Transgender youth and young adults suffer a significantly greater burden of mental health conditions and poor mental health outcomes than do nontransgender individuals, known as cisgender individuals, according to a recent study.

“Findings point to the need for gender-affirming mental health services and interventions to support transgender youth,” reported Sari L. Reisner, Sc.D., of Harvard T.H. Chan School of Public Health, Boston (J. Adolesc. Health 2015;56:274-9). “Community-based clinics should be prepared to provide mental health services or referrals for transgender patients.”

Dr. Reisner and his colleagues retrospectively analyzed medical records to compare the mental health outcomes of 106 female-to-male and 74 male-to-female transgender patients, aged 12-29 years, to 180 cisgender controls matched by gender identity, age, race/ethnicity, and visit date at a community health center in Boston between 2002 and 2011.

Cisgender refers to an individual whose self-identified gender identity matches his or her biological sex assigned at birth.

The transgender patients had four times the risk for depression, compared with the matched control patients (50.6% vs. 20.6%; relative risk = 3.95) and more than three times the risk for anxiety (26.7% vs. 10.0%; RR = 3.27), suicide ideation (31.1% vs. 11.1%; RR = 3.61) and suicide attempts (17.2% vs. 6.1%; RR = 3.20). Transgender individuals were more than four times more likely than were cisgender patients to self-harm without suicidal intent (16.7% vs. 4.4%; RR = 4.30).

Overall, 22.8% of transgender patients, compared with 11.1% of cisgender patients, used inpatient mental health care services (RR = 2.36), and 45.6% of transgender patients, compared with 16.1% of cisgender ones, accessed outpatient mental health services (RR = 4.36).

“The elevated mental health burden among transgender youth is hypothesized to result from experiences of social stress such as family rejection, bullying, violence, victimization, and discrimination, which occur due to disadvantaged social status,” all confounders not accounted for if present for these patients, the authors noted. On the other hand, the study’s lack of reliance on a gender identity disorder diagnosis “offers unique comparative data that directly compare the health and well-being of transgender and cisgender youth using a nonpathological perspective of gender variation,” they added.

Other potential limitations of the study were that transgender patients’ greater use of mental health services could have inflated prevalence estimates and that the findings, for an urban population, may not generalize to other geographic or clinical settings.

“Future research is needed to contextualize the mental health concerns of transgender adolescent and emerging adult patients in community-based clinic settings, including prospective assessment of social stressors and mental health symptoms and diagnoses over time,” the authors wrote.

The research was supported by the National Institute of Mental Health and the Eunice Kennedy Shriver National Institute of Child Health and Human Development. The authors reported no relevant financial disclosures.

Transgender youth and young adults suffer a significantly greater burden of mental health conditions and poor mental health outcomes than do nontransgender individuals, known as cisgender individuals, according to a recent study.

“Findings point to the need for gender-affirming mental health services and interventions to support transgender youth,” reported Sari L. Reisner, Sc.D., of Harvard T.H. Chan School of Public Health, Boston (J. Adolesc. Health 2015;56:274-9). “Community-based clinics should be prepared to provide mental health services or referrals for transgender patients.”

Dr. Reisner and his colleagues retrospectively analyzed medical records to compare the mental health outcomes of 106 female-to-male and 74 male-to-female transgender patients, aged 12-29 years, to 180 cisgender controls matched by gender identity, age, race/ethnicity, and visit date at a community health center in Boston between 2002 and 2011.

Cisgender refers to an individual whose self-identified gender identity matches his or her biological sex assigned at birth.

The transgender patients had four times the risk for depression, compared with the matched control patients (50.6% vs. 20.6%; relative risk = 3.95) and more than three times the risk for anxiety (26.7% vs. 10.0%; RR = 3.27), suicide ideation (31.1% vs. 11.1%; RR = 3.61) and suicide attempts (17.2% vs. 6.1%; RR = 3.20). Transgender individuals were more than four times more likely than were cisgender patients to self-harm without suicidal intent (16.7% vs. 4.4%; RR = 4.30).

Overall, 22.8% of transgender patients, compared with 11.1% of cisgender patients, used inpatient mental health care services (RR = 2.36), and 45.6% of transgender patients, compared with 16.1% of cisgender ones, accessed outpatient mental health services (RR = 4.36).

“The elevated mental health burden among transgender youth is hypothesized to result from experiences of social stress such as family rejection, bullying, violence, victimization, and discrimination, which occur due to disadvantaged social status,” all confounders not accounted for if present for these patients, the authors noted. On the other hand, the study’s lack of reliance on a gender identity disorder diagnosis “offers unique comparative data that directly compare the health and well-being of transgender and cisgender youth using a nonpathological perspective of gender variation,” they added.

Other potential limitations of the study were that transgender patients’ greater use of mental health services could have inflated prevalence estimates and that the findings, for an urban population, may not generalize to other geographic or clinical settings.

“Future research is needed to contextualize the mental health concerns of transgender adolescent and emerging adult patients in community-based clinic settings, including prospective assessment of social stressors and mental health symptoms and diagnoses over time,” the authors wrote.

The research was supported by the National Institute of Mental Health and the Eunice Kennedy Shriver National Institute of Child Health and Human Development. The authors reported no relevant financial disclosures.

Transgender youth and young adults suffer a significantly greater burden of mental health conditions and poor mental health outcomes than do nontransgender individuals, known as cisgender individuals, according to a recent study.

“Findings point to the need for gender-affirming mental health services and interventions to support transgender youth,” reported Sari L. Reisner, Sc.D., of Harvard T.H. Chan School of Public Health, Boston (J. Adolesc. Health 2015;56:274-9). “Community-based clinics should be prepared to provide mental health services or referrals for transgender patients.”

Dr. Reisner and his colleagues retrospectively analyzed medical records to compare the mental health outcomes of 106 female-to-male and 74 male-to-female transgender patients, aged 12-29 years, to 180 cisgender controls matched by gender identity, age, race/ethnicity, and visit date at a community health center in Boston between 2002 and 2011.

Cisgender refers to an individual whose self-identified gender identity matches his or her biological sex assigned at birth.

The transgender patients had four times the risk for depression, compared with the matched control patients (50.6% vs. 20.6%; relative risk = 3.95) and more than three times the risk for anxiety (26.7% vs. 10.0%; RR = 3.27), suicide ideation (31.1% vs. 11.1%; RR = 3.61) and suicide attempts (17.2% vs. 6.1%; RR = 3.20). Transgender individuals were more than four times more likely than were cisgender patients to self-harm without suicidal intent (16.7% vs. 4.4%; RR = 4.30).

Overall, 22.8% of transgender patients, compared with 11.1% of cisgender patients, used inpatient mental health care services (RR = 2.36), and 45.6% of transgender patients, compared with 16.1% of cisgender ones, accessed outpatient mental health services (RR = 4.36).

“The elevated mental health burden among transgender youth is hypothesized to result from experiences of social stress such as family rejection, bullying, violence, victimization, and discrimination, which occur due to disadvantaged social status,” all confounders not accounted for if present for these patients, the authors noted. On the other hand, the study’s lack of reliance on a gender identity disorder diagnosis “offers unique comparative data that directly compare the health and well-being of transgender and cisgender youth using a nonpathological perspective of gender variation,” they added.

Other potential limitations of the study were that transgender patients’ greater use of mental health services could have inflated prevalence estimates and that the findings, for an urban population, may not generalize to other geographic or clinical settings.

“Future research is needed to contextualize the mental health concerns of transgender adolescent and emerging adult patients in community-based clinic settings, including prospective assessment of social stressors and mental health symptoms and diagnoses over time,” the authors wrote.

The research was supported by the National Institute of Mental Health and the Eunice Kennedy Shriver National Institute of Child Health and Human Development. The authors reported no relevant financial disclosures.

Lower eyelid malposition is both a cosmetic and functional issue for many patients. It often arises from normal aging; however, it also can be due to thyroid disease, trauma, and surgery (iatrogenic). Correction of lower eyelid malposition requires a variety of surgical approaches to elevate the lower eyelid position. These procedures are not without risk. There have been reports of hyaluronic acid injections being used to help stretch the skin and give support to the sagging eyelid.

Le et al published a study (Ophthal Plast Reconstr Surg. 2014;30:504-507) on the effect of autologous fat injection on lower eyelid position. They performed a retrospective pilot study of autologous fat injections to support the lower eyelid in patients presenting for cosmetic reasons. A retrospective chart review was performed identifying 70 patients that had undergone lower eyelid and malar autologous fat injections for cosmetic improvement performed by a single surgeon. Patients were excluded if they had prior eyelid surgery. Photographs were taken in a standardized fashion and evaluated by 2 blinded evaluators. The measurements evaluated were the lower eyelid position (marginal reflex distance 2 [MRD2]) and inferior scleral show (SS).

The fat was harvested from the inner thigh and knee under tumescent anesthesia, strained, and injected with a 1.2-mm blunt cannula into various planes of the facial soft tissues. Approximately 0 to 2 mL was injected into the tear trough areas and 3 to 7 mL into the malar region, both per side. Photographs were repeated at an average of 117, 125, and 316 days.

Results showed that the MRD2 distance improved 0.5 mm bilaterally and was maintained at 316 days. Similarly, the SS measurement improved by 0.5 mm and was maintained at 125 days. Results improved slightly more in patients who had simultaneous face-lifts, but the difference was not statistically significant.

What’s the issue?

Lower eyelid malposition can make patients appear aged or tired while functionally causing dry eye or excessive tearing. Finding a way to improve this condition without surgery is key because the surgeries are fraught with risk. This study suggests that we should look more critically at lower eyelid positions in our patients who are receiving synthetic fillers or autologous fat to see if we are improving the MRD2 and SS measurements. Have you been seeing an increase in patients seeking improvement for “tired-looking eyes,” or do patients know they look tired but cannot pinpoint why?

We want to know your views! Tell us what you think.

Lower eyelid malposition is both a cosmetic and functional issue for many patients. It often arises from normal aging; however, it also can be due to thyroid disease, trauma, and surgery (iatrogenic). Correction of lower eyelid malposition requires a variety of surgical approaches to elevate the lower eyelid position. These procedures are not without risk. There have been reports of hyaluronic acid injections being used to help stretch the skin and give support to the sagging eyelid.

Le et al published a study (Ophthal Plast Reconstr Surg. 2014;30:504-507) on the effect of autologous fat injection on lower eyelid position. They performed a retrospective pilot study of autologous fat injections to support the lower eyelid in patients presenting for cosmetic reasons. A retrospective chart review was performed identifying 70 patients that had undergone lower eyelid and malar autologous fat injections for cosmetic improvement performed by a single surgeon. Patients were excluded if they had prior eyelid surgery. Photographs were taken in a standardized fashion and evaluated by 2 blinded evaluators. The measurements evaluated were the lower eyelid position (marginal reflex distance 2 [MRD2]) and inferior scleral show (SS).

The fat was harvested from the inner thigh and knee under tumescent anesthesia, strained, and injected with a 1.2-mm blunt cannula into various planes of the facial soft tissues. Approximately 0 to 2 mL was injected into the tear trough areas and 3 to 7 mL into the malar region, both per side. Photographs were repeated at an average of 117, 125, and 316 days.

Results showed that the MRD2 distance improved 0.5 mm bilaterally and was maintained at 316 days. Similarly, the SS measurement improved by 0.5 mm and was maintained at 125 days. Results improved slightly more in patients who had simultaneous face-lifts, but the difference was not statistically significant.

What’s the issue?

Lower eyelid malposition can make patients appear aged or tired while functionally causing dry eye or excessive tearing. Finding a way to improve this condition without surgery is key because the surgeries are fraught with risk. This study suggests that we should look more critically at lower eyelid positions in our patients who are receiving synthetic fillers or autologous fat to see if we are improving the MRD2 and SS measurements. Have you been seeing an increase in patients seeking improvement for “tired-looking eyes,” or do patients know they look tired but cannot pinpoint why?

We want to know your views! Tell us what you think.

Lower eyelid malposition is both a cosmetic and functional issue for many patients. It often arises from normal aging; however, it also can be due to thyroid disease, trauma, and surgery (iatrogenic). Correction of lower eyelid malposition requires a variety of surgical approaches to elevate the lower eyelid position. These procedures are not without risk. There have been reports of hyaluronic acid injections being used to help stretch the skin and give support to the sagging eyelid.

Le et al published a study (Ophthal Plast Reconstr Surg. 2014;30:504-507) on the effect of autologous fat injection on lower eyelid position. They performed a retrospective pilot study of autologous fat injections to support the lower eyelid in patients presenting for cosmetic reasons. A retrospective chart review was performed identifying 70 patients that had undergone lower eyelid and malar autologous fat injections for cosmetic improvement performed by a single surgeon. Patients were excluded if they had prior eyelid surgery. Photographs were taken in a standardized fashion and evaluated by 2 blinded evaluators. The measurements evaluated were the lower eyelid position (marginal reflex distance 2 [MRD2]) and inferior scleral show (SS).

The fat was harvested from the inner thigh and knee under tumescent anesthesia, strained, and injected with a 1.2-mm blunt cannula into various planes of the facial soft tissues. Approximately 0 to 2 mL was injected into the tear trough areas and 3 to 7 mL into the malar region, both per side. Photographs were repeated at an average of 117, 125, and 316 days.

Results showed that the MRD2 distance improved 0.5 mm bilaterally and was maintained at 316 days. Similarly, the SS measurement improved by 0.5 mm and was maintained at 125 days. Results improved slightly more in patients who had simultaneous face-lifts, but the difference was not statistically significant.

What’s the issue?

Lower eyelid malposition can make patients appear aged or tired while functionally causing dry eye or excessive tearing. Finding a way to improve this condition without surgery is key because the surgeries are fraught with risk. This study suggests that we should look more critically at lower eyelid positions in our patients who are receiving synthetic fillers or autologous fat to see if we are improving the MRD2 and SS measurements. Have you been seeing an increase in patients seeking improvement for “tired-looking eyes,” or do patients know they look tired but cannot pinpoint why?

We want to know your views! Tell us what you think.

“Decrease readmissions, and decrease them stat!” This mantra, or some, perhaps more subtle version thereof, is echoed over and over at hospitals across the country, and for good reason. Not only do readmissions have the potential to cost hospital systems millions of dollars through Medicare payment reductions, they also signal a more important, though less vocalized concern. If our patients keep returning to the hospital, are we really providing them with 100% of the resources they need?

On the surface, it may seem like there is little we can do for that two-pack-per-day smoker with end-stage chronic obstructive pulmonary disease who keeps getting readmitted with an exacerbation. And, while in reality, we may never get him to stop smoking and start taking his mediations as prescribed, perhaps we can help decrease the frequency of readmissions from three to four per year to two to three. While seemingly small, this decrease is actually quite dramatic, correlating to a 25%-50% reduction in the use of hospital services, not to mention the profound impact that fewer days spent in the hospital will have on his quality of life.

It is remarkable how much change occurs in the health care system over time. One year a drug may be touted as a huge breakthrough in treatment, and the next it may be taken off the market because of previously unrecognized, potentially fatal side effects. And just as the field of medicine is ever changing, so are all the fields that support it.

For example, the Agency for Healthcare Research and Qualify (AHRQ) has developed the Re-Engineered Discharge (RED) tool kit, which has been highly successful in reducing hospital readmissions. Originally developed by a group of AHRQ-funded researchers in Boston, RED provides evidence-based tools that help hospitals re-engineer their discharge process. One success story – within 3 months of implementing RED, the Valley Baptist Medical Center in Harlingen, Tex., decreased readmissions from 26% to 15%.

The RED model focuses on comprehensive discharge planning, educating patients about their discharge, and postdischarge follow-up care. It uses dedicated discharge advocates to help patients reconcile their medications and schedule much-needed follow-up appointments.

Other models exist as well. For instance, some hospitals have a palliative care team that focuses not only on keeping patients comfortable while in the hospital, but also on helping them access community services after discharge and make necessary appointments, geared at optimizing their health and ultimately decreasing the need for excessive hospitalizations.

As every health care dollar spent will be scrutinized more and more over time, innovative programs to help us rethink our long-established routines will likely play a major role in catapulting us from where we are to where we want to be.

Dr. Hester is a hospitalist at Baltimore-Washington Medical Center in Glen Burnie, Md. She is the creator of the Patient Whiz, a patient-engagement app for iOS. Reach her at healthsavvy@aol.com.

“Decrease readmissions, and decrease them stat!” This mantra, or some, perhaps more subtle version thereof, is echoed over and over at hospitals across the country, and for good reason. Not only do readmissions have the potential to cost hospital systems millions of dollars through Medicare payment reductions, they also signal a more important, though less vocalized concern. If our patients keep returning to the hospital, are we really providing them with 100% of the resources they need?

On the surface, it may seem like there is little we can do for that two-pack-per-day smoker with end-stage chronic obstructive pulmonary disease who keeps getting readmitted with an exacerbation. And, while in reality, we may never get him to stop smoking and start taking his mediations as prescribed, perhaps we can help decrease the frequency of readmissions from three to four per year to two to three. While seemingly small, this decrease is actually quite dramatic, correlating to a 25%-50% reduction in the use of hospital services, not to mention the profound impact that fewer days spent in the hospital will have on his quality of life.

It is remarkable how much change occurs in the health care system over time. One year a drug may be touted as a huge breakthrough in treatment, and the next it may be taken off the market because of previously unrecognized, potentially fatal side effects. And just as the field of medicine is ever changing, so are all the fields that support it.

For example, the Agency for Healthcare Research and Qualify (AHRQ) has developed the Re-Engineered Discharge (RED) tool kit, which has been highly successful in reducing hospital readmissions. Originally developed by a group of AHRQ-funded researchers in Boston, RED provides evidence-based tools that help hospitals re-engineer their discharge process. One success story – within 3 months of implementing RED, the Valley Baptist Medical Center in Harlingen, Tex., decreased readmissions from 26% to 15%.

The RED model focuses on comprehensive discharge planning, educating patients about their discharge, and postdischarge follow-up care. It uses dedicated discharge advocates to help patients reconcile their medications and schedule much-needed follow-up appointments.

Other models exist as well. For instance, some hospitals have a palliative care team that focuses not only on keeping patients comfortable while in the hospital, but also on helping them access community services after discharge and make necessary appointments, geared at optimizing their health and ultimately decreasing the need for excessive hospitalizations.

As every health care dollar spent will be scrutinized more and more over time, innovative programs to help us rethink our long-established routines will likely play a major role in catapulting us from where we are to where we want to be.

Dr. Hester is a hospitalist at Baltimore-Washington Medical Center in Glen Burnie, Md. She is the creator of the Patient Whiz, a patient-engagement app for iOS. Reach her at healthsavvy@aol.com.

“Decrease readmissions, and decrease them stat!” This mantra, or some, perhaps more subtle version thereof, is echoed over and over at hospitals across the country, and for good reason. Not only do readmissions have the potential to cost hospital systems millions of dollars through Medicare payment reductions, they also signal a more important, though less vocalized concern. If our patients keep returning to the hospital, are we really providing them with 100% of the resources they need?

On the surface, it may seem like there is little we can do for that two-pack-per-day smoker with end-stage chronic obstructive pulmonary disease who keeps getting readmitted with an exacerbation. And, while in reality, we may never get him to stop smoking and start taking his mediations as prescribed, perhaps we can help decrease the frequency of readmissions from three to four per year to two to three. While seemingly small, this decrease is actually quite dramatic, correlating to a 25%-50% reduction in the use of hospital services, not to mention the profound impact that fewer days spent in the hospital will have on his quality of life.

It is remarkable how much change occurs in the health care system over time. One year a drug may be touted as a huge breakthrough in treatment, and the next it may be taken off the market because of previously unrecognized, potentially fatal side effects. And just as the field of medicine is ever changing, so are all the fields that support it.

For example, the Agency for Healthcare Research and Qualify (AHRQ) has developed the Re-Engineered Discharge (RED) tool kit, which has been highly successful in reducing hospital readmissions. Originally developed by a group of AHRQ-funded researchers in Boston, RED provides evidence-based tools that help hospitals re-engineer their discharge process. One success story – within 3 months of implementing RED, the Valley Baptist Medical Center in Harlingen, Tex., decreased readmissions from 26% to 15%.

The RED model focuses on comprehensive discharge planning, educating patients about their discharge, and postdischarge follow-up care. It uses dedicated discharge advocates to help patients reconcile their medications and schedule much-needed follow-up appointments.

Other models exist as well. For instance, some hospitals have a palliative care team that focuses not only on keeping patients comfortable while in the hospital, but also on helping them access community services after discharge and make necessary appointments, geared at optimizing their health and ultimately decreasing the need for excessive hospitalizations.

As every health care dollar spent will be scrutinized more and more over time, innovative programs to help us rethink our long-established routines will likely play a major role in catapulting us from where we are to where we want to be.

Dr. Hester is a hospitalist at Baltimore-Washington Medical Center in Glen Burnie, Md. She is the creator of the Patient Whiz, a patient-engagement app for iOS. Reach her at healthsavvy@aol.com.

VIENNA – Sonothrombolysis proved to be an effective alternative to endovascular treatment in patients with large intracranial occlusions, but clot removal via a retrievable stent appeared to have the edge when it came to achieving a good functional outcome, according to data presented at the annual European Stroke Conference.

In the first head-to-head comparison of the two strategies, there was no difference in the primary end point of the final modified Rankin Scale (mRS) score at the end of neurorehabilitation or death within 90 days. The mean final mRS was 3.78 with endovascular treatment and 3.95 with sonothrombolysis, with a nonsignificant (P = .12) odds ratio of 1.70 favoring the noninvasive procedure.

However, patients who underwent endovascular therapy were 3.89 times more likely than were those who had sonothrombolysis to achieve the secondary end point of a good functional outcome defined as a final mRS of 0-2 (24.7% vs. 13.6%; P = .02). Early recanalization was also possible in more patients with endovascular therapy than with sonothrombolysis (82.2% vs. 32.2%; OR, 15.77; P < .001).

“At the moment, everything veers toward using stent retrieval with thrombectomy, which requires very high costs at present and cannot be performed in every center,” noted study investigator Matthias Reinhard of the University Medical Center Freiburg (Germany) in an interview. On the other hand, Dr. Reinhard said, “sonothrombolysis is much less invasive and does not need specific interventionists, and it can be done with normal ultrasound devices, which are already available in every stroke unit.”

Sonothrombolysis enhances the thrombolytic activity of recombinant tissue plasminogen activator (rTPA) near to the clot, he explained, and has been shown in a Cochrane review to double the odds for functional independence, as well as upping the chances for recanalization around threefold (Cochrane Database Syst. Rev. 2012;10:CD008348). This is on a par with the results obtained with endovascular treatment in recent trials.

Since the two methods for enhancing thrombolysis with rTPA had not been directly compared before, Dr. Reinhard and his associates decided to look back at the medical records of patients with acute anterior circulation stroke with M1 or carotid T occlusion who were treated at two adjacent medical centers that used one or other of the methods as a standard treatment. After thrombolysis with rTPA, patients at one center underwent endovascular treatment with stent retrieval while patients at the other center had sonothrombolysis.

A total of 132 patients were assessed: 73 underwent endovascular treatment and 59 had sonothrombolysis. The median age in each group was 71 and 75 years, respectively, with around half the participants in each group being male. The groups had similar mean National Institutes of Health Stroke Scale scores (15 and 13). The majority of patients in each group had M1 vessel occlusions (60% and 69%) with the remainder (40% and 31%) having carotid T vessel occlusions. The mean onset to rTPA was 117 minutes and 105 minutes, respectively.

Subgroup analysis showed a significant benefit for endovascular treatment over sonothrombolysis in patients with carotid T occlusions, with an adjusted OR of 5.61 (P = .008). However, the two methods were comparable (OR, 1.07; P = .880) in patients with M1 occlusions.

“The main finding was that sonothrombolysis might perhaps be as equally effective as endovascular treatment in moderate-size occlusions such as middle cerebral artery occlusions but not in the very proximal occlusions of the carotid T,” Dr. Reinhard said. “So, one strategy might be to first apply sonothrombolysis and if this does not work, then to move the patient to the endovascular treatment,” he suggested, noting that this might be a better strategy to test in a future clinical trial than directly comparing the methods in a larger number of patients.

In terms of safety, there was no significant advantage of using one procedure over the other, despite three (4.1%) patients in the endovascular group and none in the sonothrombolysis group experiencing symptomatic intracranial hemorrhage (P = .25). Type 1 parenchymal hematomas were more common in patients who had sonothrombolysis than in those who had endovascular therapy (15.3% vs. 5.5%, P = .09). Mortality at 90 days was around 20% in both groups.

Dr. Reinhard had no disclosures.

VIENNA – Sonothrombolysis proved to be an effective alternative to endovascular treatment in patients with large intracranial occlusions, but clot removal via a retrievable stent appeared to have the edge when it came to achieving a good functional outcome, according to data presented at the annual European Stroke Conference.

In the first head-to-head comparison of the two strategies, there was no difference in the primary end point of the final modified Rankin Scale (mRS) score at the end of neurorehabilitation or death within 90 days. The mean final mRS was 3.78 with endovascular treatment and 3.95 with sonothrombolysis, with a nonsignificant (P = .12) odds ratio of 1.70 favoring the noninvasive procedure.

However, patients who underwent endovascular therapy were 3.89 times more likely than were those who had sonothrombolysis to achieve the secondary end point of a good functional outcome defined as a final mRS of 0-2 (24.7% vs. 13.6%; P = .02). Early recanalization was also possible in more patients with endovascular therapy than with sonothrombolysis (82.2% vs. 32.2%; OR, 15.77; P < .001).

“At the moment, everything veers toward using stent retrieval with thrombectomy, which requires very high costs at present and cannot be performed in every center,” noted study investigator Matthias Reinhard of the University Medical Center Freiburg (Germany) in an interview. On the other hand, Dr. Reinhard said, “sonothrombolysis is much less invasive and does not need specific interventionists, and it can be done with normal ultrasound devices, which are already available in every stroke unit.”

Sonothrombolysis enhances the thrombolytic activity of recombinant tissue plasminogen activator (rTPA) near to the clot, he explained, and has been shown in a Cochrane review to double the odds for functional independence, as well as upping the chances for recanalization around threefold (Cochrane Database Syst. Rev. 2012;10:CD008348). This is on a par with the results obtained with endovascular treatment in recent trials.

Since the two methods for enhancing thrombolysis with rTPA had not been directly compared before, Dr. Reinhard and his associates decided to look back at the medical records of patients with acute anterior circulation stroke with M1 or carotid T occlusion who were treated at two adjacent medical centers that used one or other of the methods as a standard treatment. After thrombolysis with rTPA, patients at one center underwent endovascular treatment with stent retrieval while patients at the other center had sonothrombolysis.

A total of 132 patients were assessed: 73 underwent endovascular treatment and 59 had sonothrombolysis. The median age in each group was 71 and 75 years, respectively, with around half the participants in each group being male. The groups had similar mean National Institutes of Health Stroke Scale scores (15 and 13). The majority of patients in each group had M1 vessel occlusions (60% and 69%) with the remainder (40% and 31%) having carotid T vessel occlusions. The mean onset to rTPA was 117 minutes and 105 minutes, respectively.

Subgroup analysis showed a significant benefit for endovascular treatment over sonothrombolysis in patients with carotid T occlusions, with an adjusted OR of 5.61 (P = .008). However, the two methods were comparable (OR, 1.07; P = .880) in patients with M1 occlusions.

“The main finding was that sonothrombolysis might perhaps be as equally effective as endovascular treatment in moderate-size occlusions such as middle cerebral artery occlusions but not in the very proximal occlusions of the carotid T,” Dr. Reinhard said. “So, one strategy might be to first apply sonothrombolysis and if this does not work, then to move the patient to the endovascular treatment,” he suggested, noting that this might be a better strategy to test in a future clinical trial than directly comparing the methods in a larger number of patients.

In terms of safety, there was no significant advantage of using one procedure over the other, despite three (4.1%) patients in the endovascular group and none in the sonothrombolysis group experiencing symptomatic intracranial hemorrhage (P = .25). Type 1 parenchymal hematomas were more common in patients who had sonothrombolysis than in those who had endovascular therapy (15.3% vs. 5.5%, P = .09). Mortality at 90 days was around 20% in both groups.

Dr. Reinhard had no disclosures.

VIENNA – Sonothrombolysis proved to be an effective alternative to endovascular treatment in patients with large intracranial occlusions, but clot removal via a retrievable stent appeared to have the edge when it came to achieving a good functional outcome, according to data presented at the annual European Stroke Conference.

In the first head-to-head comparison of the two strategies, there was no difference in the primary end point of the final modified Rankin Scale (mRS) score at the end of neurorehabilitation or death within 90 days. The mean final mRS was 3.78 with endovascular treatment and 3.95 with sonothrombolysis, with a nonsignificant (P = .12) odds ratio of 1.70 favoring the noninvasive procedure.

However, patients who underwent endovascular therapy were 3.89 times more likely than were those who had sonothrombolysis to achieve the secondary end point of a good functional outcome defined as a final mRS of 0-2 (24.7% vs. 13.6%; P = .02). Early recanalization was also possible in more patients with endovascular therapy than with sonothrombolysis (82.2% vs. 32.2%; OR, 15.77; P < .001).

“At the moment, everything veers toward using stent retrieval with thrombectomy, which requires very high costs at present and cannot be performed in every center,” noted study investigator Matthias Reinhard of the University Medical Center Freiburg (Germany) in an interview. On the other hand, Dr. Reinhard said, “sonothrombolysis is much less invasive and does not need specific interventionists, and it can be done with normal ultrasound devices, which are already available in every stroke unit.”

Sonothrombolysis enhances the thrombolytic activity of recombinant tissue plasminogen activator (rTPA) near to the clot, he explained, and has been shown in a Cochrane review to double the odds for functional independence, as well as upping the chances for recanalization around threefold (Cochrane Database Syst. Rev. 2012;10:CD008348). This is on a par with the results obtained with endovascular treatment in recent trials.

Since the two methods for enhancing thrombolysis with rTPA had not been directly compared before, Dr. Reinhard and his associates decided to look back at the medical records of patients with acute anterior circulation stroke with M1 or carotid T occlusion who were treated at two adjacent medical centers that used one or other of the methods as a standard treatment. After thrombolysis with rTPA, patients at one center underwent endovascular treatment with stent retrieval while patients at the other center had sonothrombolysis.

A total of 132 patients were assessed: 73 underwent endovascular treatment and 59 had sonothrombolysis. The median age in each group was 71 and 75 years, respectively, with around half the participants in each group being male. The groups had similar mean National Institutes of Health Stroke Scale scores (15 and 13). The majority of patients in each group had M1 vessel occlusions (60% and 69%) with the remainder (40% and 31%) having carotid T vessel occlusions. The mean onset to rTPA was 117 minutes and 105 minutes, respectively.

Subgroup analysis showed a significant benefit for endovascular treatment over sonothrombolysis in patients with carotid T occlusions, with an adjusted OR of 5.61 (P = .008). However, the two methods were comparable (OR, 1.07; P = .880) in patients with M1 occlusions.

“The main finding was that sonothrombolysis might perhaps be as equally effective as endovascular treatment in moderate-size occlusions such as middle cerebral artery occlusions but not in the very proximal occlusions of the carotid T,” Dr. Reinhard said. “So, one strategy might be to first apply sonothrombolysis and if this does not work, then to move the patient to the endovascular treatment,” he suggested, noting that this might be a better strategy to test in a future clinical trial than directly comparing the methods in a larger number of patients.

In terms of safety, there was no significant advantage of using one procedure over the other, despite three (4.1%) patients in the endovascular group and none in the sonothrombolysis group experiencing symptomatic intracranial hemorrhage (P = .25). Type 1 parenchymal hematomas were more common in patients who had sonothrombolysis than in those who had endovascular therapy (15.3% vs. 5.5%, P = .09). Mortality at 90 days was around 20% in both groups.

Dr. Reinhard had no disclosures.

Brief cognitive screening is essential for assessing neurocognitive disor­ders. Such screening can give clini­cians a snapshot of patients’ cognitive abilities across a range of disorders and help tailor interventions to yield better outcomes. Appropriate administration of a brief cognitive screening using telehealth technology can improve access to care and treatment planning.

Neurocognitive decline can be a barrier to treatment
Persons with neurocognitive impairment, regardless of the cause, often face barriers when they seek treatment. Memory and attention difficulties often interfere with attending appointments; driving restric­tions, smaller social networks, caregiver burden, and medical conditions limit access to care. For such patients, tele­health assessment is a tool that physicians can use to help patients overcome these barriers.

Cognitive screening tools
Brief cognitive assessments need to dem­onstrate (1) consistent and accurate scores over time (reliability) and (2) that they are measuring the intended cognitive domain (validity). The Mini-Mental State Examination is used often; the Montreal Cognitive Assessment and the Short Blessed Test are additional cognitive screeners that have support in the literature for use with telehealth technology.¹

Telehealth assessment modalities
Modalities for telehealth assessment² include:
   • Audio-based systems. Pro: Telephone-based telehealth screening usually does not require extra equipment or advanced planning. Con: Visual information is absent and there is overreliance on verbal tasks.
   • Video-based systems. Pro: Using video­phones or video conferencing systems allow physicians to observe patients’ behaviors and their ability to complete tasks on paper. Con: A video system often requires more planning and effort to set up than other types of systems.
   • Web-based systems. Pro: Web sites on which patient and provider can interact in real time—through a combination of audio, video, and programmed applications—offer immediate access to a patient’s responses and test results, thus providing a wealth of clinical information such as exact timing and calculation of patients’ responses, abil­ity to record and review patients’ approach to construction tasks, and the capability to adapt test batteries in real-time based on patients’ ongoing performance. Con: Such systems require specialized software and infrastructure.

Support for telehealth screening
Our patients report feeling comfortable with telehealth screening; they overwhelmingly report that they prefer telehealth services to in-person services that require travel. Studies on the reliability and validity of using cog­nitive screeners have shown that telehealth screening is a feasible and acceptable prac­tice.³ Although the telehealth approaches mentioned here can all be used effectively, we have found that video-based cognitive screening might offer the best balance of flexibility, accessibility, and ease of use at this time.

Our recommendations
Consider your resources, patient popula­tion, and the scope of available telehealth services to guide your approach. Use vali­dated measures that fit the limitations of the modality you have chosen:
   • Telephone-based screenings should use verbally based measures (eg, the Short Blessed Test and the Telephone Interview for Cognitive Status).
   • Video-based screenings can include visual elements, but you need to decide how to best administer, record, and score the patient’s written responses. You might need to mail portions of tests along with a writing utensil and paper to their home. Patients can hold up their responses to the camera or send back the completed tests for scoring.
   • Adapt testing to the constraints of a particular situation, but modifications to tests should be limited as much as possible to minimize decreases in reliability and validity.
   • Have a clear policy for dealing with unexpected events, such as technological malfunctions, patient privacy concerns, and mental health emergencies.

Acknowledgement
This article was supported by the facilities and resources of the Salem VA Medical Center. The views expressed in this article are those of the authors and not necessarily those of the Department of Veterans Affairs.

Disclosures
The authors report no financial relationships with any company whose products are mentioned in this article or wiith manufacturers of competing products.

Brief cognitive screening is essential for assessing neurocognitive disor­ders. Such screening can give clini­cians a snapshot of patients’ cognitive abilities across a range of disorders and help tailor interventions to yield better outcomes. Appropriate administration of a brief cognitive screening using telehealth technology can improve access to care and treatment planning.

Neurocognitive decline can be a barrier to treatment
Persons with neurocognitive impairment, regardless of the cause, often face barriers when they seek treatment. Memory and attention difficulties often interfere with attending appointments; driving restric­tions, smaller social networks, caregiver burden, and medical conditions limit access to care. For such patients, tele­health assessment is a tool that physicians can use to help patients overcome these barriers.

Cognitive screening tools
Brief cognitive assessments need to dem­onstrate (1) consistent and accurate scores over time (reliability) and (2) that they are measuring the intended cognitive domain (validity). The Mini-Mental State Examination is used often; the Montreal Cognitive Assessment and the Short Blessed Test are additional cognitive screeners that have support in the literature for use with telehealth technology.¹

Telehealth assessment modalities
Modalities for telehealth assessment² include:
   • Audio-based systems. Pro: Telephone-based telehealth screening usually does not require extra equipment or advanced planning. Con: Visual information is absent and there is overreliance on verbal tasks.
   • Video-based systems. Pro: Using video­phones or video conferencing systems allow physicians to observe patients’ behaviors and their ability to complete tasks on paper. Con: A video system often requires more planning and effort to set up than other types of systems.
   • Web-based systems. Pro: Web sites on which patient and provider can interact in real time—through a combination of audio, video, and programmed applications—offer immediate access to a patient’s responses and test results, thus providing a wealth of clinical information such as exact timing and calculation of patients’ responses, abil­ity to record and review patients’ approach to construction tasks, and the capability to adapt test batteries in real-time based on patients’ ongoing performance. Con: Such systems require specialized software and infrastructure.

Support for telehealth screening
Our patients report feeling comfortable with telehealth screening; they overwhelmingly report that they prefer telehealth services to in-person services that require travel. Studies on the reliability and validity of using cog­nitive screeners have shown that telehealth screening is a feasible and acceptable prac­tice.³ Although the telehealth approaches mentioned here can all be used effectively, we have found that video-based cognitive screening might offer the best balance of flexibility, accessibility, and ease of use at this time.

Our recommendations
Consider your resources, patient popula­tion, and the scope of available telehealth services to guide your approach. Use vali­dated measures that fit the limitations of the modality you have chosen:
   • Telephone-based screenings should use verbally based measures (eg, the Short Blessed Test and the Telephone Interview for Cognitive Status).
   • Video-based screenings can include visual elements, but you need to decide how to best administer, record, and score the patient’s written responses. You might need to mail portions of tests along with a writing utensil and paper to their home. Patients can hold up their responses to the camera or send back the completed tests for scoring.
   • Adapt testing to the constraints of a particular situation, but modifications to tests should be limited as much as possible to minimize decreases in reliability and validity.
   • Have a clear policy for dealing with unexpected events, such as technological malfunctions, patient privacy concerns, and mental health emergencies.

Acknowledgement
This article was supported by the facilities and resources of the Salem VA Medical Center. The views expressed in this article are those of the authors and not necessarily those of the Department of Veterans Affairs.

Disclosures
The authors report no financial relationships with any company whose products are mentioned in this article or wiith manufacturers of competing products.

Brief cognitive screening is essential for assessing neurocognitive disor­ders. Such screening can give clini­cians a snapshot of patients’ cognitive abilities across a range of disorders and help tailor interventions to yield better outcomes. Appropriate administration of a brief cognitive screening using telehealth technology can improve access to care and treatment planning.

Neurocognitive decline can be a barrier to treatment
Persons with neurocognitive impairment, regardless of the cause, often face barriers when they seek treatment. Memory and attention difficulties often interfere with attending appointments; driving restric­tions, smaller social networks, caregiver burden, and medical conditions limit access to care. For such patients, tele­health assessment is a tool that physicians can use to help patients overcome these barriers.

Cognitive screening tools
Brief cognitive assessments need to dem­onstrate (1) consistent and accurate scores over time (reliability) and (2) that they are measuring the intended cognitive domain (validity). The Mini-Mental State Examination is used often; the Montreal Cognitive Assessment and the Short Blessed Test are additional cognitive screeners that have support in the literature for use with telehealth technology.¹

Telehealth assessment modalities
Modalities for telehealth assessment² include:
   • Audio-based systems. Pro: Telephone-based telehealth screening usually does not require extra equipment or advanced planning. Con: Visual information is absent and there is overreliance on verbal tasks.
   • Video-based systems. Pro: Using video­phones or video conferencing systems allow physicians to observe patients’ behaviors and their ability to complete tasks on paper. Con: A video system often requires more planning and effort to set up than other types of systems.
   • Web-based systems. Pro: Web sites on which patient and provider can interact in real time—through a combination of audio, video, and programmed applications—offer immediate access to a patient’s responses and test results, thus providing a wealth of clinical information such as exact timing and calculation of patients’ responses, abil­ity to record and review patients’ approach to construction tasks, and the capability to adapt test batteries in real-time based on patients’ ongoing performance. Con: Such systems require specialized software and infrastructure.

Support for telehealth screening
Our patients report feeling comfortable with telehealth screening; they overwhelmingly report that they prefer telehealth services to in-person services that require travel. Studies on the reliability and validity of using cog­nitive screeners have shown that telehealth screening is a feasible and acceptable prac­tice.³ Although the telehealth approaches mentioned here can all be used effectively, we have found that video-based cognitive screening might offer the best balance of flexibility, accessibility, and ease of use at this time.

Our recommendations
Consider your resources, patient popula­tion, and the scope of available telehealth services to guide your approach. Use vali­dated measures that fit the limitations of the modality you have chosen:
   • Telephone-based screenings should use verbally based measures (eg, the Short Blessed Test and the Telephone Interview for Cognitive Status).
   • Video-based screenings can include visual elements, but you need to decide how to best administer, record, and score the patient’s written responses. You might need to mail portions of tests along with a writing utensil and paper to their home. Patients can hold up their responses to the camera or send back the completed tests for scoring.
   • Adapt testing to the constraints of a particular situation, but modifications to tests should be limited as much as possible to minimize decreases in reliability and validity.
   • Have a clear policy for dealing with unexpected events, such as technological malfunctions, patient privacy concerns, and mental health emergencies.

Acknowledgement
This article was supported by the facilities and resources of the Salem VA Medical Center. The views expressed in this article are those of the authors and not necessarily those of the Department of Veterans Affairs.

Disclosures
The authors report no financial relationships with any company whose products are mentioned in this article or wiith manufacturers of competing products.

Psychiatric providers often encounter older adult patients who report dif­ficulty with memory and express the fear they are “developing dementia.” Often, after a thorough evaluation of the reported deficits and history, we find that a serious or progressive neurocognitive disorder is unlikely. However, such occasions are an opportunity to discuss lifestyle changes that may help prevent, or at least slow, development of later-life cognitive decline.

Although I inform my patients that the body of evidence supporting many of these preventive measures still is evolving, I suggest the following approach that may provide a DEFENSE against future cogni­tive disability.

Diet options that are “heart healthy” seem to be “brain healthy” as well. This may be due, in part, to the antioxidant and anti-inflammatory effects of particular foods.¹ Therefore, I suggest patients try to implement a Mediterranean-type diet that emphasizes fish (especially those rich in omega-3 fats, such as salmon and tuna), poultry, fresh fruit, and vegetables, as well as legumes.

ETOH has been shown, in a moderate amount (eg, 1 drink a day for women and 1 to 2 drinks for men), to be brain protec­tive because of the antioxidants found in the alcohol or the direct relaxation effects that are produced—or both. Although red wine often is recommended, recent stud­ies have shown that those who enjoyed an active life into their 70s and 80s had consumed a moderate amount of alcohol over their lifetime regardless of the type of spirit (eg, 12 oz of beer, 4 oz of wine, 1 oz of hard liquor).²

Friends contribute to an active, stimulating, and emotionally supported life. Having a strong social network, an antidote to lone­liness and depression, has been shown to reduce the risk of “turning on” specific genes that stimulate an inflammatory process that can lead to brain cell death and neural damage.³

Exercise might be the most important ingre­dient for a longer, healthier, and more cogni­tively intact life. Moderate exercise, several times a week, increases blood flow to the brain and, subsequently, stimulates neuronal synapses and the hippocampus.⁴ The forms of exercise include walking, biking, swimming, resistance training, and even gardening.

No tobacco! It is known that smoking leads to accelerated aging for the heart and brain, so it is our responsibility to remain vigilant in promoting smoking cessation strategies.

Sleep has received increased attention, with recent studies providing evidence that the brain uses that time to “flush out” neurotoxic by-products of cognitive activity that have accumulated throughout the day.⁵ As evi­dence continues to be examined on this pro­cess, it is reasonable to recommend adequate sleep and a consistent sleep pattern as pos­sible defenses against brain cell insult.

Engagement in tasks that are cognitively stimulating has been promoted as potential “brain exercises” to stave off future memory loss. For example, computer games that are mentally challenging; lively and frequent conversations; and learning a language all appear to increase neural activation and communication throughout the brain.⁶

As brain research continues to expand, providers will become more knowledgeable and aware of the steps our patients can take when they discuss concerns about their risk of progressive cognitive disability and mem­ory loss. For now, however, it is important to describe what we do know based on cur­rent research and help our patients develop the best defense they can against age-related cognitive decline.

Disclosure
The author reports no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

Psychiatric providers often encounter older adult patients who report dif­ficulty with memory and express the fear they are “developing dementia.” Often, after a thorough evaluation of the reported deficits and history, we find that a serious or progressive neurocognitive disorder is unlikely. However, such occasions are an opportunity to discuss lifestyle changes that may help prevent, or at least slow, development of later-life cognitive decline.

Although I inform my patients that the body of evidence supporting many of these preventive measures still is evolving, I suggest the following approach that may provide a DEFENSE against future cogni­tive disability.

Diet options that are “heart healthy” seem to be “brain healthy” as well. This may be due, in part, to the antioxidant and anti-inflammatory effects of particular foods.¹ Therefore, I suggest patients try to implement a Mediterranean-type diet that emphasizes fish (especially those rich in omega-3 fats, such as salmon and tuna), poultry, fresh fruit, and vegetables, as well as legumes.

ETOH has been shown, in a moderate amount (eg, 1 drink a day for women and 1 to 2 drinks for men), to be brain protec­tive because of the antioxidants found in the alcohol or the direct relaxation effects that are produced—or both. Although red wine often is recommended, recent stud­ies have shown that those who enjoyed an active life into their 70s and 80s had consumed a moderate amount of alcohol over their lifetime regardless of the type of spirit (eg, 12 oz of beer, 4 oz of wine, 1 oz of hard liquor).²

Friends contribute to an active, stimulating, and emotionally supported life. Having a strong social network, an antidote to lone­liness and depression, has been shown to reduce the risk of “turning on” specific genes that stimulate an inflammatory process that can lead to brain cell death and neural damage.³

Exercise might be the most important ingre­dient for a longer, healthier, and more cogni­tively intact life. Moderate exercise, several times a week, increases blood flow to the brain and, subsequently, stimulates neuronal synapses and the hippocampus.⁴ The forms of exercise include walking, biking, swimming, resistance training, and even gardening.

No tobacco! It is known that smoking leads to accelerated aging for the heart and brain, so it is our responsibility to remain vigilant in promoting smoking cessation strategies.

Sleep has received increased attention, with recent studies providing evidence that the brain uses that time to “flush out” neurotoxic by-products of cognitive activity that have accumulated throughout the day.⁵ As evi­dence continues to be examined on this pro­cess, it is reasonable to recommend adequate sleep and a consistent sleep pattern as pos­sible defenses against brain cell insult.

Engagement in tasks that are cognitively stimulating has been promoted as potential “brain exercises” to stave off future memory loss. For example, computer games that are mentally challenging; lively and frequent conversations; and learning a language all appear to increase neural activation and communication throughout the brain.⁶

As brain research continues to expand, providers will become more knowledgeable and aware of the steps our patients can take when they discuss concerns about their risk of progressive cognitive disability and mem­ory loss. For now, however, it is important to describe what we do know based on cur­rent research and help our patients develop the best defense they can against age-related cognitive decline.

Disclosure
The author reports no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

Psychiatric providers often encounter older adult patients who report dif­ficulty with memory and express the fear they are “developing dementia.” Often, after a thorough evaluation of the reported deficits and history, we find that a serious or progressive neurocognitive disorder is unlikely. However, such occasions are an opportunity to discuss lifestyle changes that may help prevent, or at least slow, development of later-life cognitive decline.

Although I inform my patients that the body of evidence supporting many of these preventive measures still is evolving, I suggest the following approach that may provide a DEFENSE against future cogni­tive disability.

Diet options that are “heart healthy” seem to be “brain healthy” as well. This may be due, in part, to the antioxidant and anti-inflammatory effects of particular foods.¹ Therefore, I suggest patients try to implement a Mediterranean-type diet that emphasizes fish (especially those rich in omega-3 fats, such as salmon and tuna), poultry, fresh fruit, and vegetables, as well as legumes.

ETOH has been shown, in a moderate amount (eg, 1 drink a day for women and 1 to 2 drinks for men), to be brain protec­tive because of the antioxidants found in the alcohol or the direct relaxation effects that are produced—or both. Although red wine often is recommended, recent stud­ies have shown that those who enjoyed an active life into their 70s and 80s had consumed a moderate amount of alcohol over their lifetime regardless of the type of spirit (eg, 12 oz of beer, 4 oz of wine, 1 oz of hard liquor).²

Friends contribute to an active, stimulating, and emotionally supported life. Having a strong social network, an antidote to lone­liness and depression, has been shown to reduce the risk of “turning on” specific genes that stimulate an inflammatory process that can lead to brain cell death and neural damage.³

Exercise might be the most important ingre­dient for a longer, healthier, and more cogni­tively intact life. Moderate exercise, several times a week, increases blood flow to the brain and, subsequently, stimulates neuronal synapses and the hippocampus.⁴ The forms of exercise include walking, biking, swimming, resistance training, and even gardening.

No tobacco! It is known that smoking leads to accelerated aging for the heart and brain, so it is our responsibility to remain vigilant in promoting smoking cessation strategies.

Sleep has received increased attention, with recent studies providing evidence that the brain uses that time to “flush out” neurotoxic by-products of cognitive activity that have accumulated throughout the day.⁵ As evi­dence continues to be examined on this pro­cess, it is reasonable to recommend adequate sleep and a consistent sleep pattern as pos­sible defenses against brain cell insult.

Engagement in tasks that are cognitively stimulating has been promoted as potential “brain exercises” to stave off future memory loss. For example, computer games that are mentally challenging; lively and frequent conversations; and learning a language all appear to increase neural activation and communication throughout the brain.⁶

As brain research continues to expand, providers will become more knowledgeable and aware of the steps our patients can take when they discuss concerns about their risk of progressive cognitive disability and mem­ory loss. For now, however, it is important to describe what we do know based on cur­rent research and help our patients develop the best defense they can against age-related cognitive decline.

Disclosure
The author reports no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

CASE Light-headed
Mr. M, age 73, is a retired project manager who feels light-headed while walking his dog, causing him to go to the emergency depart­ment. His history is significant for hyperten­sion, coronary artery disease (CAD), 3-vessel coronary artery bypass graft surgery (CABG), hyperlipidemia, erectile dysfunction, open-angle glaucoma, hemiretinal vein occlusion, symptoms suggesting rapid eye-movement behavior disorder (RBD), and major depressive disorder (MDD).

The psychiatry consultation-liaison service is asked to help manage Mr. M’s psychiat­ric medications in the context of orthostatic hypotension and cognitive deficits.

What could be causing Mr. M’s symptoms?
   a) drug adverse effect
   b) progressive cardiovascular disease
   c) MDD
   d) all of the above

HISTORY Depression, heart disease
15 years ago. Mr. M experienced his first major depressive episode. His primary care physician (PCP) commented on a history of falling asleep while driving and 1 episode of sleepwalking. His depression was treated to remission with fluoxetine and methylphenidate (dosages were not recorded), the latter also addressed his falling asleep while driving.

5 years ago. Mr. M had another depres­sive episode characterized by anxiety, difficulty sleeping, and irritability. He also described chest pain; a cardiac work-up revealed extensive CAD, which led to 3-vessel CABG later that year. He also reported dizziness upon standing, which was treated with compression stockings and an increase in sodium intake.

Mr. M continued to express feelings of depression. His cardiologist started him on par­oxetine, 10 mg/d, which he took for 2 months and decided to stop because he felt better. He declined psychiatric referral.

4 years ago. Mr. M’s PCP referred him to a psychiatrist for depressed mood, anhedonia, decreased appetite, decreased energy, and dif­ficulty concentrating. Immediate and delayed recall were found to be intact. The psychiatrist diagnosed MDD and Mr. M started escitalopram, 5 mg/d, titrated to 15 mg/d, and trazodone, 50 mg/d.

After starting treatment, Mr. M reported decreased libido. Sustained-release bupropion, 150 mg/d, was added to boost the effects of escitalopram and counteract sexual side effects.

At follow-up, Mr. M reported that his depres­sive symptoms and libido had improved, but that he had been experiencing unsteady gait when getting out of his car, which he had been noticing “for a while”—before he began trazo­done. Mr. M was referred to his PCP, who attrib­uted his symptoms to orthostasis. No treatment was indicated at the time because Mr. M’s light­headedness had resolved.

3 years ago. Mr. M reported a syncopal attack and continued “dizziness.” His PCP pre­scribed fludrocortisone, 0.1 mg/d, later to be dosed 0.2 mg/d, and symptoms improved.

Although Mr. M had a history of orthostatic hypotension, he was later noted to have supine hypertension. Mr. M’s PCP was concerned that fludrocortisone could be causing the supine hypertension but that decreasing the dosage would cause his orthostatic hypotension to return.

The PCP also was concerned that the psy­chiatric medications (escitalopram, trazodone, and bupropion) could be causing orthostasis. There was discussion among Mr. M, his PCP, and his psychiatrist of stopping the psycho­tropics to see if the symptoms would remit; however, because of concerns about Mr. M’s depression, the medications were continued. Mr. M monitored his blood pressure at home and was referred to a neurologist for work-up of potential autonomic dysfunction.

Shortly afterward, Mr. M reported intermit­tent difficulty keeping track of his thoughts and finishing sentences. His psychiatrist ordered an MRI, which showed chronic small vessel ischemic changes, and started him on donepezil, 5 mg/d.

Neuropsychological testing revealed decreased processing speed and poor rec­ognition memory; otherwise, results showed above-average intellectual ability and average or above-average performance in measures of language, attention, visuospatial/construc­tional functions, and executive functions—a pattern typically attributable to psychogenic factors, such as depression.

Mr. M reported to his neurologist that he for­gets directions while driving but can focus bet­ter if he makes a conscious effort. Physical exam was significant hypotension; flat affect; deficits in concentration and short-term recall; mild impairment of Luria motor sequence (com­posed of a go/no-go and a reciprocal motor task); and vertical and horizontal saccades.¹

Mr. M consulted with an ophthalmologist for anterior iridocyclitis and ocular hypertension, which was controlled with travoprost. He con­tinued to experience trouble with his vision and was given a diagnosis of right inferior hemireti­nal vein occlusion, macular edema, and sus­pected glaucoma. Subsequent notes recorded a history of Posner-Schlossman syndrome (a disease characterized by recurrent attacks of increased intraocular pressure in 1 eye with concomitant anterior chamber inflammation). His vision deteriorated until he was diagnosed with ocular hypertension, open-angle glau­coma, and dermatochalasis.

The authors’ observations
Involvement of multiple specialties in a patient’s care brings to question one’s philosophy on medical diagnosis. Interdisciplinary communication would seem to promote the principle of diagnostic parsimony, or Occam’s razor, which sug­gests a unifying diagnosis to explain all of the patient’s symptoms. Lack of communi­cation might favor Hickam’s dictum, which states that “patients can have as many dis­eases as they damn well please.”

HISTORY Low energy, forgetfulness
2 years ago. Mr. M noticed low energy and motivation. He continued to work full-time but thought that it was taking him longer to get work done. He was tapered off escitalo­pram and started on desvenlafaxine, 50 mg/d; donepezil was increased to 10 mg/d.

The syncopal episodes resolved but blood pressure measured at home averaged 150/70 mm Hg. Mr. M was advised to decrease fludrocortisone from 0.2 mg/d to 0.1 mg/d. He tolerated the change and blood pressure measured at home dropped on average to 120 to 130/70 mm Hg.

1 year ago. Mr. M reported that his mem­ory loss had become worse. He perceived hav­ing more stress because of forgetfulness and visual difficulties, which had led him to stop driving at night.

At a follow-up appointment with his psy­chiatrist, Mr. M reported that, first, he had not tapered escitalopram as discussed and, second, he forgot to increase the dosage of desvenlafaxine. A home blood pressure log revealed consistent hypotension; the psychia­trist was concerned that hypotension could be the cause of concentration difficulties and malaise. The psychiatrist advised Mr. M to fol­low-up with his PCP and neurologist.

Current admission. Shortly after the visit to the psychiatrist, Mr. M presented to the emergency department for increased synco­pal events. Work-up was negative for a car­diac cause. A cosyntropin stimulation test was negative, showing that adrenal insufficiency did not cause his orthostatic hypotension. Chart review showed he had been having blood pressure problems for many years, inde­pendent of antidepressants. Physical exam revealed lower extremity ataxia and a bilateral extensor plantar reflex.

What diagnosis explains Mr. M’s symptoms?
   a) Parkinson’s disease
   b) multiple system atrophy (MSA)
   c) depression due to a general medical condition
  d) dementia

The authors’ observations
MSA, previously referred to as Shy-Drager syndrome, is a rare, rapidly progressive neurodegenerative disorder with an esti­mated prevalence of 3.7 cases for every 100,000 people worldwide.² MSA primarily affects middle-aged patients; because it has no cure, most patients die in 7 to 10 years.³

MSA has 2 clinical variants^4,5:
   • parkinsonian type (MSA-P), charac­terized by striatonigral degeneration and increased spasticity
   • cerebellar type (MSA-C), character­ized by more autonomic dysfunction.

MSA has a range of symptoms, mak­ing it a challenging diagnosis (Table).⁶ Although psychiatric symptoms are not part of the diagnostic criteria, they can aid in its diagnosis. In Mr. M’s case, depres­sion, anxiety, orthostatic hypotension, and ataxia support a diagnosis of MSA.

Gilman et al⁶ delineated 3 diagnostic categories for MSA: definite MSA, prob­able MSA, and possible MSA. Clinical cri­teria shared by the 3 diagnostic categories are sporadic and progressive onset after age 30.

Definite MSA requires “neuropathological findings of widespread and abundant CNS alpha-synuclein-positive glial cytoplasmic inclusions,” along with “neurodegenera­tive changes in striatonigral or olivoponto­cerebellar structures” at autopsy.⁶

Probable MSA. Without autopsy findings required for definite MSA, the next most specific diagnostic category is probable MSA. Probable MSA also specifies that the patient show either autonomic fail­ure involving urinary incontinence—this includes erectile dysfunction in men—or, if autonomic failure is absent, orthostatic hypotension within 3 minutes of standing by at least 30 mm Hg systolic pressure or 15 mm Hg diastolic pressure.

Possible MSA has less stringent crite­ria for orthostatic hypotension. The cat­egory includes patients who have only 1 symptom that suggests autonomic failure. Criteria for possible MSA include parkin­sonism or a cerebellar syndrome in addition to symptoms of MSA listed in the Table, whereas probable MSA has specific crite­ria of either a poorly levodopa-responsive parkinsonism (MSA-P) or a cerebellar syn­drome (MSA-C). In addition to having par­kinsonism or a cerebellar syndrome, and 1 sign of autonomic failure or orthostatic hypotension, patients also must have ≥1 additional feature to be assigned a diagno­sis of possible MSA, including:
   • rapidly progressive parkinsonism
   • poor response to levodopa
   • postural instability within 3 years of motor onset
   • gait ataxia, cerebellar dysarthria, limb ataxia, or cerebellar oculomotor dysfunction
   • dysphagia within 5 years of motor onset
   • atrophy on MRI of putamen, mid­dle cerebellar peduncle, pons, or cerebellum
   • hypometabolism on fluorodeoxyglucose- PET in putamen, brainstem, or cerebellum.⁶

Diagnosing MSA can be challenging because its features are similar to those of many other disorders. Nonetheless, Gilman et al6 lists specific criteria for prob­able MSA, including autonomic dysfunc­tion, orthostatic hypotension, and either parkinsonism or cerebellar syndrome symptoms. Although a definite MSA diag­nosis only can be made by postmortem brain specimen analysis, Osaki et al⁷ found that a probable MSA diagnosis has a posi­tive predictive value of 92% with a sensi­tivity of 22% for definite MSA.

Mr. M’s symptoms were consistent with a diagnosis of probable MSA, cerebellar type (Figure).

Psychiatric manifestations of MSA
There are a few case reports of depression identified early in patients who were later given a diagnosis of MSA.⁸

Depression. In a study by Benrud-Larson et al⁹ (N = 99), 49% of patients who had MSA reported moderate or severe depres­sion, as indicated by a score of ≥17 on the Beck Depression Inventory (BDI); 80% reported at least mild depression (BDI ≥10, mean 17.0, standard deviation, 8.7).

In a similar study, by Balas et al,¹⁰ depres­sion was reported as a common symptom and was statistically significant in MSA-P patients compared with controls (P = .013).

Anxiety, another symptom that was reported by Mr. M, is another psychiat­ric manifestation described by Balas et al¹⁰ and Chang et al.¹¹ Balas et al¹⁰ noted that MSA-C and MSA-P patients had sig­nificantly more state anxiety (P = .009 and P = .022, respectively) compared with con­trols, although Chang et al¹¹ noted higher anxiety scores in MSA-C patients com­pared with controls and MSA-P patients (P < .01).

Balas et al¹⁰ hypothesized that anxiety and depression contribute to cognitive decline; their study showed that MSA-C patients had difficulty learning new ver­bal information (P < .022) and controlling attention (P < .023). Mr. M exhibited some of these cognitive difficulties in his reports of losing track of conversations, forgetting the topic of a conversation when speaking, trouble focusing, and difficulty concentrat­ing when driving.

Mr. M had depression and anxiety well before onset of autonomic dysfunction (orthostatic hypotension and erectile dys­function), which eventually led to an MSA diagnosis. Psychiatrists should under­stand additional manifestations of MSA so that they can use psychiatric symptoms to identify these conditions in their patients. One of the most well-known and early manifestations of MSA is autonomic dys­function; among men, another early sign is erectile dysfunction.⁶ Our patient also exhibited other less well-known symptoms linked to MSA and autonomic dysregula­tion, including RBD and ocular symptoms (iridocyclitis, glaucoma, decreased visual acuity).

Rapid eye-movement behavior disorder. Psychiatrists should consider screen­ing for RBD during assessment of sleep problems. Identifying RBD is important because early studies have shown a strong association between RBD and develop­ment of a neurodegenerative disorder. Mr. M’s clinicians did not consider RBD, although his symptoms of sleepwalking and falling asleep while driving suggest a possible diagnosis. Also, considering this diagnosis would aid in diagnosing a synu­cleinopathy disorder because a higher incidence of RBD was noted in patients who developed synucleinopathy disor­ders (eg, Parkinson’s disease [PD] and dementia with Lewy bodies [DLB]) com­pared with patients who developed non-synucleinopathies (eg, frontotemporal dementia, corticobasal degeneration, pro­gressive supranuclear palsy, mild cogni­tive impairment, primary progressive aphasia, and posterior cortical atrophy) or tauopathies (eg, Alzheimer’s disease).¹²

Zanigni et al¹³ reported similar findings in a later study that classified patients with RBD as having idiopathic RBD (IRBD) or RBD sec­ondary to an underlying neurodegenerative disorder, particularly an α-synucleinopathy: PD, MSA, and DLB. Most IRBD patients developed 1 of the above mentioned neuro­degenerative disorders as long as 10 years after a diagnosis of RBD.

In a study by Iranzo et al,¹⁴ patients with MSA were noted to have more severe RBD compared with PD patients. Severity is illus­trated by greater periodic leg movements during sleep (P = .001), less total sleep time (P = .023), longer sleep onset latency (P = .023), and a higher percentage of REM sleep without atonia (RSWA, P = .001). McCarter et al¹⁵ also noted a higher inci­dence of RSWA in patients with MSA.

Patients with MSA might therefore be more likely to exhibit difficulty initiating and maintaining sleep and as having RSWA years before the MSA diagnosis.

Several psychotropics (eg, first-generation antipsychotics, tricyclic anti­depressants, lithium, benzodiazepines, carbamazepine, topiramate, and selective serotonin reuptake inhibitors) can cause adverse ocular effects, such as closed-angle glaucoma in predisposed persons and retinopathy.¹⁶ Therefore, it is important for psychiatrists to ask about ocular symptoms because they might be an early sign of auto­nomic dysfunction.

Posner and Schlossman¹⁷ theorized a causal relationship between autonomic dys­function and ocular diseases after studying a group of patients who had intermittent unilateral attacks of iridocyclitis and glau­coma (now known as Posner-Schlossman syndrome). They hypothesized that a cen­tral cause in the hypothalamus, combined with underlying autonomic dysregulation, could cause the intermittent attacks.

Gherghel et al¹⁸ noted a significant differ­ence in ocular blood flow and blood pres­sure in patients with primary open-angle glaucoma (POAG) compared with con­trols. Patients with POAG did not show an increase in blood pressure or ocular blood flow when challenged by cold water, which should have increased their sympathetic activity. Gherghel et al¹⁸ concluded that this indicated possible systemic autonomic dys­function in patients with POAG. In a study by Fischer et al,¹⁹ MSA patients also were noted to have significant loss of nasal reti­nal nerve fiber layer thickness vs controls (P < .05), leading to decreased peripheral vision sensitivity.

Bottom Line
Although psychiatric symptoms are not part of the diagnostic criteria for multiple system atrophy (MSA), they may serve as a clue to consider when they occur with other MSA symptoms. Evaluate the importance of psychiatric symptoms in terms of the whole picture of the patient. Although the diagnosis might not alter the patient’s course, it can allow family members to understand the patient’s condition and prepare for complications that will arise.

Related Resources
• The MSA Coalition. www.multiplesystematrophy.org.
• National Institute of Neurological Disorders and Stroke. Multiple system atrophy fact sheet. www.ninds.nih.gov/disorders/msa/detailmsa.htm.
• Wenning GK, Fanciulli A, eds. Multiple system atrophy. Vienna, Austria: Springer-Verlag Wien; 2014.

Drug Brand Names
Bupropion • Wellbutrin                Lithium • Eskalith, Lithobid
Carbamazepine • Tegretol           Methylphenidate • Ritalin
Desvenlafaxine • Pristiq              Paroxetine • Paxil
Donepezil • Aricept                     Travoprost • Travatan
Escitalopram • Lexapro               Trazodone • Desyrel, Oleptro
Fludrocortisone • Florinef            Topiramate • Topamax
Fluoxetine • Prozac

Disclosures
The authors report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

CASE Light-headed
Mr. M, age 73, is a retired project manager who feels light-headed while walking his dog, causing him to go to the emergency depart­ment. His history is significant for hyperten­sion, coronary artery disease (CAD), 3-vessel coronary artery bypass graft surgery (CABG), hyperlipidemia, erectile dysfunction, open-angle glaucoma, hemiretinal vein occlusion, symptoms suggesting rapid eye-movement behavior disorder (RBD), and major depressive disorder (MDD).

The psychiatry consultation-liaison service is asked to help manage Mr. M’s psychiat­ric medications in the context of orthostatic hypotension and cognitive deficits.

What could be causing Mr. M’s symptoms?
   a) drug adverse effect
   b) progressive cardiovascular disease
   c) MDD
   d) all of the above

HISTORY Depression, heart disease
15 years ago. Mr. M experienced his first major depressive episode. His primary care physician (PCP) commented on a history of falling asleep while driving and 1 episode of sleepwalking. His depression was treated to remission with fluoxetine and methylphenidate (dosages were not recorded), the latter also addressed his falling asleep while driving.

5 years ago. Mr. M had another depres­sive episode characterized by anxiety, difficulty sleeping, and irritability. He also described chest pain; a cardiac work-up revealed extensive CAD, which led to 3-vessel CABG later that year. He also reported dizziness upon standing, which was treated with compression stockings and an increase in sodium intake.

Mr. M continued to express feelings of depression. His cardiologist started him on par­oxetine, 10 mg/d, which he took for 2 months and decided to stop because he felt better. He declined psychiatric referral.

4 years ago. Mr. M’s PCP referred him to a psychiatrist for depressed mood, anhedonia, decreased appetite, decreased energy, and dif­ficulty concentrating. Immediate and delayed recall were found to be intact. The psychiatrist diagnosed MDD and Mr. M started escitalopram, 5 mg/d, titrated to 15 mg/d, and trazodone, 50 mg/d.

After starting treatment, Mr. M reported decreased libido. Sustained-release bupropion, 150 mg/d, was added to boost the effects of escitalopram and counteract sexual side effects.

At follow-up, Mr. M reported that his depres­sive symptoms and libido had improved, but that he had been experiencing unsteady gait when getting out of his car, which he had been noticing “for a while”—before he began trazo­done. Mr. M was referred to his PCP, who attrib­uted his symptoms to orthostasis. No treatment was indicated at the time because Mr. M’s light­headedness had resolved.

3 years ago. Mr. M reported a syncopal attack and continued “dizziness.” His PCP pre­scribed fludrocortisone, 0.1 mg/d, later to be dosed 0.2 mg/d, and symptoms improved.

Although Mr. M had a history of orthostatic hypotension, he was later noted to have supine hypertension. Mr. M’s PCP was concerned that fludrocortisone could be causing the supine hypertension but that decreasing the dosage would cause his orthostatic hypotension to return.

The PCP also was concerned that the psy­chiatric medications (escitalopram, trazodone, and bupropion) could be causing orthostasis. There was discussion among Mr. M, his PCP, and his psychiatrist of stopping the psycho­tropics to see if the symptoms would remit; however, because of concerns about Mr. M’s depression, the medications were continued. Mr. M monitored his blood pressure at home and was referred to a neurologist for work-up of potential autonomic dysfunction.

Shortly afterward, Mr. M reported intermit­tent difficulty keeping track of his thoughts and finishing sentences. His psychiatrist ordered an MRI, which showed chronic small vessel ischemic changes, and started him on donepezil, 5 mg/d.

Neuropsychological testing revealed decreased processing speed and poor rec­ognition memory; otherwise, results showed above-average intellectual ability and average or above-average performance in measures of language, attention, visuospatial/construc­tional functions, and executive functions—a pattern typically attributable to psychogenic factors, such as depression.

Mr. M reported to his neurologist that he for­gets directions while driving but can focus bet­ter if he makes a conscious effort. Physical exam was significant hypotension; flat affect; deficits in concentration and short-term recall; mild impairment of Luria motor sequence (com­posed of a go/no-go and a reciprocal motor task); and vertical and horizontal saccades.¹

Mr. M consulted with an ophthalmologist for anterior iridocyclitis and ocular hypertension, which was controlled with travoprost. He con­tinued to experience trouble with his vision and was given a diagnosis of right inferior hemireti­nal vein occlusion, macular edema, and sus­pected glaucoma. Subsequent notes recorded a history of Posner-Schlossman syndrome (a disease characterized by recurrent attacks of increased intraocular pressure in 1 eye with concomitant anterior chamber inflammation). His vision deteriorated until he was diagnosed with ocular hypertension, open-angle glau­coma, and dermatochalasis.

The authors’ observations
Involvement of multiple specialties in a patient’s care brings to question one’s philosophy on medical diagnosis. Interdisciplinary communication would seem to promote the principle of diagnostic parsimony, or Occam’s razor, which sug­gests a unifying diagnosis to explain all of the patient’s symptoms. Lack of communi­cation might favor Hickam’s dictum, which states that “patients can have as many dis­eases as they damn well please.”

HISTORY Low energy, forgetfulness
2 years ago. Mr. M noticed low energy and motivation. He continued to work full-time but thought that it was taking him longer to get work done. He was tapered off escitalo­pram and started on desvenlafaxine, 50 mg/d; donepezil was increased to 10 mg/d.

The syncopal episodes resolved but blood pressure measured at home averaged 150/70 mm Hg. Mr. M was advised to decrease fludrocortisone from 0.2 mg/d to 0.1 mg/d. He tolerated the change and blood pressure measured at home dropped on average to 120 to 130/70 mm Hg.

1 year ago. Mr. M reported that his mem­ory loss had become worse. He perceived hav­ing more stress because of forgetfulness and visual difficulties, which had led him to stop driving at night.

At a follow-up appointment with his psy­chiatrist, Mr. M reported that, first, he had not tapered escitalopram as discussed and, second, he forgot to increase the dosage of desvenlafaxine. A home blood pressure log revealed consistent hypotension; the psychia­trist was concerned that hypotension could be the cause of concentration difficulties and malaise. The psychiatrist advised Mr. M to fol­low-up with his PCP and neurologist.

Current admission. Shortly after the visit to the psychiatrist, Mr. M presented to the emergency department for increased synco­pal events. Work-up was negative for a car­diac cause. A cosyntropin stimulation test was negative, showing that adrenal insufficiency did not cause his orthostatic hypotension. Chart review showed he had been having blood pressure problems for many years, inde­pendent of antidepressants. Physical exam revealed lower extremity ataxia and a bilateral extensor plantar reflex.

What diagnosis explains Mr. M’s symptoms?
   a) Parkinson’s disease
   b) multiple system atrophy (MSA)
   c) depression due to a general medical condition
  d) dementia

The authors’ observations
MSA, previously referred to as Shy-Drager syndrome, is a rare, rapidly progressive neurodegenerative disorder with an esti­mated prevalence of 3.7 cases for every 100,000 people worldwide.² MSA primarily affects middle-aged patients; because it has no cure, most patients die in 7 to 10 years.³

MSA has 2 clinical variants^4,5:
   • parkinsonian type (MSA-P), charac­terized by striatonigral degeneration and increased spasticity
   • cerebellar type (MSA-C), character­ized by more autonomic dysfunction.

MSA has a range of symptoms, mak­ing it a challenging diagnosis (Table).⁶ Although psychiatric symptoms are not part of the diagnostic criteria, they can aid in its diagnosis. In Mr. M’s case, depres­sion, anxiety, orthostatic hypotension, and ataxia support a diagnosis of MSA.

Gilman et al⁶ delineated 3 diagnostic categories for MSA: definite MSA, prob­able MSA, and possible MSA. Clinical cri­teria shared by the 3 diagnostic categories are sporadic and progressive onset after age 30.

Definite MSA requires “neuropathological findings of widespread and abundant CNS alpha-synuclein-positive glial cytoplasmic inclusions,” along with “neurodegenera­tive changes in striatonigral or olivoponto­cerebellar structures” at autopsy.⁶

Probable MSA. Without autopsy findings required for definite MSA, the next most specific diagnostic category is probable MSA. Probable MSA also specifies that the patient show either autonomic fail­ure involving urinary incontinence—this includes erectile dysfunction in men—or, if autonomic failure is absent, orthostatic hypotension within 3 minutes of standing by at least 30 mm Hg systolic pressure or 15 mm Hg diastolic pressure.

Possible MSA has less stringent crite­ria for orthostatic hypotension. The cat­egory includes patients who have only 1 symptom that suggests autonomic failure. Criteria for possible MSA include parkin­sonism or a cerebellar syndrome in addition to symptoms of MSA listed in the Table, whereas probable MSA has specific crite­ria of either a poorly levodopa-responsive parkinsonism (MSA-P) or a cerebellar syn­drome (MSA-C). In addition to having par­kinsonism or a cerebellar syndrome, and 1 sign of autonomic failure or orthostatic hypotension, patients also must have ≥1 additional feature to be assigned a diagno­sis of possible MSA, including:
   • rapidly progressive parkinsonism
   • poor response to levodopa
   • postural instability within 3 years of motor onset
   • gait ataxia, cerebellar dysarthria, limb ataxia, or cerebellar oculomotor dysfunction
   • dysphagia within 5 years of motor onset
   • atrophy on MRI of putamen, mid­dle cerebellar peduncle, pons, or cerebellum
   • hypometabolism on fluorodeoxyglucose- PET in putamen, brainstem, or cerebellum.⁶

Diagnosing MSA can be challenging because its features are similar to those of many other disorders. Nonetheless, Gilman et al6 lists specific criteria for prob­able MSA, including autonomic dysfunc­tion, orthostatic hypotension, and either parkinsonism or cerebellar syndrome symptoms. Although a definite MSA diag­nosis only can be made by postmortem brain specimen analysis, Osaki et al⁷ found that a probable MSA diagnosis has a posi­tive predictive value of 92% with a sensi­tivity of 22% for definite MSA.

Mr. M’s symptoms were consistent with a diagnosis of probable MSA, cerebellar type (Figure).

Psychiatric manifestations of MSA
There are a few case reports of depression identified early in patients who were later given a diagnosis of MSA.⁸

Depression. In a study by Benrud-Larson et al⁹ (N = 99), 49% of patients who had MSA reported moderate or severe depres­sion, as indicated by a score of ≥17 on the Beck Depression Inventory (BDI); 80% reported at least mild depression (BDI ≥10, mean 17.0, standard deviation, 8.7).

In a similar study, by Balas et al,¹⁰ depres­sion was reported as a common symptom and was statistically significant in MSA-P patients compared with controls (P = .013).

Anxiety, another symptom that was reported by Mr. M, is another psychiat­ric manifestation described by Balas et al¹⁰ and Chang et al.¹¹ Balas et al¹⁰ noted that MSA-C and MSA-P patients had sig­nificantly more state anxiety (P = .009 and P = .022, respectively) compared with con­trols, although Chang et al¹¹ noted higher anxiety scores in MSA-C patients com­pared with controls and MSA-P patients (P < .01).

Balas et al¹⁰ hypothesized that anxiety and depression contribute to cognitive decline; their study showed that MSA-C patients had difficulty learning new ver­bal information (P < .022) and controlling attention (P < .023). Mr. M exhibited some of these cognitive difficulties in his reports of losing track of conversations, forgetting the topic of a conversation when speaking, trouble focusing, and difficulty concentrat­ing when driving.

Mr. M had depression and anxiety well before onset of autonomic dysfunction (orthostatic hypotension and erectile dys­function), which eventually led to an MSA diagnosis. Psychiatrists should under­stand additional manifestations of MSA so that they can use psychiatric symptoms to identify these conditions in their patients. One of the most well-known and early manifestations of MSA is autonomic dys­function; among men, another early sign is erectile dysfunction.⁶ Our patient also exhibited other less well-known symptoms linked to MSA and autonomic dysregula­tion, including RBD and ocular symptoms (iridocyclitis, glaucoma, decreased visual acuity).

Rapid eye-movement behavior disorder. Psychiatrists should consider screen­ing for RBD during assessment of sleep problems. Identifying RBD is important because early studies have shown a strong association between RBD and develop­ment of a neurodegenerative disorder. Mr. M’s clinicians did not consider RBD, although his symptoms of sleepwalking and falling asleep while driving suggest a possible diagnosis. Also, considering this diagnosis would aid in diagnosing a synu­cleinopathy disorder because a higher incidence of RBD was noted in patients who developed synucleinopathy disor­ders (eg, Parkinson’s disease [PD] and dementia with Lewy bodies [DLB]) com­pared with patients who developed non-synucleinopathies (eg, frontotemporal dementia, corticobasal degeneration, pro­gressive supranuclear palsy, mild cogni­tive impairment, primary progressive aphasia, and posterior cortical atrophy) or tauopathies (eg, Alzheimer’s disease).¹²

Zanigni et al¹³ reported similar findings in a later study that classified patients with RBD as having idiopathic RBD (IRBD) or RBD sec­ondary to an underlying neurodegenerative disorder, particularly an α-synucleinopathy: PD, MSA, and DLB. Most IRBD patients developed 1 of the above mentioned neuro­degenerative disorders as long as 10 years after a diagnosis of RBD.

In a study by Iranzo et al,¹⁴ patients with MSA were noted to have more severe RBD compared with PD patients. Severity is illus­trated by greater periodic leg movements during sleep (P = .001), less total sleep time (P = .023), longer sleep onset latency (P = .023), and a higher percentage of REM sleep without atonia (RSWA, P = .001). McCarter et al¹⁵ also noted a higher inci­dence of RSWA in patients with MSA.

Patients with MSA might therefore be more likely to exhibit difficulty initiating and maintaining sleep and as having RSWA years before the MSA diagnosis.

Several psychotropics (eg, first-generation antipsychotics, tricyclic anti­depressants, lithium, benzodiazepines, carbamazepine, topiramate, and selective serotonin reuptake inhibitors) can cause adverse ocular effects, such as closed-angle glaucoma in predisposed persons and retinopathy.¹⁶ Therefore, it is important for psychiatrists to ask about ocular symptoms because they might be an early sign of auto­nomic dysfunction.

Posner and Schlossman¹⁷ theorized a causal relationship between autonomic dys­function and ocular diseases after studying a group of patients who had intermittent unilateral attacks of iridocyclitis and glau­coma (now known as Posner-Schlossman syndrome). They hypothesized that a cen­tral cause in the hypothalamus, combined with underlying autonomic dysregulation, could cause the intermittent attacks.

Gherghel et al¹⁸ noted a significant differ­ence in ocular blood flow and blood pres­sure in patients with primary open-angle glaucoma (POAG) compared with con­trols. Patients with POAG did not show an increase in blood pressure or ocular blood flow when challenged by cold water, which should have increased their sympathetic activity. Gherghel et al¹⁸ concluded that this indicated possible systemic autonomic dys­function in patients with POAG. In a study by Fischer et al,¹⁹ MSA patients also were noted to have significant loss of nasal reti­nal nerve fiber layer thickness vs controls (P < .05), leading to decreased peripheral vision sensitivity.

Bottom Line
Although psychiatric symptoms are not part of the diagnostic criteria for multiple system atrophy (MSA), they may serve as a clue to consider when they occur with other MSA symptoms. Evaluate the importance of psychiatric symptoms in terms of the whole picture of the patient. Although the diagnosis might not alter the patient’s course, it can allow family members to understand the patient’s condition and prepare for complications that will arise.

Related Resources
• The MSA Coalition. www.multiplesystematrophy.org.
• National Institute of Neurological Disorders and Stroke. Multiple system atrophy fact sheet. www.ninds.nih.gov/disorders/msa/detailmsa.htm.
• Wenning GK, Fanciulli A, eds. Multiple system atrophy. Vienna, Austria: Springer-Verlag Wien; 2014.

Drug Brand Names
Bupropion • Wellbutrin                Lithium • Eskalith, Lithobid
Carbamazepine • Tegretol           Methylphenidate • Ritalin
Desvenlafaxine • Pristiq              Paroxetine • Paxil
Donepezil • Aricept                     Travoprost • Travatan
Escitalopram • Lexapro               Trazodone • Desyrel, Oleptro
Fludrocortisone • Florinef            Topiramate • Topamax
Fluoxetine • Prozac

Disclosures
The authors report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

CASE Light-headed
Mr. M, age 73, is a retired project manager who feels light-headed while walking his dog, causing him to go to the emergency depart­ment. His history is significant for hyperten­sion, coronary artery disease (CAD), 3-vessel coronary artery bypass graft surgery (CABG), hyperlipidemia, erectile dysfunction, open-angle glaucoma, hemiretinal vein occlusion, symptoms suggesting rapid eye-movement behavior disorder (RBD), and major depressive disorder (MDD).

The psychiatry consultation-liaison service is asked to help manage Mr. M’s psychiat­ric medications in the context of orthostatic hypotension and cognitive deficits.

What could be causing Mr. M’s symptoms?
   a) drug adverse effect
   b) progressive cardiovascular disease
   c) MDD
   d) all of the above

HISTORY Depression, heart disease
15 years ago. Mr. M experienced his first major depressive episode. His primary care physician (PCP) commented on a history of falling asleep while driving and 1 episode of sleepwalking. His depression was treated to remission with fluoxetine and methylphenidate (dosages were not recorded), the latter also addressed his falling asleep while driving.

5 years ago. Mr. M had another depres­sive episode characterized by anxiety, difficulty sleeping, and irritability. He also described chest pain; a cardiac work-up revealed extensive CAD, which led to 3-vessel CABG later that year. He also reported dizziness upon standing, which was treated with compression stockings and an increase in sodium intake.

Mr. M continued to express feelings of depression. His cardiologist started him on par­oxetine, 10 mg/d, which he took for 2 months and decided to stop because he felt better. He declined psychiatric referral.

4 years ago. Mr. M’s PCP referred him to a psychiatrist for depressed mood, anhedonia, decreased appetite, decreased energy, and dif­ficulty concentrating. Immediate and delayed recall were found to be intact. The psychiatrist diagnosed MDD and Mr. M started escitalopram, 5 mg/d, titrated to 15 mg/d, and trazodone, 50 mg/d.

After starting treatment, Mr. M reported decreased libido. Sustained-release bupropion, 150 mg/d, was added to boost the effects of escitalopram and counteract sexual side effects.

At follow-up, Mr. M reported that his depres­sive symptoms and libido had improved, but that he had been experiencing unsteady gait when getting out of his car, which he had been noticing “for a while”—before he began trazo­done. Mr. M was referred to his PCP, who attrib­uted his symptoms to orthostasis. No treatment was indicated at the time because Mr. M’s light­headedness had resolved.

3 years ago. Mr. M reported a syncopal attack and continued “dizziness.” His PCP pre­scribed fludrocortisone, 0.1 mg/d, later to be dosed 0.2 mg/d, and symptoms improved.

Although Mr. M had a history of orthostatic hypotension, he was later noted to have supine hypertension. Mr. M’s PCP was concerned that fludrocortisone could be causing the supine hypertension but that decreasing the dosage would cause his orthostatic hypotension to return.

The PCP also was concerned that the psy­chiatric medications (escitalopram, trazodone, and bupropion) could be causing orthostasis. There was discussion among Mr. M, his PCP, and his psychiatrist of stopping the psycho­tropics to see if the symptoms would remit; however, because of concerns about Mr. M’s depression, the medications were continued. Mr. M monitored his blood pressure at home and was referred to a neurologist for work-up of potential autonomic dysfunction.

Shortly afterward, Mr. M reported intermit­tent difficulty keeping track of his thoughts and finishing sentences. His psychiatrist ordered an MRI, which showed chronic small vessel ischemic changes, and started him on donepezil, 5 mg/d.

Neuropsychological testing revealed decreased processing speed and poor rec­ognition memory; otherwise, results showed above-average intellectual ability and average or above-average performance in measures of language, attention, visuospatial/construc­tional functions, and executive functions—a pattern typically attributable to psychogenic factors, such as depression.

Mr. M reported to his neurologist that he for­gets directions while driving but can focus bet­ter if he makes a conscious effort. Physical exam was significant hypotension; flat affect; deficits in concentration and short-term recall; mild impairment of Luria motor sequence (com­posed of a go/no-go and a reciprocal motor task); and vertical and horizontal saccades.¹

Mr. M consulted with an ophthalmologist for anterior iridocyclitis and ocular hypertension, which was controlled with travoprost. He con­tinued to experience trouble with his vision and was given a diagnosis of right inferior hemireti­nal vein occlusion, macular edema, and sus­pected glaucoma. Subsequent notes recorded a history of Posner-Schlossman syndrome (a disease characterized by recurrent attacks of increased intraocular pressure in 1 eye with concomitant anterior chamber inflammation). His vision deteriorated until he was diagnosed with ocular hypertension, open-angle glau­coma, and dermatochalasis.

The authors’ observations
Involvement of multiple specialties in a patient’s care brings to question one’s philosophy on medical diagnosis. Interdisciplinary communication would seem to promote the principle of diagnostic parsimony, or Occam’s razor, which sug­gests a unifying diagnosis to explain all of the patient’s symptoms. Lack of communi­cation might favor Hickam’s dictum, which states that “patients can have as many dis­eases as they damn well please.”

HISTORY Low energy, forgetfulness
2 years ago. Mr. M noticed low energy and motivation. He continued to work full-time but thought that it was taking him longer to get work done. He was tapered off escitalo­pram and started on desvenlafaxine, 50 mg/d; donepezil was increased to 10 mg/d.

The syncopal episodes resolved but blood pressure measured at home averaged 150/70 mm Hg. Mr. M was advised to decrease fludrocortisone from 0.2 mg/d to 0.1 mg/d. He tolerated the change and blood pressure measured at home dropped on average to 120 to 130/70 mm Hg.

1 year ago. Mr. M reported that his mem­ory loss had become worse. He perceived hav­ing more stress because of forgetfulness and visual difficulties, which had led him to stop driving at night.

At a follow-up appointment with his psy­chiatrist, Mr. M reported that, first, he had not tapered escitalopram as discussed and, second, he forgot to increase the dosage of desvenlafaxine. A home blood pressure log revealed consistent hypotension; the psychia­trist was concerned that hypotension could be the cause of concentration difficulties and malaise. The psychiatrist advised Mr. M to fol­low-up with his PCP and neurologist.

Current admission. Shortly after the visit to the psychiatrist, Mr. M presented to the emergency department for increased synco­pal events. Work-up was negative for a car­diac cause. A cosyntropin stimulation test was negative, showing that adrenal insufficiency did not cause his orthostatic hypotension. Chart review showed he had been having blood pressure problems for many years, inde­pendent of antidepressants. Physical exam revealed lower extremity ataxia and a bilateral extensor plantar reflex.

What diagnosis explains Mr. M’s symptoms?
   a) Parkinson’s disease
   b) multiple system atrophy (MSA)
   c) depression due to a general medical condition
  d) dementia

The authors’ observations
MSA, previously referred to as Shy-Drager syndrome, is a rare, rapidly progressive neurodegenerative disorder with an esti­mated prevalence of 3.7 cases for every 100,000 people worldwide.² MSA primarily affects middle-aged patients; because it has no cure, most patients die in 7 to 10 years.³

MSA has 2 clinical variants^4,5:
   • parkinsonian type (MSA-P), charac­terized by striatonigral degeneration and increased spasticity
   • cerebellar type (MSA-C), character­ized by more autonomic dysfunction.

MSA has a range of symptoms, mak­ing it a challenging diagnosis (Table).⁶ Although psychiatric symptoms are not part of the diagnostic criteria, they can aid in its diagnosis. In Mr. M’s case, depres­sion, anxiety, orthostatic hypotension, and ataxia support a diagnosis of MSA.

Gilman et al⁶ delineated 3 diagnostic categories for MSA: definite MSA, prob­able MSA, and possible MSA. Clinical cri­teria shared by the 3 diagnostic categories are sporadic and progressive onset after age 30.

Definite MSA requires “neuropathological findings of widespread and abundant CNS alpha-synuclein-positive glial cytoplasmic inclusions,” along with “neurodegenera­tive changes in striatonigral or olivoponto­cerebellar structures” at autopsy.⁶

Probable MSA. Without autopsy findings required for definite MSA, the next most specific diagnostic category is probable MSA. Probable MSA also specifies that the patient show either autonomic fail­ure involving urinary incontinence—this includes erectile dysfunction in men—or, if autonomic failure is absent, orthostatic hypotension within 3 minutes of standing by at least 30 mm Hg systolic pressure or 15 mm Hg diastolic pressure.

Possible MSA has less stringent crite­ria for orthostatic hypotension. The cat­egory includes patients who have only 1 symptom that suggests autonomic failure. Criteria for possible MSA include parkin­sonism or a cerebellar syndrome in addition to symptoms of MSA listed in the Table, whereas probable MSA has specific crite­ria of either a poorly levodopa-responsive parkinsonism (MSA-P) or a cerebellar syn­drome (MSA-C). In addition to having par­kinsonism or a cerebellar syndrome, and 1 sign of autonomic failure or orthostatic hypotension, patients also must have ≥1 additional feature to be assigned a diagno­sis of possible MSA, including:
   • rapidly progressive parkinsonism
   • poor response to levodopa
   • postural instability within 3 years of motor onset
   • gait ataxia, cerebellar dysarthria, limb ataxia, or cerebellar oculomotor dysfunction
   • dysphagia within 5 years of motor onset
   • atrophy on MRI of putamen, mid­dle cerebellar peduncle, pons, or cerebellum
   • hypometabolism on fluorodeoxyglucose- PET in putamen, brainstem, or cerebellum.⁶

Diagnosing MSA can be challenging because its features are similar to those of many other disorders. Nonetheless, Gilman et al6 lists specific criteria for prob­able MSA, including autonomic dysfunc­tion, orthostatic hypotension, and either parkinsonism or cerebellar syndrome symptoms. Although a definite MSA diag­nosis only can be made by postmortem brain specimen analysis, Osaki et al⁷ found that a probable MSA diagnosis has a posi­tive predictive value of 92% with a sensi­tivity of 22% for definite MSA.

Mr. M’s symptoms were consistent with a diagnosis of probable MSA, cerebellar type (Figure).

Psychiatric manifestations of MSA
There are a few case reports of depression identified early in patients who were later given a diagnosis of MSA.⁸

Depression. In a study by Benrud-Larson et al⁹ (N = 99), 49% of patients who had MSA reported moderate or severe depres­sion, as indicated by a score of ≥17 on the Beck Depression Inventory (BDI); 80% reported at least mild depression (BDI ≥10, mean 17.0, standard deviation, 8.7).

In a similar study, by Balas et al,¹⁰ depres­sion was reported as a common symptom and was statistically significant in MSA-P patients compared with controls (P = .013).

Anxiety, another symptom that was reported by Mr. M, is another psychiat­ric manifestation described by Balas et al¹⁰ and Chang et al.¹¹ Balas et al¹⁰ noted that MSA-C and MSA-P patients had sig­nificantly more state anxiety (P = .009 and P = .022, respectively) compared with con­trols, although Chang et al¹¹ noted higher anxiety scores in MSA-C patients com­pared with controls and MSA-P patients (P < .01).

Balas et al¹⁰ hypothesized that anxiety and depression contribute to cognitive decline; their study showed that MSA-C patients had difficulty learning new ver­bal information (P < .022) and controlling attention (P < .023). Mr. M exhibited some of these cognitive difficulties in his reports of losing track of conversations, forgetting the topic of a conversation when speaking, trouble focusing, and difficulty concentrat­ing when driving.

Mr. M had depression and anxiety well before onset of autonomic dysfunction (orthostatic hypotension and erectile dys­function), which eventually led to an MSA diagnosis. Psychiatrists should under­stand additional manifestations of MSA so that they can use psychiatric symptoms to identify these conditions in their patients. One of the most well-known and early manifestations of MSA is autonomic dys­function; among men, another early sign is erectile dysfunction.⁶ Our patient also exhibited other less well-known symptoms linked to MSA and autonomic dysregula­tion, including RBD and ocular symptoms (iridocyclitis, glaucoma, decreased visual acuity).

Rapid eye-movement behavior disorder. Psychiatrists should consider screen­ing for RBD during assessment of sleep problems. Identifying RBD is important because early studies have shown a strong association between RBD and develop­ment of a neurodegenerative disorder. Mr. M’s clinicians did not consider RBD, although his symptoms of sleepwalking and falling asleep while driving suggest a possible diagnosis. Also, considering this diagnosis would aid in diagnosing a synu­cleinopathy disorder because a higher incidence of RBD was noted in patients who developed synucleinopathy disor­ders (eg, Parkinson’s disease [PD] and dementia with Lewy bodies [DLB]) com­pared with patients who developed non-synucleinopathies (eg, frontotemporal dementia, corticobasal degeneration, pro­gressive supranuclear palsy, mild cogni­tive impairment, primary progressive aphasia, and posterior cortical atrophy) or tauopathies (eg, Alzheimer’s disease).¹²

Zanigni et al¹³ reported similar findings in a later study that classified patients with RBD as having idiopathic RBD (IRBD) or RBD sec­ondary to an underlying neurodegenerative disorder, particularly an α-synucleinopathy: PD, MSA, and DLB. Most IRBD patients developed 1 of the above mentioned neuro­degenerative disorders as long as 10 years after a diagnosis of RBD.

In a study by Iranzo et al,¹⁴ patients with MSA were noted to have more severe RBD compared with PD patients. Severity is illus­trated by greater periodic leg movements during sleep (P = .001), less total sleep time (P = .023), longer sleep onset latency (P = .023), and a higher percentage of REM sleep without atonia (RSWA, P = .001). McCarter et al¹⁵ also noted a higher inci­dence of RSWA in patients with MSA.

Patients with MSA might therefore be more likely to exhibit difficulty initiating and maintaining sleep and as having RSWA years before the MSA diagnosis.

Several psychotropics (eg, first-generation antipsychotics, tricyclic anti­depressants, lithium, benzodiazepines, carbamazepine, topiramate, and selective serotonin reuptake inhibitors) can cause adverse ocular effects, such as closed-angle glaucoma in predisposed persons and retinopathy.¹⁶ Therefore, it is important for psychiatrists to ask about ocular symptoms because they might be an early sign of auto­nomic dysfunction.

Posner and Schlossman¹⁷ theorized a causal relationship between autonomic dys­function and ocular diseases after studying a group of patients who had intermittent unilateral attacks of iridocyclitis and glau­coma (now known as Posner-Schlossman syndrome). They hypothesized that a cen­tral cause in the hypothalamus, combined with underlying autonomic dysregulation, could cause the intermittent attacks.

Gherghel et al¹⁸ noted a significant differ­ence in ocular blood flow and blood pres­sure in patients with primary open-angle glaucoma (POAG) compared with con­trols. Patients with POAG did not show an increase in blood pressure or ocular blood flow when challenged by cold water, which should have increased their sympathetic activity. Gherghel et al¹⁸ concluded that this indicated possible systemic autonomic dys­function in patients with POAG. In a study by Fischer et al,¹⁹ MSA patients also were noted to have significant loss of nasal reti­nal nerve fiber layer thickness vs controls (P < .05), leading to decreased peripheral vision sensitivity.

Bottom Line
Although psychiatric symptoms are not part of the diagnostic criteria for multiple system atrophy (MSA), they may serve as a clue to consider when they occur with other MSA symptoms. Evaluate the importance of psychiatric symptoms in terms of the whole picture of the patient. Although the diagnosis might not alter the patient’s course, it can allow family members to understand the patient’s condition and prepare for complications that will arise.

Related Resources
• The MSA Coalition. www.multiplesystematrophy.org.
• National Institute of Neurological Disorders and Stroke. Multiple system atrophy fact sheet. www.ninds.nih.gov/disorders/msa/detailmsa.htm.
• Wenning GK, Fanciulli A, eds. Multiple system atrophy. Vienna, Austria: Springer-Verlag Wien; 2014.

Drug Brand Names
Bupropion • Wellbutrin                Lithium • Eskalith, Lithobid
Carbamazepine • Tegretol           Methylphenidate • Ritalin
Desvenlafaxine • Pristiq              Paroxetine • Paxil
Donepezil • Aricept                     Travoprost • Travatan
Escitalopram • Lexapro               Trazodone • Desyrel, Oleptro
Fludrocortisone • Florinef            Topiramate • Topamax
Fluoxetine • Prozac

Disclosures
The authors report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

Patients with knee osteoarthritis (OA) who have poor sleep habits display greater central sensitization of pain, according to a study published online ahead of print June 4 in Arthritis Care & Research. Study findings also showed that OA patients who catastrophize had increased central sensitization that was associated with greater pain.

“Our study is the largest and most comprehensive examination of the relationship between sleep disturbance, catastrophizing, and central sensitization in knee OA,” stated lead author Claudia Campbell, PhD, an Associate Professor of Psychiatry and Behavioral Sciences at Johns Hopkins University School of Medicine in Baltimore.

The case-controlled study included 208 participants who were categorized according to 4 groups: patients who have OA and insomnia, patients who have OA and normal sleep habits, healthy controls with insomnia, and healthy controls without a pain syndrome and normal sleep. In all, 72% of the study’s participants were female.

Participants completed multimodal sleep assessments (eg, questionnaire, diary, actigraphy, and polysmnography) and extensive evaluation of pain using clinical measures and quantitative sensory testing to evaluate associations between central sensitization, catastrophizing, and insomnia.

Results showed that the participants with knee OA and insomnia had the greatest amount of central sensitization compared with controls. The team found patients with poor sleep and high catastrophizing scores reported increased levels of central sensitization. In turn, central sensitization was significantly associated with increased clinical pain.

“While no causal processes may be determined from this study, our data suggest that those with low sleep efficiency and higher catastrophizing have the greatest central sensitization. Understanding the intricate relationship between sleep, central sensitization, and catastrophizing has important clinical implications for treating those with chronic pain conditions such as knee OA,” Dr. Campbell stated.

Patients with knee osteoarthritis (OA) who have poor sleep habits display greater central sensitization of pain, according to a study published online ahead of print June 4 in Arthritis Care & Research. Study findings also showed that OA patients who catastrophize had increased central sensitization that was associated with greater pain.

“Our study is the largest and most comprehensive examination of the relationship between sleep disturbance, catastrophizing, and central sensitization in knee OA,” stated lead author Claudia Campbell, PhD, an Associate Professor of Psychiatry and Behavioral Sciences at Johns Hopkins University School of Medicine in Baltimore.

The case-controlled study included 208 participants who were categorized according to 4 groups: patients who have OA and insomnia, patients who have OA and normal sleep habits, healthy controls with insomnia, and healthy controls without a pain syndrome and normal sleep. In all, 72% of the study’s participants were female.

Participants completed multimodal sleep assessments (eg, questionnaire, diary, actigraphy, and polysmnography) and extensive evaluation of pain using clinical measures and quantitative sensory testing to evaluate associations between central sensitization, catastrophizing, and insomnia.

Results showed that the participants with knee OA and insomnia had the greatest amount of central sensitization compared with controls. The team found patients with poor sleep and high catastrophizing scores reported increased levels of central sensitization. In turn, central sensitization was significantly associated with increased clinical pain.

“While no causal processes may be determined from this study, our data suggest that those with low sleep efficiency and higher catastrophizing have the greatest central sensitization. Understanding the intricate relationship between sleep, central sensitization, and catastrophizing has important clinical implications for treating those with chronic pain conditions such as knee OA,” Dr. Campbell stated.

Patients with knee osteoarthritis (OA) who have poor sleep habits display greater central sensitization of pain, according to a study published online ahead of print June 4 in Arthritis Care & Research. Study findings also showed that OA patients who catastrophize had increased central sensitization that was associated with greater pain.

“Our study is the largest and most comprehensive examination of the relationship between sleep disturbance, catastrophizing, and central sensitization in knee OA,” stated lead author Claudia Campbell, PhD, an Associate Professor of Psychiatry and Behavioral Sciences at Johns Hopkins University School of Medicine in Baltimore.

The case-controlled study included 208 participants who were categorized according to 4 groups: patients who have OA and insomnia, patients who have OA and normal sleep habits, healthy controls with insomnia, and healthy controls without a pain syndrome and normal sleep. In all, 72% of the study’s participants were female.

Participants completed multimodal sleep assessments (eg, questionnaire, diary, actigraphy, and polysmnography) and extensive evaluation of pain using clinical measures and quantitative sensory testing to evaluate associations between central sensitization, catastrophizing, and insomnia.

Results showed that the participants with knee OA and insomnia had the greatest amount of central sensitization compared with controls. The team found patients with poor sleep and high catastrophizing scores reported increased levels of central sensitization. In turn, central sensitization was significantly associated with increased clinical pain.

“While no causal processes may be determined from this study, our data suggest that those with low sleep efficiency and higher catastrophizing have the greatest central sensitization. Understanding the intricate relationship between sleep, central sensitization, and catastrophizing has important clinical implications for treating those with chronic pain conditions such as knee OA,” Dr. Campbell stated.

First-episode psychosis (FEP) in schizophrenia is char­acterized by high response rates to antipsychotic therapy, followed by frequent antipsychotic discon­tinuation and elevated relapse rates soon after mainte­nance treatment begins.^1,2 With subsequent episodes, time to response progressively increases and likelihood of response decreases.^3,4

To address these issues, this article—the second of 2 parts⁵—describes the rationale and evidence for using non­standard first-line antipsychotic therapies to manage FEP. Specifically, we discuss when clinicians might consider mono­therapy exceeding FDA-approved maximum dosages, combi­nation therapy, long-acting injectable antipsychotics (LAIA), or clozapine.

Monotherapy beyond FDA-approved dosages
Treatment guidelines for FEP recommend oral antipsy­chotic dosages in the lower half of the treatment range and lower than those that are required for multi-episode schizo­phrenia.^6-16 Ultimately, clinicians prescribe individualized dosages for their patients based on symptom improvement and tolerability. The optimal dosage at which to achieve a favorable D2 receptor occupancy likely will vary from patient to patient.¹⁷

To control symptoms, higher dosages may be needed than those used in FEP clinical tri­als, recommended by guidelines for FEP or multi-episode patients, or approved by the FDA. Patients seen in everyday practice may be more complicated (eg, have a comorbid condition or history of nonresponse) than study populations. Higher dosages also may be reasonable to overcome drug−drug interactions (eg, cigarette smoking-mediated cytochrome P450 1A2 induction, resulting in increased olanzapine metabolism),¹⁸ or to establish antipsychotic failure if adequate trials at lower dosages have resulted in a suboptimal response and the patient is not experiencing tolerability or safety concerns.

In a study of low-, full-, and high-dosage antipsychotic therapy in FEP, an additional 15% of patients responded to higher dos­ages of olanzapine and risperidone after failing to respond to a standard dosage.¹⁹ A study of data from the Recovery After an Initial Schizophrenia Episode Project’s Early Treatment Program (RAISE-ETP) found that, of participants identified who may benefit from therapy modification, 8.8% were pre­scribed an antipsychotic (often, olanzapine, risperidone, and haloperidol) at a higher-than-recommended dosage.²⁰ Of note, only olanzapine was prescribed at higher than FDA-approved dosages.

Antipsychotic combination therapy
Prescribing combinations of antipsychot­ics—antipsychotic polypharmacy (APP)— has a negative connotation because of limited efficacy and safety data,²¹ and limited endorsement in schizophrenia treatment guidelines.^9,13 Caution with APP is war­ranted; a complex medication regimen may increase the potential for adverse effects, poorer adherence, and adverse drug-drug interactions.⁹ APP has been shown to inde­pendently predict both shorter treatment duration and discontinuation before 1 year.²²

Nonetheless, the clinician and patient may share the decision to implement APP and observe whether benefits outweigh risks in situations such as:
   • to optimize neuroreceptor occupancy and targets (eg, attempting to achieve ade­quate D2 receptor blockade while minimiz­ing side effects secondary to binding other receptors)
   • to manage co-existing symptom domains (eg, mood changes, aggression, negative symptoms, disorganization, and cognitive deficits)
   • to mitigate antipsychotic-induced side effects (eg, initiating aripiprazole to treat hyperprolactinemia induced by another anti­psychotic to which the patient has achieved a favorable response).²³

Clinicians report using APP to treat as many as 50% of patients with a history of multiple psychotic episodes.²³ For FEP patients, 23% of participants in the RAISE-ETP trial who were identified as possibly benefiting from therapy modification were prescribed APP.²⁰ Regrettably, research­ers have not found evidence to support a reported rationale for using APP—that lower dosages of individual antipsychotics when used in combination may avoid high-dosage prescriptions.²⁴

Before implementing APP, thoroughly explore and manage reasons for a patient’s suboptimal response to monotherapy.25 An adequate trial with any antipsychotic should be at the highest tolerated dosage for 12 to 16 weeks. Be mindful that response to an APP trial may be the result of additional time on the original antipsychotic.

Long-acting injectable antipsychotics in FEP
Guideline recommendations. Most older guidelines for schizophrenia treat­ment suggest LAIA after multiple relapses related to medication nonadherence or when a patient prefers injected medica­tion (Table 1).^6-13 Expert consensus guide­lines also recommend considering LAIA in patients who lack insight into their illness. The Texas Medication Algorithm Project (TMAP) guidelines⁷ state LAIA can be con­sidered for inadequate adherence at any stage, whereas the 2010 British Association for Psychopharmacology (BAP) guide­lines⁹ express uncertainty about their use in FEP, because of limited evidence. Both the BAP and National Institute for Health and Care Excellence guidelines¹³ urge cli­nicians to consider LAIA when avoiding nonadherence is a treatment priority.

Barriers to LAIA use include:
   • slow dosage titration and increased time to reach steady state drug level
   • oral supplementation for some (eg, risperidone microspheres and aripiprazole long-acting injectable)
   • logistical challenges for some (eg, 3-hour post-injection monitoring for delir­ium sedation syndrome with olanzapine pamoate)
   • additional planning to coordinate care for scheduled injections
   • higher expenses up front
   • local injection site reactions
   • dosage adjustment difficulties if adverse effects occur.^28,29

Adoption rates of LAIA are low, especially for FEP.³⁰ Most surveys indicate that (1) physi­cians believe LAIA treatment is ineffective for FEP31 and (2) patients do not prefer injectable to oral antipsychotics,³² despite evidence to the contrary.^33,34 A survey of 198 psychiatrists identified 3 factors that influenced their deci­sions against using LAIA patients with FEP:
   • limited availability of SGA depot formu­lations (4, to date, in the United States)
   • frequent rejection by the patient when LAIA is offered without adequate expla­nation or encouragement
   • skepticism of FEP patients (and their family) who lack experience with relapse.³⁵

In reality, when SGA depots were intro­duced in the United Kingdom, prescribing rates of LAIA did not increase. As for patient rejection being a major reason for not pre­scribing LAIA, few patients (5% to 36%) are offered depot injections, particularly in FEP.²⁹ Most patients using LAIA are chronic, multi-episode, violent people who are receiving medications involuntarily.²⁹ Interestingly, this survey did not find 2 factors to be influential in psychiatrists’ decision not to use LAIA in FEP:
   • guidelines do not explicitly recommend depot treatment in FEP
   • treatment in FEP may be limited to 1 year, therefore depot administration is not worthwhile.³⁵

Preliminary evidence. At least a dozen stud­ies have explored LAIA treatment for FEP, with the use of fluphenazine decanoate,³⁶ per­phenazine enanthate³⁷ (discontinued), and risperidone microspheres.^37-48 The research demonstrates the efficacy and safety of LAIA in FEP as measured by these endpoints:
   • improved symptom control^{38,40-43,46,48}
   • adherence^43,44,48
   • reduced relapse rates^37,43 and rehospitalizations^37,47
   • lesser reductions in white matter brain volume⁴⁵
   • no differences in extrapyramidal side effects or prolactin-associated adverse effects.⁴⁸

A few small studies demonstrate signifi­cant differences in outcomes between ris­peridone LAIA and oral comparator groups (Table 3).^43-45 Ongoing studies of LAIA use in FEP are comparing paliperidone palmitate with risperidone microspheres and other oral antipsychotics.^49-51 No stud­ies are examining olanzapine pamoate in FEP, likely because several guidelines do not recommended its use. No studies have been published regarding aripiprazole long-acting injectable in FEP. This LAIA formulation was approved in February 2013, and robust studies of the oral formulation in FEP are limited.⁵²

Relapses begin within a few months of illness stabilization after FEP, and >50% of patients relapse within 1 or 2 years²—the recommended minimum treatment dura­tion for FEP.^8,9,13 The use of LAIA is advis­able in any patient with schizophrenia for whom long-term antipsychotic therapy is indicated.⁵⁶ LAIA administration require­ments objectively track medication adher­ence, which allows clinicians to be proactive in relapse prevention. Not using an inter­vention in FEP that improves adherence and decreases relapse rates contradicts our goal of instituting early, effective treatment to improve long-term functional outcomes (Figure 2).²⁹

Considering clozapine in FEP
Guideline recommendations. Schizo-phrenia treatment guidelines and FDA labeling⁵⁷ reserve clozapine for third-line treatment of refractory schizophrenia after 2 adequate antipsychotic trials have failed despite optimal dosing (Table 1).^6-13 Some guidelines specify 1 of the 2 failed anti­psychotic trials must include an SGA.^{6,7,10,11,13-16} Most say clozapine may be considered in patients with chronic aggression or hostility,^7-9,14,16 or suicidal thoughts and behav­iors.^6-8,14,16 TMAP guidelines recommend a clozapine trial with concomitant substance abuse, persistent positive symptoms during 2 years of consistent medication treatment, and after 5 years of inadequate response (“treatment resistance”), regardless of the number of antipsychotic trials.⁷ ­

Rationale and concerns. Clozapine is a superior choice for treatment-refractory delusions or hallucinations of schizophrenia, because it markedly enhances the response rate to antipsychotic therapy.⁵⁸ Researchers therefore have investigated whether clozap­ine, compared with other antipsychotics, would yield more favorable initial and long-term outcomes when used first-line in FEP.

Preliminary evidence. Five studies have explored the use of clozapine as first-line therapy in FEP (Table 4).^59-63 Interpreting the results is difficult because clozapine trials may be brief (mostly, 12 to 52 weeks); lack a comparator arm; suffer from a high attrition rate; enroll few patients; and lack potentially important outcome measures such as nega­tive symptoms, suicidality, and functional assessment.

At present, clozapine has not been shown superior to other antipsychotics as a first-line treatment for FEP. Research does underscore the importance of a clozapine trial as third-line treatment for FEP patients who have not responded well to 2 SGA trials.⁶³ Many of these nonresponders (77%) have demon­strated a favorable response when promptly switched to clozapine.⁶⁴

Discussion and recommendations. The limited evidence argues against using clo­zapine earlier than as third-line treatment in FEP. Perhaps the high treatment response that characterizes FEP creates a ceiling effect that obscures differences in antipsychotic efficacy at this stage.⁶⁵ Clozapine use as first-line treatment should be re-evaluated with more robust methodology. One approach could be to assess its benefit in FEP by the duration of untreated psychosis.

The odds of achieving remission have been shown to decrease by 15% for each year that psychosis has not been treated.⁵⁹ Studies exploring the use of clozapine as a second-line agent for FEP also are warranted, as anti­psychotic response during subsequent trials is substantially reduced. In fact, the Scottish Intercollegiate Guidelines Network guide­lines recommend this as an area for future research.¹¹

For now, clozapine should continue to be reserved as second- or third-line treatment in a patient with FEP. The risks of clozap­ine’s potentially serious adverse effects (eg, agranulocytosis, seizures, obesity, diabe­tes, dyslipidemia, myocarditis, pancreatitis, hypotension, sialorrhea, severe sedation, ileus) can be justified only in the treatment of severe and persistent psychotic symptoms.⁵⁷

Bottom Line
Nonstandard use of antipsychotic monotherapy dosages beyond the approved FDA limit and combination antipsychotic therapy may be reasonable for select first-episode psychosis (FEP) patients. Strongly consider long-acting injectable antipsychotics in FEP to proactively combat the high relapse rate and more easily identify antipsychotic failure. Continue to use clozapine as second- or third-line therapy in FEP: Studies have not found that it is more efficacious than other antipsychotics for first-line use.

Related Resource
• Recovery After an Initial Schizophrenia Episode (RAISE) Project Early Treatment Program. National Institute of Mental Health. http://raiseetp.org.

Drug Brand Names
Aripiprazole • Abilify, Abilify Maintena      
Chlorpromazine • Thorazine                     
Clozapine • Clozaril                              
Fluphenazine decanoate • Prolixin-D      
Haloperidol • Haldol                                      
Haloperidol decanoate • Haldol-D       
Olanzapine • Zyprexa
Olanzapine pamoate • Zyprexa Relprevv
Paliperidone palmitate • Invega Sustenna
Quetiapine • Seroquel
Risperidone • Risperdal
Risperidone microspheres • Risperdal Consta

Disclosures
Dr. Gardner reports no financial relationships with any companies whose products are mentioned in this article or with manufacturers of competing products. Dr. Nasrallah is a consultant to Acadia, Alkermes, Lundbeck, Janssen, Merck, Otsuka, and Sunovion, and is a speaker for Alkermes, Lundbeck, Janssen, Otsuka, and Sunovion.

First-episode psychosis (FEP) in schizophrenia is char­acterized by high response rates to antipsychotic therapy, followed by frequent antipsychotic discon­tinuation and elevated relapse rates soon after mainte­nance treatment begins.^1,2 With subsequent episodes, time to response progressively increases and likelihood of response decreases.^3,4

To address these issues, this article—the second of 2 parts⁵—describes the rationale and evidence for using non­standard first-line antipsychotic therapies to manage FEP. Specifically, we discuss when clinicians might consider mono­therapy exceeding FDA-approved maximum dosages, combi­nation therapy, long-acting injectable antipsychotics (LAIA), or clozapine.

Monotherapy beyond FDA-approved dosages
Treatment guidelines for FEP recommend oral antipsy­chotic dosages in the lower half of the treatment range and lower than those that are required for multi-episode schizo­phrenia.^6-16 Ultimately, clinicians prescribe individualized dosages for their patients based on symptom improvement and tolerability. The optimal dosage at which to achieve a favorable D2 receptor occupancy likely will vary from patient to patient.¹⁷

To control symptoms, higher dosages may be needed than those used in FEP clinical tri­als, recommended by guidelines for FEP or multi-episode patients, or approved by the FDA. Patients seen in everyday practice may be more complicated (eg, have a comorbid condition or history of nonresponse) than study populations. Higher dosages also may be reasonable to overcome drug−drug interactions (eg, cigarette smoking-mediated cytochrome P450 1A2 induction, resulting in increased olanzapine metabolism),¹⁸ or to establish antipsychotic failure if adequate trials at lower dosages have resulted in a suboptimal response and the patient is not experiencing tolerability or safety concerns.

In a study of low-, full-, and high-dosage antipsychotic therapy in FEP, an additional 15% of patients responded to higher dos­ages of olanzapine and risperidone after failing to respond to a standard dosage.¹⁹ A study of data from the Recovery After an Initial Schizophrenia Episode Project’s Early Treatment Program (RAISE-ETP) found that, of participants identified who may benefit from therapy modification, 8.8% were pre­scribed an antipsychotic (often, olanzapine, risperidone, and haloperidol) at a higher-than-recommended dosage.²⁰ Of note, only olanzapine was prescribed at higher than FDA-approved dosages.

Antipsychotic combination therapy
Prescribing combinations of antipsychot­ics—antipsychotic polypharmacy (APP)— has a negative connotation because of limited efficacy and safety data,²¹ and limited endorsement in schizophrenia treatment guidelines.^9,13 Caution with APP is war­ranted; a complex medication regimen may increase the potential for adverse effects, poorer adherence, and adverse drug-drug interactions.⁹ APP has been shown to inde­pendently predict both shorter treatment duration and discontinuation before 1 year.²²

Nonetheless, the clinician and patient may share the decision to implement APP and observe whether benefits outweigh risks in situations such as:
   • to optimize neuroreceptor occupancy and targets (eg, attempting to achieve ade­quate D2 receptor blockade while minimiz­ing side effects secondary to binding other receptors)
   • to manage co-existing symptom domains (eg, mood changes, aggression, negative symptoms, disorganization, and cognitive deficits)
   • to mitigate antipsychotic-induced side effects (eg, initiating aripiprazole to treat hyperprolactinemia induced by another anti­psychotic to which the patient has achieved a favorable response).²³

Clinicians report using APP to treat as many as 50% of patients with a history of multiple psychotic episodes.²³ For FEP patients, 23% of participants in the RAISE-ETP trial who were identified as possibly benefiting from therapy modification were prescribed APP.²⁰ Regrettably, research­ers have not found evidence to support a reported rationale for using APP—that lower dosages of individual antipsychotics when used in combination may avoid high-dosage prescriptions.²⁴

Before implementing APP, thoroughly explore and manage reasons for a patient’s suboptimal response to monotherapy.25 An adequate trial with any antipsychotic should be at the highest tolerated dosage for 12 to 16 weeks. Be mindful that response to an APP trial may be the result of additional time on the original antipsychotic.

Long-acting injectable antipsychotics in FEP
Guideline recommendations. Most older guidelines for schizophrenia treat­ment suggest LAIA after multiple relapses related to medication nonadherence or when a patient prefers injected medica­tion (Table 1).^6-13 Expert consensus guide­lines also recommend considering LAIA in patients who lack insight into their illness. The Texas Medication Algorithm Project (TMAP) guidelines⁷ state LAIA can be con­sidered for inadequate adherence at any stage, whereas the 2010 British Association for Psychopharmacology (BAP) guide­lines⁹ express uncertainty about their use in FEP, because of limited evidence. Both the BAP and National Institute for Health and Care Excellence guidelines¹³ urge cli­nicians to consider LAIA when avoiding nonadherence is a treatment priority.

Barriers to LAIA use include:
   • slow dosage titration and increased time to reach steady state drug level
   • oral supplementation for some (eg, risperidone microspheres and aripiprazole long-acting injectable)
   • logistical challenges for some (eg, 3-hour post-injection monitoring for delir­ium sedation syndrome with olanzapine pamoate)
   • additional planning to coordinate care for scheduled injections
   • higher expenses up front
   • local injection site reactions
   • dosage adjustment difficulties if adverse effects occur.^28,29

Adoption rates of LAIA are low, especially for FEP.³⁰ Most surveys indicate that (1) physi­cians believe LAIA treatment is ineffective for FEP31 and (2) patients do not prefer injectable to oral antipsychotics,³² despite evidence to the contrary.^33,34 A survey of 198 psychiatrists identified 3 factors that influenced their deci­sions against using LAIA patients with FEP:
   • limited availability of SGA depot formu­lations (4, to date, in the United States)
   • frequent rejection by the patient when LAIA is offered without adequate expla­nation or encouragement
   • skepticism of FEP patients (and their family) who lack experience with relapse.³⁵

In reality, when SGA depots were intro­duced in the United Kingdom, prescribing rates of LAIA did not increase. As for patient rejection being a major reason for not pre­scribing LAIA, few patients (5% to 36%) are offered depot injections, particularly in FEP.²⁹ Most patients using LAIA are chronic, multi-episode, violent people who are receiving medications involuntarily.²⁹ Interestingly, this survey did not find 2 factors to be influential in psychiatrists’ decision not to use LAIA in FEP:
   • guidelines do not explicitly recommend depot treatment in FEP
   • treatment in FEP may be limited to 1 year, therefore depot administration is not worthwhile.³⁵

Preliminary evidence. At least a dozen stud­ies have explored LAIA treatment for FEP, with the use of fluphenazine decanoate,³⁶ per­phenazine enanthate³⁷ (discontinued), and risperidone microspheres.^37-48 The research demonstrates the efficacy and safety of LAIA in FEP as measured by these endpoints:
   • improved symptom control^{38,40-43,46,48}
   • adherence^43,44,48
   • reduced relapse rates^37,43 and rehospitalizations^37,47
   • lesser reductions in white matter brain volume⁴⁵
   • no differences in extrapyramidal side effects or prolactin-associated adverse effects.⁴⁸

A few small studies demonstrate signifi­cant differences in outcomes between ris­peridone LAIA and oral comparator groups (Table 3).^43-45 Ongoing studies of LAIA use in FEP are comparing paliperidone palmitate with risperidone microspheres and other oral antipsychotics.^49-51 No stud­ies are examining olanzapine pamoate in FEP, likely because several guidelines do not recommended its use. No studies have been published regarding aripiprazole long-acting injectable in FEP. This LAIA formulation was approved in February 2013, and robust studies of the oral formulation in FEP are limited.⁵²

Relapses begin within a few months of illness stabilization after FEP, and >50% of patients relapse within 1 or 2 years²—the recommended minimum treatment dura­tion for FEP.^8,9,13 The use of LAIA is advis­able in any patient with schizophrenia for whom long-term antipsychotic therapy is indicated.⁵⁶ LAIA administration require­ments objectively track medication adher­ence, which allows clinicians to be proactive in relapse prevention. Not using an inter­vention in FEP that improves adherence and decreases relapse rates contradicts our goal of instituting early, effective treatment to improve long-term functional outcomes (Figure 2).²⁹

Considering clozapine in FEP
Guideline recommendations. Schizo-phrenia treatment guidelines and FDA labeling⁵⁷ reserve clozapine for third-line treatment of refractory schizophrenia after 2 adequate antipsychotic trials have failed despite optimal dosing (Table 1).^6-13 Some guidelines specify 1 of the 2 failed anti­psychotic trials must include an SGA.^{6,7,10,11,13-16} Most say clozapine may be considered in patients with chronic aggression or hostility,^7-9,14,16 or suicidal thoughts and behav­iors.^6-8,14,16 TMAP guidelines recommend a clozapine trial with concomitant substance abuse, persistent positive symptoms during 2 years of consistent medication treatment, and after 5 years of inadequate response (“treatment resistance”), regardless of the number of antipsychotic trials.⁷ ­

Rationale and concerns. Clozapine is a superior choice for treatment-refractory delusions or hallucinations of schizophrenia, because it markedly enhances the response rate to antipsychotic therapy.⁵⁸ Researchers therefore have investigated whether clozap­ine, compared with other antipsychotics, would yield more favorable initial and long-term outcomes when used first-line in FEP.

Preliminary evidence. Five studies have explored the use of clozapine as first-line therapy in FEP (Table 4).^59-63 Interpreting the results is difficult because clozapine trials may be brief (mostly, 12 to 52 weeks); lack a comparator arm; suffer from a high attrition rate; enroll few patients; and lack potentially important outcome measures such as nega­tive symptoms, suicidality, and functional assessment.

At present, clozapine has not been shown superior to other antipsychotics as a first-line treatment for FEP. Research does underscore the importance of a clozapine trial as third-line treatment for FEP patients who have not responded well to 2 SGA trials.⁶³ Many of these nonresponders (77%) have demon­strated a favorable response when promptly switched to clozapine.⁶⁴

Discussion and recommendations. The limited evidence argues against using clo­zapine earlier than as third-line treatment in FEP. Perhaps the high treatment response that characterizes FEP creates a ceiling effect that obscures differences in antipsychotic efficacy at this stage.⁶⁵ Clozapine use as first-line treatment should be re-evaluated with more robust methodology. One approach could be to assess its benefit in FEP by the duration of untreated psychosis.

The odds of achieving remission have been shown to decrease by 15% for each year that psychosis has not been treated.⁵⁹ Studies exploring the use of clozapine as a second-line agent for FEP also are warranted, as anti­psychotic response during subsequent trials is substantially reduced. In fact, the Scottish Intercollegiate Guidelines Network guide­lines recommend this as an area for future research.¹¹

For now, clozapine should continue to be reserved as second- or third-line treatment in a patient with FEP. The risks of clozap­ine’s potentially serious adverse effects (eg, agranulocytosis, seizures, obesity, diabe­tes, dyslipidemia, myocarditis, pancreatitis, hypotension, sialorrhea, severe sedation, ileus) can be justified only in the treatment of severe and persistent psychotic symptoms.⁵⁷

Bottom Line
Nonstandard use of antipsychotic monotherapy dosages beyond the approved FDA limit and combination antipsychotic therapy may be reasonable for select first-episode psychosis (FEP) patients. Strongly consider long-acting injectable antipsychotics in FEP to proactively combat the high relapse rate and more easily identify antipsychotic failure. Continue to use clozapine as second- or third-line therapy in FEP: Studies have not found that it is more efficacious than other antipsychotics for first-line use.

Related Resource
• Recovery After an Initial Schizophrenia Episode (RAISE) Project Early Treatment Program. National Institute of Mental Health. http://raiseetp.org.

Drug Brand Names
Aripiprazole • Abilify, Abilify Maintena      
Chlorpromazine • Thorazine                     
Clozapine • Clozaril                              
Fluphenazine decanoate • Prolixin-D      
Haloperidol • Haldol                                      
Haloperidol decanoate • Haldol-D       
Olanzapine • Zyprexa
Olanzapine pamoate • Zyprexa Relprevv
Paliperidone palmitate • Invega Sustenna
Quetiapine • Seroquel
Risperidone • Risperdal
Risperidone microspheres • Risperdal Consta

Disclosures
Dr. Gardner reports no financial relationships with any companies whose products are mentioned in this article or with manufacturers of competing products. Dr. Nasrallah is a consultant to Acadia, Alkermes, Lundbeck, Janssen, Merck, Otsuka, and Sunovion, and is a speaker for Alkermes, Lundbeck, Janssen, Otsuka, and Sunovion.

First-episode psychosis (FEP) in schizophrenia is char­acterized by high response rates to antipsychotic therapy, followed by frequent antipsychotic discon­tinuation and elevated relapse rates soon after mainte­nance treatment begins.^1,2 With subsequent episodes, time to response progressively increases and likelihood of response decreases.^3,4

To address these issues, this article—the second of 2 parts⁵—describes the rationale and evidence for using non­standard first-line antipsychotic therapies to manage FEP. Specifically, we discuss when clinicians might consider mono­therapy exceeding FDA-approved maximum dosages, combi­nation therapy, long-acting injectable antipsychotics (LAIA), or clozapine.

Monotherapy beyond FDA-approved dosages
Treatment guidelines for FEP recommend oral antipsy­chotic dosages in the lower half of the treatment range and lower than those that are required for multi-episode schizo­phrenia.^6-16 Ultimately, clinicians prescribe individualized dosages for their patients based on symptom improvement and tolerability. The optimal dosage at which to achieve a favorable D2 receptor occupancy likely will vary from patient to patient.¹⁷

To control symptoms, higher dosages may be needed than those used in FEP clinical tri­als, recommended by guidelines for FEP or multi-episode patients, or approved by the FDA. Patients seen in everyday practice may be more complicated (eg, have a comorbid condition or history of nonresponse) than study populations. Higher dosages also may be reasonable to overcome drug−drug interactions (eg, cigarette smoking-mediated cytochrome P450 1A2 induction, resulting in increased olanzapine metabolism),¹⁸ or to establish antipsychotic failure if adequate trials at lower dosages have resulted in a suboptimal response and the patient is not experiencing tolerability or safety concerns.

In a study of low-, full-, and high-dosage antipsychotic therapy in FEP, an additional 15% of patients responded to higher dos­ages of olanzapine and risperidone after failing to respond to a standard dosage.¹⁹ A study of data from the Recovery After an Initial Schizophrenia Episode Project’s Early Treatment Program (RAISE-ETP) found that, of participants identified who may benefit from therapy modification, 8.8% were pre­scribed an antipsychotic (often, olanzapine, risperidone, and haloperidol) at a higher-than-recommended dosage.²⁰ Of note, only olanzapine was prescribed at higher than FDA-approved dosages.

Antipsychotic combination therapy
Prescribing combinations of antipsychot­ics—antipsychotic polypharmacy (APP)— has a negative connotation because of limited efficacy and safety data,²¹ and limited endorsement in schizophrenia treatment guidelines.^9,13 Caution with APP is war­ranted; a complex medication regimen may increase the potential for adverse effects, poorer adherence, and adverse drug-drug interactions.⁹ APP has been shown to inde­pendently predict both shorter treatment duration and discontinuation before 1 year.²²

Nonetheless, the clinician and patient may share the decision to implement APP and observe whether benefits outweigh risks in situations such as:
   • to optimize neuroreceptor occupancy and targets (eg, attempting to achieve ade­quate D2 receptor blockade while minimiz­ing side effects secondary to binding other receptors)
   • to manage co-existing symptom domains (eg, mood changes, aggression, negative symptoms, disorganization, and cognitive deficits)
   • to mitigate antipsychotic-induced side effects (eg, initiating aripiprazole to treat hyperprolactinemia induced by another anti­psychotic to which the patient has achieved a favorable response).²³

Clinicians report using APP to treat as many as 50% of patients with a history of multiple psychotic episodes.²³ For FEP patients, 23% of participants in the RAISE-ETP trial who were identified as possibly benefiting from therapy modification were prescribed APP.²⁰ Regrettably, research­ers have not found evidence to support a reported rationale for using APP—that lower dosages of individual antipsychotics when used in combination may avoid high-dosage prescriptions.²⁴

Before implementing APP, thoroughly explore and manage reasons for a patient’s suboptimal response to monotherapy.25 An adequate trial with any antipsychotic should be at the highest tolerated dosage for 12 to 16 weeks. Be mindful that response to an APP trial may be the result of additional time on the original antipsychotic.

Long-acting injectable antipsychotics in FEP
Guideline recommendations. Most older guidelines for schizophrenia treat­ment suggest LAIA after multiple relapses related to medication nonadherence or when a patient prefers injected medica­tion (Table 1).^6-13 Expert consensus guide­lines also recommend considering LAIA in patients who lack insight into their illness. The Texas Medication Algorithm Project (TMAP) guidelines⁷ state LAIA can be con­sidered for inadequate adherence at any stage, whereas the 2010 British Association for Psychopharmacology (BAP) guide­lines⁹ express uncertainty about their use in FEP, because of limited evidence. Both the BAP and National Institute for Health and Care Excellence guidelines¹³ urge cli­nicians to consider LAIA when avoiding nonadherence is a treatment priority.

Barriers to LAIA use include:
   • slow dosage titration and increased time to reach steady state drug level
   • oral supplementation for some (eg, risperidone microspheres and aripiprazole long-acting injectable)
   • logistical challenges for some (eg, 3-hour post-injection monitoring for delir­ium sedation syndrome with olanzapine pamoate)
   • additional planning to coordinate care for scheduled injections
   • higher expenses up front
   • local injection site reactions
   • dosage adjustment difficulties if adverse effects occur.^28,29

Adoption rates of LAIA are low, especially for FEP.³⁰ Most surveys indicate that (1) physi­cians believe LAIA treatment is ineffective for FEP31 and (2) patients do not prefer injectable to oral antipsychotics,³² despite evidence to the contrary.^33,34 A survey of 198 psychiatrists identified 3 factors that influenced their deci­sions against using LAIA patients with FEP:
   • limited availability of SGA depot formu­lations (4, to date, in the United States)
   • frequent rejection by the patient when LAIA is offered without adequate expla­nation or encouragement
   • skepticism of FEP patients (and their family) who lack experience with relapse.³⁵

In reality, when SGA depots were intro­duced in the United Kingdom, prescribing rates of LAIA did not increase. As for patient rejection being a major reason for not pre­scribing LAIA, few patients (5% to 36%) are offered depot injections, particularly in FEP.²⁹ Most patients using LAIA are chronic, multi-episode, violent people who are receiving medications involuntarily.²⁹ Interestingly, this survey did not find 2 factors to be influential in psychiatrists’ decision not to use LAIA in FEP:
   • guidelines do not explicitly recommend depot treatment in FEP
   • treatment in FEP may be limited to 1 year, therefore depot administration is not worthwhile.³⁵

Preliminary evidence. At least a dozen stud­ies have explored LAIA treatment for FEP, with the use of fluphenazine decanoate,³⁶ per­phenazine enanthate³⁷ (discontinued), and risperidone microspheres.^37-48 The research demonstrates the efficacy and safety of LAIA in FEP as measured by these endpoints:
   • improved symptom control^{38,40-43,46,48}
   • adherence^43,44,48
   • reduced relapse rates^37,43 and rehospitalizations^37,47
   • lesser reductions in white matter brain volume⁴⁵
   • no differences in extrapyramidal side effects or prolactin-associated adverse effects.⁴⁸

A few small studies demonstrate signifi­cant differences in outcomes between ris­peridone LAIA and oral comparator groups (Table 3).^43-45 Ongoing studies of LAIA use in FEP are comparing paliperidone palmitate with risperidone microspheres and other oral antipsychotics.^49-51 No stud­ies are examining olanzapine pamoate in FEP, likely because several guidelines do not recommended its use. No studies have been published regarding aripiprazole long-acting injectable in FEP. This LAIA formulation was approved in February 2013, and robust studies of the oral formulation in FEP are limited.⁵²

Relapses begin within a few months of illness stabilization after FEP, and >50% of patients relapse within 1 or 2 years²—the recommended minimum treatment dura­tion for FEP.^8,9,13 The use of LAIA is advis­able in any patient with schizophrenia for whom long-term antipsychotic therapy is indicated.⁵⁶ LAIA administration require­ments objectively track medication adher­ence, which allows clinicians to be proactive in relapse prevention. Not using an inter­vention in FEP that improves adherence and decreases relapse rates contradicts our goal of instituting early, effective treatment to improve long-term functional outcomes (Figure 2).²⁹

Considering clozapine in FEP
Guideline recommendations. Schizo-phrenia treatment guidelines and FDA labeling⁵⁷ reserve clozapine for third-line treatment of refractory schizophrenia after 2 adequate antipsychotic trials have failed despite optimal dosing (Table 1).^6-13 Some guidelines specify 1 of the 2 failed anti­psychotic trials must include an SGA.^{6,7,10,11,13-16} Most say clozapine may be considered in patients with chronic aggression or hostility,^7-9,14,16 or suicidal thoughts and behav­iors.^6-8,14,16 TMAP guidelines recommend a clozapine trial with concomitant substance abuse, persistent positive symptoms during 2 years of consistent medication treatment, and after 5 years of inadequate response (“treatment resistance”), regardless of the number of antipsychotic trials.⁷ ­

Rationale and concerns. Clozapine is a superior choice for treatment-refractory delusions or hallucinations of schizophrenia, because it markedly enhances the response rate to antipsychotic therapy.⁵⁸ Researchers therefore have investigated whether clozap­ine, compared with other antipsychotics, would yield more favorable initial and long-term outcomes when used first-line in FEP.

Preliminary evidence. Five studies have explored the use of clozapine as first-line therapy in FEP (Table 4).^59-63 Interpreting the results is difficult because clozapine trials may be brief (mostly, 12 to 52 weeks); lack a comparator arm; suffer from a high attrition rate; enroll few patients; and lack potentially important outcome measures such as nega­tive symptoms, suicidality, and functional assessment.

At present, clozapine has not been shown superior to other antipsychotics as a first-line treatment for FEP. Research does underscore the importance of a clozapine trial as third-line treatment for FEP patients who have not responded well to 2 SGA trials.⁶³ Many of these nonresponders (77%) have demon­strated a favorable response when promptly switched to clozapine.⁶⁴

Discussion and recommendations. The limited evidence argues against using clo­zapine earlier than as third-line treatment in FEP. Perhaps the high treatment response that characterizes FEP creates a ceiling effect that obscures differences in antipsychotic efficacy at this stage.⁶⁵ Clozapine use as first-line treatment should be re-evaluated with more robust methodology. One approach could be to assess its benefit in FEP by the duration of untreated psychosis.

The odds of achieving remission have been shown to decrease by 15% for each year that psychosis has not been treated.⁵⁹ Studies exploring the use of clozapine as a second-line agent for FEP also are warranted, as anti­psychotic response during subsequent trials is substantially reduced. In fact, the Scottish Intercollegiate Guidelines Network guide­lines recommend this as an area for future research.¹¹

For now, clozapine should continue to be reserved as second- or third-line treatment in a patient with FEP. The risks of clozap­ine’s potentially serious adverse effects (eg, agranulocytosis, seizures, obesity, diabe­tes, dyslipidemia, myocarditis, pancreatitis, hypotension, sialorrhea, severe sedation, ileus) can be justified only in the treatment of severe and persistent psychotic symptoms.⁵⁷

Bottom Line
Nonstandard use of antipsychotic monotherapy dosages beyond the approved FDA limit and combination antipsychotic therapy may be reasonable for select first-episode psychosis (FEP) patients. Strongly consider long-acting injectable antipsychotics in FEP to proactively combat the high relapse rate and more easily identify antipsychotic failure. Continue to use clozapine as second- or third-line therapy in FEP: Studies have not found that it is more efficacious than other antipsychotics for first-line use.

Related Resource
• Recovery After an Initial Schizophrenia Episode (RAISE) Project Early Treatment Program. National Institute of Mental Health. http://raiseetp.org.

Drug Brand Names
Aripiprazole • Abilify, Abilify Maintena      
Chlorpromazine • Thorazine                     
Clozapine • Clozaril                              
Fluphenazine decanoate • Prolixin-D      
Haloperidol • Haldol                                      
Haloperidol decanoate • Haldol-D       
Olanzapine • Zyprexa
Olanzapine pamoate • Zyprexa Relprevv
Paliperidone palmitate • Invega Sustenna
Quetiapine • Seroquel
Risperidone • Risperdal
Risperidone microspheres • Risperdal Consta

Disclosures
Dr. Gardner reports no financial relationships with any companies whose products are mentioned in this article or with manufacturers of competing products. Dr. Nasrallah is a consultant to Acadia, Alkermes, Lundbeck, Janssen, Merck, Otsuka, and Sunovion, and is a speaker for Alkermes, Lundbeck, Janssen, Otsuka, and Sunovion.

Mr. T,  age 23, was given a diagnosis of bipolar disorder 1 year ago. After he experienced inadequate symp­tom relief with valproate, you switched him to extended-release lithium, 1,200 mg/d. Mr. T reported improved mood and stability with this medication adjustment. These posi­tive changes led him to resume activities he enjoyed before onset of bipolar disorder, such as running, reading, and going out to dinner with friends.

Now, Mr. T’s mother calls your office to express concern about her son’s slight

hand tremor, which appeared after 2 days of gas­trointestinal distress. She tells you that Mr. T sprained his ankle while running 1 week ago and has been taking over-the-counter ibu­profen for pain relief, which he did often in the past.

You suspect that Mr. T is experiencing lith­ium toxicity as a result of ibuprofen use.

Although mental health providers can eas­ily recognize the drug−drug interaction between lithium and nonsteroidal anti-inflammatory drugs (NSAIDs) that Mr. T experienced, interpreting the safety of a medication regimen with respect to drug− drug interactions before prescribing often is more daunting. This article reviews the basics of drug−drug interactions, while briefly highlighting common examples in psychiatric medicine (Table 1^1-5). We also provide an outline of additional points to consider when reviewing your patients’ medication regimens and encoun­tering unfamiliar drug−drug interactions.

Types of drug−drug interactions
Drug−drug interactions fall into 2 catego­ries: pharmacodynamic (PD) and pharmaco­kinetic (PK):
   • PD interactions are a result of the com­bined impact of medications on the body when there is no direct effect on absorp­tion, distribution, metabolism, or excretion characteristics, such as 2 medications that act at the same receptor or lead to similar or opposing pharmacologic effects.
   • PK interactions occur when a drug affects the absorption, distribution, metabo­lism, or excretion characteristics of another drug.

Although it is possible that drug−drug interactions will have no clinical effect, when the impact of a PD or PK drug−drug interaction is evident, it likely is the result of additive, synergistic, or antago­nistic consequences on the medications’ intended impact or side-effect profile.

Pharmacodynamic interactions
Serotonin syndrome. The potential for serotonin syndrome occurs when medica­tions that increase synaptic serotonin con­centration are used concomitantly.¹ This can occur through several mechanisms, including increased serotonin release, decreased reuptake, or decreased sero­tonin metabolism. A high serotonin con­centration in the CNS and in the periphery overstimulates serotonin receptors, lead­ing to signs and symptoms that can include diarrhea, fever, delirium, coma, and poten­tially death.

QT prolongation and anticholinergic toxicity are further examples of additive PD drug−drug interactions. Anticholinergic toxicity is possible when multiple medica­tions contribute to inhibition of the neuro-transmitter acetylcholine at muscarinic receptors. This leads to adverse effects such as dry mouth, constipation, confusion, and urinary retention.

QT prolongation, which can lead to arrhythmia, occurs when a patient is taking several medications that can increase the QT interval. Consider close monitoring and using alternative agents with less poten­tial to increase the QT interval in patients at risk of arrhythmias (geriatric patients, those with an increased QT interval at base­line, etc.).

Decreased seizure threshold. The increased risk of seizures with bupropion and other medications that lower the sei­zure threshold is another example of an additive PD drug interaction. Bupropion can increase the risk of seizures in a dose-dependent manner, which increases when bupropion is taken with other drugs that lower the seizure threshold.6 Seizure risk associated with alcohol or benzodiazepine withdrawal also may increase the risk for this interaction.

Of note, the increased risk of seizures with the combination of bupropion and alcohol in the absence of withdrawal is not well studied in humans, but positive corre­lation has been seen in an animal study.⁶

Decreased platelet function. Another example of a PD drug−drug interaction is increased risk of bleeding when a selec­tive serotonin reuptake inhibitor is used with a NSAID or oral anticoagulant. The proposed mechanism for this interaction is that blocking serotonin reuptake on platelets leads to decreased platelet func­tion and an increased risk for prolonged bleeding.7 This is somewhat controversial because, first, it has been noted that drugs with the highest degree of serotonin reup­take inhibition do not always cause the highest risk of bleeding and, second, most of the evidence for this interaction is from observational studies.⁷

This potential interaction could be most important for patients who need an anti­depressant, are on chronic NSAID or anti­coagulant therapy, and are at high risk of bleeding.

Pharmacokinetic interactions
PK interactions in psychiatry often are caused by interference of drug metabo­lizing enzymes. The cytochrome P450 (CYP450) family of metabolizing enzymes in particular is important to the break­down of medications in the body. Many drug−drug interactions involve medica­tions that can inhibit or induce metabolism of other drugs through their effect on the CYP450 system.

Inhibition interactions. When a drug’s metabolism is inhibited, the result is usu­ally increased serum concentration of that medication (because of less break­down) and a more potent impact on the primary mechanism of action or adverse effects. Sometimes, inhibiting metabo­lism can lead to decreased clinical effect. Tamoxifen (an oral agent used to treat breast cancer) and certain analgesics when used in combination with moderate or strong inhibitors of the CYP2D6 subfam­ily of CYP450 metabolizing enzymes are 2 examples of metabolism inhibition lead­ing to decreased efficacy.⁸ Both tamoxi­fen and the analgesics listed in Table 1^1-5 are prodrugs; that is, they must be metabolized to be active. When the enzymes that metabolize these drugs into their active form are inhibited, the concen­tration of active drug decreases.

Induction interactions. Alternatively, there is an increased rate of drug break­down and resulting decrease in effect when drugs that induce the activity of metabolizing enzymes are used with med­ications that are substrates of the same enzyme. Carbamazepine is commonly involved in this type of drug interaction because it is a strong inducer of CYP 1A2, 2B6, 2C19, 2C9, and 3A4, and the p-glyco­protein drug efflux pump.⁹ As a result of this rampant induction, carbamazepine can decrease the serum concentration of oral contraceptives below a reliably effec­tive level. Therefore, it is recommended that women of childbearing potential use other contraceptive methods, such as a progestin implant or an intrauterine device.¹⁰

In addition, the polycyclic aromatic hydrocarbons found in cigarettes induce activity of CYP1A2. Patients who smoke and use medications metabolized by this enzyme, such as clozapine and olanzap­ine, may need a higher dosage.

Drug elimination interactions
The last drug−drug interaction discussed here returns the discussion to Mr. T and involves drug elimination.² The NSAIDs Mr. T was using for pain likely caused decreased renal excretion of lithium. Because lithium is primarily excreted through the kidneys, Mr. T’s NSAID use, possibly in com­bination with dehydration caused by gastro­intestinal distress, resulted in lithium toxicity. This class of analgesics should be avoided or used cautiously in patients taking lithium.

Clinical applications
The relatively common drug−drug interac­tions discussed here are just a fraction of the potential interactions mental health practi­tioners see on a daily basis. Understanding the basics of PD and PK interactions in the setting of patient-specific factors can help to clarify the information found in drug−drug interaction databases, such as Micromedex, Lexicomp, Facts and Comparisons, and Epocrates. Table 2 lists additional insights into drug interactions.

Related Resources
• CredibleMeds. Online resource on QT prolonging drugs. http://crediblemeds.org.
• Madhusoodanan S, Velama U, Parmar J, et al. A current review of cytochrome P450 interactions of psychotropic drugs. Ann Clin Psychiatry. 2014;26(2):120-138.

Drug Brand Names
Benztropine • Cogentin                            Olanzapine • Zyprexa
Bupropion • Wellbutrin                             Oxycodone • Oxycontin
Carbamazepine • Tegretol                        Paroxetine • Paxil
Clozapine • Clozaril                                  Quetiapine • Seroquel
Diphenhydramine • Benadryl                     Sertraline • Zoloft
 Duloxetine • Cymbalta                             Tamoxifen • Soltamox
Fluoxetine • Prozac                                   Trazodone • Desyrel
Lithium • Eskalith, Lithobid                        Valproate • Divalproex
Haloperidol • Haldol                                  Ziprasidone • Geodon
Hydrocodone • Vicodin

Disclosure
The authors report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

Mr. T,  age 23, was given a diagnosis of bipolar disorder 1 year ago. After he experienced inadequate symp­tom relief with valproate, you switched him to extended-release lithium, 1,200 mg/d. Mr. T reported improved mood and stability with this medication adjustment. These posi­tive changes led him to resume activities he enjoyed before onset of bipolar disorder, such as running, reading, and going out to dinner with friends.

Now, Mr. T’s mother calls your office to express concern about her son’s slight

hand tremor, which appeared after 2 days of gas­trointestinal distress. She tells you that Mr. T sprained his ankle while running 1 week ago and has been taking over-the-counter ibu­profen for pain relief, which he did often in the past.

You suspect that Mr. T is experiencing lith­ium toxicity as a result of ibuprofen use.

Although mental health providers can eas­ily recognize the drug−drug interaction between lithium and nonsteroidal anti-inflammatory drugs (NSAIDs) that Mr. T experienced, interpreting the safety of a medication regimen with respect to drug− drug interactions before prescribing often is more daunting. This article reviews the basics of drug−drug interactions, while briefly highlighting common examples in psychiatric medicine (Table 1^1-5). We also provide an outline of additional points to consider when reviewing your patients’ medication regimens and encoun­tering unfamiliar drug−drug interactions.

Types of drug−drug interactions
Drug−drug interactions fall into 2 catego­ries: pharmacodynamic (PD) and pharmaco­kinetic (PK):
   • PD interactions are a result of the com­bined impact of medications on the body when there is no direct effect on absorp­tion, distribution, metabolism, or excretion characteristics, such as 2 medications that act at the same receptor or lead to similar or opposing pharmacologic effects.
   • PK interactions occur when a drug affects the absorption, distribution, metabo­lism, or excretion characteristics of another drug.

Although it is possible that drug−drug interactions will have no clinical effect, when the impact of a PD or PK drug−drug interaction is evident, it likely is the result of additive, synergistic, or antago­nistic consequences on the medications’ intended impact or side-effect profile.

Pharmacodynamic interactions
Serotonin syndrome. The potential for serotonin syndrome occurs when medica­tions that increase synaptic serotonin con­centration are used concomitantly.¹ This can occur through several mechanisms, including increased serotonin release, decreased reuptake, or decreased sero­tonin metabolism. A high serotonin con­centration in the CNS and in the periphery overstimulates serotonin receptors, lead­ing to signs and symptoms that can include diarrhea, fever, delirium, coma, and poten­tially death.

QT prolongation and anticholinergic toxicity are further examples of additive PD drug−drug interactions. Anticholinergic toxicity is possible when multiple medica­tions contribute to inhibition of the neuro-transmitter acetylcholine at muscarinic receptors. This leads to adverse effects such as dry mouth, constipation, confusion, and urinary retention.

QT prolongation, which can lead to arrhythmia, occurs when a patient is taking several medications that can increase the QT interval. Consider close monitoring and using alternative agents with less poten­tial to increase the QT interval in patients at risk of arrhythmias (geriatric patients, those with an increased QT interval at base­line, etc.).

Decreased seizure threshold. The increased risk of seizures with bupropion and other medications that lower the sei­zure threshold is another example of an additive PD drug interaction. Bupropion can increase the risk of seizures in a dose-dependent manner, which increases when bupropion is taken with other drugs that lower the seizure threshold.6 Seizure risk associated with alcohol or benzodiazepine withdrawal also may increase the risk for this interaction.

Of note, the increased risk of seizures with the combination of bupropion and alcohol in the absence of withdrawal is not well studied in humans, but positive corre­lation has been seen in an animal study.⁶

Decreased platelet function. Another example of a PD drug−drug interaction is increased risk of bleeding when a selec­tive serotonin reuptake inhibitor is used with a NSAID or oral anticoagulant. The proposed mechanism for this interaction is that blocking serotonin reuptake on platelets leads to decreased platelet func­tion and an increased risk for prolonged bleeding.7 This is somewhat controversial because, first, it has been noted that drugs with the highest degree of serotonin reup­take inhibition do not always cause the highest risk of bleeding and, second, most of the evidence for this interaction is from observational studies.⁷

This potential interaction could be most important for patients who need an anti­depressant, are on chronic NSAID or anti­coagulant therapy, and are at high risk of bleeding.

Pharmacokinetic interactions
PK interactions in psychiatry often are caused by interference of drug metabo­lizing enzymes. The cytochrome P450 (CYP450) family of metabolizing enzymes in particular is important to the break­down of medications in the body. Many drug−drug interactions involve medica­tions that can inhibit or induce metabolism of other drugs through their effect on the CYP450 system.

Inhibition interactions. When a drug’s metabolism is inhibited, the result is usu­ally increased serum concentration of that medication (because of less break­down) and a more potent impact on the primary mechanism of action or adverse effects. Sometimes, inhibiting metabo­lism can lead to decreased clinical effect. Tamoxifen (an oral agent used to treat breast cancer) and certain analgesics when used in combination with moderate or strong inhibitors of the CYP2D6 subfam­ily of CYP450 metabolizing enzymes are 2 examples of metabolism inhibition lead­ing to decreased efficacy.⁸ Both tamoxi­fen and the analgesics listed in Table 1^1-5 are prodrugs; that is, they must be metabolized to be active. When the enzymes that metabolize these drugs into their active form are inhibited, the concen­tration of active drug decreases.

Induction interactions. Alternatively, there is an increased rate of drug break­down and resulting decrease in effect when drugs that induce the activity of metabolizing enzymes are used with med­ications that are substrates of the same enzyme. Carbamazepine is commonly involved in this type of drug interaction because it is a strong inducer of CYP 1A2, 2B6, 2C19, 2C9, and 3A4, and the p-glyco­protein drug efflux pump.⁹ As a result of this rampant induction, carbamazepine can decrease the serum concentration of oral contraceptives below a reliably effec­tive level. Therefore, it is recommended that women of childbearing potential use other contraceptive methods, such as a progestin implant or an intrauterine device.¹⁰

In addition, the polycyclic aromatic hydrocarbons found in cigarettes induce activity of CYP1A2. Patients who smoke and use medications metabolized by this enzyme, such as clozapine and olanzap­ine, may need a higher dosage.

Drug elimination interactions
The last drug−drug interaction discussed here returns the discussion to Mr. T and involves drug elimination.² The NSAIDs Mr. T was using for pain likely caused decreased renal excretion of lithium. Because lithium is primarily excreted through the kidneys, Mr. T’s NSAID use, possibly in com­bination with dehydration caused by gastro­intestinal distress, resulted in lithium toxicity. This class of analgesics should be avoided or used cautiously in patients taking lithium.

Clinical applications
The relatively common drug−drug interac­tions discussed here are just a fraction of the potential interactions mental health practi­tioners see on a daily basis. Understanding the basics of PD and PK interactions in the setting of patient-specific factors can help to clarify the information found in drug−drug interaction databases, such as Micromedex, Lexicomp, Facts and Comparisons, and Epocrates. Table 2 lists additional insights into drug interactions.

Related Resources
• CredibleMeds. Online resource on QT prolonging drugs. http://crediblemeds.org.
• Madhusoodanan S, Velama U, Parmar J, et al. A current review of cytochrome P450 interactions of psychotropic drugs. Ann Clin Psychiatry. 2014;26(2):120-138.

Drug Brand Names
Benztropine • Cogentin                            Olanzapine • Zyprexa
Bupropion • Wellbutrin                             Oxycodone • Oxycontin
Carbamazepine • Tegretol                        Paroxetine • Paxil
Clozapine • Clozaril                                  Quetiapine • Seroquel
Diphenhydramine • Benadryl                     Sertraline • Zoloft
 Duloxetine • Cymbalta                             Tamoxifen • Soltamox
Fluoxetine • Prozac                                   Trazodone • Desyrel
Lithium • Eskalith, Lithobid                        Valproate • Divalproex
Haloperidol • Haldol                                  Ziprasidone • Geodon
Hydrocodone • Vicodin

Disclosure
The authors report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

Mr. T,  age 23, was given a diagnosis of bipolar disorder 1 year ago. After he experienced inadequate symp­tom relief with valproate, you switched him to extended-release lithium, 1,200 mg/d. Mr. T reported improved mood and stability with this medication adjustment. These posi­tive changes led him to resume activities he enjoyed before onset of bipolar disorder, such as running, reading, and going out to dinner with friends.

Now, Mr. T’s mother calls your office to express concern about her son’s slight

hand tremor, which appeared after 2 days of gas­trointestinal distress. She tells you that Mr. T sprained his ankle while running 1 week ago and has been taking over-the-counter ibu­profen for pain relief, which he did often in the past.

You suspect that Mr. T is experiencing lith­ium toxicity as a result of ibuprofen use.

Although mental health providers can eas­ily recognize the drug−drug interaction between lithium and nonsteroidal anti-inflammatory drugs (NSAIDs) that Mr. T experienced, interpreting the safety of a medication regimen with respect to drug− drug interactions before prescribing often is more daunting. This article reviews the basics of drug−drug interactions, while briefly highlighting common examples in psychiatric medicine (Table 1^1-5). We also provide an outline of additional points to consider when reviewing your patients’ medication regimens and encoun­tering unfamiliar drug−drug interactions.

Types of drug−drug interactions
Drug−drug interactions fall into 2 catego­ries: pharmacodynamic (PD) and pharmaco­kinetic (PK):
   • PD interactions are a result of the com­bined impact of medications on the body when there is no direct effect on absorp­tion, distribution, metabolism, or excretion characteristics, such as 2 medications that act at the same receptor or lead to similar or opposing pharmacologic effects.
   • PK interactions occur when a drug affects the absorption, distribution, metabo­lism, or excretion characteristics of another drug.

Although it is possible that drug−drug interactions will have no clinical effect, when the impact of a PD or PK drug−drug interaction is evident, it likely is the result of additive, synergistic, or antago­nistic consequences on the medications’ intended impact or side-effect profile.

Pharmacodynamic interactions
Serotonin syndrome. The potential for serotonin syndrome occurs when medica­tions that increase synaptic serotonin con­centration are used concomitantly.¹ This can occur through several mechanisms, including increased serotonin release, decreased reuptake, or decreased sero­tonin metabolism. A high serotonin con­centration in the CNS and in the periphery overstimulates serotonin receptors, lead­ing to signs and symptoms that can include diarrhea, fever, delirium, coma, and poten­tially death.

QT prolongation and anticholinergic toxicity are further examples of additive PD drug−drug interactions. Anticholinergic toxicity is possible when multiple medica­tions contribute to inhibition of the neuro-transmitter acetylcholine at muscarinic receptors. This leads to adverse effects such as dry mouth, constipation, confusion, and urinary retention.

QT prolongation, which can lead to arrhythmia, occurs when a patient is taking several medications that can increase the QT interval. Consider close monitoring and using alternative agents with less poten­tial to increase the QT interval in patients at risk of arrhythmias (geriatric patients, those with an increased QT interval at base­line, etc.).

Decreased seizure threshold. The increased risk of seizures with bupropion and other medications that lower the sei­zure threshold is another example of an additive PD drug interaction. Bupropion can increase the risk of seizures in a dose-dependent manner, which increases when bupropion is taken with other drugs that lower the seizure threshold.6 Seizure risk associated with alcohol or benzodiazepine withdrawal also may increase the risk for this interaction.

Of note, the increased risk of seizures with the combination of bupropion and alcohol in the absence of withdrawal is not well studied in humans, but positive corre­lation has been seen in an animal study.⁶

Decreased platelet function. Another example of a PD drug−drug interaction is increased risk of bleeding when a selec­tive serotonin reuptake inhibitor is used with a NSAID or oral anticoagulant. The proposed mechanism for this interaction is that blocking serotonin reuptake on platelets leads to decreased platelet func­tion and an increased risk for prolonged bleeding.7 This is somewhat controversial because, first, it has been noted that drugs with the highest degree of serotonin reup­take inhibition do not always cause the highest risk of bleeding and, second, most of the evidence for this interaction is from observational studies.⁷

This potential interaction could be most important for patients who need an anti­depressant, are on chronic NSAID or anti­coagulant therapy, and are at high risk of bleeding.

Pharmacokinetic interactions
PK interactions in psychiatry often are caused by interference of drug metabo­lizing enzymes. The cytochrome P450 (CYP450) family of metabolizing enzymes in particular is important to the break­down of medications in the body. Many drug−drug interactions involve medica­tions that can inhibit or induce metabolism of other drugs through their effect on the CYP450 system.

Inhibition interactions. When a drug’s metabolism is inhibited, the result is usu­ally increased serum concentration of that medication (because of less break­down) and a more potent impact on the primary mechanism of action or adverse effects. Sometimes, inhibiting metabo­lism can lead to decreased clinical effect. Tamoxifen (an oral agent used to treat breast cancer) and certain analgesics when used in combination with moderate or strong inhibitors of the CYP2D6 subfam­ily of CYP450 metabolizing enzymes are 2 examples of metabolism inhibition lead­ing to decreased efficacy.⁸ Both tamoxi­fen and the analgesics listed in Table 1^1-5 are prodrugs; that is, they must be metabolized to be active. When the enzymes that metabolize these drugs into their active form are inhibited, the concen­tration of active drug decreases.

Induction interactions. Alternatively, there is an increased rate of drug break­down and resulting decrease in effect when drugs that induce the activity of metabolizing enzymes are used with med­ications that are substrates of the same enzyme. Carbamazepine is commonly involved in this type of drug interaction because it is a strong inducer of CYP 1A2, 2B6, 2C19, 2C9, and 3A4, and the p-glyco­protein drug efflux pump.⁹ As a result of this rampant induction, carbamazepine can decrease the serum concentration of oral contraceptives below a reliably effec­tive level. Therefore, it is recommended that women of childbearing potential use other contraceptive methods, such as a progestin implant or an intrauterine device.¹⁰

In addition, the polycyclic aromatic hydrocarbons found in cigarettes induce activity of CYP1A2. Patients who smoke and use medications metabolized by this enzyme, such as clozapine and olanzap­ine, may need a higher dosage.

Drug elimination interactions
The last drug−drug interaction discussed here returns the discussion to Mr. T and involves drug elimination.² The NSAIDs Mr. T was using for pain likely caused decreased renal excretion of lithium. Because lithium is primarily excreted through the kidneys, Mr. T’s NSAID use, possibly in com­bination with dehydration caused by gastro­intestinal distress, resulted in lithium toxicity. This class of analgesics should be avoided or used cautiously in patients taking lithium.

Clinical applications
The relatively common drug−drug interac­tions discussed here are just a fraction of the potential interactions mental health practi­tioners see on a daily basis. Understanding the basics of PD and PK interactions in the setting of patient-specific factors can help to clarify the information found in drug−drug interaction databases, such as Micromedex, Lexicomp, Facts and Comparisons, and Epocrates. Table 2 lists additional insights into drug interactions.

Related Resources
• CredibleMeds. Online resource on QT prolonging drugs. http://crediblemeds.org.
• Madhusoodanan S, Velama U, Parmar J, et al. A current review of cytochrome P450 interactions of psychotropic drugs. Ann Clin Psychiatry. 2014;26(2):120-138.

Drug Brand Names
Benztropine • Cogentin                            Olanzapine • Zyprexa
Bupropion • Wellbutrin                             Oxycodone • Oxycontin
Carbamazepine • Tegretol                        Paroxetine • Paxil
Clozapine • Clozaril                                  Quetiapine • Seroquel
Diphenhydramine • Benadryl                     Sertraline • Zoloft
 Duloxetine • Cymbalta                             Tamoxifen • Soltamox
Fluoxetine • Prozac                                   Trazodone • Desyrel
Lithium • Eskalith, Lithobid                        Valproate • Divalproex
Haloperidol • Haldol                                  Ziprasidone • Geodon
Hydrocodone • Vicodin

Disclosure
The authors report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.