 
• The primary outcome measure was a change in PTSD symptom severity as measured with CAPS-5. This was administered before the first infusion and weekly thereafter. The Impact of Event Scale-Revised, the Montgomery–Åsberg Depression Rating Scale, and adverse effect measurements were used as secondary outcome measures. 
• Treatment response was defined as ≥30% symptom improvement 2 weeks after the first infusion as assessed with CAPS-5. 
• Individuals who responded to treatment were followed naturalistically weekly for up to 4 weeks and then monthly until loss of responder status, or up to 6 months if there was no loss of response. 

Outcomes

• At the second week, the mean CAPS-5 total score in the ketamine group was 11.88 points (SE = 3.96) lower than in the midazolam group (d = 1.13; 95% CI, 0.36 to 1.91).  
• In the ketamine group, 67% of patients responded to therapy, compared to 20% in the midazolam group.  
• Following the 2-week course of infusions, the median period until loss of response among ketamine responders was 27.5 days.  
• Ketamine infusions showed good tolerability and safety. There were no clinically significant adverse effects. 

Continue to: Conclusions/limitations

• Repeated ketamine infusions are effective in reducing symptom severity in individuals with chronic PTSD. 
• Limitations to this study include the exclusion of individuals with comorbid bipolar disorder, current alcohol or substance use disorder, or suicidal ideations, the small sample size, and a higher rate of transient dissociative symptoms in the ketamine group. 
• Future studies could evaluate the efficacy of repeated ketamine infusions in individuals with treatment-resistant PTSD. Also, further studies are required to assess the efficacy of novel interventions to prevent relapse and evaluate the efficacy, safety, and tolerability of periodic IV ketamine use as maintenance.  
• Additional research might determine whether pairing psychotherapy with ketamine administration can lessen the risk of recurrence for PTSD patients after stopping ketamine infusions. 

2. Rauch SAM, Kim HM, Powell C, et al. Efficacy of prolonged exposure therapy, sertraline hydrochloride, and their combination among combat veterans with posttraumatic stress disorder: a randomized clinical trial. JAMA Psychiatry. 2019;76(2):117-126

Clinical practice recommendations for PTSD have identified trauma-focused psychotherapies and SSRIs as very effective treatments. The few studies that have compared trauma-focused psychotherapy to SSRIs or to a combination of treatments are not generalizable, have significant limitations, or are primarily concerned with refractory disorders or augmentation techniques. This study evaluated the efficacy of prolonged exposure therapy (PE) plus placebo, PE plus sertraline, and sertraline plus enhanced medication management in the treatment of PTSD.⁸ 

Study design

• This randomized, 4-site, 24-week clinical trial divided participants into 3 subgroups: PE plus placebo, PE plus sertraline, and sertraline plus enhanced medication management. 
• Participants were veterans or service members of the Iraq and/or Afghanistan wars with combat-related PTSD and significant impairment as indicated by a CAPS score ≥50 for at least 3 months. The DSM-IV-TR version of CAPS was used because the DSM-5 version was not available at the time of the study.
• Individuals who had a current, imminent risk of suicide; active psychosis; alcohol or substance dependence in the past 8 weeks; inability to attend weekly appointments for the treatment period; prior intolerance to or failure of an adequate trial of PE or sertraline; medical illness likely to result in hospitalization or contraindication to study treatment; serious cognitive impairment; mild traumatic brain injury; or concurrent use of antidepressants, antipsychotics, benzodiazepines, prazosin, or sleep agents were excluded. 
• Participants completed up to thirteen 90-minute sessions of PE. 
• The sertraline dosage was titrated during a 10-week period and continued until Week 24. Dosages were adjusted between 50 and 200 mg/d, with the last dose increase at Week 10. 
• The primary outcome measure was symptom severity of PTSD in the past month as determined by CAPS score at Week 24.
• The secondary outcome was self-reported symptoms of PTSD (PTSD checklist [PCL] Specific Stressor Version), clinically meaningful change (reduction of ≥20 points or score ≤35 on CAPS), response (reduction of ≥50% in CAPS score), and remission (CAPS score ≤35). 

Outcomes

• At Week 24, 149 participants completed the study; 207 were included in the intent-to-treat analysis. 
• PTSD symptoms significantly decreased over 24 weeks, according to a modified intent-to-treat analysis utilizing a mixed model of repeated measurements; nevertheless, slopes were similar across therapy groups. 

Continue to: Conclusions/limitations

• Although the severity of PTSD symptoms decreased in all 3 subgroups, there was no difference in PTSD symptom severity or change in symptoms at Week 24 among all 3 subgroups.  
• The main limitation of this study was the inclusion of only combat veterans. 
• Further research should focus on enhancing treatment retention and should include administering sustained exposure therapy at brief intervals. 

3. Lehrner A, Hildebrandt T, Bierer LM, et al. A randomized, double-blind, placebo-controlled trial of hydrocortisone augmentation of prolonged exposure for PTSD in US combat veterans. Behav Res Ther. 2021;144:103924

First-line therapy for PTSD includes cognitive-behavioral therapies such as PE. However, because many people still have major adverse effects after receiving medication, improving treatment efficacy is a concern. Glucocorticoids promote extinction learning, and alterations in glucocorticoid signaling pathways have been associated with PTSD. Lehrner et al previously showed that adding hydrocortisone (HCORT) to PE therapy increased patients’ glucocorticoid sensitivity at baseline, improved treatment retention, and resulted in greater treatment improvements. This study evaluated HCORT in conjunction with PE for combat veterans with PTSD following deployment to Iraq and Afghanistan.⁹ 

Study design

• This randomized, double-blind, placebo-controlled trial administered HCORT 30 mg oral or placebo to 96 combat veterans 30 minutes before PE sessions.  
• Participants were veterans previously deployed to Afghanistan or Iraq with deployment-related PTSD >6 months with a minimum CAPS score of 60. They were unmedicated or on a stable psychotropic regimen for ≥4 weeks. 
• Exclusion criteria included a lifetime history of a primary psychotic disorder (bipolar I disorder or obsessive-compulsive disorder), medical or mental health condition other than PTSD that required immediate clinical attention, moderate to severe traumatic brain injury (TBI), substance abuse or dependence within the past 3 months, medical illness that contraindicated ingestion of hydrocortisone, acute suicide risk, and pregnancy or intent to become pregnant. 
• The primary outcome measures included PTSD severity as assessed with CAPS. 
• Secondary outcome measures included self-reported PTSD symptoms as assessed with the Posttraumatic Diagnostic Scale (PDS) and depression as assessed with the Beck Depression Inventory-II (BDI). These scales were administered pretreatment, posttreatment, and at 3-months follow-up. 

Outcomes

• Out of 96 veterans enrolled, 60 were randomized and 52 completed the treatment.  
• Five participants were considered recovered early and completed <12 sessions.
• Of those who completed treatment, 50 completed the 1-week posttreatment evaluations and 49 completed the 3-month follow-up evaluation.
• There was no difference in the proportion of dropouts (13.33%) across the conditions.
• HCORT failed to significantly improve either secondary outcomes or PTSD symptoms, according to an intent-to-treat analysis.
• However, exploratory analyses revealed that veterans with recent post-concussive symptoms and moderate TBI exposure saw a larger decrease in hyperarousal symptoms after PE therapy with HCORT augmentation.  
• The reduction in avoidance symptoms with HCORT augmentation was also larger in veterans with higher baseline glucocorticoid sensitivity. 

Continue to: Conclusions/limitations

Conclusions/limitations 

• HCORT does not improve PTSD symptoms as assessed with the CAPS and PDS, or depression as assessed with the BDI. 
• The main limitation of this study is generalizability. 
• Further studies are needed to determine whether PE with HCORT could benefit veterans with indicators of enhanced glucocorticoid sensitivity, mild TBI, or postconcussive syndrome. 

4. Inslicht SS, Niles AN, Metzler TJ, et al. Randomized controlled experimental study of hydrocortisone and D-cycloserine effects on fear extinction in PTSD. Neuropsychopharmacology. 2022;47(11):1945-1952

PE, one of the most well-researched therapies for PTSD, is based on fear extinction. Exploring pharmacotherapies that improve fear extinction learning and their potential as supplements to PE is gaining increased attention. Such pharmacotherapies aim to improve the clinical impact of PE on the extent and persistence of symptom reduction. This study evaluated the effects of HCORT and D-cycloserine (DCS), a partial agonist of the N-methyl-D-aspartate (NMDA) receptor, on the learning and consolidation of fear extinction in patients with PTSD.¹⁰ 

Study design

• This double-blind, placebo-controlled, 3-group experimental design evaluated 90 individuals with PTSD who underwent fear conditioning with stimuli that was paired (CS+) or unpaired (CS−) with shock. 
• Participants were veterans and civilians age 18 to 65 recruited from VA outpatient and community clinics and internet advertisements who met the criteria for PTSD or subsyndromal PTSD (according to DSM-IV criteria) for at least 3 months. 
• Exclusion criteria included schizophrenia, bipolar disorder, substance abuse or dependence, alcohol dependence, previous moderate or severe head injury, seizure or neurological disorder, current infectious illness, systemic illness affecting CNS function, or other conditions known to affect psychophysiological responses. Excluded medications were antipsychotics, mood stabilizers, alpha- and beta-adrenergics, benzodiazepines, anticonvulsants, antihypertensives, sympathomimetics, anticholinergics, and steroids.  
• Extinction learning took place 72 hours after extinction, and extinction retention was evaluated 1 week later. Placebo, HCORT 25 mg, or DCS 50 mg was given 1 hour before extinction learning. 
• Clinical measures included PTSD diagnosis and symptom levels as determined by interview using CAPS and skin conduction response. 

Outcomes

• The mean shock level, mean pre-stimulus skin conductance level (SCL) during habituation, and mean SC orienting response during the habituation phase did not differ between groups and were not associated with differential fear conditioning. Therefore, variations in shock level preference, resting SCL, or SC orienting response magnitude are unlikely to account for differences between groups during extinction learning and retention.
• During extinction learning, the DCS and HCORT groups showed a reduced differential CS+/CS− skin conductance response (SCR) compared to placebo. 
• One week later, during the retention testing, there was a nonsignificant trend toward a smaller differential CS+/CS− SCR in the DCS group compared to placebo. HCORT and DCS administered as a single dosage facilitated fear extinction learning in individuals with PTSD symptoms. 

Continue to: Conclusions/limitations

Conclusions/limitations 

• In traumatized people with PTSD symptoms, a single dosage of HCORT or DCS enhanced the learning of fear extinction compared to placebo. A nonsignificant trend toward better extinction retention in the DCS group but not the HCORT group was also visible. 
• These results imply that glucocorticoids and NMDA agonists have the potential to promote extinction learning in PTSD. 
• Limitations include a lack of measures of glucocorticoid receptor sensitivity or FKBP5. 
• Further studies could evaluate these findings with the addition of blood biomarker measures such as glucocorticoid receptor sensitivity or FKBP5.  

5. Mitchell JM, Bogenschutz M, Lilienstein A, et al. MDMA-assisted therapy for severe PTSD: a randomized, double-blind, placebo-controlled phase 3 study. Nat Med. 2021;27(6):1025-1033. doi:10.1038/s41591-021-01336-3

Poor PTSD treatment results are associated with numerous comorbid conditions, such as dissociation, depression, alcohol and substance use disorders, childhood trauma, and suicidal ideation, which frequently leads to treatment resistance. Therefore, it is crucial to find a treatment that works for individuals with PTSD who also have comorbid conditions. In animal models, 3,4-methylenedioxymethamphetamine (MDMA), an empathogen/entactogen with stimulant properties, has been shown to enhance fear memory extinction and modulate fear memory reconsolidation. This study evaluated the efficacy and safety of MDMA-assisted therapy for treating patients with severe PTSD, including those with common comorbidities.¹¹ 

Study design

• This randomized, double-blind, placebo-controlled, multi-site, phase 3 clinical trial evaluated individuals randomized to receive manualized therapy with MDMA or with placebo, combined with 3 preparatory and 9 integrative therapy sessions.  
• Participants were 90 individuals (46 randomized to MDMA and 44 to placebo) with PTSD with a symptom duration ≥6 months and CAPS-5 total severity score ≥35 at baseline. 
• Exclusion criteria included primary psychotic disorder, bipolar I disorder, eating disorders with active purging, major depressive disorder with psychotic features, dissociative identity disorder, personality disorders, current alcohol and substance use disorders, lactation or pregnancy, and any condition that could make receiving a sympathomimetic medication dangerous due to hypertension or tachycardia, including uncontrolled hypertension, history of arrhythmia, or marked baseline prolongation of QT and/or QTc interval. 
• Three 8-hour experimental sessions of either therapy with MDMA assistance or therapy with a placebo control were given during the treatment period, and they were spaced approximately 4 weeks apart. 
• In each session, participants received placebo or a single divided dose of MDMA 80 to 180 mg. 
• At baseline and 2 months after the last experimental sessions, PTSD symptoms were measured with CAPS-5, and functional impairment was measured with Sheehan Disability Scale (SDS). 
• The primary outcome measure was CAPS-5 total severity score at 18 weeks compared to baseline for MDMA-assisted therapy vs placebo-assisted therapy. 
• The secondary outcome measure was clinician-rated functional impairment using the mean difference in SDS total scores from baseline to 18 weeks for MDMA-assisted therapy vs placebo-assisted therapy. 

Outcomes

• MDMA was found to induce significant and robust attenuation in CAPS-5 score compared to placebo. 
• The mean change in CAPS-5 score in completers was –24.4 in the MDMA group and –13.9 in the placebo group. 
• MDMA significantly decreased the SDS total score. 
• MDMA did not induce suicidality, misuse, or QT prolongation. 

Continue to: Conclusions/limitations

• MDMA-assisted therapy is significantly more effective than manualized therapy with placebo in treating patients with severe PTSD, and it is also safe and well-tolerated, even in individuals with comorbidities. 
• No major safety issues were associated with MDMA-assisted treatment. 
• MDMA-assisted therapy should be promptly assessed for clinical usage because it has the potential to significantly transform the way PTSD is treated. 
• Limitations of this study include a smaller sample size (due to the COVID-19 pandemic); lack of ethnic and racial diversity; short duration; safety data were collected by site therapist, which limited the blinding; and the blinding of participants was difficult due to the subjective effects of MDMA, which could have resulted in expectation effects. 

6. Bonn-Miller MO, Sisley S, Riggs P, et al. The short-term impact of 3 smoked cannabis preparations versus placebo on PTSD symptoms: a randomized cross-over clinical trial. PLoS One. 2021;16(3):e0246990

Sertraline and paroxetine are the only FDA-approved medications for treating PTSD. Some evidence suggests cannabis may provide a therapeutic benefit for PTSD.¹⁵ This study examined the effects of 3 different preparations of cannabis for treating PTSD symptoms.¹²  

Study design

• This double-blind, randomized, placebo-controlled, crossover trial used 3 active treatment groups of cannabis: high delta-9-tetrahydrocannabinol (THC)/low cannabidiol (CBD), high CBD/low THC, and high THC/high CBD (THC+CBD). A low THC/low CBD preparation was used as a placebo. “High” content contained 9% to 15% concentration by weight of the respective cannabinoid, and “low” content contained <2% concentration by weight.  
• Inclusion criteria included being a US military veteran, meeting DSM-5 PTSD criteria for ≥6 months, having moderate symptom severity (CAPS-5 score ≥25), abstaining from cannabis 2 weeks prior to study and agreeing not to use any non-study cannabis during the trial, and being stable on medications/therapy prior to the study.  
• Exclusion criteria included women who were pregnant/nursing/child-bearing age and not taking an effective means of birth control; current/past serious mental illness, including psychotic and personality disorders; having a first-degree relative with a psychotic or bipolar disorder; having a high suicide risk based on Columbia-Suicide Severity Rating Scale; meeting DSM-5 criteria for moderate-severe cannabis use disorder; screening positive for illicit substances; or having significant medical disease.  
• Participants in Stage 1 (n = 80) were randomized to 1 of the 3 active treatments or placebo for 3 weeks. After a 2-week washout, participants in Stage 2 (n = 74) were randomized to receive for 3 weeks 1 of the 3 active treatments they had not previously received.
• During each stage, participants had ad libitum use for a maximum of 1.8 g/d. 
• The primary outcome was change in PTSD symptom severity by the end of Stage 1 as assessed with CAPS-5.
• Secondary outcomes included the PTSD Checklist for DSM-5 (PCL-5), the general depression subscale and anxiety subscale from the self-report Inventory of Depression and Anxiety Symptoms (IDAS), the Inventory of Psychosocial Functioning, and the Insomnia Severity Index. 

Outcomes

• Six participants did not continue to Stage 2. Three participants did not finish Stage 2 due to adverse effects, and 7 did not complete outcome measurements. The overall attrition rate was 16.3%. 
• There was no significant difference in total grams of smoked cannabis or placebo between the 4 treatment groups in Stage 1 at the end of 3 weeks. In Stage 2, there was a significant difference, with the THC+CBD group using more cannabis compared to the other 2 groups. 
• Each of the 4 groups had significant reductions in total CAPS-5 scores at the end of Stage 1, and there was no significant difference in CAPS-5 severity scores between the 4 groups.
• In Stage 1, PCL-5 scores were not significantly different between treatment groups from baseline to the end of stage. There was a significant difference in Stage 2 between the high CBD and THC+CBD groups, with the combined group reporting greater improvement of symptoms. 
• In Stage 2, the THC+CBD group reported greater reductions in pre/post IDAS social anxiety scores and IDAS general depression scores, and the high THC group reported greater reductions in pre/post IDAS social anxiety scores. 
• In Stage 1, 37 of 60 participants in the active groups reported at least 1 adverse event, and 45 of the 74 Stage 2 participants reported at least 1 adverse event. The most common adverse events were cough, throat irritation, and anxiety. Participants in the Stage 1 high THC group had a significant increase in reported withdrawal symptoms after 1 week of stopping use.  

Continue to: Conclusions/limitations

• This first randomized, placebo-control trial of cannabis in US veterans did not show a significant difference among treatment groups, including placebo, on the primary outcome of CAPS-5 score. All 4 groups had significant reductions in symptom severity on CAPS-5 and showed good tolerability.
• Prior beliefs about the effects of cannabis may have played a role in the reduction of PTSD symptoms in the placebo group.
• Many participants (n =34) were positive for THC during the screening process, so previous cannabis use/chronicity of cannabis use may have contributed.
• One limitation was that participants assigned to the Stage 1 high THC group had Cannabis Use Disorders Identification Test scores (which assesses cannabis use disorder risk) about 2 times greater than participants in other conditions.
• Another limitation was that total cannabis use was lower than expected, as participants in Stage 1 used 8.2 g to 14.6 g over 3 weeks, though they had access to up to 37.8 g. 
• There was no placebo in Stage 2.
• Future studies should look at longer treatment periods with more participants.

7. Youngstedt SD, Kline CE, Reynolds AM, et al. Bright light treatment of combat-related PTSD: a randomized controlled trial. Milit Med. 2022;187(3-4):e435-e444

Bright light therapy is an inexpensive treatment approach that may affect serotonergic pathways.¹⁶ This study examined bright light therapy for reducing PTSD symptoms and examined if improvement of PTSD is related to a shift in circadian rhythm.¹³  

Study design

• Veterans with combat-related PTSD had to have been stable on treatment for at least 8 weeks or to have not received any other PTSD treatments prior to the study.
• Participants were randomized to active treatment of 30 minutes daily 10,000 lux ultraviolet-filtered white light while sitting within 18 inches (n = 34) or a control condition of 30 minutes daily inactivated negative ion generator (n = 35) for 4 weeks.
• Inclusion criteria included a CAPS score ≥30.
•  Exclusion criteria included high suicidality, high probability of alcohol/substance abuse in the past 3 months, bipolar disorder/mania/schizophrenia/psychosis, ophthalmologic deformities, shift work in past 2 months or travel across time zones in past 2 weeks, head trauma, high outdoor light exposure, history of winter depression, history of seizures, or myocardial infarction/stroke/cancer within 3 years.
• Primary outcomes were improvement on CAPS and Clinical Global Impressions-Improvement scale (CGI-IM) score at Week 4.
• Wrist actigraphy recordings measured sleep.
• Other measurements included the Hamilton Depression Rating Scale (HAM-D), Hamilton atypical symptoms (HAM-AS), PCL-Military (PCL-M), Pittsburg Sleep Quality Index (PSQI), BDI, Spielberger State-Trait Anxiety Inventory (STAI Form Y-2), Beck Suicide Scale, and Systematic Assessment for Treatment Emergent Effects questionnaire.

Outcomes

• There was a significant decrease in CAPS score in participants who received bright light therapy compared to controls. Treatment response (defined as ≥33% reduction in score) was significantly greater in the bright light (44%) vs control (8.6%) group. No participants achieved remission. 
• There was a significant improvement in CGI-IM scores in the bright light group, but no significant difference in participants who were judged to improve “much” or “very much.”
• PCL-M scores did not change significantly between groups, although a significantly greater proportion of participants had treatment response in the bright light group (33%) vs control (6%).
• There were no significant changes in HAM-D, HAM-AS, STAI, BDI, actigraphic estimates of sleep, or PSQI scores. 
• Bright light therapy resulted in phase advancement while control treatment had phase delay. 
• There were no significant differences in adverse effects. 

Continue to: Conclusions/limitations

• Bright light therapy may be a treatment option or adjunct for combat-related PTSD as seen by improvement on CAPS and CGI scores, as well as a greater treatment response seen on CAPS and PCL-5 scores in the bright light group.  
• There was no significant difference for other measures, including depression, anxiety, and sleep.  
• Limitations include excluding patients with a wide variety of medical or psychiatric comorbidities, as well as limited long-term follow up data.  
• Other limitations include not knowing the precise amount of time participants stayed in front of the light device and loss of some actigraphic data (data from only 49 of 69 participants).  

8. Peterson AL, Mintz J, Moring JC, et al. In-office, in-home, and telehealth cognitive processing therapy for posttraumatic stress disorder in veterans: a randomized clinical trial. BMC Psychiatry. 2022;22(1):41 doi:10.1186/s12888-022-03699-4

Cognitive processing therapy (CPT), a type of trauma-focused psychotherapy, is an effective treatment for PTSD in the military population.^17,18 However, patients may not be able to or want to participate in such therapy due to barriers such as difficulty arranging transportation, being homebound due to injury, concerns about COVID-19, stigma, familial obligations, and job constraints. This study looked at if CPT delivered face-to-face at the patient’s home or via telehealth in home would be effective and increase accessibility.¹⁴  

Study design

• Participants (n = 120) were active-duty military and veterans who met DSM-5 criteria for PTSD. They were randomized to receive CPT in the office, in their home, or via telehealth. Participants could choose not to partake in 1 modality but were then randomized to 1 of the other 2. 
• Exclusion criteria included suicide/homicide risk needing intervention, items/situations pertaining to danger (ie, aggressive pet or unsafe neighborhood), significant alcohol/substance use, active psychosis, and impaired cognitive functioning. 
• The primary outcome measurement was change in PCL-5 and CAPS-5 score over 6 months. The BDI-II was used to assess depressive symptoms.  
• Secondary outcomes included the Reliable Change Index (defined as “an improvement of 10 or more points that was sustained at all subsequent assessments”) on the PCL-5 and remission on the CAPS-5.
• CPT was delivered in 60-minute sessions twice a week for 6 weeks. Participants who did not have electronic resources were loaned a telehealth apparatus. 

Outcomes

• Overall, 57% of participants opted out of 1 modality, which resulted in fewer participants being placed into the in-home arm (n = 32). Most participants chose not to do in-home treatments (54%), followed by in-office (29%), and telehealth (17%). 
• There was a significant posttreatment improvement in PCL-5 scores in all treatment arms, with improvement greater with in-home (d = 2.1) and telehealth (d = 2.0) vs in-office (d=1.3). The in-home and telehealth scores were significantly improved compared to in-office, and the difference between in-home and telehealth PCL-5 scores was minimal.
• At 6 months posttreatment, the differences between the 3 treatment groups on PCL-5 score were negligible. 
• CAPS-5 scores were significantly improved in all treatment arms, with improvement largest with in-home treatment; however, the differences between the groups were not significant.  
• BDI-II scores improved in all modalities but were larger in the in-home (d = 1.2) and telehealth (d = 1.1) arms than the in-office arm (d = 0.52). 
• Therapist time commitment was greater for the in-home and in-office arms (2 hours/session) than the telehealth arm (1 hour/session). This difference was due to commuting time for the patient or therapist.
• The dropout rate was not statistically significant between the groups.
• Adverse events did not significantly differ per group. The most commonly reported ones included nightmares, sleep difficulty, depression, anxiety, and irritability.

Conclusions/limitations

• Patients undergoing CPT had significant improvement in PTSD symptoms, with posttreatment PCL-5 improvement approximately twice as large in those who received the in-home and telehealth modalities vs in-office treatment. 
• The group differences were not seen on CAPS-5 scores at posttreatment, or PCL-5 or CAPS-5 scores at 6 months posttreatment.  
• In-home CPT was declined the most, which suggests that in-home distractions or the stigma of a mental health clinician being in their home played a role in patients’ decision-making. However, in-home CPT produced the greatest amount of improvement in PTSD symptoms. The authors concluded that in-home therapy should be reserved for those who are homebound or have travel limitations.  
• This study shows evidence that telehealth may be a good modality for CPT, as seen by improvement in PTSD symptoms and good acceptability and retention. 
• Limitations include more patients opting out of in-home CPT, and reimbursement for travel may not be available in the real-world setting.  

Posttraumatic stress disorder (PTSD) is a chronic and disabling psychiatric disorder. The lifetime prevalence among American adults is 6.8%.¹ Management of PTSD includes treating distressing symptoms, reducing avoidant behaviors, treating comorbid conditions (eg, depression, substance use disorders, or mood dysregulation), and improving adaptive functioning, which includes restoring a psychological sense of safety and trust. PTSD can be treated using evidence-based psychotherapies, pharmacotherapy, or a combination of both modalities. For adults, evidence-based treatment guidelines recommend the use of cognitive-behavioral therapy, cognitive processing therapy, cognitive therapy, and prolonged exposure therapy.² These guidelines also recommend (with some reservations) the use of brief eclectic psychotherapy, eye movement desensitization and reprocessing, and narrative exposure therapy.² Although the evidence base for the use of medications is not as strong as that for the psychotherapies listed above, the guidelines recommend the use of fluoxetine, paroxetine, sertraline, and venlafaxine.²

Currently available treatments for PTSD have significant limitations. For example, trauma-focused psychotherapies can have significant rates of nonresponse, partial response, or treatment dropout.^3,4 Additionally, such therapies are not widely accessible. As for pharmacotherapy, very few available options are supported by evidence, and the efficacy of these options is limited, as shown by the reports that only 60% of patients with PTSD show a response to selective serotonin reuptake inhibitors (SSRIs), and only 20% to 30% achieve complete remission.⁵ Additionally, it may take months for patients to achieve an acceptable level of improvement with medications. As a result, a substantial proportion of patients who seek treatment continue to remain symptomatic, with impaired levels of functioning. This lack of progress in PTSD treatment has been labeled as a national crisis, calling for an urgent need to find effective pharmacologic treatments for PTSD.⁶

In this article, we review 8 randomized controlled trials (RCTs) of treatments for PTSD published within the last 5 years (Table^7-14).

1. Feder A, Costi S, Rutter SB, et al. A randomized controlled trial of repeated ketamine administration for chronic posttraumatic stress disorder. Am J Psychiatry. 2021;178(2):193-202

Feder et al had previously found a significant and quick decrease in PTSD symptoms after a single dose of IV ketamine had. This is the first RCT to examine the effectiveness and safety of repeated IV ketamine infusions for the treatment of persistent PTSD.⁷ 

Study design

• This randomized, double-blind, parallel-arm controlled trial treated 30 individuals with chronic PTSD with 6 infusions of either ketamine (0.5 mg/kg) or midazolam (0.045 mg/kg) over 2 consecutive weeks. 
• Participants were individuals age 18 to 70 with a primary diagnosis of chronic PTSD according to the DSM-5 criteria and determined by The Structure Clinical Interview for DSM-5, with a score ≥30 on the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5).  
• Any severe or unstable medical condition, active suicidal or homicidal ideation, lifetime history of psychotic or bipolar disorder, current anorexia nervosa or bulimia, alcohol or substance use disorder within 3 months of screening, history of recreational ketamine or phencyclidine use on more than 1 occasion or any use in the previous 2 years, and ongoing treatment with a long-acting benzodiazepine or opioid medication were all considered exclusion criteria. Individuals who took short-acting benzodiazepines had their morning doses held on infusion days. Marijuana or cannabis derivatives were allowed. 
• The primary outcome measure was a change in PTSD symptom severity as measured with CAPS-5. This was administered before the first infusion and weekly thereafter. The Impact of Event Scale-Revised, the Montgomery–Åsberg Depression Rating Scale, and adverse effect measurements were used as secondary outcome measures. 
• Treatment response was defined as ≥30% symptom improvement 2 weeks after the first infusion as assessed with CAPS-5. 
• Individuals who responded to treatment were followed naturalistically weekly for up to 4 weeks and then monthly until loss of responder status, or up to 6 months if there was no loss of response. 

Outcomes

• At the second week, the mean CAPS-5 total score in the ketamine group was 11.88 points (SE = 3.96) lower than in the midazolam group (d = 1.13; 95% CI, 0.36 to 1.91).  
• In the ketamine group, 67% of patients responded to therapy, compared to 20% in the midazolam group.  
• Following the 2-week course of infusions, the median period until loss of response among ketamine responders was 27.5 days.  
• Ketamine infusions showed good tolerability and safety. There were no clinically significant adverse effects. 

Continue to: Conclusions/limitations

• Repeated ketamine infusions are effective in reducing symptom severity in individuals with chronic PTSD. 
• Limitations to this study include the exclusion of individuals with comorbid bipolar disorder, current alcohol or substance use disorder, or suicidal ideations, the small sample size, and a higher rate of transient dissociative symptoms in the ketamine group. 
• Future studies could evaluate the efficacy of repeated ketamine infusions in individuals with treatment-resistant PTSD. Also, further studies are required to assess the efficacy of novel interventions to prevent relapse and evaluate the efficacy, safety, and tolerability of periodic IV ketamine use as maintenance.  
• Additional research might determine whether pairing psychotherapy with ketamine administration can lessen the risk of recurrence for PTSD patients after stopping ketamine infusions. 

2. Rauch SAM, Kim HM, Powell C, et al. Efficacy of prolonged exposure therapy, sertraline hydrochloride, and their combination among combat veterans with posttraumatic stress disorder: a randomized clinical trial. JAMA Psychiatry. 2019;76(2):117-126

Clinical practice recommendations for PTSD have identified trauma-focused psychotherapies and SSRIs as very effective treatments. The few studies that have compared trauma-focused psychotherapy to SSRIs or to a combination of treatments are not generalizable, have significant limitations, or are primarily concerned with refractory disorders or augmentation techniques. This study evaluated the efficacy of prolonged exposure therapy (PE) plus placebo, PE plus sertraline, and sertraline plus enhanced medication management in the treatment of PTSD.⁸ 

Study design

• This randomized, 4-site, 24-week clinical trial divided participants into 3 subgroups: PE plus placebo, PE plus sertraline, and sertraline plus enhanced medication management. 
• Participants were veterans or service members of the Iraq and/or Afghanistan wars with combat-related PTSD and significant impairment as indicated by a CAPS score ≥50 for at least 3 months. The DSM-IV-TR version of CAPS was used because the DSM-5 version was not available at the time of the study.
• Individuals who had a current, imminent risk of suicide; active psychosis; alcohol or substance dependence in the past 8 weeks; inability to attend weekly appointments for the treatment period; prior intolerance to or failure of an adequate trial of PE or sertraline; medical illness likely to result in hospitalization or contraindication to study treatment; serious cognitive impairment; mild traumatic brain injury; or concurrent use of antidepressants, antipsychotics, benzodiazepines, prazosin, or sleep agents were excluded. 
• Participants completed up to thirteen 90-minute sessions of PE. 
• The sertraline dosage was titrated during a 10-week period and continued until Week 24. Dosages were adjusted between 50 and 200 mg/d, with the last dose increase at Week 10. 
• The primary outcome measure was symptom severity of PTSD in the past month as determined by CAPS score at Week 24.
• The secondary outcome was self-reported symptoms of PTSD (PTSD checklist [PCL] Specific Stressor Version), clinically meaningful change (reduction of ≥20 points or score ≤35 on CAPS), response (reduction of ≥50% in CAPS score), and remission (CAPS score ≤35). 

Outcomes

• At Week 24, 149 participants completed the study; 207 were included in the intent-to-treat analysis. 
• PTSD symptoms significantly decreased over 24 weeks, according to a modified intent-to-treat analysis utilizing a mixed model of repeated measurements; nevertheless, slopes were similar across therapy groups. 

Continue to: Conclusions/limitations

• Although the severity of PTSD symptoms decreased in all 3 subgroups, there was no difference in PTSD symptom severity or change in symptoms at Week 24 among all 3 subgroups.  
• The main limitation of this study was the inclusion of only combat veterans. 
• Further research should focus on enhancing treatment retention and should include administering sustained exposure therapy at brief intervals. 

3. Lehrner A, Hildebrandt T, Bierer LM, et al. A randomized, double-blind, placebo-controlled trial of hydrocortisone augmentation of prolonged exposure for PTSD in US combat veterans. Behav Res Ther. 2021;144:103924

First-line therapy for PTSD includes cognitive-behavioral therapies such as PE. However, because many people still have major adverse effects after receiving medication, improving treatment efficacy is a concern. Glucocorticoids promote extinction learning, and alterations in glucocorticoid signaling pathways have been associated with PTSD. Lehrner et al previously showed that adding hydrocortisone (HCORT) to PE therapy increased patients’ glucocorticoid sensitivity at baseline, improved treatment retention, and resulted in greater treatment improvements. This study evaluated HCORT in conjunction with PE for combat veterans with PTSD following deployment to Iraq and Afghanistan.⁹ 

Study design

• This randomized, double-blind, placebo-controlled trial administered HCORT 30 mg oral or placebo to 96 combat veterans 30 minutes before PE sessions.  
• Participants were veterans previously deployed to Afghanistan or Iraq with deployment-related PTSD >6 months with a minimum CAPS score of 60. They were unmedicated or on a stable psychotropic regimen for ≥4 weeks. 
• Exclusion criteria included a lifetime history of a primary psychotic disorder (bipolar I disorder or obsessive-compulsive disorder), medical or mental health condition other than PTSD that required immediate clinical attention, moderate to severe traumatic brain injury (TBI), substance abuse or dependence within the past 3 months, medical illness that contraindicated ingestion of hydrocortisone, acute suicide risk, and pregnancy or intent to become pregnant. 
• The primary outcome measures included PTSD severity as assessed with CAPS. 
• Secondary outcome measures included self-reported PTSD symptoms as assessed with the Posttraumatic Diagnostic Scale (PDS) and depression as assessed with the Beck Depression Inventory-II (BDI). These scales were administered pretreatment, posttreatment, and at 3-months follow-up. 

Outcomes

• Out of 96 veterans enrolled, 60 were randomized and 52 completed the treatment.  
• Five participants were considered recovered early and completed <12 sessions.
• Of those who completed treatment, 50 completed the 1-week posttreatment evaluations and 49 completed the 3-month follow-up evaluation.
• There was no difference in the proportion of dropouts (13.33%) across the conditions.
• HCORT failed to significantly improve either secondary outcomes or PTSD symptoms, according to an intent-to-treat analysis.
• However, exploratory analyses revealed that veterans with recent post-concussive symptoms and moderate TBI exposure saw a larger decrease in hyperarousal symptoms after PE therapy with HCORT augmentation.  
• The reduction in avoidance symptoms with HCORT augmentation was also larger in veterans with higher baseline glucocorticoid sensitivity. 

Continue to: Conclusions/limitations

Conclusions/limitations 

• HCORT does not improve PTSD symptoms as assessed with the CAPS and PDS, or depression as assessed with the BDI. 
• The main limitation of this study is generalizability. 
• Further studies are needed to determine whether PE with HCORT could benefit veterans with indicators of enhanced glucocorticoid sensitivity, mild TBI, or postconcussive syndrome. 

4. Inslicht SS, Niles AN, Metzler TJ, et al. Randomized controlled experimental study of hydrocortisone and D-cycloserine effects on fear extinction in PTSD. Neuropsychopharmacology. 2022;47(11):1945-1952

PE, one of the most well-researched therapies for PTSD, is based on fear extinction. Exploring pharmacotherapies that improve fear extinction learning and their potential as supplements to PE is gaining increased attention. Such pharmacotherapies aim to improve the clinical impact of PE on the extent and persistence of symptom reduction. This study evaluated the effects of HCORT and D-cycloserine (DCS), a partial agonist of the N-methyl-D-aspartate (NMDA) receptor, on the learning and consolidation of fear extinction in patients with PTSD.¹⁰ 

Study design

• This double-blind, placebo-controlled, 3-group experimental design evaluated 90 individuals with PTSD who underwent fear conditioning with stimuli that was paired (CS+) or unpaired (CS−) with shock. 
• Participants were veterans and civilians age 18 to 65 recruited from VA outpatient and community clinics and internet advertisements who met the criteria for PTSD or subsyndromal PTSD (according to DSM-IV criteria) for at least 3 months. 
• Exclusion criteria included schizophrenia, bipolar disorder, substance abuse or dependence, alcohol dependence, previous moderate or severe head injury, seizure or neurological disorder, current infectious illness, systemic illness affecting CNS function, or other conditions known to affect psychophysiological responses. Excluded medications were antipsychotics, mood stabilizers, alpha- and beta-adrenergics, benzodiazepines, anticonvulsants, antihypertensives, sympathomimetics, anticholinergics, and steroids.  
• Extinction learning took place 72 hours after extinction, and extinction retention was evaluated 1 week later. Placebo, HCORT 25 mg, or DCS 50 mg was given 1 hour before extinction learning. 
• Clinical measures included PTSD diagnosis and symptom levels as determined by interview using CAPS and skin conduction response. 

Outcomes

• The mean shock level, mean pre-stimulus skin conductance level (SCL) during habituation, and mean SC orienting response during the habituation phase did not differ between groups and were not associated with differential fear conditioning. Therefore, variations in shock level preference, resting SCL, or SC orienting response magnitude are unlikely to account for differences between groups during extinction learning and retention.
• During extinction learning, the DCS and HCORT groups showed a reduced differential CS+/CS− skin conductance response (SCR) compared to placebo. 
• One week later, during the retention testing, there was a nonsignificant trend toward a smaller differential CS+/CS− SCR in the DCS group compared to placebo. HCORT and DCS administered as a single dosage facilitated fear extinction learning in individuals with PTSD symptoms. 

Continue to: Conclusions/limitations

Conclusions/limitations 

• In traumatized people with PTSD symptoms, a single dosage of HCORT or DCS enhanced the learning of fear extinction compared to placebo. A nonsignificant trend toward better extinction retention in the DCS group but not the HCORT group was also visible. 
• These results imply that glucocorticoids and NMDA agonists have the potential to promote extinction learning in PTSD. 
• Limitations include a lack of measures of glucocorticoid receptor sensitivity or FKBP5. 
• Further studies could evaluate these findings with the addition of blood biomarker measures such as glucocorticoid receptor sensitivity or FKBP5.  

5. Mitchell JM, Bogenschutz M, Lilienstein A, et al. MDMA-assisted therapy for severe PTSD: a randomized, double-blind, placebo-controlled phase 3 study. Nat Med. 2021;27(6):1025-1033. doi:10.1038/s41591-021-01336-3

Poor PTSD treatment results are associated with numerous comorbid conditions, such as dissociation, depression, alcohol and substance use disorders, childhood trauma, and suicidal ideation, which frequently leads to treatment resistance. Therefore, it is crucial to find a treatment that works for individuals with PTSD who also have comorbid conditions. In animal models, 3,4-methylenedioxymethamphetamine (MDMA), an empathogen/entactogen with stimulant properties, has been shown to enhance fear memory extinction and modulate fear memory reconsolidation. This study evaluated the efficacy and safety of MDMA-assisted therapy for treating patients with severe PTSD, including those with common comorbidities.¹¹ 

Study design

• This randomized, double-blind, placebo-controlled, multi-site, phase 3 clinical trial evaluated individuals randomized to receive manualized therapy with MDMA or with placebo, combined with 3 preparatory and 9 integrative therapy sessions.  
• Participants were 90 individuals (46 randomized to MDMA and 44 to placebo) with PTSD with a symptom duration ≥6 months and CAPS-5 total severity score ≥35 at baseline. 
• Exclusion criteria included primary psychotic disorder, bipolar I disorder, eating disorders with active purging, major depressive disorder with psychotic features, dissociative identity disorder, personality disorders, current alcohol and substance use disorders, lactation or pregnancy, and any condition that could make receiving a sympathomimetic medication dangerous due to hypertension or tachycardia, including uncontrolled hypertension, history of arrhythmia, or marked baseline prolongation of QT and/or QTc interval. 
• Three 8-hour experimental sessions of either therapy with MDMA assistance or therapy with a placebo control were given during the treatment period, and they were spaced approximately 4 weeks apart. 
• In each session, participants received placebo or a single divided dose of MDMA 80 to 180 mg. 
• At baseline and 2 months after the last experimental sessions, PTSD symptoms were measured with CAPS-5, and functional impairment was measured with Sheehan Disability Scale (SDS). 
• The primary outcome measure was CAPS-5 total severity score at 18 weeks compared to baseline for MDMA-assisted therapy vs placebo-assisted therapy. 
• The secondary outcome measure was clinician-rated functional impairment using the mean difference in SDS total scores from baseline to 18 weeks for MDMA-assisted therapy vs placebo-assisted therapy. 

Outcomes

• MDMA was found to induce significant and robust attenuation in CAPS-5 score compared to placebo. 
• The mean change in CAPS-5 score in completers was –24.4 in the MDMA group and –13.9 in the placebo group. 
• MDMA significantly decreased the SDS total score. 
• MDMA did not induce suicidality, misuse, or QT prolongation. 

Continue to: Conclusions/limitations

• MDMA-assisted therapy is significantly more effective than manualized therapy with placebo in treating patients with severe PTSD, and it is also safe and well-tolerated, even in individuals with comorbidities. 
• No major safety issues were associated with MDMA-assisted treatment. 
• MDMA-assisted therapy should be promptly assessed for clinical usage because it has the potential to significantly transform the way PTSD is treated. 
• Limitations of this study include a smaller sample size (due to the COVID-19 pandemic); lack of ethnic and racial diversity; short duration; safety data were collected by site therapist, which limited the blinding; and the blinding of participants was difficult due to the subjective effects of MDMA, which could have resulted in expectation effects. 

6. Bonn-Miller MO, Sisley S, Riggs P, et al. The short-term impact of 3 smoked cannabis preparations versus placebo on PTSD symptoms: a randomized cross-over clinical trial. PLoS One. 2021;16(3):e0246990

Sertraline and paroxetine are the only FDA-approved medications for treating PTSD. Some evidence suggests cannabis may provide a therapeutic benefit for PTSD.¹⁵ This study examined the effects of 3 different preparations of cannabis for treating PTSD symptoms.¹²  

Study design

• This double-blind, randomized, placebo-controlled, crossover trial used 3 active treatment groups of cannabis: high delta-9-tetrahydrocannabinol (THC)/low cannabidiol (CBD), high CBD/low THC, and high THC/high CBD (THC+CBD). A low THC/low CBD preparation was used as a placebo. “High” content contained 9% to 15% concentration by weight of the respective cannabinoid, and “low” content contained <2% concentration by weight.  
• Inclusion criteria included being a US military veteran, meeting DSM-5 PTSD criteria for ≥6 months, having moderate symptom severity (CAPS-5 score ≥25), abstaining from cannabis 2 weeks prior to study and agreeing not to use any non-study cannabis during the trial, and being stable on medications/therapy prior to the study.  
• Exclusion criteria included women who were pregnant/nursing/child-bearing age and not taking an effective means of birth control; current/past serious mental illness, including psychotic and personality disorders; having a first-degree relative with a psychotic or bipolar disorder; having a high suicide risk based on Columbia-Suicide Severity Rating Scale; meeting DSM-5 criteria for moderate-severe cannabis use disorder; screening positive for illicit substances; or having significant medical disease.  
• Participants in Stage 1 (n = 80) were randomized to 1 of the 3 active treatments or placebo for 3 weeks. After a 2-week washout, participants in Stage 2 (n = 74) were randomized to receive for 3 weeks 1 of the 3 active treatments they had not previously received.
• During each stage, participants had ad libitum use for a maximum of 1.8 g/d. 
• The primary outcome was change in PTSD symptom severity by the end of Stage 1 as assessed with CAPS-5.
• Secondary outcomes included the PTSD Checklist for DSM-5 (PCL-5), the general depression subscale and anxiety subscale from the self-report Inventory of Depression and Anxiety Symptoms (IDAS), the Inventory of Psychosocial Functioning, and the Insomnia Severity Index. 

Outcomes

• Six participants did not continue to Stage 2. Three participants did not finish Stage 2 due to adverse effects, and 7 did not complete outcome measurements. The overall attrition rate was 16.3%. 
• There was no significant difference in total grams of smoked cannabis or placebo between the 4 treatment groups in Stage 1 at the end of 3 weeks. In Stage 2, there was a significant difference, with the THC+CBD group using more cannabis compared to the other 2 groups. 
• Each of the 4 groups had significant reductions in total CAPS-5 scores at the end of Stage 1, and there was no significant difference in CAPS-5 severity scores between the 4 groups.
• In Stage 1, PCL-5 scores were not significantly different between treatment groups from baseline to the end of stage. There was a significant difference in Stage 2 between the high CBD and THC+CBD groups, with the combined group reporting greater improvement of symptoms. 
• In Stage 2, the THC+CBD group reported greater reductions in pre/post IDAS social anxiety scores and IDAS general depression scores, and the high THC group reported greater reductions in pre/post IDAS social anxiety scores. 
• In Stage 1, 37 of 60 participants in the active groups reported at least 1 adverse event, and 45 of the 74 Stage 2 participants reported at least 1 adverse event. The most common adverse events were cough, throat irritation, and anxiety. Participants in the Stage 1 high THC group had a significant increase in reported withdrawal symptoms after 1 week of stopping use.  

Continue to: Conclusions/limitations

• This first randomized, placebo-control trial of cannabis in US veterans did not show a significant difference among treatment groups, including placebo, on the primary outcome of CAPS-5 score. All 4 groups had significant reductions in symptom severity on CAPS-5 and showed good tolerability.
• Prior beliefs about the effects of cannabis may have played a role in the reduction of PTSD symptoms in the placebo group.
• Many participants (n =34) were positive for THC during the screening process, so previous cannabis use/chronicity of cannabis use may have contributed.
• One limitation was that participants assigned to the Stage 1 high THC group had Cannabis Use Disorders Identification Test scores (which assesses cannabis use disorder risk) about 2 times greater than participants in other conditions.
• Another limitation was that total cannabis use was lower than expected, as participants in Stage 1 used 8.2 g to 14.6 g over 3 weeks, though they had access to up to 37.8 g. 
• There was no placebo in Stage 2.
• Future studies should look at longer treatment periods with more participants.

7. Youngstedt SD, Kline CE, Reynolds AM, et al. Bright light treatment of combat-related PTSD: a randomized controlled trial. Milit Med. 2022;187(3-4):e435-e444

Bright light therapy is an inexpensive treatment approach that may affect serotonergic pathways.¹⁶ This study examined bright light therapy for reducing PTSD symptoms and examined if improvement of PTSD is related to a shift in circadian rhythm.¹³  

Study design

• Veterans with combat-related PTSD had to have been stable on treatment for at least 8 weeks or to have not received any other PTSD treatments prior to the study.
• Participants were randomized to active treatment of 30 minutes daily 10,000 lux ultraviolet-filtered white light while sitting within 18 inches (n = 34) or a control condition of 30 minutes daily inactivated negative ion generator (n = 35) for 4 weeks.
• Inclusion criteria included a CAPS score ≥30.
•  Exclusion criteria included high suicidality, high probability of alcohol/substance abuse in the past 3 months, bipolar disorder/mania/schizophrenia/psychosis, ophthalmologic deformities, shift work in past 2 months or travel across time zones in past 2 weeks, head trauma, high outdoor light exposure, history of winter depression, history of seizures, or myocardial infarction/stroke/cancer within 3 years.
• Primary outcomes were improvement on CAPS and Clinical Global Impressions-Improvement scale (CGI-IM) score at Week 4.
• Wrist actigraphy recordings measured sleep.
• Other measurements included the Hamilton Depression Rating Scale (HAM-D), Hamilton atypical symptoms (HAM-AS), PCL-Military (PCL-M), Pittsburg Sleep Quality Index (PSQI), BDI, Spielberger State-Trait Anxiety Inventory (STAI Form Y-2), Beck Suicide Scale, and Systematic Assessment for Treatment Emergent Effects questionnaire.

Outcomes

• There was a significant decrease in CAPS score in participants who received bright light therapy compared to controls. Treatment response (defined as ≥33% reduction in score) was significantly greater in the bright light (44%) vs control (8.6%) group. No participants achieved remission. 
• There was a significant improvement in CGI-IM scores in the bright light group, but no significant difference in participants who were judged to improve “much” or “very much.”
• PCL-M scores did not change significantly between groups, although a significantly greater proportion of participants had treatment response in the bright light group (33%) vs control (6%).
• There were no significant changes in HAM-D, HAM-AS, STAI, BDI, actigraphic estimates of sleep, or PSQI scores. 
• Bright light therapy resulted in phase advancement while control treatment had phase delay. 
• There were no significant differences in adverse effects. 

Continue to: Conclusions/limitations

• Bright light therapy may be a treatment option or adjunct for combat-related PTSD as seen by improvement on CAPS and CGI scores, as well as a greater treatment response seen on CAPS and PCL-5 scores in the bright light group.  
• There was no significant difference for other measures, including depression, anxiety, and sleep.  
• Limitations include excluding patients with a wide variety of medical or psychiatric comorbidities, as well as limited long-term follow up data.  
• Other limitations include not knowing the precise amount of time participants stayed in front of the light device and loss of some actigraphic data (data from only 49 of 69 participants).  

8. Peterson AL, Mintz J, Moring JC, et al. In-office, in-home, and telehealth cognitive processing therapy for posttraumatic stress disorder in veterans: a randomized clinical trial. BMC Psychiatry. 2022;22(1):41 doi:10.1186/s12888-022-03699-4

Cognitive processing therapy (CPT), a type of trauma-focused psychotherapy, is an effective treatment for PTSD in the military population.^17,18 However, patients may not be able to or want to participate in such therapy due to barriers such as difficulty arranging transportation, being homebound due to injury, concerns about COVID-19, stigma, familial obligations, and job constraints. This study looked at if CPT delivered face-to-face at the patient’s home or via telehealth in home would be effective and increase accessibility.¹⁴  

Study design

• Participants (n = 120) were active-duty military and veterans who met DSM-5 criteria for PTSD. They were randomized to receive CPT in the office, in their home, or via telehealth. Participants could choose not to partake in 1 modality but were then randomized to 1 of the other 2. 
• Exclusion criteria included suicide/homicide risk needing intervention, items/situations pertaining to danger (ie, aggressive pet or unsafe neighborhood), significant alcohol/substance use, active psychosis, and impaired cognitive functioning. 
• The primary outcome measurement was change in PCL-5 and CAPS-5 score over 6 months. The BDI-II was used to assess depressive symptoms.  
• Secondary outcomes included the Reliable Change Index (defined as “an improvement of 10 or more points that was sustained at all subsequent assessments”) on the PCL-5 and remission on the CAPS-5.
• CPT was delivered in 60-minute sessions twice a week for 6 weeks. Participants who did not have electronic resources were loaned a telehealth apparatus. 

Outcomes

• Overall, 57% of participants opted out of 1 modality, which resulted in fewer participants being placed into the in-home arm (n = 32). Most participants chose not to do in-home treatments (54%), followed by in-office (29%), and telehealth (17%). 
• There was a significant posttreatment improvement in PCL-5 scores in all treatment arms, with improvement greater with in-home (d = 2.1) and telehealth (d = 2.0) vs in-office (d=1.3). The in-home and telehealth scores were significantly improved compared to in-office, and the difference between in-home and telehealth PCL-5 scores was minimal.
• At 6 months posttreatment, the differences between the 3 treatment groups on PCL-5 score were negligible. 
• CAPS-5 scores were significantly improved in all treatment arms, with improvement largest with in-home treatment; however, the differences between the groups were not significant.  
• BDI-II scores improved in all modalities but were larger in the in-home (d = 1.2) and telehealth (d = 1.1) arms than the in-office arm (d = 0.52). 
• Therapist time commitment was greater for the in-home and in-office arms (2 hours/session) than the telehealth arm (1 hour/session). This difference was due to commuting time for the patient or therapist.
• The dropout rate was not statistically significant between the groups.
• Adverse events did not significantly differ per group. The most commonly reported ones included nightmares, sleep difficulty, depression, anxiety, and irritability.

Conclusions/limitations

• Patients undergoing CPT had significant improvement in PTSD symptoms, with posttreatment PCL-5 improvement approximately twice as large in those who received the in-home and telehealth modalities vs in-office treatment. 
• The group differences were not seen on CAPS-5 scores at posttreatment, or PCL-5 or CAPS-5 scores at 6 months posttreatment.  
• In-home CPT was declined the most, which suggests that in-home distractions or the stigma of a mental health clinician being in their home played a role in patients’ decision-making. However, in-home CPT produced the greatest amount of improvement in PTSD symptoms. The authors concluded that in-home therapy should be reserved for those who are homebound or have travel limitations.  
• This study shows evidence that telehealth may be a good modality for CPT, as seen by improvement in PTSD symptoms and good acceptability and retention. 
• Limitations include more patients opting out of in-home CPT, and reimbursement for travel may not be available in the real-world setting.  

A brief aerobic exercise intervention can augment the benefits of exposure therapy for PTSD, new research suggests.

Investigators randomly assigned individuals with PTSD to receive either exposure therapy with aerobic exercise or exposure therapy with passive stretching for 9 weeks. At 6 months post intervention, participants in the aerobic exercise group showed greater reductions in PTSD severity, compared with those in the stretching group.

“There is a critical need to improve outcomes for treating people with PTSD, and this finding points to one potentially cheap and ready-to-use strategy that all clinicians could employ with most patients,” lead author Richard Bryant, MPsych, PhD, DSc, director of the Traumatic Stress Clinic and Scientia Professor of Psychology at the University of New South Wales, Sydney, told this news organization.

The study was published online in The Lancet Psychiatry.
 

Promoting BDNF

“Trauma-focused psychotherapy is the recommended treatment for PTSD, but up to half of patients do not respond to this treatment,” Dr. Bryant said.

“We know that brain-derived neurotrophic factors [BDNF] are critical for synaptic plasticity, which underpins the learning that occurs in therapy so that reminders of trauma are no longer fear-provoking,” he continued. “Preclinical animal and human research inform us that brief aerobic exercise can promote BDNF and new learning that inhibits fear responses.”

The researchers “hypothesized that brief exercise after exposure therapy to trauma memories – which is the key ingredient of trauma-focused psychotherapy – would lead to greater reductions in PTSD, relative to standard trauma-focused therapy,” he said.

To investigate the question, the researchers randomly assigned 130 adults with PTSD (mean age, 39 years; 61% female; 76% White) to receive nine 90-minute sessions of exposure therapy with either aerobic exercise or passive stretching (n = 65 in each group).

There were no differences at baseline in sociodemographic characteristics or psychopathology measures, although the mean age of the stretching group was slightly older than that of the aerobic group (40 years vs. 37 years, respectively), and there was a slightly higher proportion of women in the stretching group (68% vs. 54%).

Participants did not differ on weekly exercise either at baseline, immediately post treatment, or at 6-week follow-up.

PTSD severity (the primary outcome) was measured using the clinician-administered PTSD scale CAPS-2, with assessments conducted at baseline, 1 week post treatment, and 6 months post treatment.

The aerobic exercise regimen was tailored to each participant, based on an assessment of his/her aerobic target zone.

The exposure therapy sessions were identical for both groups. Following the exposure sessions, participants engaged in their respective exercises: Those in the passive stretching group engaged in 20 minutes of exercise, while those in the aerobic group participated in a total of 20 minutes of exercise, with 10 conducted at their personal aerobic target heart rate.

“This level of exercise was chosen because BDNF concentration in the serum is increased by two 3-minute bouts of aerobic exercise, and 10 minutes of aerobic exercise can facilitate extinction learning,” the authors explained.

The aerobic activity consisted of running on a stepper exercise platform while having cardiac activity recorded. A small portion (10%) of the therapy sessions were recorded and rated for treatment fidelity.

Change in PTSD was the primary outcome, with secondary outcomes consisting of changes in depression, anxiety, alcohol use disorder, and posttraumatic cognitions.
 

Few barriers

The researchers found no significant differences in PTSD severity, as measured by CAPS-2 score, between treatment groups at 10 weeks – that is, immediately post treatment (mean difference, 7.0; 95% confidence interval, –2.3 to 16.4; P = .14).

However, significantly greater reductions in PTSD severity were found in the aerobic versus the stretching group at 6-month follow-up (mean difference, 12.1;95% CI, 2.4-21.8; P = .023), pointing to a “moderate effect size” (d = 0.6; 95% CI, 0.1-1.1]).

Although there were no differences found at 6-month assessment between rates of PTSD diagnosis (25% of the aerobic vs 27% of the stretching group), more participants in the aerobic group reached a “minimal clinically important difference,” compared to those in the stretching group (96% vs. 84%, respectively, x² = 4.4; P = .036). 

There were also superior benefits found in the aerobic versus the stretching group on depression severity at 6 months (a secondary outcome), with a mean difference in Beck Depression Inventory-2 score of 5.7 (95% CI, 0.5-10.9; P = .022), yielding a “moderate effect size” (d = 0.5; 95% CI, 0.1-1.0]).

There were no adverse events associated with the intervention, and almost all the sessions (88%) complied with the treatment protocol.

The researchers noted several limitations. For example, they did not obtain plasma to measure BDNF concentrations, so they could not “infer whether the mechanism of change involved BDNF.”

In addition, they did not perform sex-specific analyses. “Future studies could increase the sample size to investigate sex differences because females display less BDNF change following exercise than do males,” they wrote.

Nevertheless, the study “provides initial evidence of a simple and accessible strategy that clinicians could readily apply in combination with exposure therapy,” they stated. “Whereas many pharmacologic interventions pose barriers, including cost, requirement for prescriptions, and patient resistance to drugs, exercise offers clinicians a strategy that can be implemented with few barriers.”

Dr. Bryant emphasized that one study “does not represent a body of evidence, and so it is essential that this finding be replicated in other trials before it can be recommended for clinical use.” He noted that other trials are “currently underway.”
 

Easy augmentation

In a comment, Barbara Rothbaum, PhD, professor in psychiatry and director of the Trauma and Anxiety Recovery Program at Emory University, Atlanta, called it a “well-controlled trial augmenting exposure therapy for PTSD with brief aerobic exercise and finding some benefits of the augmented condition at 6 months posttreatment but not immediately posttreatment.”

The study’s methodology – that is, using independent standard assessment of PTSD and rating audio recordings of therapy sessions for treatment fidelity and quality – can lead us to “be confident in their [the researchers’] conclusions,” she said.

Dr. Rothbaum, who was not associated with this study, described research into methods to augment exposure therapy for PTSD as “timely and clinically relevant.”

Exercise “would be an easy augmentation for many clinicians if it is helpful,” she noted.

The study was funded by the Australian National Health and Medical Research Council. The authors and Dr. Rothbaum reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

A brief aerobic exercise intervention can augment the benefits of exposure therapy for PTSD, new research suggests.

Investigators randomly assigned individuals with PTSD to receive either exposure therapy with aerobic exercise or exposure therapy with passive stretching for 9 weeks. At 6 months post intervention, participants in the aerobic exercise group showed greater reductions in PTSD severity, compared with those in the stretching group.

“There is a critical need to improve outcomes for treating people with PTSD, and this finding points to one potentially cheap and ready-to-use strategy that all clinicians could employ with most patients,” lead author Richard Bryant, MPsych, PhD, DSc, director of the Traumatic Stress Clinic and Scientia Professor of Psychology at the University of New South Wales, Sydney, told this news organization.

The study was published online in The Lancet Psychiatry.
 

Promoting BDNF

“Trauma-focused psychotherapy is the recommended treatment for PTSD, but up to half of patients do not respond to this treatment,” Dr. Bryant said.

“We know that brain-derived neurotrophic factors [BDNF] are critical for synaptic plasticity, which underpins the learning that occurs in therapy so that reminders of trauma are no longer fear-provoking,” he continued. “Preclinical animal and human research inform us that brief aerobic exercise can promote BDNF and new learning that inhibits fear responses.”

The researchers “hypothesized that brief exercise after exposure therapy to trauma memories – which is the key ingredient of trauma-focused psychotherapy – would lead to greater reductions in PTSD, relative to standard trauma-focused therapy,” he said.

To investigate the question, the researchers randomly assigned 130 adults with PTSD (mean age, 39 years; 61% female; 76% White) to receive nine 90-minute sessions of exposure therapy with either aerobic exercise or passive stretching (n = 65 in each group).

There were no differences at baseline in sociodemographic characteristics or psychopathology measures, although the mean age of the stretching group was slightly older than that of the aerobic group (40 years vs. 37 years, respectively), and there was a slightly higher proportion of women in the stretching group (68% vs. 54%).

Participants did not differ on weekly exercise either at baseline, immediately post treatment, or at 6-week follow-up.

PTSD severity (the primary outcome) was measured using the clinician-administered PTSD scale CAPS-2, with assessments conducted at baseline, 1 week post treatment, and 6 months post treatment.

The aerobic exercise regimen was tailored to each participant, based on an assessment of his/her aerobic target zone.

The exposure therapy sessions were identical for both groups. Following the exposure sessions, participants engaged in their respective exercises: Those in the passive stretching group engaged in 20 minutes of exercise, while those in the aerobic group participated in a total of 20 minutes of exercise, with 10 conducted at their personal aerobic target heart rate.

“This level of exercise was chosen because BDNF concentration in the serum is increased by two 3-minute bouts of aerobic exercise, and 10 minutes of aerobic exercise can facilitate extinction learning,” the authors explained.

The aerobic activity consisted of running on a stepper exercise platform while having cardiac activity recorded. A small portion (10%) of the therapy sessions were recorded and rated for treatment fidelity.

Change in PTSD was the primary outcome, with secondary outcomes consisting of changes in depression, anxiety, alcohol use disorder, and posttraumatic cognitions.
 

Few barriers

The researchers found no significant differences in PTSD severity, as measured by CAPS-2 score, between treatment groups at 10 weeks – that is, immediately post treatment (mean difference, 7.0; 95% confidence interval, –2.3 to 16.4; P = .14).

However, significantly greater reductions in PTSD severity were found in the aerobic versus the stretching group at 6-month follow-up (mean difference, 12.1;95% CI, 2.4-21.8; P = .023), pointing to a “moderate effect size” (d = 0.6; 95% CI, 0.1-1.1]).

Although there were no differences found at 6-month assessment between rates of PTSD diagnosis (25% of the aerobic vs 27% of the stretching group), more participants in the aerobic group reached a “minimal clinically important difference,” compared to those in the stretching group (96% vs. 84%, respectively, x² = 4.4; P = .036). 

There were also superior benefits found in the aerobic versus the stretching group on depression severity at 6 months (a secondary outcome), with a mean difference in Beck Depression Inventory-2 score of 5.7 (95% CI, 0.5-10.9; P = .022), yielding a “moderate effect size” (d = 0.5; 95% CI, 0.1-1.0]).

There were no adverse events associated with the intervention, and almost all the sessions (88%) complied with the treatment protocol.

The researchers noted several limitations. For example, they did not obtain plasma to measure BDNF concentrations, so they could not “infer whether the mechanism of change involved BDNF.”

In addition, they did not perform sex-specific analyses. “Future studies could increase the sample size to investigate sex differences because females display less BDNF change following exercise than do males,” they wrote.

Nevertheless, the study “provides initial evidence of a simple and accessible strategy that clinicians could readily apply in combination with exposure therapy,” they stated. “Whereas many pharmacologic interventions pose barriers, including cost, requirement for prescriptions, and patient resistance to drugs, exercise offers clinicians a strategy that can be implemented with few barriers.”

Dr. Bryant emphasized that one study “does not represent a body of evidence, and so it is essential that this finding be replicated in other trials before it can be recommended for clinical use.” He noted that other trials are “currently underway.”
 

Easy augmentation

In a comment, Barbara Rothbaum, PhD, professor in psychiatry and director of the Trauma and Anxiety Recovery Program at Emory University, Atlanta, called it a “well-controlled trial augmenting exposure therapy for PTSD with brief aerobic exercise and finding some benefits of the augmented condition at 6 months posttreatment but not immediately posttreatment.”

The study’s methodology – that is, using independent standard assessment of PTSD and rating audio recordings of therapy sessions for treatment fidelity and quality – can lead us to “be confident in their [the researchers’] conclusions,” she said.

Dr. Rothbaum, who was not associated with this study, described research into methods to augment exposure therapy for PTSD as “timely and clinically relevant.”

Exercise “would be an easy augmentation for many clinicians if it is helpful,” she noted.

The study was funded by the Australian National Health and Medical Research Council. The authors and Dr. Rothbaum reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

A brief aerobic exercise intervention can augment the benefits of exposure therapy for PTSD, new research suggests.

Investigators randomly assigned individuals with PTSD to receive either exposure therapy with aerobic exercise or exposure therapy with passive stretching for 9 weeks. At 6 months post intervention, participants in the aerobic exercise group showed greater reductions in PTSD severity, compared with those in the stretching group.

“There is a critical need to improve outcomes for treating people with PTSD, and this finding points to one potentially cheap and ready-to-use strategy that all clinicians could employ with most patients,” lead author Richard Bryant, MPsych, PhD, DSc, director of the Traumatic Stress Clinic and Scientia Professor of Psychology at the University of New South Wales, Sydney, told this news organization.

The study was published online in The Lancet Psychiatry.
 

Promoting BDNF

“Trauma-focused psychotherapy is the recommended treatment for PTSD, but up to half of patients do not respond to this treatment,” Dr. Bryant said.

“We know that brain-derived neurotrophic factors [BDNF] are critical for synaptic plasticity, which underpins the learning that occurs in therapy so that reminders of trauma are no longer fear-provoking,” he continued. “Preclinical animal and human research inform us that brief aerobic exercise can promote BDNF and new learning that inhibits fear responses.”

The researchers “hypothesized that brief exercise after exposure therapy to trauma memories – which is the key ingredient of trauma-focused psychotherapy – would lead to greater reductions in PTSD, relative to standard trauma-focused therapy,” he said.

To investigate the question, the researchers randomly assigned 130 adults with PTSD (mean age, 39 years; 61% female; 76% White) to receive nine 90-minute sessions of exposure therapy with either aerobic exercise or passive stretching (n = 65 in each group).

There were no differences at baseline in sociodemographic characteristics or psychopathology measures, although the mean age of the stretching group was slightly older than that of the aerobic group (40 years vs. 37 years, respectively), and there was a slightly higher proportion of women in the stretching group (68% vs. 54%).

Participants did not differ on weekly exercise either at baseline, immediately post treatment, or at 6-week follow-up.

PTSD severity (the primary outcome) was measured using the clinician-administered PTSD scale CAPS-2, with assessments conducted at baseline, 1 week post treatment, and 6 months post treatment.

The aerobic exercise regimen was tailored to each participant, based on an assessment of his/her aerobic target zone.

The exposure therapy sessions were identical for both groups. Following the exposure sessions, participants engaged in their respective exercises: Those in the passive stretching group engaged in 20 minutes of exercise, while those in the aerobic group participated in a total of 20 minutes of exercise, with 10 conducted at their personal aerobic target heart rate.

“This level of exercise was chosen because BDNF concentration in the serum is increased by two 3-minute bouts of aerobic exercise, and 10 minutes of aerobic exercise can facilitate extinction learning,” the authors explained.

The aerobic activity consisted of running on a stepper exercise platform while having cardiac activity recorded. A small portion (10%) of the therapy sessions were recorded and rated for treatment fidelity.

Change in PTSD was the primary outcome, with secondary outcomes consisting of changes in depression, anxiety, alcohol use disorder, and posttraumatic cognitions.
 

Few barriers

The researchers found no significant differences in PTSD severity, as measured by CAPS-2 score, between treatment groups at 10 weeks – that is, immediately post treatment (mean difference, 7.0; 95% confidence interval, –2.3 to 16.4; P = .14).

However, significantly greater reductions in PTSD severity were found in the aerobic versus the stretching group at 6-month follow-up (mean difference, 12.1;95% CI, 2.4-21.8; P = .023), pointing to a “moderate effect size” (d = 0.6; 95% CI, 0.1-1.1]).

Although there were no differences found at 6-month assessment between rates of PTSD diagnosis (25% of the aerobic vs 27% of the stretching group), more participants in the aerobic group reached a “minimal clinically important difference,” compared to those in the stretching group (96% vs. 84%, respectively, x² = 4.4; P = .036). 

There were also superior benefits found in the aerobic versus the stretching group on depression severity at 6 months (a secondary outcome), with a mean difference in Beck Depression Inventory-2 score of 5.7 (95% CI, 0.5-10.9; P = .022), yielding a “moderate effect size” (d = 0.5; 95% CI, 0.1-1.0]).

There were no adverse events associated with the intervention, and almost all the sessions (88%) complied with the treatment protocol.

The researchers noted several limitations. For example, they did not obtain plasma to measure BDNF concentrations, so they could not “infer whether the mechanism of change involved BDNF.”

In addition, they did not perform sex-specific analyses. “Future studies could increase the sample size to investigate sex differences because females display less BDNF change following exercise than do males,” they wrote.

Nevertheless, the study “provides initial evidence of a simple and accessible strategy that clinicians could readily apply in combination with exposure therapy,” they stated. “Whereas many pharmacologic interventions pose barriers, including cost, requirement for prescriptions, and patient resistance to drugs, exercise offers clinicians a strategy that can be implemented with few barriers.”

Dr. Bryant emphasized that one study “does not represent a body of evidence, and so it is essential that this finding be replicated in other trials before it can be recommended for clinical use.” He noted that other trials are “currently underway.”
 

Easy augmentation

In a comment, Barbara Rothbaum, PhD, professor in psychiatry and director of the Trauma and Anxiety Recovery Program at Emory University, Atlanta, called it a “well-controlled trial augmenting exposure therapy for PTSD with brief aerobic exercise and finding some benefits of the augmented condition at 6 months posttreatment but not immediately posttreatment.”

The study’s methodology – that is, using independent standard assessment of PTSD and rating audio recordings of therapy sessions for treatment fidelity and quality – can lead us to “be confident in their [the researchers’] conclusions,” she said.

Dr. Rothbaum, who was not associated with this study, described research into methods to augment exposure therapy for PTSD as “timely and clinically relevant.”

Exercise “would be an easy augmentation for many clinicians if it is helpful,” she noted.

The study was funded by the Australian National Health and Medical Research Council. The authors and Dr. Rothbaum reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

When I was growing up, I can remember experiencing “duck and cover” drills at school. If a flash appeared in our peripheral vision, we were told we should not look at it but crawl under our desks. My classmates and I were being taught how to protect ourselves in case of a nuclear attack.

Clearly, had there been such an attack, ducking under our desks would not have saved us. Thankfully, such a conflict never occurred – and hopefully never will. Still, the warning did penetrate our psyches. In those days, families and children in schools were worried, and some were scared.

The situation is quite different today. Our children and grandchildren are being taught to protect themselves not from actions overseas – that never happened – but from what someone living in their community might do that has been occurring in real time. According to my daughter-in-law, her young children are taught during “lockdowns” to hide in their classrooms’ closets. During these drills, some children are directed to line up against a wall that would be out of sight of a shooter, and to stay as still as possible.

Since 2017, the number of intentional shootings in U.S. kindergarten through grade 12 schools increased precipitously (Prev Med. 2022 Dec. doi: 10.1016/j.ypmed.2022.107280). Imagine the psychological impact that the vigilance required to deal with such impending threats must be having on our children, as they learn to fear injury and possible death every day they go to school. I’ve talked with numerous parents about this, including my own adult children, and this is clearly a new dimension of life that is on everyone’s minds. Schools, once bastions of safety, are no longer that safe.

For many years, I’ve written about the need to destigmatize mental illness so that it is treated on a par with physical illness. As we look at the challenges faced by young people, reframing mental illness is more important now than ever. This means finding ways to increase the funding of studies that help us understand young people with mental health issues. It also means encouraging patients to pursue treatment from psychiatrists, psychologists, or mental health counselors who specialize in short-term therapy.

The emphasis here on short-term therapy is not to discourage longer-term care when needed, but clearly short-term care strategies, such as cognitive-behavioral therapies, not only work for problem resolution, they also help in the destigmatization of mental health care – as the circumscribed treatment with a clear beginning, middle, and end is consistent with CBT and consistent with much of medical care for physical disorders.

Furthermore, as we aim to destigmatize mental health care, it’s important to equate it with physical care. For example, taking a day or two from school or work for a sprained ankle, seeing a dentist, or an eye exam, plus a myriad of physical issues is quite acceptable. Why is it not also acceptable for a mental health issue and evaluation, such as for anxiety or PTSD, plus being able to talk about it without stigma? Seeing the “shrink” needs to be removed as a negative but viewed as a very positive move toward care for oneself.

In addition, children and adolescents are battling countless other health challenges that could have implications for mental health professionals, for example:

• During the height of the coronavirus pandemic, pediatric endocrinologists reportedly saw a surge of referrals for girls experiencing early puberty. Puberty should never be medicalized, but early maturation has been linked to numerous psychiatric disorders such as depression, anxiety, and eating disorders (J Pediatr Adolec Gynecol. 2022 Oct. doi: 10.1016/j.jpag.2022.05.005).
• A global epidemiologic study of children estimates that nearly 8 million youth lost a parent or caregiver because of a pandemic-related cause between Jan. 1, 2020, and May 1, 2022. An additional 2.5 million children were affected by the loss of secondary caregivers such as grandparents (JAMA Pediatr. 2022 Sept. doi: 10.1001/jamapediatrics.2022.3157).
• The inpatient and outpatient volume of adolescents and young adults receiving care for eating disorders skyrocketed before and after the pandemic, according to the results of case study series (JAMA Pediatrics. 2022 Nov 7. doi: 10.1001/jamapediatrics.2022.4346).
• Children and adolescents who developed COVID-19 suffered tremendously during the height of the pandemic. A nationwide analysis shows that COVID-19 nearly tripled children’s risks of developing new mental health illnesses, such as attention-deficit/hyperactivity disorder, anxiety, trauma, or stress disorder (Psychiatric Services. 2022 Jun 2. doi: 10.1176/appi.ps.202100646).

In addition to those challenges, young children are facing an increase in respiratory syncytial virus (RSV) infection. We were told the “flu” would be quite bad this year and to beware of monkeypox. However, very little mention is made of the equally distressing “epidemic” of mental health issues, PTSD, anxiety, and depression as we are still in the midst of the COVID pandemic in the United States with almost 400 deaths a day – a very unacceptable number.

Interestingly, we seem to have abandoned the use of masks as protection against COVID and other respiratory diseases, despite their effectiveness. A study in Boston that looked at children in two school districts that did not lift mask mandates demonstrated that mask wearing does indeed lead to significant reductions in the number of pediatric COVID cases. In addition to societal violence and school shootings – which certainly exacerbate anxiety – the fear of dying or the death of a loved one, tied to COVID, may lead to epidemic proportions of PTSD in children. As an article in WebMD noted, “pediatricians are imploring the federal government to declare a national emergency as cases of pediatric respiratory illnesses continue to soar.”

In light of the acknowledged mental health crisis in children, which appears epidemic, I would hope the psychiatric and psychological associations would publicly sound an alarm so that resources could be brought to bear to address this critical issue. I believe doing so would also aid in destigmatizing mental disorders, and increase education and treatment.

Layered on top of those issues are natural disasters, such as the fallout from Tropical Storm Nicole when it recently caused devastation across western Florida. The mental health trauma caused by recent tropical storms seems all but forgotten – except for those who are still suffering. All of this adds up to a society-wide mental health crisis, which seems far more expansive than monkeypox, for example. Yet monkeypox, which did lead to thousands of cases and approximately 29 deaths in the United States, was declared a national public health emergency.

Additionally, RSV killed 100-500 U.S. children under age 5 each year before the pandemic, according to the Centers for Disease Control and Prevention, and currently it appears even worse. Yet despite the seriousness of RSV, it nowhere matches the emotional toll COVID has taken on children globally.

Let’s make it standard practice for children – and of course, adults – to be taught that anxiety is a normal response at times. We should teach that, in some cases, feeling “down” or in despair and even experiencing symptoms of PTSD based on what’s going on personally and within our environment (i.e., COVID, school shootings, etc.) are triggers and responses that can be addressed and often quickly treated by talking with a mental health professional.

Dr. London is a practicing psychiatrist and has been a newspaper columnist for 35 years, specializing in and writing about short-term therapy, including cognitive-behavioral therapy and guided imagery. He is author of “Find Freedom Fast” (New York: Kettlehole Publishing, 2019). He has no conflicts of interest.

When I was growing up, I can remember experiencing “duck and cover” drills at school. If a flash appeared in our peripheral vision, we were told we should not look at it but crawl under our desks. My classmates and I were being taught how to protect ourselves in case of a nuclear attack.

Clearly, had there been such an attack, ducking under our desks would not have saved us. Thankfully, such a conflict never occurred – and hopefully never will. Still, the warning did penetrate our psyches. In those days, families and children in schools were worried, and some were scared.

The situation is quite different today. Our children and grandchildren are being taught to protect themselves not from actions overseas – that never happened – but from what someone living in their community might do that has been occurring in real time. According to my daughter-in-law, her young children are taught during “lockdowns” to hide in their classrooms’ closets. During these drills, some children are directed to line up against a wall that would be out of sight of a shooter, and to stay as still as possible.

Since 2017, the number of intentional shootings in U.S. kindergarten through grade 12 schools increased precipitously (Prev Med. 2022 Dec. doi: 10.1016/j.ypmed.2022.107280). Imagine the psychological impact that the vigilance required to deal with such impending threats must be having on our children, as they learn to fear injury and possible death every day they go to school. I’ve talked with numerous parents about this, including my own adult children, and this is clearly a new dimension of life that is on everyone’s minds. Schools, once bastions of safety, are no longer that safe.

For many years, I’ve written about the need to destigmatize mental illness so that it is treated on a par with physical illness. As we look at the challenges faced by young people, reframing mental illness is more important now than ever. This means finding ways to increase the funding of studies that help us understand young people with mental health issues. It also means encouraging patients to pursue treatment from psychiatrists, psychologists, or mental health counselors who specialize in short-term therapy.

The emphasis here on short-term therapy is not to discourage longer-term care when needed, but clearly short-term care strategies, such as cognitive-behavioral therapies, not only work for problem resolution, they also help in the destigmatization of mental health care – as the circumscribed treatment with a clear beginning, middle, and end is consistent with CBT and consistent with much of medical care for physical disorders.

Furthermore, as we aim to destigmatize mental health care, it’s important to equate it with physical care. For example, taking a day or two from school or work for a sprained ankle, seeing a dentist, or an eye exam, plus a myriad of physical issues is quite acceptable. Why is it not also acceptable for a mental health issue and evaluation, such as for anxiety or PTSD, plus being able to talk about it without stigma? Seeing the “shrink” needs to be removed as a negative but viewed as a very positive move toward care for oneself.

In addition, children and adolescents are battling countless other health challenges that could have implications for mental health professionals, for example:

• During the height of the coronavirus pandemic, pediatric endocrinologists reportedly saw a surge of referrals for girls experiencing early puberty. Puberty should never be medicalized, but early maturation has been linked to numerous psychiatric disorders such as depression, anxiety, and eating disorders (J Pediatr Adolec Gynecol. 2022 Oct. doi: 10.1016/j.jpag.2022.05.005).
• A global epidemiologic study of children estimates that nearly 8 million youth lost a parent or caregiver because of a pandemic-related cause between Jan. 1, 2020, and May 1, 2022. An additional 2.5 million children were affected by the loss of secondary caregivers such as grandparents (JAMA Pediatr. 2022 Sept. doi: 10.1001/jamapediatrics.2022.3157).
• The inpatient and outpatient volume of adolescents and young adults receiving care for eating disorders skyrocketed before and after the pandemic, according to the results of case study series (JAMA Pediatrics. 2022 Nov 7. doi: 10.1001/jamapediatrics.2022.4346).
• Children and adolescents who developed COVID-19 suffered tremendously during the height of the pandemic. A nationwide analysis shows that COVID-19 nearly tripled children’s risks of developing new mental health illnesses, such as attention-deficit/hyperactivity disorder, anxiety, trauma, or stress disorder (Psychiatric Services. 2022 Jun 2. doi: 10.1176/appi.ps.202100646).

In addition to those challenges, young children are facing an increase in respiratory syncytial virus (RSV) infection. We were told the “flu” would be quite bad this year and to beware of monkeypox. However, very little mention is made of the equally distressing “epidemic” of mental health issues, PTSD, anxiety, and depression as we are still in the midst of the COVID pandemic in the United States with almost 400 deaths a day – a very unacceptable number.

Interestingly, we seem to have abandoned the use of masks as protection against COVID and other respiratory diseases, despite their effectiveness. A study in Boston that looked at children in two school districts that did not lift mask mandates demonstrated that mask wearing does indeed lead to significant reductions in the number of pediatric COVID cases. In addition to societal violence and school shootings – which certainly exacerbate anxiety – the fear of dying or the death of a loved one, tied to COVID, may lead to epidemic proportions of PTSD in children. As an article in WebMD noted, “pediatricians are imploring the federal government to declare a national emergency as cases of pediatric respiratory illnesses continue to soar.”

In light of the acknowledged mental health crisis in children, which appears epidemic, I would hope the psychiatric and psychological associations would publicly sound an alarm so that resources could be brought to bear to address this critical issue. I believe doing so would also aid in destigmatizing mental disorders, and increase education and treatment.

Layered on top of those issues are natural disasters, such as the fallout from Tropical Storm Nicole when it recently caused devastation across western Florida. The mental health trauma caused by recent tropical storms seems all but forgotten – except for those who are still suffering. All of this adds up to a society-wide mental health crisis, which seems far more expansive than monkeypox, for example. Yet monkeypox, which did lead to thousands of cases and approximately 29 deaths in the United States, was declared a national public health emergency.

Additionally, RSV killed 100-500 U.S. children under age 5 each year before the pandemic, according to the Centers for Disease Control and Prevention, and currently it appears even worse. Yet despite the seriousness of RSV, it nowhere matches the emotional toll COVID has taken on children globally.

Let’s make it standard practice for children – and of course, adults – to be taught that anxiety is a normal response at times. We should teach that, in some cases, feeling “down” or in despair and even experiencing symptoms of PTSD based on what’s going on personally and within our environment (i.e., COVID, school shootings, etc.) are triggers and responses that can be addressed and often quickly treated by talking with a mental health professional.

Dr. London is a practicing psychiatrist and has been a newspaper columnist for 35 years, specializing in and writing about short-term therapy, including cognitive-behavioral therapy and guided imagery. He is author of “Find Freedom Fast” (New York: Kettlehole Publishing, 2019). He has no conflicts of interest.

When I was growing up, I can remember experiencing “duck and cover” drills at school. If a flash appeared in our peripheral vision, we were told we should not look at it but crawl under our desks. My classmates and I were being taught how to protect ourselves in case of a nuclear attack.

Clearly, had there been such an attack, ducking under our desks would not have saved us. Thankfully, such a conflict never occurred – and hopefully never will. Still, the warning did penetrate our psyches. In those days, families and children in schools were worried, and some were scared.

The situation is quite different today. Our children and grandchildren are being taught to protect themselves not from actions overseas – that never happened – but from what someone living in their community might do that has been occurring in real time. According to my daughter-in-law, her young children are taught during “lockdowns” to hide in their classrooms’ closets. During these drills, some children are directed to line up against a wall that would be out of sight of a shooter, and to stay as still as possible.

Since 2017, the number of intentional shootings in U.S. kindergarten through grade 12 schools increased precipitously (Prev Med. 2022 Dec. doi: 10.1016/j.ypmed.2022.107280). Imagine the psychological impact that the vigilance required to deal with such impending threats must be having on our children, as they learn to fear injury and possible death every day they go to school. I’ve talked with numerous parents about this, including my own adult children, and this is clearly a new dimension of life that is on everyone’s minds. Schools, once bastions of safety, are no longer that safe.

For many years, I’ve written about the need to destigmatize mental illness so that it is treated on a par with physical illness. As we look at the challenges faced by young people, reframing mental illness is more important now than ever. This means finding ways to increase the funding of studies that help us understand young people with mental health issues. It also means encouraging patients to pursue treatment from psychiatrists, psychologists, or mental health counselors who specialize in short-term therapy.

The emphasis here on short-term therapy is not to discourage longer-term care when needed, but clearly short-term care strategies, such as cognitive-behavioral therapies, not only work for problem resolution, they also help in the destigmatization of mental health care – as the circumscribed treatment with a clear beginning, middle, and end is consistent with CBT and consistent with much of medical care for physical disorders.

Furthermore, as we aim to destigmatize mental health care, it’s important to equate it with physical care. For example, taking a day or two from school or work for a sprained ankle, seeing a dentist, or an eye exam, plus a myriad of physical issues is quite acceptable. Why is it not also acceptable for a mental health issue and evaluation, such as for anxiety or PTSD, plus being able to talk about it without stigma? Seeing the “shrink” needs to be removed as a negative but viewed as a very positive move toward care for oneself.

In addition, children and adolescents are battling countless other health challenges that could have implications for mental health professionals, for example:

• During the height of the coronavirus pandemic, pediatric endocrinologists reportedly saw a surge of referrals for girls experiencing early puberty. Puberty should never be medicalized, but early maturation has been linked to numerous psychiatric disorders such as depression, anxiety, and eating disorders (J Pediatr Adolec Gynecol. 2022 Oct. doi: 10.1016/j.jpag.2022.05.005).
• A global epidemiologic study of children estimates that nearly 8 million youth lost a parent or caregiver because of a pandemic-related cause between Jan. 1, 2020, and May 1, 2022. An additional 2.5 million children were affected by the loss of secondary caregivers such as grandparents (JAMA Pediatr. 2022 Sept. doi: 10.1001/jamapediatrics.2022.3157).
• The inpatient and outpatient volume of adolescents and young adults receiving care for eating disorders skyrocketed before and after the pandemic, according to the results of case study series (JAMA Pediatrics. 2022 Nov 7. doi: 10.1001/jamapediatrics.2022.4346).
• Children and adolescents who developed COVID-19 suffered tremendously during the height of the pandemic. A nationwide analysis shows that COVID-19 nearly tripled children’s risks of developing new mental health illnesses, such as attention-deficit/hyperactivity disorder, anxiety, trauma, or stress disorder (Psychiatric Services. 2022 Jun 2. doi: 10.1176/appi.ps.202100646).

In addition to those challenges, young children are facing an increase in respiratory syncytial virus (RSV) infection. We were told the “flu” would be quite bad this year and to beware of monkeypox. However, very little mention is made of the equally distressing “epidemic” of mental health issues, PTSD, anxiety, and depression as we are still in the midst of the COVID pandemic in the United States with almost 400 deaths a day – a very unacceptable number.

Interestingly, we seem to have abandoned the use of masks as protection against COVID and other respiratory diseases, despite their effectiveness. A study in Boston that looked at children in two school districts that did not lift mask mandates demonstrated that mask wearing does indeed lead to significant reductions in the number of pediatric COVID cases. In addition to societal violence and school shootings – which certainly exacerbate anxiety – the fear of dying or the death of a loved one, tied to COVID, may lead to epidemic proportions of PTSD in children. As an article in WebMD noted, “pediatricians are imploring the federal government to declare a national emergency as cases of pediatric respiratory illnesses continue to soar.”

In light of the acknowledged mental health crisis in children, which appears epidemic, I would hope the psychiatric and psychological associations would publicly sound an alarm so that resources could be brought to bear to address this critical issue. I believe doing so would also aid in destigmatizing mental disorders, and increase education and treatment.

Layered on top of those issues are natural disasters, such as the fallout from Tropical Storm Nicole when it recently caused devastation across western Florida. The mental health trauma caused by recent tropical storms seems all but forgotten – except for those who are still suffering. All of this adds up to a society-wide mental health crisis, which seems far more expansive than monkeypox, for example. Yet monkeypox, which did lead to thousands of cases and approximately 29 deaths in the United States, was declared a national public health emergency.

Additionally, RSV killed 100-500 U.S. children under age 5 each year before the pandemic, according to the Centers for Disease Control and Prevention, and currently it appears even worse. Yet despite the seriousness of RSV, it nowhere matches the emotional toll COVID has taken on children globally.

Let’s make it standard practice for children – and of course, adults – to be taught that anxiety is a normal response at times. We should teach that, in some cases, feeling “down” or in despair and even experiencing symptoms of PTSD based on what’s going on personally and within our environment (i.e., COVID, school shootings, etc.) are triggers and responses that can be addressed and often quickly treated by talking with a mental health professional.

Dr. London is a practicing psychiatrist and has been a newspaper columnist for 35 years, specializing in and writing about short-term therapy, including cognitive-behavioral therapy and guided imagery. He is author of “Find Freedom Fast” (New York: Kettlehole Publishing, 2019). He has no conflicts of interest.

Postpartum depression, anxiety, and posttraumatic stress disorder that persist 2-3 years after birth are associated with a dysregulated immune system that is characterized by increased inflammatory signaling, according to investigators.

These findings suggest that mental health screening for women who have given birth should continue beyond the first year post partum, reported lead author Jennifer M. Nicoloro-SantaBarbara, PhD, of Brigham and Women’s Hospital, Harvard Medical School, Boston, and colleagues.

“Delayed postpartum depression, also known as late-onset postpartum depression, can affect women up to 18 months after delivery,” the investigators wrote in the American Journal of Reproductive Immunology. “It can appear even later in some women, depending on the hormonal changes that occur after having a baby (for example, timing of weaning). However, the majority of research on maternal mental health focuses on the first year post birth, leaving a gap in research beyond 12 months post partum.”

To address this gap, the investigators enrolled 33 women who were 2-3 years post partum. Participants completed self-guided questionnaires on PTSD, depression, and anxiety, and provided blood samples for gene expression analysis.

Sixteen of the 33 women had clinically significant mood disturbances. Compared with the other participants, these 16 women had significant upregulation of genes driving inflammatory pathways and significantly reduced activation of genes associated with viral response.

“The results provide preliminary evidence of a mechanism (e.g., immune dysregulation) that might be contributing to mood disorders and bring us closer to the goal of identifying targetable biomarkers for mood disorders,” Dr. Nicoloro-SantaBarbara said in a written comment. “This work highlights the need for standardized and continual depression and anxiety screening in ob.gyn. and primary care settings that extends beyond the 6-week maternal visit and possibly beyond the first postpartum year.”
 

Findings draw skepticism

“The authors argue that mothers need to be screened for depression/anxiety longer than the first year post partum, and this is true, but it has nothing to do with their findings,” said Jennifer L. Payne, MD, an expert in reproductive psychiatry at the University of Virginia, Charlottesville.

In a written comment, she explained that the cross-sectional design makes it impossible to know whether the mood disturbances were linked with delivery at all.

“It is unclear if the depression/anxiety symptoms began after delivery or not,” Dr. Payne said. “In addition, it is unclear if the findings are causative or a result of depression/anxiety symptoms (the authors admit this in the limitations section). It is likely that the findings are not specific or even related to having delivered a child, but rather reflect a more general process related to depression/anxiety outside of the postpartum time period.”

Only prospective studies can answer these questions, she said.

Dr. Nicoloro-SantaBarbara agreed that further research is needed.

“Our findings are exciting, but still need to be replicated in larger samples with diverse women in order to make sure they generalize,” she said. “More work is needed to understand why inflammation plays a role in postpartum mental illness for some women and not others.”

The study was supported by a Cedars-Sinai Precision Health Grant, the Cousins Center for Psychoneuroimmunology, University of California, Los Angeles, and the National Institute of Mental Health. The investigators and Dr. Payne disclosed no relevant conflicts of interest.

Postpartum depression, anxiety, and posttraumatic stress disorder that persist 2-3 years after birth are associated with a dysregulated immune system that is characterized by increased inflammatory signaling, according to investigators.

These findings suggest that mental health screening for women who have given birth should continue beyond the first year post partum, reported lead author Jennifer M. Nicoloro-SantaBarbara, PhD, of Brigham and Women’s Hospital, Harvard Medical School, Boston, and colleagues.

“Delayed postpartum depression, also known as late-onset postpartum depression, can affect women up to 18 months after delivery,” the investigators wrote in the American Journal of Reproductive Immunology. “It can appear even later in some women, depending on the hormonal changes that occur after having a baby (for example, timing of weaning). However, the majority of research on maternal mental health focuses on the first year post birth, leaving a gap in research beyond 12 months post partum.”

To address this gap, the investigators enrolled 33 women who were 2-3 years post partum. Participants completed self-guided questionnaires on PTSD, depression, and anxiety, and provided blood samples for gene expression analysis.

Sixteen of the 33 women had clinically significant mood disturbances. Compared with the other participants, these 16 women had significant upregulation of genes driving inflammatory pathways and significantly reduced activation of genes associated with viral response.

“The results provide preliminary evidence of a mechanism (e.g., immune dysregulation) that might be contributing to mood disorders and bring us closer to the goal of identifying targetable biomarkers for mood disorders,” Dr. Nicoloro-SantaBarbara said in a written comment. “This work highlights the need for standardized and continual depression and anxiety screening in ob.gyn. and primary care settings that extends beyond the 6-week maternal visit and possibly beyond the first postpartum year.”
 

Findings draw skepticism

“The authors argue that mothers need to be screened for depression/anxiety longer than the first year post partum, and this is true, but it has nothing to do with their findings,” said Jennifer L. Payne, MD, an expert in reproductive psychiatry at the University of Virginia, Charlottesville.

In a written comment, she explained that the cross-sectional design makes it impossible to know whether the mood disturbances were linked with delivery at all.

“It is unclear if the depression/anxiety symptoms began after delivery or not,” Dr. Payne said. “In addition, it is unclear if the findings are causative or a result of depression/anxiety symptoms (the authors admit this in the limitations section). It is likely that the findings are not specific or even related to having delivered a child, but rather reflect a more general process related to depression/anxiety outside of the postpartum time period.”

Only prospective studies can answer these questions, she said.

Dr. Nicoloro-SantaBarbara agreed that further research is needed.

“Our findings are exciting, but still need to be replicated in larger samples with diverse women in order to make sure they generalize,” she said. “More work is needed to understand why inflammation plays a role in postpartum mental illness for some women and not others.”

The study was supported by a Cedars-Sinai Precision Health Grant, the Cousins Center for Psychoneuroimmunology, University of California, Los Angeles, and the National Institute of Mental Health. The investigators and Dr. Payne disclosed no relevant conflicts of interest.

Postpartum depression, anxiety, and posttraumatic stress disorder that persist 2-3 years after birth are associated with a dysregulated immune system that is characterized by increased inflammatory signaling, according to investigators.

These findings suggest that mental health screening for women who have given birth should continue beyond the first year post partum, reported lead author Jennifer M. Nicoloro-SantaBarbara, PhD, of Brigham and Women’s Hospital, Harvard Medical School, Boston, and colleagues.

“Delayed postpartum depression, also known as late-onset postpartum depression, can affect women up to 18 months after delivery,” the investigators wrote in the American Journal of Reproductive Immunology. “It can appear even later in some women, depending on the hormonal changes that occur after having a baby (for example, timing of weaning). However, the majority of research on maternal mental health focuses on the first year post birth, leaving a gap in research beyond 12 months post partum.”

To address this gap, the investigators enrolled 33 women who were 2-3 years post partum. Participants completed self-guided questionnaires on PTSD, depression, and anxiety, and provided blood samples for gene expression analysis.

Sixteen of the 33 women had clinically significant mood disturbances. Compared with the other participants, these 16 women had significant upregulation of genes driving inflammatory pathways and significantly reduced activation of genes associated with viral response.

“The results provide preliminary evidence of a mechanism (e.g., immune dysregulation) that might be contributing to mood disorders and bring us closer to the goal of identifying targetable biomarkers for mood disorders,” Dr. Nicoloro-SantaBarbara said in a written comment. “This work highlights the need for standardized and continual depression and anxiety screening in ob.gyn. and primary care settings that extends beyond the 6-week maternal visit and possibly beyond the first postpartum year.”
 

Findings draw skepticism

“The authors argue that mothers need to be screened for depression/anxiety longer than the first year post partum, and this is true, but it has nothing to do with their findings,” said Jennifer L. Payne, MD, an expert in reproductive psychiatry at the University of Virginia, Charlottesville.

In a written comment, she explained that the cross-sectional design makes it impossible to know whether the mood disturbances were linked with delivery at all.

“It is unclear if the depression/anxiety symptoms began after delivery or not,” Dr. Payne said. “In addition, it is unclear if the findings are causative or a result of depression/anxiety symptoms (the authors admit this in the limitations section). It is likely that the findings are not specific or even related to having delivered a child, but rather reflect a more general process related to depression/anxiety outside of the postpartum time period.”

Only prospective studies can answer these questions, she said.

Dr. Nicoloro-SantaBarbara agreed that further research is needed.

“Our findings are exciting, but still need to be replicated in larger samples with diverse women in order to make sure they generalize,” she said. “More work is needed to understand why inflammation plays a role in postpartum mental illness for some women and not others.”

The study was supported by a Cedars-Sinai Precision Health Grant, the Cousins Center for Psychoneuroimmunology, University of California, Los Angeles, and the National Institute of Mental Health. The investigators and Dr. Payne disclosed no relevant conflicts of interest.

A digital intervention may offer a new and effective treatment option for panic disorder (PD) and posttraumatic stress disorder, new research suggests.

The 28-day home-based treatment, known as the capnometry guided respiratory intervention (CGRI), uses an app-based feedback protocol to normalize respiration and increase patients’ ability to cope with symptoms of stress, anxiety, and panic by providing real time breath-to-breath feedback of respiratory rate and carbon dioxide (CO₂) levels via a nasal cannula.

Freespira

Results from the large real-world study showed that over 65% of patients with PD and over 72% of those with PTSD responded to the treatment. In addition, almost 75% of participants adhered to the study protocol, with low dropout rates.

“The brief duration of treatment, high adherence rates, and clinical benefit suggests that CGRI provides an important addition to treatment options for PD and PTSD,” the investigators write.

The study was published online in Frontiers in Digital Health.
 

‘New kid on the block’

The “respiratory dysregulation hypothesis” links CO₂ sensitivity to panic attacks and PD, and similar reactivity has been identified in PTSD, but a “common limitation of psychotherapeutic and pharmacologic approaches to PD and PTSD is that neither address the role of respiratory physiology and breathing style,” the investigators note.

The most widely studied treatment for PTSD is trauma-focused psychotherapy, in which the patient reviews and revisits the trauma, but it has a high dropout rate, study investigator Michael Telch, PhD, director of the Laboratory for the Study of Anxiety Disorders, University of Texas, Austin, told this news organization.

He described CGRI for PTSD as a “relatively new kid on the block, so to speak.” The intervention was cleared by the U.S. Food and Drug Administration for treatment of PD and PTSD in 2013 and 2018, respectively, and is currently available through the Veterans Administration for veterans with PTSD. It is also covered by some commercial insurance plans.

“The underlying assumption [of CGRI] is that a person can learn to develop skills for controlling some of their physiological reactions that are triggered as a result of trauma,” said Dr. Telch.

The device uses a biofeedback approach to give patients “greater control over their physiological reactions, such as hyperventilation and increased respiration rate, and the focus is on providing a sense of mastery,” he said.

Participants with PTSD were assigned to a health coach. The device was delivered to the patient’s home, and patients met with the trained coach weekly and could check in between visits via text or e-mail. Twice-daily sessions were recommended.

“The coach gets feedback about what’s happening with the patient’s respiration and end-tidal CO₂ levels [etCO₂] and instructs participants how to keep their respiration rate and etCO₂ at a more normal level,” said Dr. Telch.

The CGRI “teaches a specific breathing style via a system providing real-time feedback of respiratory rate (RR) and exhaled carbon dioxide levels facilitated by data capture,” the authors note.
 

Sense of mastery

Of the 1,569 participants, 1,395 had PD and 174 had PTSD (mean age, 39.2 [standard deviation, 13.9] years and 40.9 [SD, 14.9] years, respectively; 76% and 73% female, respectively). Those with PD completed the Panic Disorder Severity Scale (PDSS) and those with PTSD completed the Posttraumatic Stress Disorder Checklist for DSM-5 (PCL-5), before and after the intervention.

The treatment response rate for PD was defined as a 40% or greater reduction in PDSS total scores, whereas treatment response rate for PTSD was defined as a 10-point or greater reduction in PCL-5 scores.

At baseline, patients were classified either as normocapnic or hypocapnic (etCO₂ ≥ 37 or < 37, respectively), with 65% classified as normocapnic and 35% classified as hypocapnic.

Among patients with PD, there was a 50.2% mean pre- to posttreatment reduction in total PDSS scores (P < .001; d = 1.31), with a treatment response rate of 65.3% of patients.

Among patients with PTSD, there was a 41.1% pre- to posttreatment reduction in total PCL-5 scores (P < .001; d = 1.16), with a treatment response rate of 72.4%.

When investigators analyzed the response at the individual level, they found that 55.7% of patients with PD and 53.5% of those with PTSD were classified as treatment responders. This determination was based on a two-pronged approach that first calculated the Reliable Change Index (RCI) for each participant, and, in participants showing statistically reliable improvement, whether the posttreatment score was closer to the distribution of scores for patients without or with the given disorder.

“Patients with both normal and below-normal baseline exhaled CO2 levels experienced comparable benefit,” the authors report.

‘A viable alternative’

Commenting on the research, Charles Marmar, MD, chair and Peter H. Schub Professor of Psychiatry, department of psychiatry, New York University, said that the study has some limitations, probably the most significant of which is that most participants had normal baseline CO₂ levels.

“The treatment is fundamentally designed for people who hyperventilate and blow off too much CO₂ so they can breathe in a more calm, relaxed way, but most people in the trial had normal CO₂ to begin with,” said Dr. Marmar, who was not involved with the study.

“It’s likely that the major benefits were the relaxation from doing the breathing exercises rather than the change in CO₂ levels,” he speculated.

The treatment is “probably a good thing for those patients who actually have abnormal CO₂ levels. This treatment could be used in precision medicine, where you tailor treatments to those who actually need them rather than giving the same treatment to everyone,” he said.

“For patients who don’t respond to trauma-focused therapy or it’s too aversive for them to undergo, this new intervention provides a viable alternative,” Dr. Telch added.

The study was internally funded by Freespira. Dr. Telch is a scientific advisor at Freespira and receives compensation by way of stock options. The other authors’ disclosures are listed on the original paper. Dr. Marmar has declared no relevant financial relationships.

A version of this article first appeared on Medscape.com.

A digital intervention may offer a new and effective treatment option for panic disorder (PD) and posttraumatic stress disorder, new research suggests.

The 28-day home-based treatment, known as the capnometry guided respiratory intervention (CGRI), uses an app-based feedback protocol to normalize respiration and increase patients’ ability to cope with symptoms of stress, anxiety, and panic by providing real time breath-to-breath feedback of respiratory rate and carbon dioxide (CO₂) levels via a nasal cannula.

Freespira

Results from the large real-world study showed that over 65% of patients with PD and over 72% of those with PTSD responded to the treatment. In addition, almost 75% of participants adhered to the study protocol, with low dropout rates.

“The brief duration of treatment, high adherence rates, and clinical benefit suggests that CGRI provides an important addition to treatment options for PD and PTSD,” the investigators write.

The study was published online in Frontiers in Digital Health.
 

‘New kid on the block’

The “respiratory dysregulation hypothesis” links CO₂ sensitivity to panic attacks and PD, and similar reactivity has been identified in PTSD, but a “common limitation of psychotherapeutic and pharmacologic approaches to PD and PTSD is that neither address the role of respiratory physiology and breathing style,” the investigators note.

The most widely studied treatment for PTSD is trauma-focused psychotherapy, in which the patient reviews and revisits the trauma, but it has a high dropout rate, study investigator Michael Telch, PhD, director of the Laboratory for the Study of Anxiety Disorders, University of Texas, Austin, told this news organization.

He described CGRI for PTSD as a “relatively new kid on the block, so to speak.” The intervention was cleared by the U.S. Food and Drug Administration for treatment of PD and PTSD in 2013 and 2018, respectively, and is currently available through the Veterans Administration for veterans with PTSD. It is also covered by some commercial insurance plans.

“The underlying assumption [of CGRI] is that a person can learn to develop skills for controlling some of their physiological reactions that are triggered as a result of trauma,” said Dr. Telch.

The device uses a biofeedback approach to give patients “greater control over their physiological reactions, such as hyperventilation and increased respiration rate, and the focus is on providing a sense of mastery,” he said.

Participants with PTSD were assigned to a health coach. The device was delivered to the patient’s home, and patients met with the trained coach weekly and could check in between visits via text or e-mail. Twice-daily sessions were recommended.

“The coach gets feedback about what’s happening with the patient’s respiration and end-tidal CO₂ levels [etCO₂] and instructs participants how to keep their respiration rate and etCO₂ at a more normal level,” said Dr. Telch.

The CGRI “teaches a specific breathing style via a system providing real-time feedback of respiratory rate (RR) and exhaled carbon dioxide levels facilitated by data capture,” the authors note.
 

Sense of mastery

Of the 1,569 participants, 1,395 had PD and 174 had PTSD (mean age, 39.2 [standard deviation, 13.9] years and 40.9 [SD, 14.9] years, respectively; 76% and 73% female, respectively). Those with PD completed the Panic Disorder Severity Scale (PDSS) and those with PTSD completed the Posttraumatic Stress Disorder Checklist for DSM-5 (PCL-5), before and after the intervention.

The treatment response rate for PD was defined as a 40% or greater reduction in PDSS total scores, whereas treatment response rate for PTSD was defined as a 10-point or greater reduction in PCL-5 scores.

At baseline, patients were classified either as normocapnic or hypocapnic (etCO₂ ≥ 37 or < 37, respectively), with 65% classified as normocapnic and 35% classified as hypocapnic.

Among patients with PD, there was a 50.2% mean pre- to posttreatment reduction in total PDSS scores (P < .001; d = 1.31), with a treatment response rate of 65.3% of patients.

Among patients with PTSD, there was a 41.1% pre- to posttreatment reduction in total PCL-5 scores (P < .001; d = 1.16), with a treatment response rate of 72.4%.

When investigators analyzed the response at the individual level, they found that 55.7% of patients with PD and 53.5% of those with PTSD were classified as treatment responders. This determination was based on a two-pronged approach that first calculated the Reliable Change Index (RCI) for each participant, and, in participants showing statistically reliable improvement, whether the posttreatment score was closer to the distribution of scores for patients without or with the given disorder.

“Patients with both normal and below-normal baseline exhaled CO2 levels experienced comparable benefit,” the authors report.

‘A viable alternative’

Commenting on the research, Charles Marmar, MD, chair and Peter H. Schub Professor of Psychiatry, department of psychiatry, New York University, said that the study has some limitations, probably the most significant of which is that most participants had normal baseline CO₂ levels.

“The treatment is fundamentally designed for people who hyperventilate and blow off too much CO₂ so they can breathe in a more calm, relaxed way, but most people in the trial had normal CO₂ to begin with,” said Dr. Marmar, who was not involved with the study.

“It’s likely that the major benefits were the relaxation from doing the breathing exercises rather than the change in CO₂ levels,” he speculated.

The treatment is “probably a good thing for those patients who actually have abnormal CO₂ levels. This treatment could be used in precision medicine, where you tailor treatments to those who actually need them rather than giving the same treatment to everyone,” he said.

“For patients who don’t respond to trauma-focused therapy or it’s too aversive for them to undergo, this new intervention provides a viable alternative,” Dr. Telch added.

The study was internally funded by Freespira. Dr. Telch is a scientific advisor at Freespira and receives compensation by way of stock options. The other authors’ disclosures are listed on the original paper. Dr. Marmar has declared no relevant financial relationships.

A version of this article first appeared on Medscape.com.

A digital intervention may offer a new and effective treatment option for panic disorder (PD) and posttraumatic stress disorder, new research suggests.

The 28-day home-based treatment, known as the capnometry guided respiratory intervention (CGRI), uses an app-based feedback protocol to normalize respiration and increase patients’ ability to cope with symptoms of stress, anxiety, and panic by providing real time breath-to-breath feedback of respiratory rate and carbon dioxide (CO₂) levels via a nasal cannula.

Freespira

Results from the large real-world study showed that over 65% of patients with PD and over 72% of those with PTSD responded to the treatment. In addition, almost 75% of participants adhered to the study protocol, with low dropout rates.

“The brief duration of treatment, high adherence rates, and clinical benefit suggests that CGRI provides an important addition to treatment options for PD and PTSD,” the investigators write.

The study was published online in Frontiers in Digital Health.
 

‘New kid on the block’

The “respiratory dysregulation hypothesis” links CO₂ sensitivity to panic attacks and PD, and similar reactivity has been identified in PTSD, but a “common limitation of psychotherapeutic and pharmacologic approaches to PD and PTSD is that neither address the role of respiratory physiology and breathing style,” the investigators note.

The most widely studied treatment for PTSD is trauma-focused psychotherapy, in which the patient reviews and revisits the trauma, but it has a high dropout rate, study investigator Michael Telch, PhD, director of the Laboratory for the Study of Anxiety Disorders, University of Texas, Austin, told this news organization.

He described CGRI for PTSD as a “relatively new kid on the block, so to speak.” The intervention was cleared by the U.S. Food and Drug Administration for treatment of PD and PTSD in 2013 and 2018, respectively, and is currently available through the Veterans Administration for veterans with PTSD. It is also covered by some commercial insurance plans.

“The underlying assumption [of CGRI] is that a person can learn to develop skills for controlling some of their physiological reactions that are triggered as a result of trauma,” said Dr. Telch.

The device uses a biofeedback approach to give patients “greater control over their physiological reactions, such as hyperventilation and increased respiration rate, and the focus is on providing a sense of mastery,” he said.

Participants with PTSD were assigned to a health coach. The device was delivered to the patient’s home, and patients met with the trained coach weekly and could check in between visits via text or e-mail. Twice-daily sessions were recommended.

“The coach gets feedback about what’s happening with the patient’s respiration and end-tidal CO₂ levels [etCO₂] and instructs participants how to keep their respiration rate and etCO₂ at a more normal level,” said Dr. Telch.

The CGRI “teaches a specific breathing style via a system providing real-time feedback of respiratory rate (RR) and exhaled carbon dioxide levels facilitated by data capture,” the authors note.
 

Sense of mastery

Of the 1,569 participants, 1,395 had PD and 174 had PTSD (mean age, 39.2 [standard deviation, 13.9] years and 40.9 [SD, 14.9] years, respectively; 76% and 73% female, respectively). Those with PD completed the Panic Disorder Severity Scale (PDSS) and those with PTSD completed the Posttraumatic Stress Disorder Checklist for DSM-5 (PCL-5), before and after the intervention.

The treatment response rate for PD was defined as a 40% or greater reduction in PDSS total scores, whereas treatment response rate for PTSD was defined as a 10-point or greater reduction in PCL-5 scores.

At baseline, patients were classified either as normocapnic or hypocapnic (etCO₂ ≥ 37 or < 37, respectively), with 65% classified as normocapnic and 35% classified as hypocapnic.

Among patients with PD, there was a 50.2% mean pre- to posttreatment reduction in total PDSS scores (P < .001; d = 1.31), with a treatment response rate of 65.3% of patients.

Among patients with PTSD, there was a 41.1% pre- to posttreatment reduction in total PCL-5 scores (P < .001; d = 1.16), with a treatment response rate of 72.4%.

When investigators analyzed the response at the individual level, they found that 55.7% of patients with PD and 53.5% of those with PTSD were classified as treatment responders. This determination was based on a two-pronged approach that first calculated the Reliable Change Index (RCI) for each participant, and, in participants showing statistically reliable improvement, whether the posttreatment score was closer to the distribution of scores for patients without or with the given disorder.

“Patients with both normal and below-normal baseline exhaled CO2 levels experienced comparable benefit,” the authors report.

‘A viable alternative’

Commenting on the research, Charles Marmar, MD, chair and Peter H. Schub Professor of Psychiatry, department of psychiatry, New York University, said that the study has some limitations, probably the most significant of which is that most participants had normal baseline CO₂ levels.

“The treatment is fundamentally designed for people who hyperventilate and blow off too much CO₂ so they can breathe in a more calm, relaxed way, but most people in the trial had normal CO₂ to begin with,” said Dr. Marmar, who was not involved with the study.

“It’s likely that the major benefits were the relaxation from doing the breathing exercises rather than the change in CO₂ levels,” he speculated.

The treatment is “probably a good thing for those patients who actually have abnormal CO₂ levels. This treatment could be used in precision medicine, where you tailor treatments to those who actually need them rather than giving the same treatment to everyone,” he said.

“For patients who don’t respond to trauma-focused therapy or it’s too aversive for them to undergo, this new intervention provides a viable alternative,” Dr. Telch added.

The study was internally funded by Freespira. Dr. Telch is a scientific advisor at Freespira and receives compensation by way of stock options. The other authors’ disclosures are listed on the original paper. Dr. Marmar has declared no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Psychedelics are a class of substances known to produce alterations in consciousness and perception. In the last 2 decades, psychedelic research has garnered increasing attention from scientists, therapists, entrepreneurs, and the public. While many of these compounds remain illegal in the United States and in many parts of the world (Box¹), a recent resurrection of psychedelic research has motivated the FDA to designate multiple psychedelic compounds as “breakthrough therapies,” thereby expediting the investigation, development, and review of psychedelic treatments.

Box

There is growing evidence that psychedelics may be efficacious for treating a range of psychiatric disorders. Potential clinical indications for psychedelics include some forms of depression, posttraumatic stress disorder (PTSD), and substance use disorders (Table 1^2,3). In most instances, the clinical use of psychedelics is being investigated and offered in the context of psychedelic-assisted psychotherapy, though ketamine is a prominent exception. Ketamine and esketamine are already being used to treat depression, and FDA approval is anticipated for other psychedelics. An examination of the safety considerations of psychedelics for the treatment of psychiatric disorders is therefore highly relevant and timely.

This article examines the adverse effect profile of classical (psilocybin [“mushrooms”], lysergic acid diethylamide [LSD], and N,N-dimethyltryptamine [DMT]/ayahuasca) and nonclassical (the entactogen 3,4-methylenedioxymethamphetamine [MDMA, known as “ecstasy”] and the dissociative anesthetic ketamine) psychedelics.

Psilocybin

Psilocybin is typically administered as a single dose of 10 to 30 mg and used in conjunction with preintegration and postintegration psychotherapy. Administration of psilocybin typically produces perceptual distortions and mind-altering effects, which are mediated through 5-HT2A brain receptor agonistic action.⁴ The acute effects last approximately 6 hours.⁵ While psilocybin has generated promising results in early clinical trials,³ the adverse effects of these agents have received less attention.

The adverse effect profile of psilocybin in adults appears promising but its powerful psychoactive effects necessitate cautious use.⁶ It has a very wide therapeutic index, and in a recent meta-analysis of psilocybin for depression, no serious adverse effects were reported in any of the 7 included studies.⁷ Common adverse effects in the context of clinical use include anxiety, dysphoria, confusion, and an increase in blood pressure and heart rate.⁶ Due to potential cardiac effects, psilocybin is contraindicated in individuals with cardiovascular and cerebrovascular disease.⁸ In recreational/nonclinical use, reactions such as suicidality, violence, convulsions, panic attacks, paranoia, confusion, prolonged dissociation, and mania have been reported.^9,10 Animal and human studies indicate the risk of abuse and physical dependence is low. Major national surveys indicate low rates of abuse, treatment-seeking, and harm.¹¹ In a recent 6-week randomized controlled trial (RCT) of psilocybin vs escitalopram for depression,¹² no serious adverse events were reported. Adverse events reported in the psilocybin group in this trial are listed in Table 2.¹²

A recent phase 2 double-blind trial of single-dose psilocybin (1 mg, 10 mg, and 25 mg) for treatment-resistant depression (N = 233) sheds more light on the risk of adverse effects.¹³ The percentage of individuals experiencing adverse effects on Day 1 of administration was high: 61% in the 25 mg psilocybin group. Headache, nausea, fatigue, and dizziness were the most common effects. The incidence of any adverse event in the 25 mg group was 56% from Day 2 to Week 3, and 29% from Week 3 to Week 12. Suicidal ideation, suicidal behavior, or self-injury occurred in all 3 dose groups. Overall, 14% in the 25 mg group, 17% in the 10 mg group, and 9% in the 1 mg group showed worsening of suicidality from baseline to Week 3. Suicidal behavior was reported by 3 individuals in the 25 mg group after Week 3. The new-onset or worsening of preexisting suicidality with psilocybin reported in this study requires further investigation.

Lysergic acid diethylamide

LSD is similar to psilocybin in its agonistic action at the 5-HT2A brain receptors.⁴ It is typically administered as a single 100 to 200 μg dose and is used in conjunction with preintegration and postintegration psychotherapy.¹⁴ Its acute effects last approximately 12 hours.¹⁵

Continue to: Like psilocybin...

Like psilocybin, LSD has a wide therapeutic index. Commonly reported adverse effects of LSD are increased anxiety, dysphoria, and confusion. LSD can also lead to physiological adverse effects, such as increased blood pressure and heart rate, and thus is contraindicated in patients with severe heart disease.⁶ In a systematic review of the therapeutic use of LSD that included 567 participants,¹⁶ 2 cases of serious adverse events were reported: a tonic-clonic seizure in a patient with a prior history of seizures, and a case of prolonged psychosis in a 21-year-old with a history of psychotic disorder.

Though few psychedelic studies have examined the adverse effects of these agents in older adults, a recent phase 1 study that recruited 48 healthy older adults (age 55 to 75) found that, compared to placebo, low doses (5 to 20 μg) of LSD 2 times a week for 3 weeks had similar adverse effects, cognitive impairment, or balance impairment.¹⁷ The only adverse effect noted to be different between the placebo group and active treatment groups was headache (50% for LSD 10 μg, 25% for LSD 20 μg, and 8% for placebo). Because the dose range (5 to 20 μg) used in this study was substantially lower than the typical therapeutic dose range of 100 to 200 μg, these results should not be interpreted as supporting the safety of LSD at higher doses in older adults.

DMT/ayahuasca

Ayahuasca is a plant-based psychedelic that contains an admixture of substances, including DMT, which acts as a 5-HT2A receptor agonist. In addition to DMT, ayahuasca also contains the alkaloid harmaline, which acts as a monoamine inhibitor. Use of ayahuasca can therefore pose a particular risk for individuals taking other serotonergic or noradrenergic medications or substances. The acute effects of DMT last approximately 4 hours,¹⁸ and acute administration of ayahuasca leads to a transient modified state of consciousness that is characterized by introspection, visions, enhanced emotions, and recall of personal memories.¹⁹ Research shows ayahuasca has been dosed at approximately 0.36 mg/kg of DMT for 1 dosing session alongside 6 2-hour therapy sessions.²⁰

A recent review by Orsolini et al²¹ consolidated 40 preclinical, observational, and experimental studies of ayahuasca, and this compound appeared to be safe and well-tolerated; the most common adverse effects were transient emesis and nausea. In an RCT by Palhano-Fontes et al,²⁰ nausea was observed in 71% of participants in the ayahuasca group (vs 26% placebo), vomiting in 57% of participants (vs 0% placebo), and restlessness in 50% of participants (vs 20% placebo). The authors noted that for some participants the ayahuasca session “was not necessarily a pleasant experience,” and was accompanied by psychological distress.²⁰ Vomiting is traditionally viewed as an expected part of the purging process of ayahuasca religious ceremonies. Another review found that there appears to be good long-term tolerability of ayahuasca consumption among individuals who use this compound in religious ceremonies.²²

MDMA

Entactogens (or empathogens) are a class of psychoactive substances that produce experiences of emotional openness and connection. MDMA is an entactogen known to release serotonin, norepinephrine, and dopamine by inhibiting reuptake.²³ This process leads to the stimulation of neurohormonal signaling of oxytocin, cortisol, and other signaling molecules such as brain-derived neurotrophic factor.²⁴ Memory reconsolidation and fear extinction may also play a therapeutic role, enabled by reduced activity in the amygdala and insula, and increased connectivity between the amygdala and hippocampus.²⁴ MDMA has been reported to enhance feelings of well-being and increase prosocial behavior.²⁵ In the therapeutic setting, MDMA has been generally dosed at 75 to 125 mg in 2 to 3 sessions alongside 10 therapy sessions. Administration of MDMA gives the user a subjective experience of energy and distortions in time and perception.²⁶ These acute effects last approximately 2 to 4 hours.²⁷

Continue to: A meta-analysis...

A meta-analysis of 5 RCTs of MDMA-assisted therapy for PTSD in adults demonstrated that MDMA was well-tolerated, and few serious adverse events were reported.²⁸ Two trials from 2018 that were included in this meta-analysis—Mithoefer et al²⁹ and Ot’alora et al³⁰—illustrate the incidence of specific adverse effects. In a randomized, double-blind trial of 26 veterans and first responders with chronic PTSD, Mithoefer et al²⁹ found the most commonly reported reactions during experimental sessions with MDMA were anxiety (81%), headache (69%), fatigue (62%), muscle tension (62%), and jaw clenching or tight jaw (50%). The most commonly reported reactions during 7 days of contact were fatigue (88%), anxiety (73%), insomnia (69%), headache (46%), muscle tension (46%), and increased irritability (46%). One instance of suicidal ideation was severe enough to require psychiatric hospitalization (this was the only instance of suicidal ideation among the 106 patients in the meta-analysis by Bahji et al²⁸); the patient subsequently completed the trial. Transient elevation in pulse, blood pressure, and body temperature were noted during sessions that did not require medical intervention.²⁹ Ot’alora et al³⁰ found similar common adverse reactions: anxiety, dizziness, fatigue, headache, jaw clenching, muscle tension, and irritability. There were no serious adverse effects.

While the use of MDMA in controlled interventional settings has resulted in relatively few adverse events, robust literature describes the risks associated with the nonclinical/recreational use of MDMA. In cases of MDMA toxicity, death has been reported.³¹ Acutely, MDMA may lead to sympathomimetic effects, including serotonin syndrome.³¹ Longer-term studies of MDMA users have found chronic recreational use to be associated with worse sleep, poor mood, anxiety disturbances, memory deficits, and attention problems.³² MDMA has also been found to have moderate potential for abuse.³³

Ketamine/esketamine

Ketamine is a dissociative anesthetic with some hallucinogenic effects. It is an N-methyl-d-aspartate (NMDA) antagonist frequently used in anesthesia, and it can induce a state of sedation, immobility, pain relief, and amnesia. In low doses, ketamine is used off-label to treat major depressive disorder and treatment-resistant depression. Most clinical trials of ketamine for depression have dosed IV ketamine from 0.5 to 1 mg/kg 1 to 3 times a week. It can also be administered as an IM, intranasal, oral, subcutaneous, or sublingual formulation.³⁴

Esketamine, the S(+)-enantiomer of ketamine, is also an NDMA antagonist. It has been developed as an intranasal formulation, typically dosed between 56 and 84 mg 2 times a week for 1 month, once a week for the following month, and once every 1 to 2 weeks thereafter.³⁵ In most ketamine and esketamine trials, these compounds have been used without psychotherapy, although some interventions have integrated psychotherapy with ketamine treatment.³⁶

Bennett et al³⁷ elaborated on 3 paradigms for ketamine treatment: biochemical, psychotherapeutic, and psychedelic. The biochemical model examines the neuro­biological effects of the medication. The psychotherapeutic model views ketamine as a way of assisting the psychotherapy process. The psychedelic model utilizes ketamine’s dissociative and psychedelic properties to induce an altered state of consciousness for therapeutic purposes and psychospiritual exploration.

Continue to: A systematic review...

A systematic review of the common adverse effects associated with ketamine use in clinical trials for depression reported dissociation, sedation, perceptual disturbances, anxiety, agitation, euphoria, hypertension, tachycardia, headache, and dizziness.³⁸ Adverse effects experienced with esketamine in clinical trials include dissociation, dizziness, sedation, hypertension, hypoesthesia, gastrointestinal symptoms, and euphoric mood (Table 3³⁹). A recent systemic review found both ketamine and esketamine demonstrated higher adverse events than control conditions. IV ketamine also demonstrated lower dropouts and adverse events when compared to intranasal esketamine.⁴⁰

Nonclinical/recreational use of ketamine is notable for urinary toxicity; 20% to 30% of frequent users of ketamine experience urinary problems that can range from ketamine-induced cystitis to hydronephrosis and kidney failure.⁴¹ Liver toxicity has also been reported with chronic use of high-dose ketamine. Ketamine is liable to abuse, dependence, and tolerance. There is evidence that nonclinical use of ketamine may lead to morbidity; impairment of memory, cognition, and attention; and urinary, gastric, and hepatic pathology.⁴²

The FDA prescribing information for esketamine lists aneurysmal vascular disease, arteriovenous malformation, and intracerebral hemorrhage as contraindications.³⁹ Patients with cardiovascular and cerebrovascular conditions and risk factors may be at increased risk of adverse effects due to an increase in blood pressure. Esketamine can impair attention, judgment, thinking, reaction speed, and motor skills. Other adverse effects of esketamine noted in the prescribing information include dissociation, dizziness, nausea, sedation, vertigo, hypoesthesia, anxiety, lethargy, vomiting, feeling drunk, and euphoric mood.³⁹A study of postmarketing safety concerns with esketamine using reports submitted to the FDA Adverse Event Reporting System (FAERS) revealed signals for suicidal ideation (reporting odds ratio [ROR] 24.03; 95% CI, 18.72 to 30.84), and completed suicide (ROR 5.75; 95% CI, 3.18 to 10.41).⁴³ The signals for suicidal and self-injurious ideation remained significant when compared to venlafaxine in the FAERS database, while suicide attempts and fatal suicide attempts were no longer significant.⁴³ Concerns regarding acute ketamine withdrawal have also been described in case reports.⁴⁴

Other safety considerations of psychedelics

Hallucinogen persisting perception disorder

Hallucinogen persisting perception disorder (HPPD) is a rare condition associated with hallucinogen use. It is characterized by the recurrence of perceptual disturbances that an individual experienced while using hallucinogenic substances that creates significant distress or impairment.⁴⁵ Because HPPD is a rare disorder, the exact prevalence is not well characterized, but DSM-5 suggests it is approximately 4.2%.⁴⁶ HPPD is associated with numerous psychoactive substances, including psilocybin, ayahuasca, MDMA, and ketamine, but is most associated with LSD.⁴⁵ HPPD is more likely to arise in individuals with histories of psychiatric illness or substance use disorders.⁴⁷

Serotonin toxicity and other serotonergic interactions

Serotonin toxicity is a risk of serotonergic psychedelics, particularly when such agents are used in combination with serotonergic psychotropic medications. The most severe manifestation of serotonin toxicity is serotonin syndrome, which manifests as a life-threatening condition characterized by myoclonus, rigidity, agitation, delirium, and unstable cardiovascular functioning. Many psychedelic compounds have transient serotonin-related adverse effects, but serotonin toxicity due to psychedelic use is rare.⁴⁸ Due to their mechanism of action, classical psychedelics are relatively safe in combination with monoamine oxidase inhibitors (MAOIs) and selective serotonin reuptake inhibitors. MDMA is a serotonin-releasing agent that has a higher risk of serotonin syndrome or hypertensive crisis when used in combination with MAOIs.⁴⁸

Boundary violations in psychedelic-assisted psychotherapy

A key task facing psychedelic research is to establish parameters for the safe and ethical use of these agents. This is particularly relevant given the hype that surrounds the psychedelic resurgence and what we know about the controversial history of these substances. Anderson et al⁴⁹ argued that “psychedelics can have lingering effects that include increased suggestibility and affective instability, as well as altered ego structure, social behaviour, and philosophical worldview. Stated simply, psychedelics can induce a vulnerable state both during and after treatment sessions.”

Continue to: Psychedelic treatment...

Psychedelic treatments such as psilocybin and MDMA are typically offered within the context of psychedelic-assisted psychotherapy, and some researchers have raised concerns regarding boundary violations,⁵⁰ given the patients’ particularly vulnerable states. In addition to concerns about sexual harassment, the financial exploitation of older adults is also a possible risk.⁵¹

Caveats to consider

Novel psychedelics therapies have demonstrated promising preliminary results for a broad range of psychiatric indications, including depression, end-of-life distress, substance use disorders, PTSD, and improving well-being. To date, psychedelics are generally well-tolerated in adults in clinical trials.

However, when it comes to adverse effects, there are challenges in regards to interpreting the psychedelic state.⁵² Some consider any unpleasant or unsettling psychedelic experience as an adverse reaction, while others consider it part of the therapeutic process. This is exemplified by the case of vomiting during ayahuasca ceremonies, which is generally considered part of the ritual. In such instances, it is essential to obtain informed consent and ensure participants are aware of these aspects of the experience. Compared to substances such as alcohol, opioids, and cocaine, psychedelics are remarkably safe from a physiological perspective, especially with regards to the risks of toxicity, mortality, and dependence.⁵³ Their psychological safety is less established, and more caution and research is needed. The high incidence of adverse effects and suicidality noted in the recent phase 2 trial of psilocybin in treatment resistant depression are a reminder of this.¹³

There is uncertainty regarding the magnitude of risk in real-world clinical practice, particularly regarding addiction, suicidality, and precipitation or worsening of psychotic disorders. For example, note the extensive exclusion criteria used in the psilocybin vs escitalopram RCT by Carhart-Harris et al¹²: currently or previously diagnosed psychotic disorder, immediate family member with a diagnosed psychotic disorder, significant medical comorbidity (eg, diabetes, epilepsy, severe cardiovascular disease, hepatic or renal failure), history of suicide attempts requiring hospitalization, history of mania, pregnancy, and abnormal QT interval prolongation, among others. It would be prudent to keep these contraindications in mind regarding the clinical use of psychedelics in the future. This is particularly important in older adults because such patients often have substantial medical comorbidities and are at greater risk for adverse effects. For ketamine, research has implicated the role of mu opioid agonism in mediating ketamine’s antidepressant effects.⁵⁴ This raises concerns about abuse, dependence, and addiction, especially with long-term use. There are also concerns regarding protracted withdrawal symptoms and associated suicidality.⁵⁵

The therapeutic use of psychedelics is an exciting and promising avenue, with ongoing research and a rapidly evolving literature. An attitude of cautious optimism is warranted, but efficacy and safety should be demonstrated in well-designed and rigorous trials with adequate long-term follow-up before routine clinical use is recommended.

Bottom Line

In clinical trials for psychiatric disorders, psychedelics have been associated with a range of cognitive, psychiatric, and psychoactive adverse effects but generally have been well-tolerated, with a low incidence of serious adverse effects.

Related Resources

• American Psychiatric Association. Position Statement on the Use of Psychedelic and Empathogenic Agents for Mental Health Conditions. Updated July 2022. Accessed October 24, 2022. https://www.psychiatry.org/getattachment/d5c13619-ca1f-491f-a7a8-b7141c800904/Position-Use-of-Psychedelic-Empathogenic-Agents.pdf
• Johns Hopkins Center for Psychedelic & Consciousness Research. https://hopkinspsychedelic.org/
• Multidisciplinary Association for Psychedelic Studies (MAPS). https://maps.org/

Drug Brand Names

Esketamine • Spravato
Ketamine • Ketalar
Venlafaxine • Effexor

Psychedelics are a class of substances known to produce alterations in consciousness and perception. In the last 2 decades, psychedelic research has garnered increasing attention from scientists, therapists, entrepreneurs, and the public. While many of these compounds remain illegal in the United States and in many parts of the world (Box¹), a recent resurrection of psychedelic research has motivated the FDA to designate multiple psychedelic compounds as “breakthrough therapies,” thereby expediting the investigation, development, and review of psychedelic treatments.

Box

There is growing evidence that psychedelics may be efficacious for treating a range of psychiatric disorders. Potential clinical indications for psychedelics include some forms of depression, posttraumatic stress disorder (PTSD), and substance use disorders (Table 1^2,3). In most instances, the clinical use of psychedelics is being investigated and offered in the context of psychedelic-assisted psychotherapy, though ketamine is a prominent exception. Ketamine and esketamine are already being used to treat depression, and FDA approval is anticipated for other psychedelics. An examination of the safety considerations of psychedelics for the treatment of psychiatric disorders is therefore highly relevant and timely.

This article examines the adverse effect profile of classical (psilocybin [“mushrooms”], lysergic acid diethylamide [LSD], and N,N-dimethyltryptamine [DMT]/ayahuasca) and nonclassical (the entactogen 3,4-methylenedioxymethamphetamine [MDMA, known as “ecstasy”] and the dissociative anesthetic ketamine) psychedelics.

Psilocybin

Psilocybin is typically administered as a single dose of 10 to 30 mg and used in conjunction with preintegration and postintegration psychotherapy. Administration of psilocybin typically produces perceptual distortions and mind-altering effects, which are mediated through 5-HT2A brain receptor agonistic action.⁴ The acute effects last approximately 6 hours.⁵ While psilocybin has generated promising results in early clinical trials,³ the adverse effects of these agents have received less attention.

The adverse effect profile of psilocybin in adults appears promising but its powerful psychoactive effects necessitate cautious use.⁶ It has a very wide therapeutic index, and in a recent meta-analysis of psilocybin for depression, no serious adverse effects were reported in any of the 7 included studies.⁷ Common adverse effects in the context of clinical use include anxiety, dysphoria, confusion, and an increase in blood pressure and heart rate.⁶ Due to potential cardiac effects, psilocybin is contraindicated in individuals with cardiovascular and cerebrovascular disease.⁸ In recreational/nonclinical use, reactions such as suicidality, violence, convulsions, panic attacks, paranoia, confusion, prolonged dissociation, and mania have been reported.^9,10 Animal and human studies indicate the risk of abuse and physical dependence is low. Major national surveys indicate low rates of abuse, treatment-seeking, and harm.¹¹ In a recent 6-week randomized controlled trial (RCT) of psilocybin vs escitalopram for depression,¹² no serious adverse events were reported. Adverse events reported in the psilocybin group in this trial are listed in Table 2.¹²

A recent phase 2 double-blind trial of single-dose psilocybin (1 mg, 10 mg, and 25 mg) for treatment-resistant depression (N = 233) sheds more light on the risk of adverse effects.¹³ The percentage of individuals experiencing adverse effects on Day 1 of administration was high: 61% in the 25 mg psilocybin group. Headache, nausea, fatigue, and dizziness were the most common effects. The incidence of any adverse event in the 25 mg group was 56% from Day 2 to Week 3, and 29% from Week 3 to Week 12. Suicidal ideation, suicidal behavior, or self-injury occurred in all 3 dose groups. Overall, 14% in the 25 mg group, 17% in the 10 mg group, and 9% in the 1 mg group showed worsening of suicidality from baseline to Week 3. Suicidal behavior was reported by 3 individuals in the 25 mg group after Week 3. The new-onset or worsening of preexisting suicidality with psilocybin reported in this study requires further investigation.

Lysergic acid diethylamide

LSD is similar to psilocybin in its agonistic action at the 5-HT2A brain receptors.⁴ It is typically administered as a single 100 to 200 μg dose and is used in conjunction with preintegration and postintegration psychotherapy.¹⁴ Its acute effects last approximately 12 hours.¹⁵

Continue to: Like psilocybin...

Like psilocybin, LSD has a wide therapeutic index. Commonly reported adverse effects of LSD are increased anxiety, dysphoria, and confusion. LSD can also lead to physiological adverse effects, such as increased blood pressure and heart rate, and thus is contraindicated in patients with severe heart disease.⁶ In a systematic review of the therapeutic use of LSD that included 567 participants,¹⁶ 2 cases of serious adverse events were reported: a tonic-clonic seizure in a patient with a prior history of seizures, and a case of prolonged psychosis in a 21-year-old with a history of psychotic disorder.

Though few psychedelic studies have examined the adverse effects of these agents in older adults, a recent phase 1 study that recruited 48 healthy older adults (age 55 to 75) found that, compared to placebo, low doses (5 to 20 μg) of LSD 2 times a week for 3 weeks had similar adverse effects, cognitive impairment, or balance impairment.¹⁷ The only adverse effect noted to be different between the placebo group and active treatment groups was headache (50% for LSD 10 μg, 25% for LSD 20 μg, and 8% for placebo). Because the dose range (5 to 20 μg) used in this study was substantially lower than the typical therapeutic dose range of 100 to 200 μg, these results should not be interpreted as supporting the safety of LSD at higher doses in older adults.

DMT/ayahuasca

Ayahuasca is a plant-based psychedelic that contains an admixture of substances, including DMT, which acts as a 5-HT2A receptor agonist. In addition to DMT, ayahuasca also contains the alkaloid harmaline, which acts as a monoamine inhibitor. Use of ayahuasca can therefore pose a particular risk for individuals taking other serotonergic or noradrenergic medications or substances. The acute effects of DMT last approximately 4 hours,¹⁸ and acute administration of ayahuasca leads to a transient modified state of consciousness that is characterized by introspection, visions, enhanced emotions, and recall of personal memories.¹⁹ Research shows ayahuasca has been dosed at approximately 0.36 mg/kg of DMT for 1 dosing session alongside 6 2-hour therapy sessions.²⁰

A recent review by Orsolini et al²¹ consolidated 40 preclinical, observational, and experimental studies of ayahuasca, and this compound appeared to be safe and well-tolerated; the most common adverse effects were transient emesis and nausea. In an RCT by Palhano-Fontes et al,²⁰ nausea was observed in 71% of participants in the ayahuasca group (vs 26% placebo), vomiting in 57% of participants (vs 0% placebo), and restlessness in 50% of participants (vs 20% placebo). The authors noted that for some participants the ayahuasca session “was not necessarily a pleasant experience,” and was accompanied by psychological distress.²⁰ Vomiting is traditionally viewed as an expected part of the purging process of ayahuasca religious ceremonies. Another review found that there appears to be good long-term tolerability of ayahuasca consumption among individuals who use this compound in religious ceremonies.²²

MDMA

Entactogens (or empathogens) are a class of psychoactive substances that produce experiences of emotional openness and connection. MDMA is an entactogen known to release serotonin, norepinephrine, and dopamine by inhibiting reuptake.²³ This process leads to the stimulation of neurohormonal signaling of oxytocin, cortisol, and other signaling molecules such as brain-derived neurotrophic factor.²⁴ Memory reconsolidation and fear extinction may also play a therapeutic role, enabled by reduced activity in the amygdala and insula, and increased connectivity between the amygdala and hippocampus.²⁴ MDMA has been reported to enhance feelings of well-being and increase prosocial behavior.²⁵ In the therapeutic setting, MDMA has been generally dosed at 75 to 125 mg in 2 to 3 sessions alongside 10 therapy sessions. Administration of MDMA gives the user a subjective experience of energy and distortions in time and perception.²⁶ These acute effects last approximately 2 to 4 hours.²⁷

Continue to: A meta-analysis...

A meta-analysis of 5 RCTs of MDMA-assisted therapy for PTSD in adults demonstrated that MDMA was well-tolerated, and few serious adverse events were reported.²⁸ Two trials from 2018 that were included in this meta-analysis—Mithoefer et al²⁹ and Ot’alora et al³⁰—illustrate the incidence of specific adverse effects. In a randomized, double-blind trial of 26 veterans and first responders with chronic PTSD, Mithoefer et al²⁹ found the most commonly reported reactions during experimental sessions with MDMA were anxiety (81%), headache (69%), fatigue (62%), muscle tension (62%), and jaw clenching or tight jaw (50%). The most commonly reported reactions during 7 days of contact were fatigue (88%), anxiety (73%), insomnia (69%), headache (46%), muscle tension (46%), and increased irritability (46%). One instance of suicidal ideation was severe enough to require psychiatric hospitalization (this was the only instance of suicidal ideation among the 106 patients in the meta-analysis by Bahji et al²⁸); the patient subsequently completed the trial. Transient elevation in pulse, blood pressure, and body temperature were noted during sessions that did not require medical intervention.²⁹ Ot’alora et al³⁰ found similar common adverse reactions: anxiety, dizziness, fatigue, headache, jaw clenching, muscle tension, and irritability. There were no serious adverse effects.

While the use of MDMA in controlled interventional settings has resulted in relatively few adverse events, robust literature describes the risks associated with the nonclinical/recreational use of MDMA. In cases of MDMA toxicity, death has been reported.³¹ Acutely, MDMA may lead to sympathomimetic effects, including serotonin syndrome.³¹ Longer-term studies of MDMA users have found chronic recreational use to be associated with worse sleep, poor mood, anxiety disturbances, memory deficits, and attention problems.³² MDMA has also been found to have moderate potential for abuse.³³

Ketamine/esketamine

Ketamine is a dissociative anesthetic with some hallucinogenic effects. It is an N-methyl-d-aspartate (NMDA) antagonist frequently used in anesthesia, and it can induce a state of sedation, immobility, pain relief, and amnesia. In low doses, ketamine is used off-label to treat major depressive disorder and treatment-resistant depression. Most clinical trials of ketamine for depression have dosed IV ketamine from 0.5 to 1 mg/kg 1 to 3 times a week. It can also be administered as an IM, intranasal, oral, subcutaneous, or sublingual formulation.³⁴

Esketamine, the S(+)-enantiomer of ketamine, is also an NDMA antagonist. It has been developed as an intranasal formulation, typically dosed between 56 and 84 mg 2 times a week for 1 month, once a week for the following month, and once every 1 to 2 weeks thereafter.³⁵ In most ketamine and esketamine trials, these compounds have been used without psychotherapy, although some interventions have integrated psychotherapy with ketamine treatment.³⁶

Bennett et al³⁷ elaborated on 3 paradigms for ketamine treatment: biochemical, psychotherapeutic, and psychedelic. The biochemical model examines the neuro­biological effects of the medication. The psychotherapeutic model views ketamine as a way of assisting the psychotherapy process. The psychedelic model utilizes ketamine’s dissociative and psychedelic properties to induce an altered state of consciousness for therapeutic purposes and psychospiritual exploration.

Continue to: A systematic review...

A systematic review of the common adverse effects associated with ketamine use in clinical trials for depression reported dissociation, sedation, perceptual disturbances, anxiety, agitation, euphoria, hypertension, tachycardia, headache, and dizziness.³⁸ Adverse effects experienced with esketamine in clinical trials include dissociation, dizziness, sedation, hypertension, hypoesthesia, gastrointestinal symptoms, and euphoric mood (Table 3³⁹). A recent systemic review found both ketamine and esketamine demonstrated higher adverse events than control conditions. IV ketamine also demonstrated lower dropouts and adverse events when compared to intranasal esketamine.⁴⁰

Nonclinical/recreational use of ketamine is notable for urinary toxicity; 20% to 30% of frequent users of ketamine experience urinary problems that can range from ketamine-induced cystitis to hydronephrosis and kidney failure.⁴¹ Liver toxicity has also been reported with chronic use of high-dose ketamine. Ketamine is liable to abuse, dependence, and tolerance. There is evidence that nonclinical use of ketamine may lead to morbidity; impairment of memory, cognition, and attention; and urinary, gastric, and hepatic pathology.⁴²

The FDA prescribing information for esketamine lists aneurysmal vascular disease, arteriovenous malformation, and intracerebral hemorrhage as contraindications.³⁹ Patients with cardiovascular and cerebrovascular conditions and risk factors may be at increased risk of adverse effects due to an increase in blood pressure. Esketamine can impair attention, judgment, thinking, reaction speed, and motor skills. Other adverse effects of esketamine noted in the prescribing information include dissociation, dizziness, nausea, sedation, vertigo, hypoesthesia, anxiety, lethargy, vomiting, feeling drunk, and euphoric mood.³⁹A study of postmarketing safety concerns with esketamine using reports submitted to the FDA Adverse Event Reporting System (FAERS) revealed signals for suicidal ideation (reporting odds ratio [ROR] 24.03; 95% CI, 18.72 to 30.84), and completed suicide (ROR 5.75; 95% CI, 3.18 to 10.41).⁴³ The signals for suicidal and self-injurious ideation remained significant when compared to venlafaxine in the FAERS database, while suicide attempts and fatal suicide attempts were no longer significant.⁴³ Concerns regarding acute ketamine withdrawal have also been described in case reports.⁴⁴

Other safety considerations of psychedelics

Hallucinogen persisting perception disorder

Hallucinogen persisting perception disorder (HPPD) is a rare condition associated with hallucinogen use. It is characterized by the recurrence of perceptual disturbances that an individual experienced while using hallucinogenic substances that creates significant distress or impairment.⁴⁵ Because HPPD is a rare disorder, the exact prevalence is not well characterized, but DSM-5 suggests it is approximately 4.2%.⁴⁶ HPPD is associated with numerous psychoactive substances, including psilocybin, ayahuasca, MDMA, and ketamine, but is most associated with LSD.⁴⁵ HPPD is more likely to arise in individuals with histories of psychiatric illness or substance use disorders.⁴⁷

Serotonin toxicity and other serotonergic interactions

Serotonin toxicity is a risk of serotonergic psychedelics, particularly when such agents are used in combination with serotonergic psychotropic medications. The most severe manifestation of serotonin toxicity is serotonin syndrome, which manifests as a life-threatening condition characterized by myoclonus, rigidity, agitation, delirium, and unstable cardiovascular functioning. Many psychedelic compounds have transient serotonin-related adverse effects, but serotonin toxicity due to psychedelic use is rare.⁴⁸ Due to their mechanism of action, classical psychedelics are relatively safe in combination with monoamine oxidase inhibitors (MAOIs) and selective serotonin reuptake inhibitors. MDMA is a serotonin-releasing agent that has a higher risk of serotonin syndrome or hypertensive crisis when used in combination with MAOIs.⁴⁸

Boundary violations in psychedelic-assisted psychotherapy

A key task facing psychedelic research is to establish parameters for the safe and ethical use of these agents. This is particularly relevant given the hype that surrounds the psychedelic resurgence and what we know about the controversial history of these substances. Anderson et al⁴⁹ argued that “psychedelics can have lingering effects that include increased suggestibility and affective instability, as well as altered ego structure, social behaviour, and philosophical worldview. Stated simply, psychedelics can induce a vulnerable state both during and after treatment sessions.”

Continue to: Psychedelic treatment...

Psychedelic treatments such as psilocybin and MDMA are typically offered within the context of psychedelic-assisted psychotherapy, and some researchers have raised concerns regarding boundary violations,⁵⁰ given the patients’ particularly vulnerable states. In addition to concerns about sexual harassment, the financial exploitation of older adults is also a possible risk.⁵¹

Caveats to consider

Novel psychedelics therapies have demonstrated promising preliminary results for a broad range of psychiatric indications, including depression, end-of-life distress, substance use disorders, PTSD, and improving well-being. To date, psychedelics are generally well-tolerated in adults in clinical trials.

However, when it comes to adverse effects, there are challenges in regards to interpreting the psychedelic state.⁵² Some consider any unpleasant or unsettling psychedelic experience as an adverse reaction, while others consider it part of the therapeutic process. This is exemplified by the case of vomiting during ayahuasca ceremonies, which is generally considered part of the ritual. In such instances, it is essential to obtain informed consent and ensure participants are aware of these aspects of the experience. Compared to substances such as alcohol, opioids, and cocaine, psychedelics are remarkably safe from a physiological perspective, especially with regards to the risks of toxicity, mortality, and dependence.⁵³ Their psychological safety is less established, and more caution and research is needed. The high incidence of adverse effects and suicidality noted in the recent phase 2 trial of psilocybin in treatment resistant depression are a reminder of this.¹³

There is uncertainty regarding the magnitude of risk in real-world clinical practice, particularly regarding addiction, suicidality, and precipitation or worsening of psychotic disorders. For example, note the extensive exclusion criteria used in the psilocybin vs escitalopram RCT by Carhart-Harris et al¹²: currently or previously diagnosed psychotic disorder, immediate family member with a diagnosed psychotic disorder, significant medical comorbidity (eg, diabetes, epilepsy, severe cardiovascular disease, hepatic or renal failure), history of suicide attempts requiring hospitalization, history of mania, pregnancy, and abnormal QT interval prolongation, among others. It would be prudent to keep these contraindications in mind regarding the clinical use of psychedelics in the future. This is particularly important in older adults because such patients often have substantial medical comorbidities and are at greater risk for adverse effects. For ketamine, research has implicated the role of mu opioid agonism in mediating ketamine’s antidepressant effects.⁵⁴ This raises concerns about abuse, dependence, and addiction, especially with long-term use. There are also concerns regarding protracted withdrawal symptoms and associated suicidality.⁵⁵

The therapeutic use of psychedelics is an exciting and promising avenue, with ongoing research and a rapidly evolving literature. An attitude of cautious optimism is warranted, but efficacy and safety should be demonstrated in well-designed and rigorous trials with adequate long-term follow-up before routine clinical use is recommended.

Bottom Line

In clinical trials for psychiatric disorders, psychedelics have been associated with a range of cognitive, psychiatric, and psychoactive adverse effects but generally have been well-tolerated, with a low incidence of serious adverse effects.

Related Resources

• American Psychiatric Association. Position Statement on the Use of Psychedelic and Empathogenic Agents for Mental Health Conditions. Updated July 2022. Accessed October 24, 2022. https://www.psychiatry.org/getattachment/d5c13619-ca1f-491f-a7a8-b7141c800904/Position-Use-of-Psychedelic-Empathogenic-Agents.pdf
• Johns Hopkins Center for Psychedelic & Consciousness Research. https://hopkinspsychedelic.org/
• Multidisciplinary Association for Psychedelic Studies (MAPS). https://maps.org/

Drug Brand Names

Esketamine • Spravato
Ketamine • Ketalar
Venlafaxine • Effexor

Psychedelics are a class of substances known to produce alterations in consciousness and perception. In the last 2 decades, psychedelic research has garnered increasing attention from scientists, therapists, entrepreneurs, and the public. While many of these compounds remain illegal in the United States and in many parts of the world (Box¹), a recent resurrection of psychedelic research has motivated the FDA to designate multiple psychedelic compounds as “breakthrough therapies,” thereby expediting the investigation, development, and review of psychedelic treatments.

Box

There is growing evidence that psychedelics may be efficacious for treating a range of psychiatric disorders. Potential clinical indications for psychedelics include some forms of depression, posttraumatic stress disorder (PTSD), and substance use disorders (Table 1^2,3). In most instances, the clinical use of psychedelics is being investigated and offered in the context of psychedelic-assisted psychotherapy, though ketamine is a prominent exception. Ketamine and esketamine are already being used to treat depression, and FDA approval is anticipated for other psychedelics. An examination of the safety considerations of psychedelics for the treatment of psychiatric disorders is therefore highly relevant and timely.

This article examines the adverse effect profile of classical (psilocybin [“mushrooms”], lysergic acid diethylamide [LSD], and N,N-dimethyltryptamine [DMT]/ayahuasca) and nonclassical (the entactogen 3,4-methylenedioxymethamphetamine [MDMA, known as “ecstasy”] and the dissociative anesthetic ketamine) psychedelics.

Psilocybin

Psilocybin is typically administered as a single dose of 10 to 30 mg and used in conjunction with preintegration and postintegration psychotherapy. Administration of psilocybin typically produces perceptual distortions and mind-altering effects, which are mediated through 5-HT2A brain receptor agonistic action.⁴ The acute effects last approximately 6 hours.⁵ While psilocybin has generated promising results in early clinical trials,³ the adverse effects of these agents have received less attention.

The adverse effect profile of psilocybin in adults appears promising but its powerful psychoactive effects necessitate cautious use.⁶ It has a very wide therapeutic index, and in a recent meta-analysis of psilocybin for depression, no serious adverse effects were reported in any of the 7 included studies.⁷ Common adverse effects in the context of clinical use include anxiety, dysphoria, confusion, and an increase in blood pressure and heart rate.⁶ Due to potential cardiac effects, psilocybin is contraindicated in individuals with cardiovascular and cerebrovascular disease.⁸ In recreational/nonclinical use, reactions such as suicidality, violence, convulsions, panic attacks, paranoia, confusion, prolonged dissociation, and mania have been reported.^9,10 Animal and human studies indicate the risk of abuse and physical dependence is low. Major national surveys indicate low rates of abuse, treatment-seeking, and harm.¹¹ In a recent 6-week randomized controlled trial (RCT) of psilocybin vs escitalopram for depression,¹² no serious adverse events were reported. Adverse events reported in the psilocybin group in this trial are listed in Table 2.¹²

A recent phase 2 double-blind trial of single-dose psilocybin (1 mg, 10 mg, and 25 mg) for treatment-resistant depression (N = 233) sheds more light on the risk of adverse effects.¹³ The percentage of individuals experiencing adverse effects on Day 1 of administration was high: 61% in the 25 mg psilocybin group. Headache, nausea, fatigue, and dizziness were the most common effects. The incidence of any adverse event in the 25 mg group was 56% from Day 2 to Week 3, and 29% from Week 3 to Week 12. Suicidal ideation, suicidal behavior, or self-injury occurred in all 3 dose groups. Overall, 14% in the 25 mg group, 17% in the 10 mg group, and 9% in the 1 mg group showed worsening of suicidality from baseline to Week 3. Suicidal behavior was reported by 3 individuals in the 25 mg group after Week 3. The new-onset or worsening of preexisting suicidality with psilocybin reported in this study requires further investigation.

Lysergic acid diethylamide

LSD is similar to psilocybin in its agonistic action at the 5-HT2A brain receptors.⁴ It is typically administered as a single 100 to 200 μg dose and is used in conjunction with preintegration and postintegration psychotherapy.¹⁴ Its acute effects last approximately 12 hours.¹⁵

Continue to: Like psilocybin...

Like psilocybin, LSD has a wide therapeutic index. Commonly reported adverse effects of LSD are increased anxiety, dysphoria, and confusion. LSD can also lead to physiological adverse effects, such as increased blood pressure and heart rate, and thus is contraindicated in patients with severe heart disease.⁶ In a systematic review of the therapeutic use of LSD that included 567 participants,¹⁶ 2 cases of serious adverse events were reported: a tonic-clonic seizure in a patient with a prior history of seizures, and a case of prolonged psychosis in a 21-year-old with a history of psychotic disorder.

Though few psychedelic studies have examined the adverse effects of these agents in older adults, a recent phase 1 study that recruited 48 healthy older adults (age 55 to 75) found that, compared to placebo, low doses (5 to 20 μg) of LSD 2 times a week for 3 weeks had similar adverse effects, cognitive impairment, or balance impairment.¹⁷ The only adverse effect noted to be different between the placebo group and active treatment groups was headache (50% for LSD 10 μg, 25% for LSD 20 μg, and 8% for placebo). Because the dose range (5 to 20 μg) used in this study was substantially lower than the typical therapeutic dose range of 100 to 200 μg, these results should not be interpreted as supporting the safety of LSD at higher doses in older adults.

DMT/ayahuasca

Ayahuasca is a plant-based psychedelic that contains an admixture of substances, including DMT, which acts as a 5-HT2A receptor agonist. In addition to DMT, ayahuasca also contains the alkaloid harmaline, which acts as a monoamine inhibitor. Use of ayahuasca can therefore pose a particular risk for individuals taking other serotonergic or noradrenergic medications or substances. The acute effects of DMT last approximately 4 hours,¹⁸ and acute administration of ayahuasca leads to a transient modified state of consciousness that is characterized by introspection, visions, enhanced emotions, and recall of personal memories.¹⁹ Research shows ayahuasca has been dosed at approximately 0.36 mg/kg of DMT for 1 dosing session alongside 6 2-hour therapy sessions.²⁰

A recent review by Orsolini et al²¹ consolidated 40 preclinical, observational, and experimental studies of ayahuasca, and this compound appeared to be safe and well-tolerated; the most common adverse effects were transient emesis and nausea. In an RCT by Palhano-Fontes et al,²⁰ nausea was observed in 71% of participants in the ayahuasca group (vs 26% placebo), vomiting in 57% of participants (vs 0% placebo), and restlessness in 50% of participants (vs 20% placebo). The authors noted that for some participants the ayahuasca session “was not necessarily a pleasant experience,” and was accompanied by psychological distress.²⁰ Vomiting is traditionally viewed as an expected part of the purging process of ayahuasca religious ceremonies. Another review found that there appears to be good long-term tolerability of ayahuasca consumption among individuals who use this compound in religious ceremonies.²²

MDMA

Entactogens (or empathogens) are a class of psychoactive substances that produce experiences of emotional openness and connection. MDMA is an entactogen known to release serotonin, norepinephrine, and dopamine by inhibiting reuptake.²³ This process leads to the stimulation of neurohormonal signaling of oxytocin, cortisol, and other signaling molecules such as brain-derived neurotrophic factor.²⁴ Memory reconsolidation and fear extinction may also play a therapeutic role, enabled by reduced activity in the amygdala and insula, and increased connectivity between the amygdala and hippocampus.²⁴ MDMA has been reported to enhance feelings of well-being and increase prosocial behavior.²⁵ In the therapeutic setting, MDMA has been generally dosed at 75 to 125 mg in 2 to 3 sessions alongside 10 therapy sessions. Administration of MDMA gives the user a subjective experience of energy and distortions in time and perception.²⁶ These acute effects last approximately 2 to 4 hours.²⁷

Continue to: A meta-analysis...

A meta-analysis of 5 RCTs of MDMA-assisted therapy for PTSD in adults demonstrated that MDMA was well-tolerated, and few serious adverse events were reported.²⁸ Two trials from 2018 that were included in this meta-analysis—Mithoefer et al²⁹ and Ot’alora et al³⁰—illustrate the incidence of specific adverse effects. In a randomized, double-blind trial of 26 veterans and first responders with chronic PTSD, Mithoefer et al²⁹ found the most commonly reported reactions during experimental sessions with MDMA were anxiety (81%), headache (69%), fatigue (62%), muscle tension (62%), and jaw clenching or tight jaw (50%). The most commonly reported reactions during 7 days of contact were fatigue (88%), anxiety (73%), insomnia (69%), headache (46%), muscle tension (46%), and increased irritability (46%). One instance of suicidal ideation was severe enough to require psychiatric hospitalization (this was the only instance of suicidal ideation among the 106 patients in the meta-analysis by Bahji et al²⁸); the patient subsequently completed the trial. Transient elevation in pulse, blood pressure, and body temperature were noted during sessions that did not require medical intervention.²⁹ Ot’alora et al³⁰ found similar common adverse reactions: anxiety, dizziness, fatigue, headache, jaw clenching, muscle tension, and irritability. There were no serious adverse effects.

While the use of MDMA in controlled interventional settings has resulted in relatively few adverse events, robust literature describes the risks associated with the nonclinical/recreational use of MDMA. In cases of MDMA toxicity, death has been reported.³¹ Acutely, MDMA may lead to sympathomimetic effects, including serotonin syndrome.³¹ Longer-term studies of MDMA users have found chronic recreational use to be associated with worse sleep, poor mood, anxiety disturbances, memory deficits, and attention problems.³² MDMA has also been found to have moderate potential for abuse.³³

Ketamine/esketamine

Ketamine is a dissociative anesthetic with some hallucinogenic effects. It is an N-methyl-d-aspartate (NMDA) antagonist frequently used in anesthesia, and it can induce a state of sedation, immobility, pain relief, and amnesia. In low doses, ketamine is used off-label to treat major depressive disorder and treatment-resistant depression. Most clinical trials of ketamine for depression have dosed IV ketamine from 0.5 to 1 mg/kg 1 to 3 times a week. It can also be administered as an IM, intranasal, oral, subcutaneous, or sublingual formulation.³⁴

Esketamine, the S(+)-enantiomer of ketamine, is also an NDMA antagonist. It has been developed as an intranasal formulation, typically dosed between 56 and 84 mg 2 times a week for 1 month, once a week for the following month, and once every 1 to 2 weeks thereafter.³⁵ In most ketamine and esketamine trials, these compounds have been used without psychotherapy, although some interventions have integrated psychotherapy with ketamine treatment.³⁶

Bennett et al³⁷ elaborated on 3 paradigms for ketamine treatment: biochemical, psychotherapeutic, and psychedelic. The biochemical model examines the neuro­biological effects of the medication. The psychotherapeutic model views ketamine as a way of assisting the psychotherapy process. The psychedelic model utilizes ketamine’s dissociative and psychedelic properties to induce an altered state of consciousness for therapeutic purposes and psychospiritual exploration.

Continue to: A systematic review...

A systematic review of the common adverse effects associated with ketamine use in clinical trials for depression reported dissociation, sedation, perceptual disturbances, anxiety, agitation, euphoria, hypertension, tachycardia, headache, and dizziness.³⁸ Adverse effects experienced with esketamine in clinical trials include dissociation, dizziness, sedation, hypertension, hypoesthesia, gastrointestinal symptoms, and euphoric mood (Table 3³⁹). A recent systemic review found both ketamine and esketamine demonstrated higher adverse events than control conditions. IV ketamine also demonstrated lower dropouts and adverse events when compared to intranasal esketamine.⁴⁰

Nonclinical/recreational use of ketamine is notable for urinary toxicity; 20% to 30% of frequent users of ketamine experience urinary problems that can range from ketamine-induced cystitis to hydronephrosis and kidney failure.⁴¹ Liver toxicity has also been reported with chronic use of high-dose ketamine. Ketamine is liable to abuse, dependence, and tolerance. There is evidence that nonclinical use of ketamine may lead to morbidity; impairment of memory, cognition, and attention; and urinary, gastric, and hepatic pathology.⁴²

The FDA prescribing information for esketamine lists aneurysmal vascular disease, arteriovenous malformation, and intracerebral hemorrhage as contraindications.³⁹ Patients with cardiovascular and cerebrovascular conditions and risk factors may be at increased risk of adverse effects due to an increase in blood pressure. Esketamine can impair attention, judgment, thinking, reaction speed, and motor skills. Other adverse effects of esketamine noted in the prescribing information include dissociation, dizziness, nausea, sedation, vertigo, hypoesthesia, anxiety, lethargy, vomiting, feeling drunk, and euphoric mood.³⁹A study of postmarketing safety concerns with esketamine using reports submitted to the FDA Adverse Event Reporting System (FAERS) revealed signals for suicidal ideation (reporting odds ratio [ROR] 24.03; 95% CI, 18.72 to 30.84), and completed suicide (ROR 5.75; 95% CI, 3.18 to 10.41).⁴³ The signals for suicidal and self-injurious ideation remained significant when compared to venlafaxine in the FAERS database, while suicide attempts and fatal suicide attempts were no longer significant.⁴³ Concerns regarding acute ketamine withdrawal have also been described in case reports.⁴⁴

Other safety considerations of psychedelics

Hallucinogen persisting perception disorder

Hallucinogen persisting perception disorder (HPPD) is a rare condition associated with hallucinogen use. It is characterized by the recurrence of perceptual disturbances that an individual experienced while using hallucinogenic substances that creates significant distress or impairment.⁴⁵ Because HPPD is a rare disorder, the exact prevalence is not well characterized, but DSM-5 suggests it is approximately 4.2%.⁴⁶ HPPD is associated with numerous psychoactive substances, including psilocybin, ayahuasca, MDMA, and ketamine, but is most associated with LSD.⁴⁵ HPPD is more likely to arise in individuals with histories of psychiatric illness or substance use disorders.⁴⁷

Serotonin toxicity and other serotonergic interactions

Serotonin toxicity is a risk of serotonergic psychedelics, particularly when such agents are used in combination with serotonergic psychotropic medications. The most severe manifestation of serotonin toxicity is serotonin syndrome, which manifests as a life-threatening condition characterized by myoclonus, rigidity, agitation, delirium, and unstable cardiovascular functioning. Many psychedelic compounds have transient serotonin-related adverse effects, but serotonin toxicity due to psychedelic use is rare.⁴⁸ Due to their mechanism of action, classical psychedelics are relatively safe in combination with monoamine oxidase inhibitors (MAOIs) and selective serotonin reuptake inhibitors. MDMA is a serotonin-releasing agent that has a higher risk of serotonin syndrome or hypertensive crisis when used in combination with MAOIs.⁴⁸

Boundary violations in psychedelic-assisted psychotherapy

A key task facing psychedelic research is to establish parameters for the safe and ethical use of these agents. This is particularly relevant given the hype that surrounds the psychedelic resurgence and what we know about the controversial history of these substances. Anderson et al⁴⁹ argued that “psychedelics can have lingering effects that include increased suggestibility and affective instability, as well as altered ego structure, social behaviour, and philosophical worldview. Stated simply, psychedelics can induce a vulnerable state both during and after treatment sessions.”

Continue to: Psychedelic treatment...

Psychedelic treatments such as psilocybin and MDMA are typically offered within the context of psychedelic-assisted psychotherapy, and some researchers have raised concerns regarding boundary violations,⁵⁰ given the patients’ particularly vulnerable states. In addition to concerns about sexual harassment, the financial exploitation of older adults is also a possible risk.⁵¹

Caveats to consider

Novel psychedelics therapies have demonstrated promising preliminary results for a broad range of psychiatric indications, including depression, end-of-life distress, substance use disorders, PTSD, and improving well-being. To date, psychedelics are generally well-tolerated in adults in clinical trials.

However, when it comes to adverse effects, there are challenges in regards to interpreting the psychedelic state.⁵² Some consider any unpleasant or unsettling psychedelic experience as an adverse reaction, while others consider it part of the therapeutic process. This is exemplified by the case of vomiting during ayahuasca ceremonies, which is generally considered part of the ritual. In such instances, it is essential to obtain informed consent and ensure participants are aware of these aspects of the experience. Compared to substances such as alcohol, opioids, and cocaine, psychedelics are remarkably safe from a physiological perspective, especially with regards to the risks of toxicity, mortality, and dependence.⁵³ Their psychological safety is less established, and more caution and research is needed. The high incidence of adverse effects and suicidality noted in the recent phase 2 trial of psilocybin in treatment resistant depression are a reminder of this.¹³

There is uncertainty regarding the magnitude of risk in real-world clinical practice, particularly regarding addiction, suicidality, and precipitation or worsening of psychotic disorders. For example, note the extensive exclusion criteria used in the psilocybin vs escitalopram RCT by Carhart-Harris et al¹²: currently or previously diagnosed psychotic disorder, immediate family member with a diagnosed psychotic disorder, significant medical comorbidity (eg, diabetes, epilepsy, severe cardiovascular disease, hepatic or renal failure), history of suicide attempts requiring hospitalization, history of mania, pregnancy, and abnormal QT interval prolongation, among others. It would be prudent to keep these contraindications in mind regarding the clinical use of psychedelics in the future. This is particularly important in older adults because such patients often have substantial medical comorbidities and are at greater risk for adverse effects. For ketamine, research has implicated the role of mu opioid agonism in mediating ketamine’s antidepressant effects.⁵⁴ This raises concerns about abuse, dependence, and addiction, especially with long-term use. There are also concerns regarding protracted withdrawal symptoms and associated suicidality.⁵⁵

The therapeutic use of psychedelics is an exciting and promising avenue, with ongoing research and a rapidly evolving literature. An attitude of cautious optimism is warranted, but efficacy and safety should be demonstrated in well-designed and rigorous trials with adequate long-term follow-up before routine clinical use is recommended.

Bottom Line

In clinical trials for psychiatric disorders, psychedelics have been associated with a range of cognitive, psychiatric, and psychoactive adverse effects but generally have been well-tolerated, with a low incidence of serious adverse effects.

Related Resources

• American Psychiatric Association. Position Statement on the Use of Psychedelic and Empathogenic Agents for Mental Health Conditions. Updated July 2022. Accessed October 24, 2022. https://www.psychiatry.org/getattachment/d5c13619-ca1f-491f-a7a8-b7141c800904/Position-Use-of-Psychedelic-Empathogenic-Agents.pdf
• Johns Hopkins Center for Psychedelic & Consciousness Research. https://hopkinspsychedelic.org/
• Multidisciplinary Association for Psychedelic Studies (MAPS). https://maps.org/

Drug Brand Names

Esketamine • Spravato
Ketamine • Ketalar
Venlafaxine • Effexor

PAU, FRANCE – Postpartum posttraumatic stress disorder tends to get worse over the months following the birth of a child. Therefore, it’s necessary to screen for it as early on as possible and to ensure that women who are affected are given the proper treatment. This was the message delivered during the Infogyn 2022 conference by Ludivine Franchitto, MD, a child psychiatrist at Toulouse University Hospital, France. Because postpartum PTSD is still not fully recognized, treatment remains inadequate and poorly documented.

Impact on the caregivers as well

“The situation is the same as what we saw with postpartum depression. The debate went on for 20 years before its existence was formally declared,” Dr. Franchitto noted. But for her, the important thing is not knowing whether a traumatic stress state may be experienced by the mother who had complications during pregnancy or delivery. Instead, it’s about focusing on the repercussions for the child.

During her presentation, Dr. Franchitto also pointed out that it’s necessary to recognize that caregivers who work in maternity wards may also be negatively impacted, as they routinely see the complications that women have during pregnancy and delivery. These workers may also develop a PTSD state, requiring support so that they can properly carry out their duties.

According to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-V), posttraumatic stress disorder arises after exposure to actual (or threatened) death, serious injury, or sexual violence. Individuals who have witnessed a traumatic event in person or who have experienced repeated (or extreme) exposure to aversive details of traumatic events may also develop PTSD.

Dr. Franchitto mentioned some of the criteria needed to make the diagnosis. “Intrusive distressing memories of the event, recurrent distressing dreams related to the event, persistent avoidance of stimuli associated with the traumatic event, or negative alterations in cognitions and mood associated with the traumatic event. And the duration of the disturbance is more than 1 month.” There may also be marked alterations in arousal and reactivity associated with the traumatic event (for example, irritable behavior, loss of awareness of present surroundings).
 

Prevalent in 18% of women in high-risk groups

According to the studies, there is a wide variability of PTSD rates. If referring only to traumatic symptoms (for example, depressive syndrome, suicidal ideation, hyperreactivity, and persistent avoidance), the rate could reach up to 40%. A 2016 meta-analysis of 59 studies found that the prevalence of childbirth-related PTSD was 5.9%.

The authors distinguished two groups of women: those without complications during pregnancy or during delivery and those with severe complications related to the pregnancy, a fear of giving birth, a difficult delivery, an emergency C-section, a baby born prematurely with birth defects, etc. Their analysis showed PTSD rates of 4% and 18.5%, respectively.

Surprisingly, the major risk factor for PTSD turned out to be uncontrollable vomiting during pregnancy (seen in 40% of postpartum PTSD cases). The birth of a baby with birth defects was the second risk factor (35%), and the third, a history of violence in the mother’s childhood (34%). Women who experienced depression during the delivery were also at higher risk.

Other risk factors identified were lack of communication with the health care team, lack of consent, lack of support from the medical staff, and a long labor. Conversely, a sense of control and the support of a partner play a protective role.
 

Early screening

“If the symptoms of posttraumatic stress disorder aren’t treated after delivery, they tend to get worse over the period of 1 to 6 months following the child’s birth,” Dr. Franchitto indicated. This is why it’s necessary to screen for it as early as possible – in particular, by having the women fill out the City Birth Trauma Scale questionnaire – and provide proper treatment accordingly. When seeking to limit the effects of stress, early intervention by a psychologist may be beneficial.

Psychotherapy is the recommended first-line treatment for PTSD, especially cognitive behavioral therapy and Eye Movement Desensitization and Reprocessing therapy. This approach aims to limit the mental and behavioral avoidance that prevents the traumatic memory from being integrated and processed as a regular memory.

The consequences that the mother’s PTSD state has on the child are well documented. “Children whose mothers had PTSD during pregnancy have a lower birth weight and a shorter breast-feeding duration,” Dr. Franchitto reported. With respect to the quality of the mother-child relationship and the long-term development of the child, “the studies have highly conflicting findings.”

At the end of the presentation, Professor Israël Nisand, MD, an ob.gyn. at the American Hospital of Paris and the former president of the National College of French Gynecologists and Obstetricians, made the following comment: “I often think that we underestimate the consequences that the mother’s posttraumatic stress has on the child postpartum.” He added, “Postpartum posttraumatic stress disorder is a reality. Yet it isn’t screened for, let alone treated, even though it has serious consequences for the child.”

Dr. Franchitto also brought up the impact on members of the health care staff, the “second victims” of the traumatic events that occur while caring for the women in the maternity ward. “The estimated prevalence of PTSD symptoms among midwives is 22.9%,” which could lead to “a loss of confidence and a desire to leave the profession.”
 

Providing psychoeducation to health care staff

Dr. Franchitto believes that it’s essential to also protect caregivers who work in maternity wards. “It’s important to have the support of colleagues” – in particular, of team leaders – “and to share one’s experiences,” as long as one knows how to recognize the symptoms of posttraumatic stress through one’s emotions and is able to verbalize them.

She went on to say that providing psychoeducation to health care staff is therefore to be encouraged, as is “simulation-based training, for learning how to manage problematic situations.”

This content was originally published on Medscape French edition. A translated version appeared on Medscape.com.

PAU, FRANCE – Postpartum posttraumatic stress disorder tends to get worse over the months following the birth of a child. Therefore, it’s necessary to screen for it as early on as possible and to ensure that women who are affected are given the proper treatment. This was the message delivered during the Infogyn 2022 conference by Ludivine Franchitto, MD, a child psychiatrist at Toulouse University Hospital, France. Because postpartum PTSD is still not fully recognized, treatment remains inadequate and poorly documented.

Impact on the caregivers as well

“The situation is the same as what we saw with postpartum depression. The debate went on for 20 years before its existence was formally declared,” Dr. Franchitto noted. But for her, the important thing is not knowing whether a traumatic stress state may be experienced by the mother who had complications during pregnancy or delivery. Instead, it’s about focusing on the repercussions for the child.

During her presentation, Dr. Franchitto also pointed out that it’s necessary to recognize that caregivers who work in maternity wards may also be negatively impacted, as they routinely see the complications that women have during pregnancy and delivery. These workers may also develop a PTSD state, requiring support so that they can properly carry out their duties.

According to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-V), posttraumatic stress disorder arises after exposure to actual (or threatened) death, serious injury, or sexual violence. Individuals who have witnessed a traumatic event in person or who have experienced repeated (or extreme) exposure to aversive details of traumatic events may also develop PTSD.

Dr. Franchitto mentioned some of the criteria needed to make the diagnosis. “Intrusive distressing memories of the event, recurrent distressing dreams related to the event, persistent avoidance of stimuli associated with the traumatic event, or negative alterations in cognitions and mood associated with the traumatic event. And the duration of the disturbance is more than 1 month.” There may also be marked alterations in arousal and reactivity associated with the traumatic event (for example, irritable behavior, loss of awareness of present surroundings).
 

Prevalent in 18% of women in high-risk groups

According to the studies, there is a wide variability of PTSD rates. If referring only to traumatic symptoms (for example, depressive syndrome, suicidal ideation, hyperreactivity, and persistent avoidance), the rate could reach up to 40%. A 2016 meta-analysis of 59 studies found that the prevalence of childbirth-related PTSD was 5.9%.

The authors distinguished two groups of women: those without complications during pregnancy or during delivery and those with severe complications related to the pregnancy, a fear of giving birth, a difficult delivery, an emergency C-section, a baby born prematurely with birth defects, etc. Their analysis showed PTSD rates of 4% and 18.5%, respectively.

Surprisingly, the major risk factor for PTSD turned out to be uncontrollable vomiting during pregnancy (seen in 40% of postpartum PTSD cases). The birth of a baby with birth defects was the second risk factor (35%), and the third, a history of violence in the mother’s childhood (34%). Women who experienced depression during the delivery were also at higher risk.

Other risk factors identified were lack of communication with the health care team, lack of consent, lack of support from the medical staff, and a long labor. Conversely, a sense of control and the support of a partner play a protective role.
 

Early screening

“If the symptoms of posttraumatic stress disorder aren’t treated after delivery, they tend to get worse over the period of 1 to 6 months following the child’s birth,” Dr. Franchitto indicated. This is why it’s necessary to screen for it as early as possible – in particular, by having the women fill out the City Birth Trauma Scale questionnaire – and provide proper treatment accordingly. When seeking to limit the effects of stress, early intervention by a psychologist may be beneficial.

Psychotherapy is the recommended first-line treatment for PTSD, especially cognitive behavioral therapy and Eye Movement Desensitization and Reprocessing therapy. This approach aims to limit the mental and behavioral avoidance that prevents the traumatic memory from being integrated and processed as a regular memory.

The consequences that the mother’s PTSD state has on the child are well documented. “Children whose mothers had PTSD during pregnancy have a lower birth weight and a shorter breast-feeding duration,” Dr. Franchitto reported. With respect to the quality of the mother-child relationship and the long-term development of the child, “the studies have highly conflicting findings.”

At the end of the presentation, Professor Israël Nisand, MD, an ob.gyn. at the American Hospital of Paris and the former president of the National College of French Gynecologists and Obstetricians, made the following comment: “I often think that we underestimate the consequences that the mother’s posttraumatic stress has on the child postpartum.” He added, “Postpartum posttraumatic stress disorder is a reality. Yet it isn’t screened for, let alone treated, even though it has serious consequences for the child.”

Dr. Franchitto also brought up the impact on members of the health care staff, the “second victims” of the traumatic events that occur while caring for the women in the maternity ward. “The estimated prevalence of PTSD symptoms among midwives is 22.9%,” which could lead to “a loss of confidence and a desire to leave the profession.”
 

Providing psychoeducation to health care staff

Dr. Franchitto believes that it’s essential to also protect caregivers who work in maternity wards. “It’s important to have the support of colleagues” – in particular, of team leaders – “and to share one’s experiences,” as long as one knows how to recognize the symptoms of posttraumatic stress through one’s emotions and is able to verbalize them.

She went on to say that providing psychoeducation to health care staff is therefore to be encouraged, as is “simulation-based training, for learning how to manage problematic situations.”

This content was originally published on Medscape French edition. A translated version appeared on Medscape.com.

PAU, FRANCE – Postpartum posttraumatic stress disorder tends to get worse over the months following the birth of a child. Therefore, it’s necessary to screen for it as early on as possible and to ensure that women who are affected are given the proper treatment. This was the message delivered during the Infogyn 2022 conference by Ludivine Franchitto, MD, a child psychiatrist at Toulouse University Hospital, France. Because postpartum PTSD is still not fully recognized, treatment remains inadequate and poorly documented.

Impact on the caregivers as well

“The situation is the same as what we saw with postpartum depression. The debate went on for 20 years before its existence was formally declared,” Dr. Franchitto noted. But for her, the important thing is not knowing whether a traumatic stress state may be experienced by the mother who had complications during pregnancy or delivery. Instead, it’s about focusing on the repercussions for the child.

During her presentation, Dr. Franchitto also pointed out that it’s necessary to recognize that caregivers who work in maternity wards may also be negatively impacted, as they routinely see the complications that women have during pregnancy and delivery. These workers may also develop a PTSD state, requiring support so that they can properly carry out their duties.

According to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-V), posttraumatic stress disorder arises after exposure to actual (or threatened) death, serious injury, or sexual violence. Individuals who have witnessed a traumatic event in person or who have experienced repeated (or extreme) exposure to aversive details of traumatic events may also develop PTSD.

Dr. Franchitto mentioned some of the criteria needed to make the diagnosis. “Intrusive distressing memories of the event, recurrent distressing dreams related to the event, persistent avoidance of stimuli associated with the traumatic event, or negative alterations in cognitions and mood associated with the traumatic event. And the duration of the disturbance is more than 1 month.” There may also be marked alterations in arousal and reactivity associated with the traumatic event (for example, irritable behavior, loss of awareness of present surroundings).
 

Prevalent in 18% of women in high-risk groups

According to the studies, there is a wide variability of PTSD rates. If referring only to traumatic symptoms (for example, depressive syndrome, suicidal ideation, hyperreactivity, and persistent avoidance), the rate could reach up to 40%. A 2016 meta-analysis of 59 studies found that the prevalence of childbirth-related PTSD was 5.9%.

The authors distinguished two groups of women: those without complications during pregnancy or during delivery and those with severe complications related to the pregnancy, a fear of giving birth, a difficult delivery, an emergency C-section, a baby born prematurely with birth defects, etc. Their analysis showed PTSD rates of 4% and 18.5%, respectively.

Surprisingly, the major risk factor for PTSD turned out to be uncontrollable vomiting during pregnancy (seen in 40% of postpartum PTSD cases). The birth of a baby with birth defects was the second risk factor (35%), and the third, a history of violence in the mother’s childhood (34%). Women who experienced depression during the delivery were also at higher risk.

Other risk factors identified were lack of communication with the health care team, lack of consent, lack of support from the medical staff, and a long labor. Conversely, a sense of control and the support of a partner play a protective role.
 

Early screening

“If the symptoms of posttraumatic stress disorder aren’t treated after delivery, they tend to get worse over the period of 1 to 6 months following the child’s birth,” Dr. Franchitto indicated. This is why it’s necessary to screen for it as early as possible – in particular, by having the women fill out the City Birth Trauma Scale questionnaire – and provide proper treatment accordingly. When seeking to limit the effects of stress, early intervention by a psychologist may be beneficial.

Psychotherapy is the recommended first-line treatment for PTSD, especially cognitive behavioral therapy and Eye Movement Desensitization and Reprocessing therapy. This approach aims to limit the mental and behavioral avoidance that prevents the traumatic memory from being integrated and processed as a regular memory.

The consequences that the mother’s PTSD state has on the child are well documented. “Children whose mothers had PTSD during pregnancy have a lower birth weight and a shorter breast-feeding duration,” Dr. Franchitto reported. With respect to the quality of the mother-child relationship and the long-term development of the child, “the studies have highly conflicting findings.”

At the end of the presentation, Professor Israël Nisand, MD, an ob.gyn. at the American Hospital of Paris and the former president of the National College of French Gynecologists and Obstetricians, made the following comment: “I often think that we underestimate the consequences that the mother’s posttraumatic stress has on the child postpartum.” He added, “Postpartum posttraumatic stress disorder is a reality. Yet it isn’t screened for, let alone treated, even though it has serious consequences for the child.”

Dr. Franchitto also brought up the impact on members of the health care staff, the “second victims” of the traumatic events that occur while caring for the women in the maternity ward. “The estimated prevalence of PTSD symptoms among midwives is 22.9%,” which could lead to “a loss of confidence and a desire to leave the profession.”
 

Providing psychoeducation to health care staff

Dr. Franchitto believes that it’s essential to also protect caregivers who work in maternity wards. “It’s important to have the support of colleagues” – in particular, of team leaders – “and to share one’s experiences,” as long as one knows how to recognize the symptoms of posttraumatic stress through one’s emotions and is able to verbalize them.

She went on to say that providing psychoeducation to health care staff is therefore to be encouraged, as is “simulation-based training, for learning how to manage problematic situations.”

This content was originally published on Medscape French edition. A translated version appeared on Medscape.com.

Trauma-related dissociation consists of several subtypes, with unique brain signatures depending on type of dissociative disorders, new research suggests.

Results from a neuroimaging study showed that different dissociative symptoms were linked to hyperconnectivity within several key regions of the brain, including the central executive, default, and salience networks as well as decreased connectivity of the central executive and salience networks with other brain areas.

Depersonalization/derealization showed a different brain signature than partially dissociated intrusions, and participants with posttraumatic stress disorder showed a different brain signature, compared with those who had dissociative identity disorder (DID).

“Dissociation is a complex, subjective set of symptoms that are largely experienced internally and, contrary to media portrayal, are not usually overtly observable,” lead author Lauren Lebois, PhD, director of the Dissociative Disorders and Trauma Research Program, McLean Hospital, Belmont, Mass., and assistant professor of psychiatry at Harvard Medical School, Boston, told this news organization.

“However, we have shown that you can objectively measure dissociation and link it to robust brain signatures. We hope these results will encourage clinicians to screen for dissociation and approach reports of these experiences seriously, empathetically, and with awareness that they can be treated effectively,” Dr. Lebois said.

The findings were published online  in Neuropsychopharmacology.
 

Detachment, discontinuity

Pathological dissociation is “the experience of detachment from or discontinuity in one’s internal experience, sense of self, or surroundings” and is common in the aftermath of trauma, the investigators write.

Previous research into trauma-related pathological dissociation suggests it encompasses a range of experiences or “subtypes,” some of which frequently occur in PTSD and DID.

“Depersonalization and derealization involve feelings of detachment or disconnection from one’s sense of self, body, and environment,” the current researchers write. “Individuals report feeling like their body or surroundings are unreal or like they are in a movie.”

Dissociation also includes “experiences of self-alteration common in DID, in which people lose a sense of agency and ownership over their thoughts, emotions, actions, and body [and] experience some thoughts, emotions, etc. as partially dissociated intrusions,” Dr. Lebois said.

She added that dissociative symptoms are “common and disabling.” And dissociation and severe dissociative disorders such as DID “remain at best underappreciated and, at worst, frequently go undiagnosed or misdiagnosed,” with a high cost of stigmatization and misunderstanding preventing individuals from accessing effective treatment.

In addition, “given that DID disproportionately affects women, gender disparity is an important issue in this context,” Dr. Lebois noted.

Her team was motivated to conduct the study “to learn more about how different types of dissociation manifest in brain activity and to help combat the stigma around dissociation and DID.”
 

Filling the gap

The investigators drew on the “Triple Network” model of psychopathology, which “offers an integrative framework based in systems neuroscience for understanding cognitive and affective dysfunction across psychiatric conditions,” they write.

This model “implicates altered intrinsic organization and interactions between three large-scale brain networks across disorders,” they add.

The brain networks included in the study were the right-lateralized central executive network (rCEN), with the lateral frontoparietal brain region; the medial temporal subnetwork of the default network (tDN), with the medial frontoparietal brain region; and the cingulo-opercular subnetwork (cSN), with the midcingulo-insular brain region.

Previous neuroimaging research into dissociative disorders has implicated altered connectivity in these regions. However, although previous studies covered dissociation subtypes, they did not directly compare these subtypes. This study was designed to fill that gap, the investigators note.

They assessed 91 women with and without a history of childhood trauma, current PTSD, and with varying degrees of dissociation.

This included 19 with conventional PTSD (mean age, 33.4 years), 18 with PTSD dissociative subtype (mean age, 29.5 years), 26 with DID (mean age, 37.4 years), and 28 who acted as the healthy control group (mean age, 32 years).

Participants completed several scales regarding symptoms of PTSD, dissociation, and childhood trauma. They also underwent functional magnetic resonance imaging. Covariates included age, childhood maltreatment, and PTSD severity.
 

Connectivity alterations

Results showed the rCEN was “most impacted” by pathological dissociation, with 39 clusters linked to connectivity alterations.

Ten clusters within tDN exhibited within-network hyperconnectivity related to dissociation but only of the depersonalization/derealization subtype.

Eight clusters within cSN were linked to dissociation – specifically, within-network hyperconnectivity and decreased connectivity between regions in rCEN with cSN, with “no significant unique contributions of dissociation subtypes,” the researchers report.

“Depersonalization and derealization symptoms were associated with increased communication between a brain network involved in reasoning, attention, inhibition, and working memory and a brain region implicated in out-of-body experiences. This may, in part, contribute to depersonalization/derealization feelings of detachment, strangeness or unreality experienced with your body and surroundings,” Dr. Lebois said.

“In contrast, partially dissociated intrusion symptoms central to DID were linked to increased communication between a brain network involved in autobiographical memory and your sense of self and a brain network involved in reasoning, attention, inhibition, and working memory,” she added.

She noted that this matches how patients with DID describe their mental experiences: as sometimes feeling as if they lost a sense of ownership over their own thoughts and feelings, which can “intrude into their mental landscape.”

In the future, Dr. Lebois hopes that “we may be able to monitor dissociative brain signatures during psychotherapy to help assess recovery or relapse, or we could target brain activity directly with neurofeedback or neuromodulatory techniques as a dissociation treatment in and of itself.”
 

A first step?

Commenting on the study, Richard Loewenstein, MD, adjunct professor, department of psychiatry, University of Maryland School of Medicine, Baltimore, called the paper a “first step in more sophisticated studies of pathological dissociation using cutting-edge concepts of brain connectivity, methodology based on naturalistic, dimensional symptoms categories, and innovative statistical methods.”

Dr. Loewenstein, who was not involved with the current study, added that there is an “oversimplified conflation of hallucinations and other symptoms of dissociation with psychosis.” So studies may “incorrectly relate phenomena such as racism-based trauma to psychosis, rather than pathological dissociation and racism-based PTSD,” he said.

He noted that the implications are “profound, as pathological dissociation is not treatable with antipsychotic medications and requires treatment with psychotherapy specifically targeting symptoms of pathological dissociation.”

The study was funded by the Julia Kasparian Fund for Neuroscience Research and the National Institute of Mental Health. Dr. Lebois reported unpaid membership on the Scientific Committee for the International Society for the Study of Trauma and Dissociation, grant support from the NIMH and the Julia Kasparian Fund for Neuroscience Research, and spousal IP payments from Vanderbilt University for technology licensed to Acadia Pharmaceuticals unrelated to the present work. The other investigators’ disclosures are listed in the original paper. Dr. Loewenstein has disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Trauma-related dissociation consists of several subtypes, with unique brain signatures depending on type of dissociative disorders, new research suggests.

Results from a neuroimaging study showed that different dissociative symptoms were linked to hyperconnectivity within several key regions of the brain, including the central executive, default, and salience networks as well as decreased connectivity of the central executive and salience networks with other brain areas.

Depersonalization/derealization showed a different brain signature than partially dissociated intrusions, and participants with posttraumatic stress disorder showed a different brain signature, compared with those who had dissociative identity disorder (DID).

“Dissociation is a complex, subjective set of symptoms that are largely experienced internally and, contrary to media portrayal, are not usually overtly observable,” lead author Lauren Lebois, PhD, director of the Dissociative Disorders and Trauma Research Program, McLean Hospital, Belmont, Mass., and assistant professor of psychiatry at Harvard Medical School, Boston, told this news organization.

“However, we have shown that you can objectively measure dissociation and link it to robust brain signatures. We hope these results will encourage clinicians to screen for dissociation and approach reports of these experiences seriously, empathetically, and with awareness that they can be treated effectively,” Dr. Lebois said.

The findings were published online  in Neuropsychopharmacology.
 

Detachment, discontinuity

Pathological dissociation is “the experience of detachment from or discontinuity in one’s internal experience, sense of self, or surroundings” and is common in the aftermath of trauma, the investigators write.

Previous research into trauma-related pathological dissociation suggests it encompasses a range of experiences or “subtypes,” some of which frequently occur in PTSD and DID.

“Depersonalization and derealization involve feelings of detachment or disconnection from one’s sense of self, body, and environment,” the current researchers write. “Individuals report feeling like their body or surroundings are unreal or like they are in a movie.”

Dissociation also includes “experiences of self-alteration common in DID, in which people lose a sense of agency and ownership over their thoughts, emotions, actions, and body [and] experience some thoughts, emotions, etc. as partially dissociated intrusions,” Dr. Lebois said.

She added that dissociative symptoms are “common and disabling.” And dissociation and severe dissociative disorders such as DID “remain at best underappreciated and, at worst, frequently go undiagnosed or misdiagnosed,” with a high cost of stigmatization and misunderstanding preventing individuals from accessing effective treatment.

In addition, “given that DID disproportionately affects women, gender disparity is an important issue in this context,” Dr. Lebois noted.

Her team was motivated to conduct the study “to learn more about how different types of dissociation manifest in brain activity and to help combat the stigma around dissociation and DID.”
 

Filling the gap

The investigators drew on the “Triple Network” model of psychopathology, which “offers an integrative framework based in systems neuroscience for understanding cognitive and affective dysfunction across psychiatric conditions,” they write.

This model “implicates altered intrinsic organization and interactions between three large-scale brain networks across disorders,” they add.

The brain networks included in the study were the right-lateralized central executive network (rCEN), with the lateral frontoparietal brain region; the medial temporal subnetwork of the default network (tDN), with the medial frontoparietal brain region; and the cingulo-opercular subnetwork (cSN), with the midcingulo-insular brain region.

Previous neuroimaging research into dissociative disorders has implicated altered connectivity in these regions. However, although previous studies covered dissociation subtypes, they did not directly compare these subtypes. This study was designed to fill that gap, the investigators note.

They assessed 91 women with and without a history of childhood trauma, current PTSD, and with varying degrees of dissociation.

This included 19 with conventional PTSD (mean age, 33.4 years), 18 with PTSD dissociative subtype (mean age, 29.5 years), 26 with DID (mean age, 37.4 years), and 28 who acted as the healthy control group (mean age, 32 years).

Participants completed several scales regarding symptoms of PTSD, dissociation, and childhood trauma. They also underwent functional magnetic resonance imaging. Covariates included age, childhood maltreatment, and PTSD severity.
 

Connectivity alterations

Results showed the rCEN was “most impacted” by pathological dissociation, with 39 clusters linked to connectivity alterations.

Ten clusters within tDN exhibited within-network hyperconnectivity related to dissociation but only of the depersonalization/derealization subtype.

Eight clusters within cSN were linked to dissociation – specifically, within-network hyperconnectivity and decreased connectivity between regions in rCEN with cSN, with “no significant unique contributions of dissociation subtypes,” the researchers report.

“Depersonalization and derealization symptoms were associated with increased communication between a brain network involved in reasoning, attention, inhibition, and working memory and a brain region implicated in out-of-body experiences. This may, in part, contribute to depersonalization/derealization feelings of detachment, strangeness or unreality experienced with your body and surroundings,” Dr. Lebois said.

“In contrast, partially dissociated intrusion symptoms central to DID were linked to increased communication between a brain network involved in autobiographical memory and your sense of self and a brain network involved in reasoning, attention, inhibition, and working memory,” she added.

She noted that this matches how patients with DID describe their mental experiences: as sometimes feeling as if they lost a sense of ownership over their own thoughts and feelings, which can “intrude into their mental landscape.”

In the future, Dr. Lebois hopes that “we may be able to monitor dissociative brain signatures during psychotherapy to help assess recovery or relapse, or we could target brain activity directly with neurofeedback or neuromodulatory techniques as a dissociation treatment in and of itself.”
 

A first step?

Commenting on the study, Richard Loewenstein, MD, adjunct professor, department of psychiatry, University of Maryland School of Medicine, Baltimore, called the paper a “first step in more sophisticated studies of pathological dissociation using cutting-edge concepts of brain connectivity, methodology based on naturalistic, dimensional symptoms categories, and innovative statistical methods.”

Dr. Loewenstein, who was not involved with the current study, added that there is an “oversimplified conflation of hallucinations and other symptoms of dissociation with psychosis.” So studies may “incorrectly relate phenomena such as racism-based trauma to psychosis, rather than pathological dissociation and racism-based PTSD,” he said.

He noted that the implications are “profound, as pathological dissociation is not treatable with antipsychotic medications and requires treatment with psychotherapy specifically targeting symptoms of pathological dissociation.”

The study was funded by the Julia Kasparian Fund for Neuroscience Research and the National Institute of Mental Health. Dr. Lebois reported unpaid membership on the Scientific Committee for the International Society for the Study of Trauma and Dissociation, grant support from the NIMH and the Julia Kasparian Fund for Neuroscience Research, and spousal IP payments from Vanderbilt University for technology licensed to Acadia Pharmaceuticals unrelated to the present work. The other investigators’ disclosures are listed in the original paper. Dr. Loewenstein has disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Trauma-related dissociation consists of several subtypes, with unique brain signatures depending on type of dissociative disorders, new research suggests.

Results from a neuroimaging study showed that different dissociative symptoms were linked to hyperconnectivity within several key regions of the brain, including the central executive, default, and salience networks as well as decreased connectivity of the central executive and salience networks with other brain areas.

Depersonalization/derealization showed a different brain signature than partially dissociated intrusions, and participants with posttraumatic stress disorder showed a different brain signature, compared with those who had dissociative identity disorder (DID).

“Dissociation is a complex, subjective set of symptoms that are largely experienced internally and, contrary to media portrayal, are not usually overtly observable,” lead author Lauren Lebois, PhD, director of the Dissociative Disorders and Trauma Research Program, McLean Hospital, Belmont, Mass., and assistant professor of psychiatry at Harvard Medical School, Boston, told this news organization.

“However, we have shown that you can objectively measure dissociation and link it to robust brain signatures. We hope these results will encourage clinicians to screen for dissociation and approach reports of these experiences seriously, empathetically, and with awareness that they can be treated effectively,” Dr. Lebois said.

The findings were published online  in Neuropsychopharmacology.
 

Detachment, discontinuity

Pathological dissociation is “the experience of detachment from or discontinuity in one’s internal experience, sense of self, or surroundings” and is common in the aftermath of trauma, the investigators write.

Previous research into trauma-related pathological dissociation suggests it encompasses a range of experiences or “subtypes,” some of which frequently occur in PTSD and DID.

“Depersonalization and derealization involve feelings of detachment or disconnection from one’s sense of self, body, and environment,” the current researchers write. “Individuals report feeling like their body or surroundings are unreal or like they are in a movie.”

Dissociation also includes “experiences of self-alteration common in DID, in which people lose a sense of agency and ownership over their thoughts, emotions, actions, and body [and] experience some thoughts, emotions, etc. as partially dissociated intrusions,” Dr. Lebois said.

She added that dissociative symptoms are “common and disabling.” And dissociation and severe dissociative disorders such as DID “remain at best underappreciated and, at worst, frequently go undiagnosed or misdiagnosed,” with a high cost of stigmatization and misunderstanding preventing individuals from accessing effective treatment.

In addition, “given that DID disproportionately affects women, gender disparity is an important issue in this context,” Dr. Lebois noted.

Her team was motivated to conduct the study “to learn more about how different types of dissociation manifest in brain activity and to help combat the stigma around dissociation and DID.”
 

Filling the gap

The investigators drew on the “Triple Network” model of psychopathology, which “offers an integrative framework based in systems neuroscience for understanding cognitive and affective dysfunction across psychiatric conditions,” they write.

This model “implicates altered intrinsic organization and interactions between three large-scale brain networks across disorders,” they add.

The brain networks included in the study were the right-lateralized central executive network (rCEN), with the lateral frontoparietal brain region; the medial temporal subnetwork of the default network (tDN), with the medial frontoparietal brain region; and the cingulo-opercular subnetwork (cSN), with the midcingulo-insular brain region.

Previous neuroimaging research into dissociative disorders has implicated altered connectivity in these regions. However, although previous studies covered dissociation subtypes, they did not directly compare these subtypes. This study was designed to fill that gap, the investigators note.

They assessed 91 women with and without a history of childhood trauma, current PTSD, and with varying degrees of dissociation.

This included 19 with conventional PTSD (mean age, 33.4 years), 18 with PTSD dissociative subtype (mean age, 29.5 years), 26 with DID (mean age, 37.4 years), and 28 who acted as the healthy control group (mean age, 32 years).

Participants completed several scales regarding symptoms of PTSD, dissociation, and childhood trauma. They also underwent functional magnetic resonance imaging. Covariates included age, childhood maltreatment, and PTSD severity.
 

Connectivity alterations

Results showed the rCEN was “most impacted” by pathological dissociation, with 39 clusters linked to connectivity alterations.

Ten clusters within tDN exhibited within-network hyperconnectivity related to dissociation but only of the depersonalization/derealization subtype.

Eight clusters within cSN were linked to dissociation – specifically, within-network hyperconnectivity and decreased connectivity between regions in rCEN with cSN, with “no significant unique contributions of dissociation subtypes,” the researchers report.

“Depersonalization and derealization symptoms were associated with increased communication between a brain network involved in reasoning, attention, inhibition, and working memory and a brain region implicated in out-of-body experiences. This may, in part, contribute to depersonalization/derealization feelings of detachment, strangeness or unreality experienced with your body and surroundings,” Dr. Lebois said.

“In contrast, partially dissociated intrusion symptoms central to DID were linked to increased communication between a brain network involved in autobiographical memory and your sense of self and a brain network involved in reasoning, attention, inhibition, and working memory,” she added.

She noted that this matches how patients with DID describe their mental experiences: as sometimes feeling as if they lost a sense of ownership over their own thoughts and feelings, which can “intrude into their mental landscape.”

In the future, Dr. Lebois hopes that “we may be able to monitor dissociative brain signatures during psychotherapy to help assess recovery or relapse, or we could target brain activity directly with neurofeedback or neuromodulatory techniques as a dissociation treatment in and of itself.”
 

A first step?

Commenting on the study, Richard Loewenstein, MD, adjunct professor, department of psychiatry, University of Maryland School of Medicine, Baltimore, called the paper a “first step in more sophisticated studies of pathological dissociation using cutting-edge concepts of brain connectivity, methodology based on naturalistic, dimensional symptoms categories, and innovative statistical methods.”

Dr. Loewenstein, who was not involved with the current study, added that there is an “oversimplified conflation of hallucinations and other symptoms of dissociation with psychosis.” So studies may “incorrectly relate phenomena such as racism-based trauma to psychosis, rather than pathological dissociation and racism-based PTSD,” he said.

He noted that the implications are “profound, as pathological dissociation is not treatable with antipsychotic medications and requires treatment with psychotherapy specifically targeting symptoms of pathological dissociation.”

The study was funded by the Julia Kasparian Fund for Neuroscience Research and the National Institute of Mental Health. Dr. Lebois reported unpaid membership on the Scientific Committee for the International Society for the Study of Trauma and Dissociation, grant support from the NIMH and the Julia Kasparian Fund for Neuroscience Research, and spousal IP payments from Vanderbilt University for technology licensed to Acadia Pharmaceuticals unrelated to the present work. The other investigators’ disclosures are listed in the original paper. Dr. Loewenstein has disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Transgender and gender-diverse (TGD) individuals with mental illness appear to have higher rates of posttraumatic stress disorder (PTSD) and borderline personality disorder (BPD) compared with their cisgender counterparts, new research shows.

Although mood disorders, depression, and anxiety were the most common diagnoses in both TGD and cisgender patients, “when we compared the diagnostic profiles [of TGD patients] to those of cisgender patients, we found an increased prevalence of PTSD and BPD,” study investigator Mark Zimmerman, MD, professor of psychiatry and human behavior, Brown University, Providence, R.I., told this news organization.

“What we concluded is that psychiatric programs that wish to treat TGD patients should either have or should develop expertise in treating PTSD and BPD, not just mood and anxiety disorders,” Dr. Zimmerman said.

The study was published online September 26 in the Journal of Clinical Psychiatry.
 

‘Piecemeal literature’

TGD individuals “experience high rates of various forms of psychopathology in general and when compared with cisgender persons,” the investigators note.

They point out that most empirical evidence has relied upon the use of brief, unstructured psychodiagnostic assessment measures and assessment of a “limited constellation of psychiatric symptoms domains,” resulting in a “piecemeal literature wherein each piece of research documents elevations in one – or a few – diagnostic domains.”

Studies pointing to broader psychosocial health variables have often relied upon self-reported measures. In addition, in studies that utilized a structured interview approach, none “used a formal interview procedure to assess psychiatric diagnoses” and most focused only on a “limited number of psychiatric conditions based on self-reports of past diagnosis.”

The goal of the current study was to use semistructured interviews administered by professionals to compare the diagnostic profiles of a samples of TGD and cisgender patients who presented for treatment at a single naturalistic, clinically acute setting – a partial hospital program.

Dr. Zimmerman said that there was an additional motive for conducting the study. “There has been discussion in the field as to whether or not transgender or gender-diverse individuals all have borderline personality disorder, but that hasn’t been our clinical impression.”

Rather, Dr. Zimmerman and colleagues believe TGD people “may have had more difficult childhoods and more difficult adjustments in society because of societal attitudes and have to deal with that stress, whether it be microaggressions or overt bullying and aggression.” The study was designed to investigate this issue.

In addition, studies conducted in primary care programs in individuals seeking gender-affirming surgery have “reported a limited number of psychiatric diagnoses, but we were wondering whether, amongst psychiatric patients specifically, there were differences in diagnostic profiles between transgender and gender-diverse patients and cisgender patients. If so, what might the implications be for providing care for this population?”
 

TGD not synonymous with borderline

To investigate, the researchers administered semistructured diagnostic interviews for DSM-IV disorders to 2,212 psychiatric patients (66% cisgender women, 30.8% cisgender men, 3.1% TGD; mean [standard deviation] age 36.7 [14.4] years) presenting to the Rhode Island Hospital Department of Psychiatry Partial Hospital Program between April 2014 and January 2021.

Patients also completed a demographic questionnaire including their assigned sex at birth and their current gender identity.

Most patients (44.9%) were single, followed by 23.5% who were married, 14.1% living in a relationship as if married, 12.0% divorced, 3.6% separated, and 1.9% widowed.

Almost three-quarters of participants (73.2%) identified as White, followed by Hispanic (10.7%), Black (6.7%), “other” or a combination of racial/ethnic backgrounds (6.6%), and Asian (2.7%).

There were no differences between cisgender and TGD groups in terms of race or education, but the TGD patients were significantly younger compared with their cisgender counterparts and were significantly more likely to have never been married.

The average number of psychiatric diagnoses in the sample was 3.05 (± 1.73), with TGD patients having a larger number of psychiatric diagnoses than did their cisgender peers (an average of 3.54 ± 1.88 vs. 3.04 ± 1.72, respectively; t = 2.37; P = .02).

Major depressive disorder (MDD) and generalized anxiety disorder (GAD) were the most common disorders among both cisgender and TGD patients. However, after controlling for age, the researchers found that TGD patients were significantly more likely than were the cisgender patients to be diagnosed with PTSD and BPD (P < .05 for both).

A representative sample?

Commenting on the study, Jack Drescher, MD, distinguished life fellow of the American Psychiatric Association and clinical professor of psychiatry, Columbia University, New York, called the findings “interesting” but noted that a limitation of the study is that it included “a patient population with likely more severe psychiatric illness, since they were all day hospital patients.”

The question is whether similar findings would be obtained in a less severely ill population, said Dr. Drescher, who is also a senior consulting analyst for sexuality and gender at Columbia University and was not involved with the study. “The patients in the study may not be representative of the general population, either cisgender or transgender.”

Dr. Drescher was “not surprised” by the finding regarding PTSD because the finding “is consistent with our understanding of the kinds of traumas that transgender people go through in day-to-day life.”

He noted that some people misunderstand the diagnostic criterion in BPD of identity confusion and think that because people with gender dysphoria may be confused about their identity, it means that all people who are transgender have borderline personality disorder, “but that’s not true.”

Dr. Zimmerman agreed. “The vast majority of individuals with BPD do not have a transgender or gender-diverse identity, and TGD should not be equated with BPD,” he said.

No source of study funding was disclosed. Dr. Zimmerman and coauthors and Dr. Drescher report no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Transgender and gender-diverse (TGD) individuals with mental illness appear to have higher rates of posttraumatic stress disorder (PTSD) and borderline personality disorder (BPD) compared with their cisgender counterparts, new research shows.

Although mood disorders, depression, and anxiety were the most common diagnoses in both TGD and cisgender patients, “when we compared the diagnostic profiles [of TGD patients] to those of cisgender patients, we found an increased prevalence of PTSD and BPD,” study investigator Mark Zimmerman, MD, professor of psychiatry and human behavior, Brown University, Providence, R.I., told this news organization.

“What we concluded is that psychiatric programs that wish to treat TGD patients should either have or should develop expertise in treating PTSD and BPD, not just mood and anxiety disorders,” Dr. Zimmerman said.

The study was published online September 26 in the Journal of Clinical Psychiatry.
 

‘Piecemeal literature’

TGD individuals “experience high rates of various forms of psychopathology in general and when compared with cisgender persons,” the investigators note.

They point out that most empirical evidence has relied upon the use of brief, unstructured psychodiagnostic assessment measures and assessment of a “limited constellation of psychiatric symptoms domains,” resulting in a “piecemeal literature wherein each piece of research documents elevations in one – or a few – diagnostic domains.”

Studies pointing to broader psychosocial health variables have often relied upon self-reported measures. In addition, in studies that utilized a structured interview approach, none “used a formal interview procedure to assess psychiatric diagnoses” and most focused only on a “limited number of psychiatric conditions based on self-reports of past diagnosis.”

The goal of the current study was to use semistructured interviews administered by professionals to compare the diagnostic profiles of a samples of TGD and cisgender patients who presented for treatment at a single naturalistic, clinically acute setting – a partial hospital program.

Dr. Zimmerman said that there was an additional motive for conducting the study. “There has been discussion in the field as to whether or not transgender or gender-diverse individuals all have borderline personality disorder, but that hasn’t been our clinical impression.”

Rather, Dr. Zimmerman and colleagues believe TGD people “may have had more difficult childhoods and more difficult adjustments in society because of societal attitudes and have to deal with that stress, whether it be microaggressions or overt bullying and aggression.” The study was designed to investigate this issue.

In addition, studies conducted in primary care programs in individuals seeking gender-affirming surgery have “reported a limited number of psychiatric diagnoses, but we were wondering whether, amongst psychiatric patients specifically, there were differences in diagnostic profiles between transgender and gender-diverse patients and cisgender patients. If so, what might the implications be for providing care for this population?”
 

TGD not synonymous with borderline

To investigate, the researchers administered semistructured diagnostic interviews for DSM-IV disorders to 2,212 psychiatric patients (66% cisgender women, 30.8% cisgender men, 3.1% TGD; mean [standard deviation] age 36.7 [14.4] years) presenting to the Rhode Island Hospital Department of Psychiatry Partial Hospital Program between April 2014 and January 2021.

Patients also completed a demographic questionnaire including their assigned sex at birth and their current gender identity.

Most patients (44.9%) were single, followed by 23.5% who were married, 14.1% living in a relationship as if married, 12.0% divorced, 3.6% separated, and 1.9% widowed.

Almost three-quarters of participants (73.2%) identified as White, followed by Hispanic (10.7%), Black (6.7%), “other” or a combination of racial/ethnic backgrounds (6.6%), and Asian (2.7%).

There were no differences between cisgender and TGD groups in terms of race or education, but the TGD patients were significantly younger compared with their cisgender counterparts and were significantly more likely to have never been married.

The average number of psychiatric diagnoses in the sample was 3.05 (± 1.73), with TGD patients having a larger number of psychiatric diagnoses than did their cisgender peers (an average of 3.54 ± 1.88 vs. 3.04 ± 1.72, respectively; t = 2.37; P = .02).

Major depressive disorder (MDD) and generalized anxiety disorder (GAD) were the most common disorders among both cisgender and TGD patients. However, after controlling for age, the researchers found that TGD patients were significantly more likely than were the cisgender patients to be diagnosed with PTSD and BPD (P < .05 for both).

A representative sample?

Commenting on the study, Jack Drescher, MD, distinguished life fellow of the American Psychiatric Association and clinical professor of psychiatry, Columbia University, New York, called the findings “interesting” but noted that a limitation of the study is that it included “a patient population with likely more severe psychiatric illness, since they were all day hospital patients.”

The question is whether similar findings would be obtained in a less severely ill population, said Dr. Drescher, who is also a senior consulting analyst for sexuality and gender at Columbia University and was not involved with the study. “The patients in the study may not be representative of the general population, either cisgender or transgender.”

Dr. Drescher was “not surprised” by the finding regarding PTSD because the finding “is consistent with our understanding of the kinds of traumas that transgender people go through in day-to-day life.”

He noted that some people misunderstand the diagnostic criterion in BPD of identity confusion and think that because people with gender dysphoria may be confused about their identity, it means that all people who are transgender have borderline personality disorder, “but that’s not true.”

Dr. Zimmerman agreed. “The vast majority of individuals with BPD do not have a transgender or gender-diverse identity, and TGD should not be equated with BPD,” he said.

No source of study funding was disclosed. Dr. Zimmerman and coauthors and Dr. Drescher report no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Transgender and gender-diverse (TGD) individuals with mental illness appear to have higher rates of posttraumatic stress disorder (PTSD) and borderline personality disorder (BPD) compared with their cisgender counterparts, new research shows.

Although mood disorders, depression, and anxiety were the most common diagnoses in both TGD and cisgender patients, “when we compared the diagnostic profiles [of TGD patients] to those of cisgender patients, we found an increased prevalence of PTSD and BPD,” study investigator Mark Zimmerman, MD, professor of psychiatry and human behavior, Brown University, Providence, R.I., told this news organization.

“What we concluded is that psychiatric programs that wish to treat TGD patients should either have or should develop expertise in treating PTSD and BPD, not just mood and anxiety disorders,” Dr. Zimmerman said.

The study was published online September 26 in the Journal of Clinical Psychiatry.
 

‘Piecemeal literature’

TGD individuals “experience high rates of various forms of psychopathology in general and when compared with cisgender persons,” the investigators note.

They point out that most empirical evidence has relied upon the use of brief, unstructured psychodiagnostic assessment measures and assessment of a “limited constellation of psychiatric symptoms domains,” resulting in a “piecemeal literature wherein each piece of research documents elevations in one – or a few – diagnostic domains.”

Studies pointing to broader psychosocial health variables have often relied upon self-reported measures. In addition, in studies that utilized a structured interview approach, none “used a formal interview procedure to assess psychiatric diagnoses” and most focused only on a “limited number of psychiatric conditions based on self-reports of past diagnosis.”

The goal of the current study was to use semistructured interviews administered by professionals to compare the diagnostic profiles of a samples of TGD and cisgender patients who presented for treatment at a single naturalistic, clinically acute setting – a partial hospital program.

Dr. Zimmerman said that there was an additional motive for conducting the study. “There has been discussion in the field as to whether or not transgender or gender-diverse individuals all have borderline personality disorder, but that hasn’t been our clinical impression.”

Rather, Dr. Zimmerman and colleagues believe TGD people “may have had more difficult childhoods and more difficult adjustments in society because of societal attitudes and have to deal with that stress, whether it be microaggressions or overt bullying and aggression.” The study was designed to investigate this issue.

In addition, studies conducted in primary care programs in individuals seeking gender-affirming surgery have “reported a limited number of psychiatric diagnoses, but we were wondering whether, amongst psychiatric patients specifically, there were differences in diagnostic profiles between transgender and gender-diverse patients and cisgender patients. If so, what might the implications be for providing care for this population?”
 

TGD not synonymous with borderline

To investigate, the researchers administered semistructured diagnostic interviews for DSM-IV disorders to 2,212 psychiatric patients (66% cisgender women, 30.8% cisgender men, 3.1% TGD; mean [standard deviation] age 36.7 [14.4] years) presenting to the Rhode Island Hospital Department of Psychiatry Partial Hospital Program between April 2014 and January 2021.

Patients also completed a demographic questionnaire including their assigned sex at birth and their current gender identity.

Most patients (44.9%) were single, followed by 23.5% who were married, 14.1% living in a relationship as if married, 12.0% divorced, 3.6% separated, and 1.9% widowed.

Almost three-quarters of participants (73.2%) identified as White, followed by Hispanic (10.7%), Black (6.7%), “other” or a combination of racial/ethnic backgrounds (6.6%), and Asian (2.7%).

There were no differences between cisgender and TGD groups in terms of race or education, but the TGD patients were significantly younger compared with their cisgender counterparts and were significantly more likely to have never been married.

The average number of psychiatric diagnoses in the sample was 3.05 (± 1.73), with TGD patients having a larger number of psychiatric diagnoses than did their cisgender peers (an average of 3.54 ± 1.88 vs. 3.04 ± 1.72, respectively; t = 2.37; P = .02).

Major depressive disorder (MDD) and generalized anxiety disorder (GAD) were the most common disorders among both cisgender and TGD patients. However, after controlling for age, the researchers found that TGD patients were significantly more likely than were the cisgender patients to be diagnosed with PTSD and BPD (P < .05 for both).

A representative sample?

Commenting on the study, Jack Drescher, MD, distinguished life fellow of the American Psychiatric Association and clinical professor of psychiatry, Columbia University, New York, called the findings “interesting” but noted that a limitation of the study is that it included “a patient population with likely more severe psychiatric illness, since they were all day hospital patients.”

The question is whether similar findings would be obtained in a less severely ill population, said Dr. Drescher, who is also a senior consulting analyst for sexuality and gender at Columbia University and was not involved with the study. “The patients in the study may not be representative of the general population, either cisgender or transgender.”

Dr. Drescher was “not surprised” by the finding regarding PTSD because the finding “is consistent with our understanding of the kinds of traumas that transgender people go through in day-to-day life.”

He noted that some people misunderstand the diagnostic criterion in BPD of identity confusion and think that because people with gender dysphoria may be confused about their identity, it means that all people who are transgender have borderline personality disorder, “but that’s not true.”

Dr. Zimmerman agreed. “The vast majority of individuals with BPD do not have a transgender or gender-diverse identity, and TGD should not be equated with BPD,” he said.

No source of study funding was disclosed. Dr. Zimmerman and coauthors and Dr. Drescher report no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Visits to emergency departments following sexual assault increased 15-fold from 2006 through 2019, as determined from a national database of visits to hospitals in the United States.

Data from the Federal Bureau of Investigation show an increase in reported rapes and sexual assaults (SAs) since 2006, and studies of victims show an increased risk of conditions such as suicidal ideation, PTSD, depression, substance use, and chronic conditions, write Emily L. Vogt of the University of Michigan, Ann Arbor, and colleagues.

However, trends and disparities in ED use by adults seeking care following SA have not been explored, they said.

For a study that was published in JAMA Network Open, researchers reviewed data from the Nationwide Emergency Department Sample (NEDS), a large, nationally representative database managed by the Agency for Healthcare Research and Quality. The dataset consisted of 120 million to 143 million weighted ED visits reported annually from 2006 through 2016. The study population included adults aged 18-65 years who had made an ED visit that was recorded in the NEDS and that was coded as an SA. SA was defined using ICD-9 codes until the fourth quarter of 2015, at which time ICD-10 codes came into use.

Overall, the number of SA-related ED visits increased by 1,533.0% during the study period, from 3,607 in 2006 to 55,296 in 2019. The average annual percentage change was 23.0% (P < .001). The greatest increase occurred from 2015 to 2016, when annual visits increased from 17,709 to 47,732. This increase likely reflected the updated ICD-10 codes, in which there are categories for suspected adult rape, confirmed adult rape, and adult forced sexual exploitation, the researchers note.

Patients presenting to the ED after an SA were mainly women (91.5%). Individuals aged 18-25 years accounted for nearly half of the presentations. Individuals in the lowest and second-lowest income quartiles also were overrepresented.

Despite the increased presentation to EDs, admission rates for SA decreased, from 12.6% to 4.3%, the researchers note. Patients who were older and were insured through Medicaid were more likely to be admitted than persons of other demographic groups.

The researchers also found that increases in ED presentations outpaced increases in SA reports to law enforcement. They compared the ED trends with FBI-reported rapes/SAs from 2015 to 2019 and found increases of 7% and 22% during the times of ICD-9 and ICD-10 codes, respectively. However, in 2019, the number of SA survivors who sought ED care remained below the number who reported to law enforcement (55,296 vs. 139,815, as determined on the basis of revised SA definitions).

“Although the association between increased coding specificity and documentation of SA is still unclear, ICD-10 likely contributed to increased ED documentation of SA,” but the data show steady increases that are independent of the coding change, the researchers write.

The study findings were limited by several factors, including the potential for multiple representations of patients, coding errors associated with the NEDS database, and the reliance on voluntary reports in the NEDS and FBI datasets, the researchers note. The results were strengthened by the large, diverse sample size and by the inclusion of hospital admissions and crime data for comparison, they say.

“As few as 21% of survivors seek medical care after SA, meaning that the survivors captured in this study represent a fraction of total SA-related care need,” the researchers write. “Our finding that most SA ED visits are by young, female, and low-income survivors can inform policy changes to better support these individuals,” which could include the development of outpatient and longitudinal care settings to better serve these populations, they conclude.

Better understanding not only of the trends underlying SA reporting but also of the demographics of survivors who seek treatment and evaluation after SA is vital, said Robert Glatter, MD, in an interview.

“Being able to better understand how social and societal movements affect a patient’s comfort in reporting an SA is vital in tracking the numbers of people who seek care in the ED,” said Dr. Glatter, an emergency medicine physician at Lenox Hill Hospital at Northwell Health, New York, and also of Hofstra University, Hempstead, N.Y.

Dr. Glatter said he was not surprised by the significant increase in sexual assault presentations, especially in light of increased awareness and the influence of the #MeToo movement and other social justice movements over the past decade.

“While I believe that victims of sexual violence may now feel more empowered to report an assault, the volume of SA that go unreported remains a serious public health issue and concern” in the United States and globally, he emphasized.

A key message from the current study is that there is a need for investment in “compassionate and comprehensive care for all survivors of SA,” Dr. Glatter said. “This includes recognition of the extensive mental health consequences of SA that can lead to not only depression, PTSD, and anxiety but also to suicidal ideation and suicide. The longer-term medical effects become life altering, permeating families and future generations,” he emphasized.

“As a society, we must also place a strong emphasis on caring for all SA survivors, but particularly those who come from economically or socially disadvantaged backgrounds who are uninsured or underinsured,” Dr. Glatter said. Issues of race, gender identity, and sexual identity among SA survivors also must be taken into consideration, he added.

“We need to better understand how our health care system can provide more nuanced follow-up care and reporting for survivors in outpatient settings. … Making access easier, while ensuring confidentiality, will allow more survivors of SA to seek treatment and care,” he said. “We also need to understand how using forensic nurses in this capacity, and beyond the ED, can better serve minority and racially diverse communities” and to increase the recruitment and training of such specialized nurses to care for SA victims, Dr. Glatter noted.

The study was supported by internal funding from the University of Michigan and the department of obstetrics and gynecology. Corresponding author Erica C. Marsh, MD, has received personal fees from Myovant Sciences and Pfizer unrelated to the current study. Dr. Glatter has disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Visits to emergency departments following sexual assault increased 15-fold from 2006 through 2019, as determined from a national database of visits to hospitals in the United States.

Data from the Federal Bureau of Investigation show an increase in reported rapes and sexual assaults (SAs) since 2006, and studies of victims show an increased risk of conditions such as suicidal ideation, PTSD, depression, substance use, and chronic conditions, write Emily L. Vogt of the University of Michigan, Ann Arbor, and colleagues.

However, trends and disparities in ED use by adults seeking care following SA have not been explored, they said.

For a study that was published in JAMA Network Open, researchers reviewed data from the Nationwide Emergency Department Sample (NEDS), a large, nationally representative database managed by the Agency for Healthcare Research and Quality. The dataset consisted of 120 million to 143 million weighted ED visits reported annually from 2006 through 2016. The study population included adults aged 18-65 years who had made an ED visit that was recorded in the NEDS and that was coded as an SA. SA was defined using ICD-9 codes until the fourth quarter of 2015, at which time ICD-10 codes came into use.

Overall, the number of SA-related ED visits increased by 1,533.0% during the study period, from 3,607 in 2006 to 55,296 in 2019. The average annual percentage change was 23.0% (P < .001). The greatest increase occurred from 2015 to 2016, when annual visits increased from 17,709 to 47,732. This increase likely reflected the updated ICD-10 codes, in which there are categories for suspected adult rape, confirmed adult rape, and adult forced sexual exploitation, the researchers note.

Patients presenting to the ED after an SA were mainly women (91.5%). Individuals aged 18-25 years accounted for nearly half of the presentations. Individuals in the lowest and second-lowest income quartiles also were overrepresented.

Despite the increased presentation to EDs, admission rates for SA decreased, from 12.6% to 4.3%, the researchers note. Patients who were older and were insured through Medicaid were more likely to be admitted than persons of other demographic groups.

The researchers also found that increases in ED presentations outpaced increases in SA reports to law enforcement. They compared the ED trends with FBI-reported rapes/SAs from 2015 to 2019 and found increases of 7% and 22% during the times of ICD-9 and ICD-10 codes, respectively. However, in 2019, the number of SA survivors who sought ED care remained below the number who reported to law enforcement (55,296 vs. 139,815, as determined on the basis of revised SA definitions).

“Although the association between increased coding specificity and documentation of SA is still unclear, ICD-10 likely contributed to increased ED documentation of SA,” but the data show steady increases that are independent of the coding change, the researchers write.

The study findings were limited by several factors, including the potential for multiple representations of patients, coding errors associated with the NEDS database, and the reliance on voluntary reports in the NEDS and FBI datasets, the researchers note. The results were strengthened by the large, diverse sample size and by the inclusion of hospital admissions and crime data for comparison, they say.

“As few as 21% of survivors seek medical care after SA, meaning that the survivors captured in this study represent a fraction of total SA-related care need,” the researchers write. “Our finding that most SA ED visits are by young, female, and low-income survivors can inform policy changes to better support these individuals,” which could include the development of outpatient and longitudinal care settings to better serve these populations, they conclude.

Better understanding not only of the trends underlying SA reporting but also of the demographics of survivors who seek treatment and evaluation after SA is vital, said Robert Glatter, MD, in an interview.

“Being able to better understand how social and societal movements affect a patient’s comfort in reporting an SA is vital in tracking the numbers of people who seek care in the ED,” said Dr. Glatter, an emergency medicine physician at Lenox Hill Hospital at Northwell Health, New York, and also of Hofstra University, Hempstead, N.Y.

Dr. Glatter said he was not surprised by the significant increase in sexual assault presentations, especially in light of increased awareness and the influence of the #MeToo movement and other social justice movements over the past decade.

“While I believe that victims of sexual violence may now feel more empowered to report an assault, the volume of SA that go unreported remains a serious public health issue and concern” in the United States and globally, he emphasized.

A key message from the current study is that there is a need for investment in “compassionate and comprehensive care for all survivors of SA,” Dr. Glatter said. “This includes recognition of the extensive mental health consequences of SA that can lead to not only depression, PTSD, and anxiety but also to suicidal ideation and suicide. The longer-term medical effects become life altering, permeating families and future generations,” he emphasized.

“As a society, we must also place a strong emphasis on caring for all SA survivors, but particularly those who come from economically or socially disadvantaged backgrounds who are uninsured or underinsured,” Dr. Glatter said. Issues of race, gender identity, and sexual identity among SA survivors also must be taken into consideration, he added.

“We need to better understand how our health care system can provide more nuanced follow-up care and reporting for survivors in outpatient settings. … Making access easier, while ensuring confidentiality, will allow more survivors of SA to seek treatment and care,” he said. “We also need to understand how using forensic nurses in this capacity, and beyond the ED, can better serve minority and racially diverse communities” and to increase the recruitment and training of such specialized nurses to care for SA victims, Dr. Glatter noted.

The study was supported by internal funding from the University of Michigan and the department of obstetrics and gynecology. Corresponding author Erica C. Marsh, MD, has received personal fees from Myovant Sciences and Pfizer unrelated to the current study. Dr. Glatter has disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Visits to emergency departments following sexual assault increased 15-fold from 2006 through 2019, as determined from a national database of visits to hospitals in the United States.

Data from the Federal Bureau of Investigation show an increase in reported rapes and sexual assaults (SAs) since 2006, and studies of victims show an increased risk of conditions such as suicidal ideation, PTSD, depression, substance use, and chronic conditions, write Emily L. Vogt of the University of Michigan, Ann Arbor, and colleagues.

However, trends and disparities in ED use by adults seeking care following SA have not been explored, they said.

For a study that was published in JAMA Network Open, researchers reviewed data from the Nationwide Emergency Department Sample (NEDS), a large, nationally representative database managed by the Agency for Healthcare Research and Quality. The dataset consisted of 120 million to 143 million weighted ED visits reported annually from 2006 through 2016. The study population included adults aged 18-65 years who had made an ED visit that was recorded in the NEDS and that was coded as an SA. SA was defined using ICD-9 codes until the fourth quarter of 2015, at which time ICD-10 codes came into use.

Overall, the number of SA-related ED visits increased by 1,533.0% during the study period, from 3,607 in 2006 to 55,296 in 2019. The average annual percentage change was 23.0% (P < .001). The greatest increase occurred from 2015 to 2016, when annual visits increased from 17,709 to 47,732. This increase likely reflected the updated ICD-10 codes, in which there are categories for suspected adult rape, confirmed adult rape, and adult forced sexual exploitation, the researchers note.

Patients presenting to the ED after an SA were mainly women (91.5%). Individuals aged 18-25 years accounted for nearly half of the presentations. Individuals in the lowest and second-lowest income quartiles also were overrepresented.

Despite the increased presentation to EDs, admission rates for SA decreased, from 12.6% to 4.3%, the researchers note. Patients who were older and were insured through Medicaid were more likely to be admitted than persons of other demographic groups.

The researchers also found that increases in ED presentations outpaced increases in SA reports to law enforcement. They compared the ED trends with FBI-reported rapes/SAs from 2015 to 2019 and found increases of 7% and 22% during the times of ICD-9 and ICD-10 codes, respectively. However, in 2019, the number of SA survivors who sought ED care remained below the number who reported to law enforcement (55,296 vs. 139,815, as determined on the basis of revised SA definitions).

“Although the association between increased coding specificity and documentation of SA is still unclear, ICD-10 likely contributed to increased ED documentation of SA,” but the data show steady increases that are independent of the coding change, the researchers write.

The study findings were limited by several factors, including the potential for multiple representations of patients, coding errors associated with the NEDS database, and the reliance on voluntary reports in the NEDS and FBI datasets, the researchers note. The results were strengthened by the large, diverse sample size and by the inclusion of hospital admissions and crime data for comparison, they say.

“As few as 21% of survivors seek medical care after SA, meaning that the survivors captured in this study represent a fraction of total SA-related care need,” the researchers write. “Our finding that most SA ED visits are by young, female, and low-income survivors can inform policy changes to better support these individuals,” which could include the development of outpatient and longitudinal care settings to better serve these populations, they conclude.

Better understanding not only of the trends underlying SA reporting but also of the demographics of survivors who seek treatment and evaluation after SA is vital, said Robert Glatter, MD, in an interview.

“Being able to better understand how social and societal movements affect a patient’s comfort in reporting an SA is vital in tracking the numbers of people who seek care in the ED,” said Dr. Glatter, an emergency medicine physician at Lenox Hill Hospital at Northwell Health, New York, and also of Hofstra University, Hempstead, N.Y.

Dr. Glatter said he was not surprised by the significant increase in sexual assault presentations, especially in light of increased awareness and the influence of the #MeToo movement and other social justice movements over the past decade.

“While I believe that victims of sexual violence may now feel more empowered to report an assault, the volume of SA that go unreported remains a serious public health issue and concern” in the United States and globally, he emphasized.

A key message from the current study is that there is a need for investment in “compassionate and comprehensive care for all survivors of SA,” Dr. Glatter said. “This includes recognition of the extensive mental health consequences of SA that can lead to not only depression, PTSD, and anxiety but also to suicidal ideation and suicide. The longer-term medical effects become life altering, permeating families and future generations,” he emphasized.

“As a society, we must also place a strong emphasis on caring for all SA survivors, but particularly those who come from economically or socially disadvantaged backgrounds who are uninsured or underinsured,” Dr. Glatter said. Issues of race, gender identity, and sexual identity among SA survivors also must be taken into consideration, he added.

“We need to better understand how our health care system can provide more nuanced follow-up care and reporting for survivors in outpatient settings. … Making access easier, while ensuring confidentiality, will allow more survivors of SA to seek treatment and care,” he said. “We also need to understand how using forensic nurses in this capacity, and beyond the ED, can better serve minority and racially diverse communities” and to increase the recruitment and training of such specialized nurses to care for SA victims, Dr. Glatter noted.

The study was supported by internal funding from the University of Michigan and the department of obstetrics and gynecology. Corresponding author Erica C. Marsh, MD, has received personal fees from Myovant Sciences and Pfizer unrelated to the current study. Dr. Glatter has disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.