THURSDAY, MARCH 22, 2018

MORNING SESSION

Henry A. Nasrallah, MD, Saint Louis University, began the conference by presenting the latest information on several recent advances in schizophrenia, including genetic and nongenetic etiologies, abnormalities in the mitochondria and microglia activation leading to oxidative stress and inflammation, and emerging treatment and prevention strategies.

Next, Dr. Nasrallah described how to identify and treat the schizophrenia prodrome. He covered frequently used assessment tools, neuroimaging findings, and the consequences of delayed treatment.

Michael J. Gitlin, MD, University of California, Los Angeles, described current uses of stimulants for treating psychiatric disorders. He covered their use for attention-deficit/hyperactivity disorder (ADHD), unipolar depression, bipolar depression, and other conditions.

AFTERNOON SESSION

The afternoon began with Donald W. Black, MD, University of Iowa, providing an update on obsessive-compulsive disorder and related conditions. He reviewed the efficacy of several treatments, including pharmacologic and behavior therapies.

Next, Dr. Gitlin covered the potential relationships between depression and several comorbid disorders, including borderline personality disorder, schizophrenia, alcohol use disorders, and other mental illnesses.

Dr. Black presented an update on hoarding. He detailed the differential diagnosis, clinical characteristics, and clinical management strategies for addressing this challenging disorder.

Tracy D. Gunter, MD, Indiana University, identified common legal issues encountered by clinical psychiatrists and the challenges they pose. She described how to develop strategies for approaching common clinical problems while minimizing medicolegal risk.

Continue to: Friday sessions

FRIDAY, MARCH 23, 2018

MORNING SESSION

To start Day 2, Marlene P. Freeman, MD, Massachusetts General Hospital, focused on bipolar disorder in women. She described factors to consider when treating a pregnant woman with this illness.

Dr. Freeman continued with a unique session that covered topics attendees had requested in advance. These included the relationship between polycystic ovarian syndrome and depression, infertility and psychiatry, and nonpharmacologic treatments for depression in pregnant women.

Dr. Gunter presented a session on correctional psychiatry, including the major differences between office-based clinical psychiatry and on-site correctional psychiatry and some of the challenges of working in this setting.

AFTERNOON SESSION

Robert M. McCarron, DO, University of California, Irvine, described how to treat psychiatric patients who have chronic pain. He covered the responsible use of opioid analgesics and how to diagnose and treat somatic symptom disorders.

Anthony L. Rostain, MD, MS, University of Pennsylvania, discussed practical approaches to managing ADHD comorbidities. He outlined pharmacologic and psychosocial strategies for patients who have ADHD and comorbid anxiety, depression, substance use disorders, and certain medical conditions.

Dr. McCarron continued the afternoon with a session that focused on preventing endocrine and cardiovascular disorders. He provided prevention and diagnostic measures for metabolic syndrome and tips for preventing and diagnosing dyslipidemia and diabetes.

Dr. Rostain continued by presenting a session on autistic spectrum disorders in adults. He covered clinical features, common comorbidities, and medication management.

The day concluded with a special AACP Members’ Reception.

Continue to: Saturday session

SATURDAY, MARCH 24, 2018

MORNING SESSION

George T. Grossberg, MD, Saint Louis University, began the day by covering the neuroanatomic and neurochemical substrates of behavioral symptoms in Alzheimer’s disease and their implications for treatment. He described behavioral and pharmacologic treatments for agitation and behavioral symptoms in patients with dementia.

Next came a special keynote address by Mark A. Frye, MD, Mayo Clinic, Rochester, titled Ketamine Update: What Should Clinicians Know and Expect.

Stephen B. Levine, MD, Case Western Reserve University, described assessing and treating patients with sexual dysfunction. He covered a range of sexual dysfunctions within and outside of DSM-5.

Dr. Grossberg presented on aging, traumatic brain injury, chronic traumatic encephalopathy, and Alzheimer’s disease. He covered the sequelae, prevention, and treatment of these conditions.

Dr. Levine concluded the conference by providing a clinical overview of transgender issues. He included a discussion of the role mental health professionals should play in gender affirmation.

Continue to: SPONSORS AND SUPPORTERS

SPONSORS AND SUPPORTERS

• Admera Health
• Alkermes
• Alpha Genomix Laboratories
• Alzheimer's Association
• Amita Health Alexian Brothers Behavioral Health Hospital
• Aurora Health Care
• Bellin Psychiatric Center
• GeneSight
• Genoa Telepsychiatry
• Howard Brown Health
• Jaymac Pharmaceuticals
• Legally Mine
• Professional Risk Management Services, Inc.  
• Pine Rest Christian Mental Health Services
• Sunovion Pharmaceuticals, Inc.
• Supernus Pharmaceuticals, Inc.
• Takeda Pharmaceuticals U.S.A., Inc. / Lundbeck
• U.S. Army Medicine Civilian Corps
• Wexford Health Sources
• Wolters Kluwer

The meeting organizers acknowledge the support provided by our sponsors. Determination of educational content for this program and the selection of speakers are responsibilities of the program director and co-chairs. Sponsors and supporters did not have input in these areas.

THURSDAY, MARCH 22, 2018

MORNING SESSION

Henry A. Nasrallah, MD, Saint Louis University, began the conference by presenting the latest information on several recent advances in schizophrenia, including genetic and nongenetic etiologies, abnormalities in the mitochondria and microglia activation leading to oxidative stress and inflammation, and emerging treatment and prevention strategies.

Next, Dr. Nasrallah described how to identify and treat the schizophrenia prodrome. He covered frequently used assessment tools, neuroimaging findings, and the consequences of delayed treatment.

Michael J. Gitlin, MD, University of California, Los Angeles, described current uses of stimulants for treating psychiatric disorders. He covered their use for attention-deficit/hyperactivity disorder (ADHD), unipolar depression, bipolar depression, and other conditions.

AFTERNOON SESSION

The afternoon began with Donald W. Black, MD, University of Iowa, providing an update on obsessive-compulsive disorder and related conditions. He reviewed the efficacy of several treatments, including pharmacologic and behavior therapies.

Next, Dr. Gitlin covered the potential relationships between depression and several comorbid disorders, including borderline personality disorder, schizophrenia, alcohol use disorders, and other mental illnesses.

Dr. Black presented an update on hoarding. He detailed the differential diagnosis, clinical characteristics, and clinical management strategies for addressing this challenging disorder.

Tracy D. Gunter, MD, Indiana University, identified common legal issues encountered by clinical psychiatrists and the challenges they pose. She described how to develop strategies for approaching common clinical problems while minimizing medicolegal risk.

Continue to: Friday sessions

FRIDAY, MARCH 23, 2018

MORNING SESSION

To start Day 2, Marlene P. Freeman, MD, Massachusetts General Hospital, focused on bipolar disorder in women. She described factors to consider when treating a pregnant woman with this illness.

Dr. Freeman continued with a unique session that covered topics attendees had requested in advance. These included the relationship between polycystic ovarian syndrome and depression, infertility and psychiatry, and nonpharmacologic treatments for depression in pregnant women.

Dr. Gunter presented a session on correctional psychiatry, including the major differences between office-based clinical psychiatry and on-site correctional psychiatry and some of the challenges of working in this setting.

AFTERNOON SESSION

Robert M. McCarron, DO, University of California, Irvine, described how to treat psychiatric patients who have chronic pain. He covered the responsible use of opioid analgesics and how to diagnose and treat somatic symptom disorders.

Anthony L. Rostain, MD, MS, University of Pennsylvania, discussed practical approaches to managing ADHD comorbidities. He outlined pharmacologic and psychosocial strategies for patients who have ADHD and comorbid anxiety, depression, substance use disorders, and certain medical conditions.

Dr. McCarron continued the afternoon with a session that focused on preventing endocrine and cardiovascular disorders. He provided prevention and diagnostic measures for metabolic syndrome and tips for preventing and diagnosing dyslipidemia and diabetes.

Dr. Rostain continued by presenting a session on autistic spectrum disorders in adults. He covered clinical features, common comorbidities, and medication management.

The day concluded with a special AACP Members’ Reception.

Continue to: Saturday session

SATURDAY, MARCH 24, 2018

MORNING SESSION

George T. Grossberg, MD, Saint Louis University, began the day by covering the neuroanatomic and neurochemical substrates of behavioral symptoms in Alzheimer’s disease and their implications for treatment. He described behavioral and pharmacologic treatments for agitation and behavioral symptoms in patients with dementia.

Next came a special keynote address by Mark A. Frye, MD, Mayo Clinic, Rochester, titled Ketamine Update: What Should Clinicians Know and Expect.

Stephen B. Levine, MD, Case Western Reserve University, described assessing and treating patients with sexual dysfunction. He covered a range of sexual dysfunctions within and outside of DSM-5.

Dr. Grossberg presented on aging, traumatic brain injury, chronic traumatic encephalopathy, and Alzheimer’s disease. He covered the sequelae, prevention, and treatment of these conditions.

Dr. Levine concluded the conference by providing a clinical overview of transgender issues. He included a discussion of the role mental health professionals should play in gender affirmation.

Continue to: SPONSORS AND SUPPORTERS

SPONSORS AND SUPPORTERS

• Admera Health
• Alkermes
• Alpha Genomix Laboratories
• Alzheimer's Association
• Amita Health Alexian Brothers Behavioral Health Hospital
• Aurora Health Care
• Bellin Psychiatric Center
• GeneSight
• Genoa Telepsychiatry
• Howard Brown Health
• Jaymac Pharmaceuticals
• Legally Mine
• Professional Risk Management Services, Inc.  
• Pine Rest Christian Mental Health Services
• Sunovion Pharmaceuticals, Inc.
• Supernus Pharmaceuticals, Inc.
• Takeda Pharmaceuticals U.S.A., Inc. / Lundbeck
• U.S. Army Medicine Civilian Corps
• Wexford Health Sources
• Wolters Kluwer

The meeting organizers acknowledge the support provided by our sponsors. Determination of educational content for this program and the selection of speakers are responsibilities of the program director and co-chairs. Sponsors and supporters did not have input in these areas.

THURSDAY, MARCH 22, 2018

MORNING SESSION

Henry A. Nasrallah, MD, Saint Louis University, began the conference by presenting the latest information on several recent advances in schizophrenia, including genetic and nongenetic etiologies, abnormalities in the mitochondria and microglia activation leading to oxidative stress and inflammation, and emerging treatment and prevention strategies.

Next, Dr. Nasrallah described how to identify and treat the schizophrenia prodrome. He covered frequently used assessment tools, neuroimaging findings, and the consequences of delayed treatment.

Michael J. Gitlin, MD, University of California, Los Angeles, described current uses of stimulants for treating psychiatric disorders. He covered their use for attention-deficit/hyperactivity disorder (ADHD), unipolar depression, bipolar depression, and other conditions.

AFTERNOON SESSION

The afternoon began with Donald W. Black, MD, University of Iowa, providing an update on obsessive-compulsive disorder and related conditions. He reviewed the efficacy of several treatments, including pharmacologic and behavior therapies.

Next, Dr. Gitlin covered the potential relationships between depression and several comorbid disorders, including borderline personality disorder, schizophrenia, alcohol use disorders, and other mental illnesses.

Dr. Black presented an update on hoarding. He detailed the differential diagnosis, clinical characteristics, and clinical management strategies for addressing this challenging disorder.

Tracy D. Gunter, MD, Indiana University, identified common legal issues encountered by clinical psychiatrists and the challenges they pose. She described how to develop strategies for approaching common clinical problems while minimizing medicolegal risk.

Continue to: Friday sessions

FRIDAY, MARCH 23, 2018

MORNING SESSION

To start Day 2, Marlene P. Freeman, MD, Massachusetts General Hospital, focused on bipolar disorder in women. She described factors to consider when treating a pregnant woman with this illness.

Dr. Freeman continued with a unique session that covered topics attendees had requested in advance. These included the relationship between polycystic ovarian syndrome and depression, infertility and psychiatry, and nonpharmacologic treatments for depression in pregnant women.

Dr. Gunter presented a session on correctional psychiatry, including the major differences between office-based clinical psychiatry and on-site correctional psychiatry and some of the challenges of working in this setting.

AFTERNOON SESSION

Robert M. McCarron, DO, University of California, Irvine, described how to treat psychiatric patients who have chronic pain. He covered the responsible use of opioid analgesics and how to diagnose and treat somatic symptom disorders.

Anthony L. Rostain, MD, MS, University of Pennsylvania, discussed practical approaches to managing ADHD comorbidities. He outlined pharmacologic and psychosocial strategies for patients who have ADHD and comorbid anxiety, depression, substance use disorders, and certain medical conditions.

Dr. McCarron continued the afternoon with a session that focused on preventing endocrine and cardiovascular disorders. He provided prevention and diagnostic measures for metabolic syndrome and tips for preventing and diagnosing dyslipidemia and diabetes.

Dr. Rostain continued by presenting a session on autistic spectrum disorders in adults. He covered clinical features, common comorbidities, and medication management.

The day concluded with a special AACP Members’ Reception.

Continue to: Saturday session

SATURDAY, MARCH 24, 2018

MORNING SESSION

George T. Grossberg, MD, Saint Louis University, began the day by covering the neuroanatomic and neurochemical substrates of behavioral symptoms in Alzheimer’s disease and their implications for treatment. He described behavioral and pharmacologic treatments for agitation and behavioral symptoms in patients with dementia.

Next came a special keynote address by Mark A. Frye, MD, Mayo Clinic, Rochester, titled Ketamine Update: What Should Clinicians Know and Expect.

Stephen B. Levine, MD, Case Western Reserve University, described assessing and treating patients with sexual dysfunction. He covered a range of sexual dysfunctions within and outside of DSM-5.

Dr. Grossberg presented on aging, traumatic brain injury, chronic traumatic encephalopathy, and Alzheimer’s disease. He covered the sequelae, prevention, and treatment of these conditions.

Dr. Levine concluded the conference by providing a clinical overview of transgender issues. He included a discussion of the role mental health professionals should play in gender affirmation.

Continue to: SPONSORS AND SUPPORTERS

SPONSORS AND SUPPORTERS

• Admera Health
• Alkermes
• Alpha Genomix Laboratories
• Alzheimer's Association
• Amita Health Alexian Brothers Behavioral Health Hospital
• Aurora Health Care
• Bellin Psychiatric Center
• GeneSight
• Genoa Telepsychiatry
• Howard Brown Health
• Jaymac Pharmaceuticals
• Legally Mine
• Professional Risk Management Services, Inc.  
• Pine Rest Christian Mental Health Services
• Sunovion Pharmaceuticals, Inc.
• Supernus Pharmaceuticals, Inc.
• Takeda Pharmaceuticals U.S.A., Inc. / Lundbeck
• U.S. Army Medicine Civilian Corps
• Wexford Health Sources
• Wolters Kluwer

The meeting organizers acknowledge the support provided by our sponsors. Determination of educational content for this program and the selection of speakers are responsibilities of the program director and co-chairs. Sponsors and supporters did not have input in these areas.

CASE A rapid decline

Ms. D, age 62, presents to a psychiatric emergency room (ER) after experiencing visual hallucinations, exhibiting odd behaviors, and having memory problems. On interview, she is disoriented, distractible, tearful, and tangential. She plays with her shirt and glasses, and occasionally shouts. She perseverates on “the aerialists,” acrobatic children she has been seeing in her apartment. She becomes distressed and shouts, “I would love to just get them!”

Ms. D is unable to provide an account of her history. Collateral information is obtained from her daughter, who has brought Ms. D to the ER for evaluation. She reports that her mother has no relevant medical or psychiatric history, and does not take any medications, except a mixture of Chinese herbs that she brews into a tea.

Ms. D’s daughter says that her mother began to deteriorate 5 months ago, after she traveled to California to care for her sister, who was seriously ill and passed away. After Ms. D returned, she would cry frequently. She also appeared “spaced out,” complained of feeling dizzy, and frequently misplaced belongings. Three months before presenting to the ER, she began to experience weakness, fatigue, and difficulty walking. Her daughter became more worried 2 months ago, when Ms. D began sleeping with her purse and hiding her belongings around their house. When asked about these odd behaviors, Ms. D claimed that “the aerialists” were climbing through her windows at night and stealing her things.

A week before seeking treatment at the ER, Ms. D’s daughter had taken her to a neurologist at another facility for clinical evaluation. An MRI of the brain showed minimal dilation in the subarachnoid space and a focal 1 cm lipoma in the anterior falx cerebri, but was otherwise unremarkable. However, Ms. D’s symptoms continued to worsen, and began to interfere with her ability to care for herself.

The team in the psychiatric ER attributes Ms. D’s symptoms to a severe, psychotic depressive episode. They admit her to the psychiatric inpatient unit for further evaluation.

[polldaddy:10012742]

Continue to: The authors' observations

Ms. D was plagued by several mood and psychotic symptoms. Such symptoms can arise from many different psychiatric or organic etiologies. In Ms. D’s case, several aspects of her presentation suggest that her illness was psychiatric. The severe illness of a beloved family member is a significant stressor that could cause a great deal of grief and devastation, possibly leading to depression. Indeed, Ms. D’s daughter noticed that her mother was crying frequently, which is consistent with grief or depression.

Memory problems, which might manifest as misplacing belongings, can also indicate a depressive illness, especially in older patients. Moreover, impaired concentration, which can cause one to appear “spaced out” or distractible, is a core symptom of major depressive disorder. Sadness and grief also can be appropriate during bereavement and in response to significant losses. Therefore, in Ms. D’s case, it is possible her frequent crying, “spaced out” appearance, and other mood symptoms she experienced immediately after caring for her sister were an appropriate response to her sister’s illness and death.

However, other aspects of Ms. D’s presentation suggested an organic etiology. Her rapid deterioration and symptom onset relatively late in life were consistent with dementia and malignancy. Her complaint of feeling dizzy suggested a neurologic process was affecting her vestibular system. Finally, while psychiatric disorders can certainly cause visual hallucinations, they occur in only a small percentage of cases.¹ Visual hallucinations are commonly associated with delirium, intoxication, and neurologic illness.

Continue to: EVALUATION Severe impairment

On the psychiatric inpatient unit, Ms. D remains unable to give a coherent account of her illness or recent events. During interviews, she abruptly shifts from laughing to crying for no apparent reason. While answering questions, her responses trail off and she appears to forget what she had been saying. However, she continues to speak at length about “the aerialists,” stating that she sees them living in her wardrobe and jumping from rooftop to rooftop in her neighborhood.

A mental status examination finds evidence of severe cognitive impairment. Ms. D is unable to identify the correct date, time, or place, and appears surprised when told she is in a hospital. She can repeat the names of 3 objects but cannot recall them a few minutes later. Finally, she scores a 14 on the Mini-Mental State Examination (MMSE) and a 5 on the Montreal Cognitive Assessment (MoCA), indicating severe impairment.

On the unit, Ms. D cannot remember the location of her room or bathroom, and even when given directions, she needs to be escorted to her destination. Her gait is unsteady and wide-spaced, and she walks on her toes at times. When food is placed before her, she needs to be shown how to take the lids off containers, pick up utensils, and start eating.

All laboratory results are unremarkable, including a complete blood count, basic metabolic panel, liver function tests, gamma-glutamyl transpeptidase, magnesium, phosphate, thyroid-stimulating hormone, vitamin B12, methylmalonic acid, homocysteine, folate, erythrocyte sedimentation rate, C-reactive protein, antinuclear antibodies, rapid plasma reagin, human immunodeficiency virus, and Lyme titers. The team also considers Ms. D’s history of herbal medicine use, because herbal mixtures can contain heavy metals and other contaminants. However, all toxicology results are normal, including arsenic, mercury, lead, copper, and zinc.

To address her symptoms, Ms. D is given risperidone, 0.5 mg twice a day, and donepezil, 5 mg/d.

[polldaddy:10012743]

Continue to: The authors' observations

Despite her persistent psychiatric symptoms, Ms. D had several neurologic symptoms that warranted further investigation. Her abrupt shifts from laughter to tears for no apparent reason were consistent with pseudobulbar affect. Her inability to remember how to use utensils during meals was consistent with apraxia. Finally, her abnormal gait raised concern for a process affecting her motor system.

OUTCOME A rare disorder

Given the psychiatry team’s suspicions for a neurologic etiology of Ms. D’s symptoms, an MRI of her brain is repeated. The results are notable for abnormal restricted diffusion in the caudate and putamen bilaterally, which is consistent with Creutzfeldt-Jakob disease (CJD). EEG shows moderate diffuse cerebral dysfunction, frontal intermittent delta activity, and diffuse cortical hyperexcitability, consistent with early- to mid-onset prion disease. Upon evaluation by the neurology team, Ms. D appears fearful, suspicious, and disorganized, but her examination does not reveal additional significant sensorimotor findings.

Ms. D is transferred to the neurology service for further workup and management. A lumbar puncture is positive for real-time quaking-induced conversion (RT-QuIC) and 14-3-3 protein with elevated tau proteins; these findings also are consistent with CJD. She develops transaminitis, with an alanine transaminase (ALT) of 127 and aspartate transaminase (AST) of 355, and a malignancy is suspected. However, CT scans of the chest, abdomen, and pelvis show no evidence of malignancy, and an extensive gastrointestinal workup is unremarkable, including anti-smooth muscle antibodies, anti-liver-kidney microsomal antibody, antimitochondrial antibodies, gliadin antibody, alpha-1 antitrypsin, liver/kidney microsomal antibody, and hepatitis serologies. While on the neurology service, risperidone and donepezil are discontinued because the findings indicate she has CJD and there are concerns that risperidone may be contributing to her transaminitis.

After discontinuing these medications, she is evaluated by the psychiatry consult team for mood lability. The psychiatry consult team recommends quetiapine, which is later started at 25 mg nightly at bedtime.

Clinically, Ms. D’s mental status continues to deteriorate. She becomes nonverbal and minimally able to follow commands. She is ultimately discharged to an inpatient hospice for end-of-life care and the team recommends that she continue with quetiapine once there.

Continue to: The authors' observations

CJD is a rare, rapidly progressive, fatal form of dementia. In the United States, the incidence is approximately 1 to 1.5 cases per 1 million people each year.² There are various forms of the disease. Sporadic CJD is the most common, representing 85% of cases.³ Sporadic CJD typically occurs in patients in their 60s and quickly leads to death—50% of patients die within 5 months, and 90% of patients die within 1 year.^2,3 The illness is hypothesized to arise from the production of misfolded prion proteins, ultimately leading to vacuolation, neuronal loss, and the spongiform appearance characteristic of CJD.^3,4

Psychiatric symptoms have long been acknowledged as a feature of CJD. Recent data indicates that psychiatric symptoms occur in 90% to 92% of cases.^5,6 Sleep disturbances and depressive symptoms, including vegetative symptoms, anhedonia, and tearfulness, appear to be most common.⁵ Psychotic symptoms occur in approximately 42% of cases and may include persecutory and paranoid delusions, as well as an array of vivid auditory, visual, and tactile hallucinations.^5,7

There is also evidence that psychiatric symptoms may be an early marker of CJD.^5,8 A Mayo Clinic study found that psychiatric symptoms occurred within the prodromal phase of CJD in 26% of cases, and psychiatric symptoms occurred within the first 100 days of illness in 86% of cases.⁵

Case reports have described patients with CJD who initially presented with depression, psychosis, and other psychiatric symptoms.^9-11 Interestingly, there have been cases with only psychiatric symptoms, and no neurologic symptoms until relatively late in the illness.^10,11 Several patients with CJD have been evaluated in psychiatric ERs, admitted to psychiatric hospitals, and treated with psychiatric medications and ECT.^5,9 In one study, 44% of CJD cases were misdiagnosed as “psychiatric patients” due to the prominence of their psychiatric symptomatology.⁸

Continue to: Making the diagnosis in psychiatric settings

Making the diagnosis in psychiatric settings. Often, the most difficult aspect of CJD is making the diagnosis.^3,12 Sporadic CJD in particular can vary widely in its clinical presentation.³ The core clinical feature of CJD is rapidly progressive dementia, so suspect CJD in these patients. However, CJD can be difficult to distinguish from other rapidly progressive dementias, such as autoimmune and paraneoplastic encephalopathies.^2,3 The presence of neurologic features, specifically myoclonus, akinetic mutism, and visual, cerebellar, and extrapyramidal symptoms, should also be considered a red flag for the disorder³ (Table).

Finally, positive findings on MRI, EEG, or CSF assay can indicate a probable diagnosis of CJD.¹³ MRI, particularly diffusion weighted imaging (DWI) and fluid-attenuated inversion recovery (FLAIR), is recog­nized as the most studied, sensitive, and overall useful neuroimaging modality for detecting CJD.^2,3,12 Although the appearance of CJD on MRI can vary widely, asymmetric hyperintensities in ≥3 cortical gyri, particularly in the frontal and parietal lobes, provide strong evidence of CJD and are observed in 80% to 81% of cases.^4,12 Asymmetric hyperintensities in the basal ganglia, particularly the caudate and rostral putamen, are observed in 69% to 70% of cases.^4,12,13

EEG and CSF assay also can be useful for making the diagnosis. While diffuse slowing and frontal rhythmic delta activity appear early in the course of CJD, periodic sharp wave complexes emerge later in the illness.⁴ However, EEG findings are not diagnostic, because periodic sharp wave complexes are seen in only two-thirds of CJD cases and also occur in other neurologic illnesses.^3,4 In recent years, lumbar puncture with subsequent CSF testing has become increasingly useful in detecting the illness. The presence of the 14-3-3 protein and tau protein is highly sensitive, although not specific, for CJD.³ A definite diagnosis of CJD requires discovery of the misfolded prion proteins, such as by RT-QuIC or brain biopsy.^2,3,13

Management of CJD in psychiatric patients. CJD is an invariably fatal disease for which there is no effective cure or disease modifying treatment.² Therefore, supportive therapies are the mainstay of care. Psychotropic medications can be used to provide symptom relief. While the sleep disturbances, anxiety, and agitation/hallucinations associated with CJD appear to respond well to hypnotic, anxiolytic, and antipsychotic medications, respectively, antidepressants and mood-stabilizing medications appear to have little benefit for patients with CJD.⁵ During the final stages of the disease, patients may suffer from akinetic mutism and inability to swallow, which often leads to aspiration pneumonia.¹⁴ Patients should also be offered end-of-life counseling, planning, and care, and provided with other comfort measures wherever possible (Figure).

Continue to: Bottom Line

Patients with Creutzfeldt-Jakob disease (CJD) may present to psychiatric settings, particularly to a psychiatric emergency room. Consider CJD as a possible etiology in patients with rapidly progressive dementia, depression, and psychosis. CJD is invariably fatal and there is no effective disease-modifying treatment. Supportive therapies are the mainstay of care.

Related Resources

• National Institute of Neurological Disorders and Stroke. Creutzfeldt-Jakob disease fact sheet. http://www.ninds.nih.gov/disorders/cjd/detail_cjd.htm.  
• Centers for Disease Control and Prevention. Creutzfeldt-Jakob disease, classic (CJD). http://www.cdc.gov/prions/cjd. 

Drug Brand Names

Donepezil • Aricept
Risperidone • Risperdal
Quetiapine • Seroquel

CASE A rapid decline

Ms. D, age 62, presents to a psychiatric emergency room (ER) after experiencing visual hallucinations, exhibiting odd behaviors, and having memory problems. On interview, she is disoriented, distractible, tearful, and tangential. She plays with her shirt and glasses, and occasionally shouts. She perseverates on “the aerialists,” acrobatic children she has been seeing in her apartment. She becomes distressed and shouts, “I would love to just get them!”

Ms. D is unable to provide an account of her history. Collateral information is obtained from her daughter, who has brought Ms. D to the ER for evaluation. She reports that her mother has no relevant medical or psychiatric history, and does not take any medications, except a mixture of Chinese herbs that she brews into a tea.

Ms. D’s daughter says that her mother began to deteriorate 5 months ago, after she traveled to California to care for her sister, who was seriously ill and passed away. After Ms. D returned, she would cry frequently. She also appeared “spaced out,” complained of feeling dizzy, and frequently misplaced belongings. Three months before presenting to the ER, she began to experience weakness, fatigue, and difficulty walking. Her daughter became more worried 2 months ago, when Ms. D began sleeping with her purse and hiding her belongings around their house. When asked about these odd behaviors, Ms. D claimed that “the aerialists” were climbing through her windows at night and stealing her things.

A week before seeking treatment at the ER, Ms. D’s daughter had taken her to a neurologist at another facility for clinical evaluation. An MRI of the brain showed minimal dilation in the subarachnoid space and a focal 1 cm lipoma in the anterior falx cerebri, but was otherwise unremarkable. However, Ms. D’s symptoms continued to worsen, and began to interfere with her ability to care for herself.

The team in the psychiatric ER attributes Ms. D’s symptoms to a severe, psychotic depressive episode. They admit her to the psychiatric inpatient unit for further evaluation.

[polldaddy:10012742]

Continue to: The authors' observations

Ms. D was plagued by several mood and psychotic symptoms. Such symptoms can arise from many different psychiatric or organic etiologies. In Ms. D’s case, several aspects of her presentation suggest that her illness was psychiatric. The severe illness of a beloved family member is a significant stressor that could cause a great deal of grief and devastation, possibly leading to depression. Indeed, Ms. D’s daughter noticed that her mother was crying frequently, which is consistent with grief or depression.

Memory problems, which might manifest as misplacing belongings, can also indicate a depressive illness, especially in older patients. Moreover, impaired concentration, which can cause one to appear “spaced out” or distractible, is a core symptom of major depressive disorder. Sadness and grief also can be appropriate during bereavement and in response to significant losses. Therefore, in Ms. D’s case, it is possible her frequent crying, “spaced out” appearance, and other mood symptoms she experienced immediately after caring for her sister were an appropriate response to her sister’s illness and death.

However, other aspects of Ms. D’s presentation suggested an organic etiology. Her rapid deterioration and symptom onset relatively late in life were consistent with dementia and malignancy. Her complaint of feeling dizzy suggested a neurologic process was affecting her vestibular system. Finally, while psychiatric disorders can certainly cause visual hallucinations, they occur in only a small percentage of cases.¹ Visual hallucinations are commonly associated with delirium, intoxication, and neurologic illness.

Continue to: EVALUATION Severe impairment

On the psychiatric inpatient unit, Ms. D remains unable to give a coherent account of her illness or recent events. During interviews, she abruptly shifts from laughing to crying for no apparent reason. While answering questions, her responses trail off and she appears to forget what she had been saying. However, she continues to speak at length about “the aerialists,” stating that she sees them living in her wardrobe and jumping from rooftop to rooftop in her neighborhood.

A mental status examination finds evidence of severe cognitive impairment. Ms. D is unable to identify the correct date, time, or place, and appears surprised when told she is in a hospital. She can repeat the names of 3 objects but cannot recall them a few minutes later. Finally, she scores a 14 on the Mini-Mental State Examination (MMSE) and a 5 on the Montreal Cognitive Assessment (MoCA), indicating severe impairment.

On the unit, Ms. D cannot remember the location of her room or bathroom, and even when given directions, she needs to be escorted to her destination. Her gait is unsteady and wide-spaced, and she walks on her toes at times. When food is placed before her, she needs to be shown how to take the lids off containers, pick up utensils, and start eating.

All laboratory results are unremarkable, including a complete blood count, basic metabolic panel, liver function tests, gamma-glutamyl transpeptidase, magnesium, phosphate, thyroid-stimulating hormone, vitamin B12, methylmalonic acid, homocysteine, folate, erythrocyte sedimentation rate, C-reactive protein, antinuclear antibodies, rapid plasma reagin, human immunodeficiency virus, and Lyme titers. The team also considers Ms. D’s history of herbal medicine use, because herbal mixtures can contain heavy metals and other contaminants. However, all toxicology results are normal, including arsenic, mercury, lead, copper, and zinc.

To address her symptoms, Ms. D is given risperidone, 0.5 mg twice a day, and donepezil, 5 mg/d.

[polldaddy:10012743]

Continue to: The authors' observations

Despite her persistent psychiatric symptoms, Ms. D had several neurologic symptoms that warranted further investigation. Her abrupt shifts from laughter to tears for no apparent reason were consistent with pseudobulbar affect. Her inability to remember how to use utensils during meals was consistent with apraxia. Finally, her abnormal gait raised concern for a process affecting her motor system.

OUTCOME A rare disorder

Given the psychiatry team’s suspicions for a neurologic etiology of Ms. D’s symptoms, an MRI of her brain is repeated. The results are notable for abnormal restricted diffusion in the caudate and putamen bilaterally, which is consistent with Creutzfeldt-Jakob disease (CJD). EEG shows moderate diffuse cerebral dysfunction, frontal intermittent delta activity, and diffuse cortical hyperexcitability, consistent with early- to mid-onset prion disease. Upon evaluation by the neurology team, Ms. D appears fearful, suspicious, and disorganized, but her examination does not reveal additional significant sensorimotor findings.

Ms. D is transferred to the neurology service for further workup and management. A lumbar puncture is positive for real-time quaking-induced conversion (RT-QuIC) and 14-3-3 protein with elevated tau proteins; these findings also are consistent with CJD. She develops transaminitis, with an alanine transaminase (ALT) of 127 and aspartate transaminase (AST) of 355, and a malignancy is suspected. However, CT scans of the chest, abdomen, and pelvis show no evidence of malignancy, and an extensive gastrointestinal workup is unremarkable, including anti-smooth muscle antibodies, anti-liver-kidney microsomal antibody, antimitochondrial antibodies, gliadin antibody, alpha-1 antitrypsin, liver/kidney microsomal antibody, and hepatitis serologies. While on the neurology service, risperidone and donepezil are discontinued because the findings indicate she has CJD and there are concerns that risperidone may be contributing to her transaminitis.

After discontinuing these medications, she is evaluated by the psychiatry consult team for mood lability. The psychiatry consult team recommends quetiapine, which is later started at 25 mg nightly at bedtime.

Clinically, Ms. D’s mental status continues to deteriorate. She becomes nonverbal and minimally able to follow commands. She is ultimately discharged to an inpatient hospice for end-of-life care and the team recommends that she continue with quetiapine once there.

Continue to: The authors' observations

CJD is a rare, rapidly progressive, fatal form of dementia. In the United States, the incidence is approximately 1 to 1.5 cases per 1 million people each year.² There are various forms of the disease. Sporadic CJD is the most common, representing 85% of cases.³ Sporadic CJD typically occurs in patients in their 60s and quickly leads to death—50% of patients die within 5 months, and 90% of patients die within 1 year.^2,3 The illness is hypothesized to arise from the production of misfolded prion proteins, ultimately leading to vacuolation, neuronal loss, and the spongiform appearance characteristic of CJD.^3,4

Psychiatric symptoms have long been acknowledged as a feature of CJD. Recent data indicates that psychiatric symptoms occur in 90% to 92% of cases.^5,6 Sleep disturbances and depressive symptoms, including vegetative symptoms, anhedonia, and tearfulness, appear to be most common.⁵ Psychotic symptoms occur in approximately 42% of cases and may include persecutory and paranoid delusions, as well as an array of vivid auditory, visual, and tactile hallucinations.^5,7

There is also evidence that psychiatric symptoms may be an early marker of CJD.^5,8 A Mayo Clinic study found that psychiatric symptoms occurred within the prodromal phase of CJD in 26% of cases, and psychiatric symptoms occurred within the first 100 days of illness in 86% of cases.⁵

Case reports have described patients with CJD who initially presented with depression, psychosis, and other psychiatric symptoms.^9-11 Interestingly, there have been cases with only psychiatric symptoms, and no neurologic symptoms until relatively late in the illness.^10,11 Several patients with CJD have been evaluated in psychiatric ERs, admitted to psychiatric hospitals, and treated with psychiatric medications and ECT.^5,9 In one study, 44% of CJD cases were misdiagnosed as “psychiatric patients” due to the prominence of their psychiatric symptomatology.⁸

Continue to: Making the diagnosis in psychiatric settings

Making the diagnosis in psychiatric settings. Often, the most difficult aspect of CJD is making the diagnosis.^3,12 Sporadic CJD in particular can vary widely in its clinical presentation.³ The core clinical feature of CJD is rapidly progressive dementia, so suspect CJD in these patients. However, CJD can be difficult to distinguish from other rapidly progressive dementias, such as autoimmune and paraneoplastic encephalopathies.^2,3 The presence of neurologic features, specifically myoclonus, akinetic mutism, and visual, cerebellar, and extrapyramidal symptoms, should also be considered a red flag for the disorder³ (Table).

Finally, positive findings on MRI, EEG, or CSF assay can indicate a probable diagnosis of CJD.¹³ MRI, particularly diffusion weighted imaging (DWI) and fluid-attenuated inversion recovery (FLAIR), is recog­nized as the most studied, sensitive, and overall useful neuroimaging modality for detecting CJD.^2,3,12 Although the appearance of CJD on MRI can vary widely, asymmetric hyperintensities in ≥3 cortical gyri, particularly in the frontal and parietal lobes, provide strong evidence of CJD and are observed in 80% to 81% of cases.^4,12 Asymmetric hyperintensities in the basal ganglia, particularly the caudate and rostral putamen, are observed in 69% to 70% of cases.^4,12,13

EEG and CSF assay also can be useful for making the diagnosis. While diffuse slowing and frontal rhythmic delta activity appear early in the course of CJD, periodic sharp wave complexes emerge later in the illness.⁴ However, EEG findings are not diagnostic, because periodic sharp wave complexes are seen in only two-thirds of CJD cases and also occur in other neurologic illnesses.^3,4 In recent years, lumbar puncture with subsequent CSF testing has become increasingly useful in detecting the illness. The presence of the 14-3-3 protein and tau protein is highly sensitive, although not specific, for CJD.³ A definite diagnosis of CJD requires discovery of the misfolded prion proteins, such as by RT-QuIC or brain biopsy.^2,3,13

Management of CJD in psychiatric patients. CJD is an invariably fatal disease for which there is no effective cure or disease modifying treatment.² Therefore, supportive therapies are the mainstay of care. Psychotropic medications can be used to provide symptom relief. While the sleep disturbances, anxiety, and agitation/hallucinations associated with CJD appear to respond well to hypnotic, anxiolytic, and antipsychotic medications, respectively, antidepressants and mood-stabilizing medications appear to have little benefit for patients with CJD.⁵ During the final stages of the disease, patients may suffer from akinetic mutism and inability to swallow, which often leads to aspiration pneumonia.¹⁴ Patients should also be offered end-of-life counseling, planning, and care, and provided with other comfort measures wherever possible (Figure).

Continue to: Bottom Line

Patients with Creutzfeldt-Jakob disease (CJD) may present to psychiatric settings, particularly to a psychiatric emergency room. Consider CJD as a possible etiology in patients with rapidly progressive dementia, depression, and psychosis. CJD is invariably fatal and there is no effective disease-modifying treatment. Supportive therapies are the mainstay of care.

Related Resources

• National Institute of Neurological Disorders and Stroke. Creutzfeldt-Jakob disease fact sheet. http://www.ninds.nih.gov/disorders/cjd/detail_cjd.htm.  
• Centers for Disease Control and Prevention. Creutzfeldt-Jakob disease, classic (CJD). http://www.cdc.gov/prions/cjd. 

Drug Brand Names

Donepezil • Aricept
Risperidone • Risperdal
Quetiapine • Seroquel

CASE A rapid decline

Ms. D, age 62, presents to a psychiatric emergency room (ER) after experiencing visual hallucinations, exhibiting odd behaviors, and having memory problems. On interview, she is disoriented, distractible, tearful, and tangential. She plays with her shirt and glasses, and occasionally shouts. She perseverates on “the aerialists,” acrobatic children she has been seeing in her apartment. She becomes distressed and shouts, “I would love to just get them!”

Ms. D is unable to provide an account of her history. Collateral information is obtained from her daughter, who has brought Ms. D to the ER for evaluation. She reports that her mother has no relevant medical or psychiatric history, and does not take any medications, except a mixture of Chinese herbs that she brews into a tea.

Ms. D’s daughter says that her mother began to deteriorate 5 months ago, after she traveled to California to care for her sister, who was seriously ill and passed away. After Ms. D returned, she would cry frequently. She also appeared “spaced out,” complained of feeling dizzy, and frequently misplaced belongings. Three months before presenting to the ER, she began to experience weakness, fatigue, and difficulty walking. Her daughter became more worried 2 months ago, when Ms. D began sleeping with her purse and hiding her belongings around their house. When asked about these odd behaviors, Ms. D claimed that “the aerialists” were climbing through her windows at night and stealing her things.

A week before seeking treatment at the ER, Ms. D’s daughter had taken her to a neurologist at another facility for clinical evaluation. An MRI of the brain showed minimal dilation in the subarachnoid space and a focal 1 cm lipoma in the anterior falx cerebri, but was otherwise unremarkable. However, Ms. D’s symptoms continued to worsen, and began to interfere with her ability to care for herself.

The team in the psychiatric ER attributes Ms. D’s symptoms to a severe, psychotic depressive episode. They admit her to the psychiatric inpatient unit for further evaluation.

[polldaddy:10012742]

Continue to: The authors' observations

Ms. D was plagued by several mood and psychotic symptoms. Such symptoms can arise from many different psychiatric or organic etiologies. In Ms. D’s case, several aspects of her presentation suggest that her illness was psychiatric. The severe illness of a beloved family member is a significant stressor that could cause a great deal of grief and devastation, possibly leading to depression. Indeed, Ms. D’s daughter noticed that her mother was crying frequently, which is consistent with grief or depression.

Memory problems, which might manifest as misplacing belongings, can also indicate a depressive illness, especially in older patients. Moreover, impaired concentration, which can cause one to appear “spaced out” or distractible, is a core symptom of major depressive disorder. Sadness and grief also can be appropriate during bereavement and in response to significant losses. Therefore, in Ms. D’s case, it is possible her frequent crying, “spaced out” appearance, and other mood symptoms she experienced immediately after caring for her sister were an appropriate response to her sister’s illness and death.

However, other aspects of Ms. D’s presentation suggested an organic etiology. Her rapid deterioration and symptom onset relatively late in life were consistent with dementia and malignancy. Her complaint of feeling dizzy suggested a neurologic process was affecting her vestibular system. Finally, while psychiatric disorders can certainly cause visual hallucinations, they occur in only a small percentage of cases.¹ Visual hallucinations are commonly associated with delirium, intoxication, and neurologic illness.

Continue to: EVALUATION Severe impairment

On the psychiatric inpatient unit, Ms. D remains unable to give a coherent account of her illness or recent events. During interviews, she abruptly shifts from laughing to crying for no apparent reason. While answering questions, her responses trail off and she appears to forget what she had been saying. However, she continues to speak at length about “the aerialists,” stating that she sees them living in her wardrobe and jumping from rooftop to rooftop in her neighborhood.

A mental status examination finds evidence of severe cognitive impairment. Ms. D is unable to identify the correct date, time, or place, and appears surprised when told she is in a hospital. She can repeat the names of 3 objects but cannot recall them a few minutes later. Finally, she scores a 14 on the Mini-Mental State Examination (MMSE) and a 5 on the Montreal Cognitive Assessment (MoCA), indicating severe impairment.

On the unit, Ms. D cannot remember the location of her room or bathroom, and even when given directions, she needs to be escorted to her destination. Her gait is unsteady and wide-spaced, and she walks on her toes at times. When food is placed before her, she needs to be shown how to take the lids off containers, pick up utensils, and start eating.

All laboratory results are unremarkable, including a complete blood count, basic metabolic panel, liver function tests, gamma-glutamyl transpeptidase, magnesium, phosphate, thyroid-stimulating hormone, vitamin B12, methylmalonic acid, homocysteine, folate, erythrocyte sedimentation rate, C-reactive protein, antinuclear antibodies, rapid plasma reagin, human immunodeficiency virus, and Lyme titers. The team also considers Ms. D’s history of herbal medicine use, because herbal mixtures can contain heavy metals and other contaminants. However, all toxicology results are normal, including arsenic, mercury, lead, copper, and zinc.

To address her symptoms, Ms. D is given risperidone, 0.5 mg twice a day, and donepezil, 5 mg/d.

[polldaddy:10012743]

Continue to: The authors' observations

Despite her persistent psychiatric symptoms, Ms. D had several neurologic symptoms that warranted further investigation. Her abrupt shifts from laughter to tears for no apparent reason were consistent with pseudobulbar affect. Her inability to remember how to use utensils during meals was consistent with apraxia. Finally, her abnormal gait raised concern for a process affecting her motor system.

OUTCOME A rare disorder

Given the psychiatry team’s suspicions for a neurologic etiology of Ms. D’s symptoms, an MRI of her brain is repeated. The results are notable for abnormal restricted diffusion in the caudate and putamen bilaterally, which is consistent with Creutzfeldt-Jakob disease (CJD). EEG shows moderate diffuse cerebral dysfunction, frontal intermittent delta activity, and diffuse cortical hyperexcitability, consistent with early- to mid-onset prion disease. Upon evaluation by the neurology team, Ms. D appears fearful, suspicious, and disorganized, but her examination does not reveal additional significant sensorimotor findings.

Ms. D is transferred to the neurology service for further workup and management. A lumbar puncture is positive for real-time quaking-induced conversion (RT-QuIC) and 14-3-3 protein with elevated tau proteins; these findings also are consistent with CJD. She develops transaminitis, with an alanine transaminase (ALT) of 127 and aspartate transaminase (AST) of 355, and a malignancy is suspected. However, CT scans of the chest, abdomen, and pelvis show no evidence of malignancy, and an extensive gastrointestinal workup is unremarkable, including anti-smooth muscle antibodies, anti-liver-kidney microsomal antibody, antimitochondrial antibodies, gliadin antibody, alpha-1 antitrypsin, liver/kidney microsomal antibody, and hepatitis serologies. While on the neurology service, risperidone and donepezil are discontinued because the findings indicate she has CJD and there are concerns that risperidone may be contributing to her transaminitis.

After discontinuing these medications, she is evaluated by the psychiatry consult team for mood lability. The psychiatry consult team recommends quetiapine, which is later started at 25 mg nightly at bedtime.

Clinically, Ms. D’s mental status continues to deteriorate. She becomes nonverbal and minimally able to follow commands. She is ultimately discharged to an inpatient hospice for end-of-life care and the team recommends that she continue with quetiapine once there.

Continue to: The authors' observations

CJD is a rare, rapidly progressive, fatal form of dementia. In the United States, the incidence is approximately 1 to 1.5 cases per 1 million people each year.² There are various forms of the disease. Sporadic CJD is the most common, representing 85% of cases.³ Sporadic CJD typically occurs in patients in their 60s and quickly leads to death—50% of patients die within 5 months, and 90% of patients die within 1 year.^2,3 The illness is hypothesized to arise from the production of misfolded prion proteins, ultimately leading to vacuolation, neuronal loss, and the spongiform appearance characteristic of CJD.^3,4

Psychiatric symptoms have long been acknowledged as a feature of CJD. Recent data indicates that psychiatric symptoms occur in 90% to 92% of cases.^5,6 Sleep disturbances and depressive symptoms, including vegetative symptoms, anhedonia, and tearfulness, appear to be most common.⁵ Psychotic symptoms occur in approximately 42% of cases and may include persecutory and paranoid delusions, as well as an array of vivid auditory, visual, and tactile hallucinations.^5,7

There is also evidence that psychiatric symptoms may be an early marker of CJD.^5,8 A Mayo Clinic study found that psychiatric symptoms occurred within the prodromal phase of CJD in 26% of cases, and psychiatric symptoms occurred within the first 100 days of illness in 86% of cases.⁵

Case reports have described patients with CJD who initially presented with depression, psychosis, and other psychiatric symptoms.^9-11 Interestingly, there have been cases with only psychiatric symptoms, and no neurologic symptoms until relatively late in the illness.^10,11 Several patients with CJD have been evaluated in psychiatric ERs, admitted to psychiatric hospitals, and treated with psychiatric medications and ECT.^5,9 In one study, 44% of CJD cases were misdiagnosed as “psychiatric patients” due to the prominence of their psychiatric symptomatology.⁸

Continue to: Making the diagnosis in psychiatric settings

Making the diagnosis in psychiatric settings. Often, the most difficult aspect of CJD is making the diagnosis.^3,12 Sporadic CJD in particular can vary widely in its clinical presentation.³ The core clinical feature of CJD is rapidly progressive dementia, so suspect CJD in these patients. However, CJD can be difficult to distinguish from other rapidly progressive dementias, such as autoimmune and paraneoplastic encephalopathies.^2,3 The presence of neurologic features, specifically myoclonus, akinetic mutism, and visual, cerebellar, and extrapyramidal symptoms, should also be considered a red flag for the disorder³ (Table).

Finally, positive findings on MRI, EEG, or CSF assay can indicate a probable diagnosis of CJD.¹³ MRI, particularly diffusion weighted imaging (DWI) and fluid-attenuated inversion recovery (FLAIR), is recog­nized as the most studied, sensitive, and overall useful neuroimaging modality for detecting CJD.^2,3,12 Although the appearance of CJD on MRI can vary widely, asymmetric hyperintensities in ≥3 cortical gyri, particularly in the frontal and parietal lobes, provide strong evidence of CJD and are observed in 80% to 81% of cases.^4,12 Asymmetric hyperintensities in the basal ganglia, particularly the caudate and rostral putamen, are observed in 69% to 70% of cases.^4,12,13

EEG and CSF assay also can be useful for making the diagnosis. While diffuse slowing and frontal rhythmic delta activity appear early in the course of CJD, periodic sharp wave complexes emerge later in the illness.⁴ However, EEG findings are not diagnostic, because periodic sharp wave complexes are seen in only two-thirds of CJD cases and also occur in other neurologic illnesses.^3,4 In recent years, lumbar puncture with subsequent CSF testing has become increasingly useful in detecting the illness. The presence of the 14-3-3 protein and tau protein is highly sensitive, although not specific, for CJD.³ A definite diagnosis of CJD requires discovery of the misfolded prion proteins, such as by RT-QuIC or brain biopsy.^2,3,13

Management of CJD in psychiatric patients. CJD is an invariably fatal disease for which there is no effective cure or disease modifying treatment.² Therefore, supportive therapies are the mainstay of care. Psychotropic medications can be used to provide symptom relief. While the sleep disturbances, anxiety, and agitation/hallucinations associated with CJD appear to respond well to hypnotic, anxiolytic, and antipsychotic medications, respectively, antidepressants and mood-stabilizing medications appear to have little benefit for patients with CJD.⁵ During the final stages of the disease, patients may suffer from akinetic mutism and inability to swallow, which often leads to aspiration pneumonia.¹⁴ Patients should also be offered end-of-life counseling, planning, and care, and provided with other comfort measures wherever possible (Figure).

Continue to: Bottom Line

Patients with Creutzfeldt-Jakob disease (CJD) may present to psychiatric settings, particularly to a psychiatric emergency room. Consider CJD as a possible etiology in patients with rapidly progressive dementia, depression, and psychosis. CJD is invariably fatal and there is no effective disease-modifying treatment. Supportive therapies are the mainstay of care.

Related Resources

• National Institute of Neurological Disorders and Stroke. Creutzfeldt-Jakob disease fact sheet. http://www.ninds.nih.gov/disorders/cjd/detail_cjd.htm.  
• Centers for Disease Control and Prevention. Creutzfeldt-Jakob disease, classic (CJD). http://www.cdc.gov/prions/cjd. 

Drug Brand Names

Donepezil • Aricept
Risperidone • Risperdal
Quetiapine • Seroquel

Physicians are not immune to chronic illness. Those who choose to continue working after being diagnosed with a chronic illness need to decide whether or not to tell their patients. The idea of physicians being a “blank slate” to their patients would be challenged by such self-disclosure. But ignoring an obvious change in the therapeutic space could be detrimental to your patient’s therapy.¹ Every patient has his or her own ideas or perceptions about their physician that contribute to how likely they are to continue to engage in therapy or take prescribed medications. Could letting your patients know you have a chronic illness threaten the image they have of you, and potentially jeopardize their treatment?

Physician factors

Once diagnosed with a chronic illness, a physician who previously defined his or her identity as a clinician now must also assume the role of a patient. This transition gives rise to anxiety. Patient encounters may give a physician the opportunity to feel safe to discuss such anxiety.² However, patients often view their physicians as omnipotent. When their physician admits weakness and vulnerability, that perception may be damaged.³ This damage could manifest as medication nonadherence, missed appointments, or even termination of treatment. A fear of such abandonment may lead a physician to not disclose his or her illness. To avoid discussing this uncomfortable topic, a physician might be more defensive in his or her interactions with the patient.²

Patient factors

Every patient presents with unique characteristics that contribute to the patient–physician relationship. Receiving news that one’s physician has a chronic or severe illness will elicit different reactions in each patient. These reactions will vary depending upon the patient’s pathology, stage of treatment, and background.³ The previous work done between the patient and physician is crucial in predicting the treatment course after the physician discloses that he or she has a chronic illness. Also, patients may notice the physical changes of their physician’s illness. Deciding to disclose—or to not disclose—something that is obvious can elicit feelings of worry, anger, or even triumph in the patient.³

CASES

Two patients, two different responses

Dr. T recently was diagnosed with leukemia and has begun to receive treatment. He decides to continue working. Since receiving the diagnosis, he finds himself more anxious. Adding to his anxiety is the question of whether or not he should tell his patients about his diagnosis. He decides to tell 2 of his patients—Mr. G and Ms. N—and receives a drastically different response from each of them.

Mr. G, age 45, has been Dr. T’s patient for 2 years. He is married, has 2 children, and works at a car dealership. Mr. G initially presented for treatment of depressive symptoms after his mother died. Those symptoms were stabilized with medication and supportive therapy. He now is working with Dr. T to cope with the impending loss of his father, who is dying of colon cancer.

Dr. T discloses the news of his illness to Mr. G at their next appointment. Mr. G offers his condolences and speaks about how on one hand, he is sympathetic and wishes to be supportive, but on the other hand, he fears another loss in his life. Mr. G thanks Dr. T for disclosing this news and hopes they can begin to discuss this situation in therapy. He remains compliant with appointments.

Ms. N, age 59, has been Dr. T’s patient for 6 months. She was diagnosed with schizophrenia when she was in her early 20s. She is single, unemployed, lives alone, and lacks social support. Ms. N has a history of multiple hospitalizations. She has a pattern of presenting to an emergency department and asking to be admitted whenever she faces an acute stressor.

Continue to: Ms. N came to Dr. T through another psychiatrist...

Ms. N came to Dr. T through another psychiatrist and Dr. T continues to provide medication management. He has implemented a biweekly appointment schedule for supportive therapy to work on Ms. N’s personal goals to cook more, clean her house, and lose weight. They also address issues regarding her father and his absence in her life since she was age 18.

During their next appointment, Dr. T discloses the news of his illness to Ms. N. Ms. N asks, “Are you sure?” Dr. T confirms and asks her how she feels about this news. She replies, “It’s fine.” Soon after, she stops attending her biweekly appointments and is lost to follow-up.

Consider your patient’s ability to cope

Dr. T faced the challenge of whether to disclose his diagnosis to his patients. He understood the potential implications on his therapeutic work and his battles with his own anxiety. Ultimately, he decided to tell his patients, but he did not consider how they might have been able to handle such news.

Mr. G was receptive to the news and remained engaged in treatment after learning of Dr. T’s illness. His ability to do so likely was the result of many factors. Mr. G is a high-functioning individual who seems to have a secure attachment style. He is able to express his conflicts. He has had good relationships in his life, was able to work through his mother’s death, and is engaged in treatment to help him cope with the inevitable loss of his father. Mr. G can handle the potential loss of his physician because he has shown his ability to cope with such losses in his life.

Continue to: On the other hand...

On the other hand, although Ms. N stated that the news of Dr. T’s diagnosis was “fine,” she was soon lost to follow-up, which suggests she was unable to handle the news. This is supported by her history of unstable relationships. Her insecure attachment style likely contributed to her inability to handle stressors, as evidenced by her frequent requests for admission. Dr. T also should have considered the possibility of transference, given that Ms. N struggled with abandonment by her father. Dr. T’s potential departure could represent such abandonment. In a patient such as Ms. N, being upfront about having a chronic illness would be more harmful than beneficial.

Maintain a patient-focused view

Receiving a diagnosis of a severe or chronic illness can be extremely stressful for physicians. Adopting the new identity of patient in addition to that of physician can cause tremendous anxiety. If you decide to continue working with your patients, it is crucial to be mindful of this anxiety and its potential to influence your decision to disclose your diagnosis to your patients. Do not allow your anxiety to contaminate the therapeutic work. Maintaining a patient-focused view of treatment will allow you to determine each patient’s ability to process disclosure vs nondisclosure of your diagnosis. Ultimately, this will help determine which patients you should tell, and which ones you should not.

Physicians are not immune to chronic illness. Those who choose to continue working after being diagnosed with a chronic illness need to decide whether or not to tell their patients. The idea of physicians being a “blank slate” to their patients would be challenged by such self-disclosure. But ignoring an obvious change in the therapeutic space could be detrimental to your patient’s therapy.¹ Every patient has his or her own ideas or perceptions about their physician that contribute to how likely they are to continue to engage in therapy or take prescribed medications. Could letting your patients know you have a chronic illness threaten the image they have of you, and potentially jeopardize their treatment?

Physician factors

Once diagnosed with a chronic illness, a physician who previously defined his or her identity as a clinician now must also assume the role of a patient. This transition gives rise to anxiety. Patient encounters may give a physician the opportunity to feel safe to discuss such anxiety.² However, patients often view their physicians as omnipotent. When their physician admits weakness and vulnerability, that perception may be damaged.³ This damage could manifest as medication nonadherence, missed appointments, or even termination of treatment. A fear of such abandonment may lead a physician to not disclose his or her illness. To avoid discussing this uncomfortable topic, a physician might be more defensive in his or her interactions with the patient.²

Patient factors

Every patient presents with unique characteristics that contribute to the patient–physician relationship. Receiving news that one’s physician has a chronic or severe illness will elicit different reactions in each patient. These reactions will vary depending upon the patient’s pathology, stage of treatment, and background.³ The previous work done between the patient and physician is crucial in predicting the treatment course after the physician discloses that he or she has a chronic illness. Also, patients may notice the physical changes of their physician’s illness. Deciding to disclose—or to not disclose—something that is obvious can elicit feelings of worry, anger, or even triumph in the patient.³

CASES

Two patients, two different responses

Dr. T recently was diagnosed with leukemia and has begun to receive treatment. He decides to continue working. Since receiving the diagnosis, he finds himself more anxious. Adding to his anxiety is the question of whether or not he should tell his patients about his diagnosis. He decides to tell 2 of his patients—Mr. G and Ms. N—and receives a drastically different response from each of them.

Mr. G, age 45, has been Dr. T’s patient for 2 years. He is married, has 2 children, and works at a car dealership. Mr. G initially presented for treatment of depressive symptoms after his mother died. Those symptoms were stabilized with medication and supportive therapy. He now is working with Dr. T to cope with the impending loss of his father, who is dying of colon cancer.

Dr. T discloses the news of his illness to Mr. G at their next appointment. Mr. G offers his condolences and speaks about how on one hand, he is sympathetic and wishes to be supportive, but on the other hand, he fears another loss in his life. Mr. G thanks Dr. T for disclosing this news and hopes they can begin to discuss this situation in therapy. He remains compliant with appointments.

Ms. N, age 59, has been Dr. T’s patient for 6 months. She was diagnosed with schizophrenia when she was in her early 20s. She is single, unemployed, lives alone, and lacks social support. Ms. N has a history of multiple hospitalizations. She has a pattern of presenting to an emergency department and asking to be admitted whenever she faces an acute stressor.

Continue to: Ms. N came to Dr. T through another psychiatrist...

Ms. N came to Dr. T through another psychiatrist and Dr. T continues to provide medication management. He has implemented a biweekly appointment schedule for supportive therapy to work on Ms. N’s personal goals to cook more, clean her house, and lose weight. They also address issues regarding her father and his absence in her life since she was age 18.

During their next appointment, Dr. T discloses the news of his illness to Ms. N. Ms. N asks, “Are you sure?” Dr. T confirms and asks her how she feels about this news. She replies, “It’s fine.” Soon after, she stops attending her biweekly appointments and is lost to follow-up.

Consider your patient’s ability to cope

Dr. T faced the challenge of whether to disclose his diagnosis to his patients. He understood the potential implications on his therapeutic work and his battles with his own anxiety. Ultimately, he decided to tell his patients, but he did not consider how they might have been able to handle such news.

Mr. G was receptive to the news and remained engaged in treatment after learning of Dr. T’s illness. His ability to do so likely was the result of many factors. Mr. G is a high-functioning individual who seems to have a secure attachment style. He is able to express his conflicts. He has had good relationships in his life, was able to work through his mother’s death, and is engaged in treatment to help him cope with the inevitable loss of his father. Mr. G can handle the potential loss of his physician because he has shown his ability to cope with such losses in his life.

Continue to: On the other hand...

On the other hand, although Ms. N stated that the news of Dr. T’s diagnosis was “fine,” she was soon lost to follow-up, which suggests she was unable to handle the news. This is supported by her history of unstable relationships. Her insecure attachment style likely contributed to her inability to handle stressors, as evidenced by her frequent requests for admission. Dr. T also should have considered the possibility of transference, given that Ms. N struggled with abandonment by her father. Dr. T’s potential departure could represent such abandonment. In a patient such as Ms. N, being upfront about having a chronic illness would be more harmful than beneficial.

Maintain a patient-focused view

Receiving a diagnosis of a severe or chronic illness can be extremely stressful for physicians. Adopting the new identity of patient in addition to that of physician can cause tremendous anxiety. If you decide to continue working with your patients, it is crucial to be mindful of this anxiety and its potential to influence your decision to disclose your diagnosis to your patients. Do not allow your anxiety to contaminate the therapeutic work. Maintaining a patient-focused view of treatment will allow you to determine each patient’s ability to process disclosure vs nondisclosure of your diagnosis. Ultimately, this will help determine which patients you should tell, and which ones you should not.

Physicians are not immune to chronic illness. Those who choose to continue working after being diagnosed with a chronic illness need to decide whether or not to tell their patients. The idea of physicians being a “blank slate” to their patients would be challenged by such self-disclosure. But ignoring an obvious change in the therapeutic space could be detrimental to your patient’s therapy.¹ Every patient has his or her own ideas or perceptions about their physician that contribute to how likely they are to continue to engage in therapy or take prescribed medications. Could letting your patients know you have a chronic illness threaten the image they have of you, and potentially jeopardize their treatment?

Physician factors

Once diagnosed with a chronic illness, a physician who previously defined his or her identity as a clinician now must also assume the role of a patient. This transition gives rise to anxiety. Patient encounters may give a physician the opportunity to feel safe to discuss such anxiety.² However, patients often view their physicians as omnipotent. When their physician admits weakness and vulnerability, that perception may be damaged.³ This damage could manifest as medication nonadherence, missed appointments, or even termination of treatment. A fear of such abandonment may lead a physician to not disclose his or her illness. To avoid discussing this uncomfortable topic, a physician might be more defensive in his or her interactions with the patient.²

Patient factors

Every patient presents with unique characteristics that contribute to the patient–physician relationship. Receiving news that one’s physician has a chronic or severe illness will elicit different reactions in each patient. These reactions will vary depending upon the patient’s pathology, stage of treatment, and background.³ The previous work done between the patient and physician is crucial in predicting the treatment course after the physician discloses that he or she has a chronic illness. Also, patients may notice the physical changes of their physician’s illness. Deciding to disclose—or to not disclose—something that is obvious can elicit feelings of worry, anger, or even triumph in the patient.³

CASES

Two patients, two different responses

Dr. T recently was diagnosed with leukemia and has begun to receive treatment. He decides to continue working. Since receiving the diagnosis, he finds himself more anxious. Adding to his anxiety is the question of whether or not he should tell his patients about his diagnosis. He decides to tell 2 of his patients—Mr. G and Ms. N—and receives a drastically different response from each of them.

Mr. G, age 45, has been Dr. T’s patient for 2 years. He is married, has 2 children, and works at a car dealership. Mr. G initially presented for treatment of depressive symptoms after his mother died. Those symptoms were stabilized with medication and supportive therapy. He now is working with Dr. T to cope with the impending loss of his father, who is dying of colon cancer.

Dr. T discloses the news of his illness to Mr. G at their next appointment. Mr. G offers his condolences and speaks about how on one hand, he is sympathetic and wishes to be supportive, but on the other hand, he fears another loss in his life. Mr. G thanks Dr. T for disclosing this news and hopes they can begin to discuss this situation in therapy. He remains compliant with appointments.

Ms. N, age 59, has been Dr. T’s patient for 6 months. She was diagnosed with schizophrenia when she was in her early 20s. She is single, unemployed, lives alone, and lacks social support. Ms. N has a history of multiple hospitalizations. She has a pattern of presenting to an emergency department and asking to be admitted whenever she faces an acute stressor.

Continue to: Ms. N came to Dr. T through another psychiatrist...

Ms. N came to Dr. T through another psychiatrist and Dr. T continues to provide medication management. He has implemented a biweekly appointment schedule for supportive therapy to work on Ms. N’s personal goals to cook more, clean her house, and lose weight. They also address issues regarding her father and his absence in her life since she was age 18.

During their next appointment, Dr. T discloses the news of his illness to Ms. N. Ms. N asks, “Are you sure?” Dr. T confirms and asks her how she feels about this news. She replies, “It’s fine.” Soon after, she stops attending her biweekly appointments and is lost to follow-up.

Consider your patient’s ability to cope

Dr. T faced the challenge of whether to disclose his diagnosis to his patients. He understood the potential implications on his therapeutic work and his battles with his own anxiety. Ultimately, he decided to tell his patients, but he did not consider how they might have been able to handle such news.

Mr. G was receptive to the news and remained engaged in treatment after learning of Dr. T’s illness. His ability to do so likely was the result of many factors. Mr. G is a high-functioning individual who seems to have a secure attachment style. He is able to express his conflicts. He has had good relationships in his life, was able to work through his mother’s death, and is engaged in treatment to help him cope with the inevitable loss of his father. Mr. G can handle the potential loss of his physician because he has shown his ability to cope with such losses in his life.

Continue to: On the other hand...

On the other hand, although Ms. N stated that the news of Dr. T’s diagnosis was “fine,” she was soon lost to follow-up, which suggests she was unable to handle the news. This is supported by her history of unstable relationships. Her insecure attachment style likely contributed to her inability to handle stressors, as evidenced by her frequent requests for admission. Dr. T also should have considered the possibility of transference, given that Ms. N struggled with abandonment by her father. Dr. T’s potential departure could represent such abandonment. In a patient such as Ms. N, being upfront about having a chronic illness would be more harmful than beneficial.

Maintain a patient-focused view

Receiving a diagnosis of a severe or chronic illness can be extremely stressful for physicians. Adopting the new identity of patient in addition to that of physician can cause tremendous anxiety. If you decide to continue working with your patients, it is crucial to be mindful of this anxiety and its potential to influence your decision to disclose your diagnosis to your patients. Do not allow your anxiety to contaminate the therapeutic work. Maintaining a patient-focused view of treatment will allow you to determine each patient’s ability to process disclosure vs nondisclosure of your diagnosis. Ultimately, this will help determine which patients you should tell, and which ones you should not.

Working at a long-term psychiatric hospital can present challenges similar to those found in other institutions, such as correctional facilities¹; however, in this setting, additional obstacles that could affect treatment may not readily come to mind. Following the 2 simple approaches described here can help you to understand your patient’s point of view and improve the treatment relationship.

Allow patients some control. Many patients in long-term psychiatric hospitals are prescribed medications that can result in metabolic complications such as weight gain or hyperlipidemia. To avoid these complications, we may need to institute dietary restrictions. Despite our explanations of why these restrictions are necessary, some patients may continue to insist on eating food that we believe will worsen their physical health; they may feel that they have little control in their lives and have nothing to look forward to except for what they can eat.²

For patients in long-term psychiatric hospitals, everyday life usually is structured from morning to evening. This includes when meals and snacks are served, as well as what they are allowed to eat. Food is a basic human necessity, and we often forget its psychological significance. Because most patients can control what they put in their mouths, food allows them to exert control in an environment where they may believe they have no influence. This may explain why patients insist on certain meals, purchase unhealthy food, or engage in a surreptitious snack distribution system with other patients. We usually can decide what and when we eat, but many of our hospitalized patients do not have that opportunity. Within reason, negotiating meals and snacks could provide patients with a sense of control, and might increase treatment compliance.²

Mind what you say. At the hospital, patients are acutely aware that we are there for a short period each day. For these patients, the hospital serves as their home. Many will live there for months to years; some will spend the remainder of their lives there. The way these patients view us can become adversely affected when they see that we occasionally bring a negative attitude toward having to spend the day in their living space, telling them how to behave and what to do. This daily temporary relationship between hospital staff and patients can greatly affect treatment.

Although the hospital can serve as a home, patients do not have input into how we should behave in their home. Be mindful of your actions and the comments you make while in the hospital. We would not appreciate someone making a negative comment about our homes, so it is likely that our patients do not want to hear us complain about the hospital. Furthermore, they likely do not enjoy hearing hospital staff discussing plans they have made in their personal lives. Many patients do not enjoy being in the hospital, and they could view such expressions as “rubbing it in,” which could adversely affect treatment.

Working at a long-term psychiatric hospital can present challenges similar to those found in other institutions, such as correctional facilities¹; however, in this setting, additional obstacles that could affect treatment may not readily come to mind. Following the 2 simple approaches described here can help you to understand your patient’s point of view and improve the treatment relationship.

Allow patients some control. Many patients in long-term psychiatric hospitals are prescribed medications that can result in metabolic complications such as weight gain or hyperlipidemia. To avoid these complications, we may need to institute dietary restrictions. Despite our explanations of why these restrictions are necessary, some patients may continue to insist on eating food that we believe will worsen their physical health; they may feel that they have little control in their lives and have nothing to look forward to except for what they can eat.²

For patients in long-term psychiatric hospitals, everyday life usually is structured from morning to evening. This includes when meals and snacks are served, as well as what they are allowed to eat. Food is a basic human necessity, and we often forget its psychological significance. Because most patients can control what they put in their mouths, food allows them to exert control in an environment where they may believe they have no influence. This may explain why patients insist on certain meals, purchase unhealthy food, or engage in a surreptitious snack distribution system with other patients. We usually can decide what and when we eat, but many of our hospitalized patients do not have that opportunity. Within reason, negotiating meals and snacks could provide patients with a sense of control, and might increase treatment compliance.²

Mind what you say. At the hospital, patients are acutely aware that we are there for a short period each day. For these patients, the hospital serves as their home. Many will live there for months to years; some will spend the remainder of their lives there. The way these patients view us can become adversely affected when they see that we occasionally bring a negative attitude toward having to spend the day in their living space, telling them how to behave and what to do. This daily temporary relationship between hospital staff and patients can greatly affect treatment.

Although the hospital can serve as a home, patients do not have input into how we should behave in their home. Be mindful of your actions and the comments you make while in the hospital. We would not appreciate someone making a negative comment about our homes, so it is likely that our patients do not want to hear us complain about the hospital. Furthermore, they likely do not enjoy hearing hospital staff discussing plans they have made in their personal lives. Many patients do not enjoy being in the hospital, and they could view such expressions as “rubbing it in,” which could adversely affect treatment.

Working at a long-term psychiatric hospital can present challenges similar to those found in other institutions, such as correctional facilities¹; however, in this setting, additional obstacles that could affect treatment may not readily come to mind. Following the 2 simple approaches described here can help you to understand your patient’s point of view and improve the treatment relationship.

Allow patients some control. Many patients in long-term psychiatric hospitals are prescribed medications that can result in metabolic complications such as weight gain or hyperlipidemia. To avoid these complications, we may need to institute dietary restrictions. Despite our explanations of why these restrictions are necessary, some patients may continue to insist on eating food that we believe will worsen their physical health; they may feel that they have little control in their lives and have nothing to look forward to except for what they can eat.²

For patients in long-term psychiatric hospitals, everyday life usually is structured from morning to evening. This includes when meals and snacks are served, as well as what they are allowed to eat. Food is a basic human necessity, and we often forget its psychological significance. Because most patients can control what they put in their mouths, food allows them to exert control in an environment where they may believe they have no influence. This may explain why patients insist on certain meals, purchase unhealthy food, or engage in a surreptitious snack distribution system with other patients. We usually can decide what and when we eat, but many of our hospitalized patients do not have that opportunity. Within reason, negotiating meals and snacks could provide patients with a sense of control, and might increase treatment compliance.²

Mind what you say. At the hospital, patients are acutely aware that we are there for a short period each day. For these patients, the hospital serves as their home. Many will live there for months to years; some will spend the remainder of their lives there. The way these patients view us can become adversely affected when they see that we occasionally bring a negative attitude toward having to spend the day in their living space, telling them how to behave and what to do. This daily temporary relationship between hospital staff and patients can greatly affect treatment.

Although the hospital can serve as a home, patients do not have input into how we should behave in their home. Be mindful of your actions and the comments you make while in the hospital. We would not appreciate someone making a negative comment about our homes, so it is likely that our patients do not want to hear us complain about the hospital. Furthermore, they likely do not enjoy hearing hospital staff discussing plans they have made in their personal lives. Many patients do not enjoy being in the hospital, and they could view such expressions as “rubbing it in,” which could adversely affect treatment.

Psychiatrists often fail to adequately address their patients’ smoking, and often underestimate the impact of ongoing tobacco use. Evidence suggests that heavy smoking is a risk factor for major depressive disorder; it also is associated with increased suicidal ideations and attempts.^1,2 Tobacco use also has a mood-altering impact that can change the trajectory of mental illness, and alters the metabolism of most psychotropics.

Previously, psychiatrists may have been reluctant to prescribe the most effective interventions for smoking cessation—varenicline and bupropion—because these medications carried an FDA “black-box” warning of neuropsychiatric adverse effects, including increased aggression and suicidality. However, a large study called the EAGLES trial³ found that the neuropsychiatric risks associated with these medications were lower than previously thought. Consequently, in December 2016, the FDA removed the black-box warning related to serious mental health adverse effects from the labeling of varenicline and bupropion.⁴

The EAGLES trial was a large, multi-site global trial that included patients with and without mental illness. Its primary objective was to assess the risk of “clinically significant” adverse effects for individuals receiving varenicline, bupropion, nicotine replacement therapy (NRT), or placebo, and whether having a history of psychiatric conditions increased the risk of developing adverse effects when taking these therapies. Overall, 2% of smokers without mental illness experienced adverse effects, compared with 5% to 7% in the psychiatric cohort, regardless of treatment arm. The rate of neuropsychiatric events and scores on suicide severity scales were similar across treatment arms in both cohorts.³

We should take lessons from the EAGLES trial. We propose that clinicians ask themselves the following 6 questions when forming a treatment plan to address their patients’ tobacco use:

1. Does the patient meet DSM-5 criteria for nicotine use disorder and, if yes, what is the severity of his or her nicotine dependence? The Fagerstrom Test for Nicotine Dependence (FTND)⁵ is a 6-question instrument for evaluating the quantity of cigarette consumption, compulsion to use, and dependence. It provides clinicians with guidelines on preventing withdrawal by implementing NRTs, such as lozenges, an inhaler, patches, and/or gum. A score of 1 to 2 (low dependence) indicates that no NRT is needed; a score of 3 to 4 (low to moderate dependence) requires 1 NRT; and scores of 5 to 7 (moderate dependence) and ≥8 (high dependence) require a combination of NRTs.

In the EAGLES trial, all participants smoked at least 10 cigarettes per day, and had moderate dependence, with an average FTND score of 5 to 6.

2. What stage of change is the patient in, and how many times has he or she attempted to quit? Based on the answers, motivational interviewing may be appropriate.

Continue to: In the EAGLES trial...

In the EAGLES trial, the participants were motivated individuals who had on average 3 past quit attempts. Research suggests that even patients who have a serious mental illness can be motivated to quit (Box).^6-9

Box
Mental illness and motivation to quit smoking

3. What is the patient’s mental health status? What is the patient’s psychi­atric diagnosis and how clinically stable is he or she? What is his or her suicide risk? Consider using the Columbia Suicide Severity Rating Scale (C-SSRS).¹⁰

In the EAGLES trial, the psychiatric cohort included only patients who had been clinically stable for the past 6 months and had received the same medication regimen for at least the past 3 months, with no expected changes for 12 weeks. Patients with certain diagnoses were excluded (eg, delusional disorder, schizophreniform disorder, impulse control disorders), and only 1% had a personality disorder, which increases mood lability and likelihood of suicidality behavior.

Continue to: Does the patient have another comorbid substance use disorder?

4. Does the patient have another comorbid substance use disorder? In the EAGLES trial, those who had active substance use in the past year or were receiving methadone or buprenorphine/naloxone were excluded.

5. Does the patient have any medical conditions? Does he or she have a history of seizures or eating disorders? It is important to determine if a patient has a seizure disorder or another medical condition that is a contraindication for using varenicline or bupropion.

In the EAGLES trial, most adverse effects related to the medications administered involved sleep (insomnia) or the gastrointestinal system (nausea). The psychiatric cohort reported some anxiety with bupropion.

6. Have you discussed smoking cessation and a treatment plan with the patient at every visit? In the EAGLES trial, participants received 10-minute cessation counseling at every outpatient visit.

Continue to: When it comes time to select a medication regimen...

When it comes time to select a medication regimen, for bupropion, consider starting the patient with 150 mg/d, and increasing the dose to 150 mg twice a day 4 days later. The target quit date should be 7 days after starting the medication. Monitor the patient for symptoms of anxiety and insomnia.

For varenicline, start the patient at 0.5 mg/d, and increase the dose to 0.5 mg twice a day 4 days later. After another 4 days, increase the dose to 1 mg twice a day. Set a target quit date for 7 days after starting medication. Monitor the patient for nausea, insomnia, and abnormal dreams.

Psychiatrists often fail to adequately address their patients’ smoking, and often underestimate the impact of ongoing tobacco use. Evidence suggests that heavy smoking is a risk factor for major depressive disorder; it also is associated with increased suicidal ideations and attempts.^1,2 Tobacco use also has a mood-altering impact that can change the trajectory of mental illness, and alters the metabolism of most psychotropics.

Previously, psychiatrists may have been reluctant to prescribe the most effective interventions for smoking cessation—varenicline and bupropion—because these medications carried an FDA “black-box” warning of neuropsychiatric adverse effects, including increased aggression and suicidality. However, a large study called the EAGLES trial³ found that the neuropsychiatric risks associated with these medications were lower than previously thought. Consequently, in December 2016, the FDA removed the black-box warning related to serious mental health adverse effects from the labeling of varenicline and bupropion.⁴

The EAGLES trial was a large, multi-site global trial that included patients with and without mental illness. Its primary objective was to assess the risk of “clinically significant” adverse effects for individuals receiving varenicline, bupropion, nicotine replacement therapy (NRT), or placebo, and whether having a history of psychiatric conditions increased the risk of developing adverse effects when taking these therapies. Overall, 2% of smokers without mental illness experienced adverse effects, compared with 5% to 7% in the psychiatric cohort, regardless of treatment arm. The rate of neuropsychiatric events and scores on suicide severity scales were similar across treatment arms in both cohorts.³

We should take lessons from the EAGLES trial. We propose that clinicians ask themselves the following 6 questions when forming a treatment plan to address their patients’ tobacco use:

1. Does the patient meet DSM-5 criteria for nicotine use disorder and, if yes, what is the severity of his or her nicotine dependence? The Fagerstrom Test for Nicotine Dependence (FTND)⁵ is a 6-question instrument for evaluating the quantity of cigarette consumption, compulsion to use, and dependence. It provides clinicians with guidelines on preventing withdrawal by implementing NRTs, such as lozenges, an inhaler, patches, and/or gum. A score of 1 to 2 (low dependence) indicates that no NRT is needed; a score of 3 to 4 (low to moderate dependence) requires 1 NRT; and scores of 5 to 7 (moderate dependence) and ≥8 (high dependence) require a combination of NRTs.

In the EAGLES trial, all participants smoked at least 10 cigarettes per day, and had moderate dependence, with an average FTND score of 5 to 6.

2. What stage of change is the patient in, and how many times has he or she attempted to quit? Based on the answers, motivational interviewing may be appropriate.

Continue to: In the EAGLES trial...

In the EAGLES trial, the participants were motivated individuals who had on average 3 past quit attempts. Research suggests that even patients who have a serious mental illness can be motivated to quit (Box).^6-9

Box
Mental illness and motivation to quit smoking

3. What is the patient’s mental health status? What is the patient’s psychi­atric diagnosis and how clinically stable is he or she? What is his or her suicide risk? Consider using the Columbia Suicide Severity Rating Scale (C-SSRS).¹⁰

In the EAGLES trial, the psychiatric cohort included only patients who had been clinically stable for the past 6 months and had received the same medication regimen for at least the past 3 months, with no expected changes for 12 weeks. Patients with certain diagnoses were excluded (eg, delusional disorder, schizophreniform disorder, impulse control disorders), and only 1% had a personality disorder, which increases mood lability and likelihood of suicidality behavior.

Continue to: Does the patient have another comorbid substance use disorder?

4. Does the patient have another comorbid substance use disorder? In the EAGLES trial, those who had active substance use in the past year or were receiving methadone or buprenorphine/naloxone were excluded.

5. Does the patient have any medical conditions? Does he or she have a history of seizures or eating disorders? It is important to determine if a patient has a seizure disorder or another medical condition that is a contraindication for using varenicline or bupropion.

In the EAGLES trial, most adverse effects related to the medications administered involved sleep (insomnia) or the gastrointestinal system (nausea). The psychiatric cohort reported some anxiety with bupropion.

6. Have you discussed smoking cessation and a treatment plan with the patient at every visit? In the EAGLES trial, participants received 10-minute cessation counseling at every outpatient visit.

Continue to: When it comes time to select a medication regimen...

When it comes time to select a medication regimen, for bupropion, consider starting the patient with 150 mg/d, and increasing the dose to 150 mg twice a day 4 days later. The target quit date should be 7 days after starting the medication. Monitor the patient for symptoms of anxiety and insomnia.

For varenicline, start the patient at 0.5 mg/d, and increase the dose to 0.5 mg twice a day 4 days later. After another 4 days, increase the dose to 1 mg twice a day. Set a target quit date for 7 days after starting medication. Monitor the patient for nausea, insomnia, and abnormal dreams.

Psychiatrists often fail to adequately address their patients’ smoking, and often underestimate the impact of ongoing tobacco use. Evidence suggests that heavy smoking is a risk factor for major depressive disorder; it also is associated with increased suicidal ideations and attempts.^1,2 Tobacco use also has a mood-altering impact that can change the trajectory of mental illness, and alters the metabolism of most psychotropics.

Previously, psychiatrists may have been reluctant to prescribe the most effective interventions for smoking cessation—varenicline and bupropion—because these medications carried an FDA “black-box” warning of neuropsychiatric adverse effects, including increased aggression and suicidality. However, a large study called the EAGLES trial³ found that the neuropsychiatric risks associated with these medications were lower than previously thought. Consequently, in December 2016, the FDA removed the black-box warning related to serious mental health adverse effects from the labeling of varenicline and bupropion.⁴

The EAGLES trial was a large, multi-site global trial that included patients with and without mental illness. Its primary objective was to assess the risk of “clinically significant” adverse effects for individuals receiving varenicline, bupropion, nicotine replacement therapy (NRT), or placebo, and whether having a history of psychiatric conditions increased the risk of developing adverse effects when taking these therapies. Overall, 2% of smokers without mental illness experienced adverse effects, compared with 5% to 7% in the psychiatric cohort, regardless of treatment arm. The rate of neuropsychiatric events and scores on suicide severity scales were similar across treatment arms in both cohorts.³

We should take lessons from the EAGLES trial. We propose that clinicians ask themselves the following 6 questions when forming a treatment plan to address their patients’ tobacco use:

1. Does the patient meet DSM-5 criteria for nicotine use disorder and, if yes, what is the severity of his or her nicotine dependence? The Fagerstrom Test for Nicotine Dependence (FTND)⁵ is a 6-question instrument for evaluating the quantity of cigarette consumption, compulsion to use, and dependence. It provides clinicians with guidelines on preventing withdrawal by implementing NRTs, such as lozenges, an inhaler, patches, and/or gum. A score of 1 to 2 (low dependence) indicates that no NRT is needed; a score of 3 to 4 (low to moderate dependence) requires 1 NRT; and scores of 5 to 7 (moderate dependence) and ≥8 (high dependence) require a combination of NRTs.

In the EAGLES trial, all participants smoked at least 10 cigarettes per day, and had moderate dependence, with an average FTND score of 5 to 6.

2. What stage of change is the patient in, and how many times has he or she attempted to quit? Based on the answers, motivational interviewing may be appropriate.

Continue to: In the EAGLES trial...

In the EAGLES trial, the participants were motivated individuals who had on average 3 past quit attempts. Research suggests that even patients who have a serious mental illness can be motivated to quit (Box).^6-9

Box
Mental illness and motivation to quit smoking

3. What is the patient’s mental health status? What is the patient’s psychi­atric diagnosis and how clinically stable is he or she? What is his or her suicide risk? Consider using the Columbia Suicide Severity Rating Scale (C-SSRS).¹⁰

In the EAGLES trial, the psychiatric cohort included only patients who had been clinically stable for the past 6 months and had received the same medication regimen for at least the past 3 months, with no expected changes for 12 weeks. Patients with certain diagnoses were excluded (eg, delusional disorder, schizophreniform disorder, impulse control disorders), and only 1% had a personality disorder, which increases mood lability and likelihood of suicidality behavior.

Continue to: Does the patient have another comorbid substance use disorder?

4. Does the patient have another comorbid substance use disorder? In the EAGLES trial, those who had active substance use in the past year or were receiving methadone or buprenorphine/naloxone were excluded.

5. Does the patient have any medical conditions? Does he or she have a history of seizures or eating disorders? It is important to determine if a patient has a seizure disorder or another medical condition that is a contraindication for using varenicline or bupropion.

In the EAGLES trial, most adverse effects related to the medications administered involved sleep (insomnia) or the gastrointestinal system (nausea). The psychiatric cohort reported some anxiety with bupropion.

6. Have you discussed smoking cessation and a treatment plan with the patient at every visit? In the EAGLES trial, participants received 10-minute cessation counseling at every outpatient visit.

Continue to: When it comes time to select a medication regimen...

When it comes time to select a medication regimen, for bupropion, consider starting the patient with 150 mg/d, and increasing the dose to 150 mg twice a day 4 days later. The target quit date should be 7 days after starting the medication. Monitor the patient for symptoms of anxiety and insomnia.

For varenicline, start the patient at 0.5 mg/d, and increase the dose to 0.5 mg twice a day 4 days later. After another 4 days, increase the dose to 1 mg twice a day. Set a target quit date for 7 days after starting medication. Monitor the patient for nausea, insomnia, and abnormal dreams.

Over the past decade, bipolar disorder (BD) has gained widespread recognition in mainstream culture and in the media,¹ and awareness of this condition has increased substantially. As a result, patients commonly present with preconceived ideas about bipolarity that may or may not actually correspond with this diagnosis. In anticipation of seeing such patients, I offer 4 recommendations to help clinicians more accurately diagnose BD.

1. Screen for periods of manic or hypomanic mood. Effective screening questions include:

• “Have you ever had periods when you felt too happy, too angry, or on top of the world for several days in a row?”
• “Have you had periods when you would go several days without much sleep and still feel fine during the day?”

If the patient reports irritability rather than euphoria, try to better understand the phenomenology of his or her irritable mood. Among patients who experience mania, irritability often results from impatience, which in turn seems to be secondary to grandiosity, increased energy, and accelerated thought processes.²

2. Avoid using terms with low specificity, such as “mood swings” and “racing thoughts,” when you screen for manic symptoms. If the patient mentions these phrases, do not take them at face value; ask him or her to characterize them in detail. Differentiate chronic, quick fluctuations in affect—which are usually triggered by environmental factors and typically are reported by patients with personality disorders—from more persistent periods of mood polarization. Similarly, anxious patients commonly report having “racing thoughts.”

3. Distinguish patients who have a chronic, ongoing preoccupation with shopping from those who exhibit intermittent periods of excessive shopping and prodigality, which usually are associated with other manic symptoms.³ Spending money in excess is often cited as a classic symptom of mania or hypomania, but it may be an indicator of other conditions, such as compulsive buying.

4. Ask about any increases in goal-directed activity. This is a good way to identify true manic or hypomanic periods. Patients with anxiety or agitated depression may report an increase in psychomotor activity, but this is usually characterized more by restlessness and wandering, and not by a true increase in activity.

Consider a temporary diagnosis

When in doubt, it may be advisable to establish a temporary diagnosis of unspecified mood disorder, until you can learn more about the patient, obtain collateral information from family or friends, and request past medical records.

Over the past decade, bipolar disorder (BD) has gained widespread recognition in mainstream culture and in the media,¹ and awareness of this condition has increased substantially. As a result, patients commonly present with preconceived ideas about bipolarity that may or may not actually correspond with this diagnosis. In anticipation of seeing such patients, I offer 4 recommendations to help clinicians more accurately diagnose BD.

1. Screen for periods of manic or hypomanic mood. Effective screening questions include:

• “Have you ever had periods when you felt too happy, too angry, or on top of the world for several days in a row?”
• “Have you had periods when you would go several days without much sleep and still feel fine during the day?”

If the patient reports irritability rather than euphoria, try to better understand the phenomenology of his or her irritable mood. Among patients who experience mania, irritability often results from impatience, which in turn seems to be secondary to grandiosity, increased energy, and accelerated thought processes.²

2. Avoid using terms with low specificity, such as “mood swings” and “racing thoughts,” when you screen for manic symptoms. If the patient mentions these phrases, do not take them at face value; ask him or her to characterize them in detail. Differentiate chronic, quick fluctuations in affect—which are usually triggered by environmental factors and typically are reported by patients with personality disorders—from more persistent periods of mood polarization. Similarly, anxious patients commonly report having “racing thoughts.”

3. Distinguish patients who have a chronic, ongoing preoccupation with shopping from those who exhibit intermittent periods of excessive shopping and prodigality, which usually are associated with other manic symptoms.³ Spending money in excess is often cited as a classic symptom of mania or hypomania, but it may be an indicator of other conditions, such as compulsive buying.

4. Ask about any increases in goal-directed activity. This is a good way to identify true manic or hypomanic periods. Patients with anxiety or agitated depression may report an increase in psychomotor activity, but this is usually characterized more by restlessness and wandering, and not by a true increase in activity.

Consider a temporary diagnosis

When in doubt, it may be advisable to establish a temporary diagnosis of unspecified mood disorder, until you can learn more about the patient, obtain collateral information from family or friends, and request past medical records.

Over the past decade, bipolar disorder (BD) has gained widespread recognition in mainstream culture and in the media,¹ and awareness of this condition has increased substantially. As a result, patients commonly present with preconceived ideas about bipolarity that may or may not actually correspond with this diagnosis. In anticipation of seeing such patients, I offer 4 recommendations to help clinicians more accurately diagnose BD.

1. Screen for periods of manic or hypomanic mood. Effective screening questions include:

• “Have you ever had periods when you felt too happy, too angry, or on top of the world for several days in a row?”
• “Have you had periods when you would go several days without much sleep and still feel fine during the day?”

If the patient reports irritability rather than euphoria, try to better understand the phenomenology of his or her irritable mood. Among patients who experience mania, irritability often results from impatience, which in turn seems to be secondary to grandiosity, increased energy, and accelerated thought processes.²

2. Avoid using terms with low specificity, such as “mood swings” and “racing thoughts,” when you screen for manic symptoms. If the patient mentions these phrases, do not take them at face value; ask him or her to characterize them in detail. Differentiate chronic, quick fluctuations in affect—which are usually triggered by environmental factors and typically are reported by patients with personality disorders—from more persistent periods of mood polarization. Similarly, anxious patients commonly report having “racing thoughts.”

3. Distinguish patients who have a chronic, ongoing preoccupation with shopping from those who exhibit intermittent periods of excessive shopping and prodigality, which usually are associated with other manic symptoms.³ Spending money in excess is often cited as a classic symptom of mania or hypomania, but it may be an indicator of other conditions, such as compulsive buying.

4. Ask about any increases in goal-directed activity. This is a good way to identify true manic or hypomanic periods. Patients with anxiety or agitated depression may report an increase in psychomotor activity, but this is usually characterized more by restlessness and wandering, and not by a true increase in activity.

Consider a temporary diagnosis

When in doubt, it may be advisable to establish a temporary diagnosis of unspecified mood disorder, until you can learn more about the patient, obtain collateral information from family or friends, and request past medical records.

Sexual harassment hit a peak of cultural awareness over the past year. Will medicine be the next field to experience a reckoning?

In 2017, Time magazine’s Person of the Year Award went to the Silence Breakers who spoke out against sexual assault and harassment.¹ The exposure of predatory behavior exhibited by once-celebrated movie producers, newscasters, and actors has given rise to a powerful change. The #MeToo movement has risen to support survivors and end sexual violence.

Just like show business, other industries have rich histories of discrimination and power. Think Wall Street, Silicon Valley, hospitality services, and the list goes on and on.² But what about medicine? To answer this question, this article aims to:

• review the dilemma
• explore our duty to our patients and each other
• discuss solutions to address the problem.

Sexual harassment: A brief history

Decades ago, Anita Hill accused U.S. Supreme Court nominee Clarence Thomas, her boss at the U.S. Department of Education and the Equal Employment Opportunity Commission (EEOC), of sexual harassment.³

The year was 1991, and President George H. W. Bush had nominated Thomas, a federal Circuit Judge, to succeed retiring Associate Supreme Court Justice Thurgood Marshall. With Thomas’s good character presented as a primary qualification, he appeared to be a sure thing.

Continue to: That was until an FBI interview...

That was until an FBI interview of Hill was leaked to the press. Hill asserted that Thomas had sexually harassed her while he was her supervisor at the Department of Education and the EEOC.⁴ Heavily scrutinized for her choice to follow Thomas to a second job after he had already allegedly harassed her, Hill was in a conundrum shared by many women—putting up with abuse in exchange for a reputable position and the opportunity to fulfill a career ambition.

Hill is a trailblazer for women yearning to speak the truth, and she brought national attention to sexual harassment in the early 1990s. On December 16, 2017, the Commission on Sexual Harassment and Advancing Equality in the Workplace was formed. Hill was selected to lead the charge against sexual harassment in the entertainment industry.⁵

A forensic assessment of harassment

Hill’s courageous story is one of many touched upon in the 2016 book Because of Sex.⁶ Author Gillian Thomas, a senior staff attorney with the American Civil Liberties Union’s Women’s Rights Project, explores how Title VII of the Civil Rights Act of 1964 made it illegal to discriminate “because of sex.”

The field of forensic psychiatry has long been attentive to themes of sexual harassment and discrimination. The American Academy of Psychiatry and Law has a robust list of landmark cases thought to be especially important and significant for forensic psychiatry.⁷ This list includes cases brought forth by tenacious, yet ordinary women who used the law to advocate, and some have taken their fight all the way to the Supreme Court. Let’s consider 2 such cases:

Meritor Savings Bank, FSB v Vinson (1986).⁸ This was a U.S. labor law case. Michelle Vinson rose through the ranks at Meritor Savings Bank, only to be fired for excessive sick leave. She filed a Title VII suit against the bank. Vinson alleged that the bank was liable for sexual harassment perpetrated by its employee and vice president, Sidney Taylor. Vinson claimed that there had been 40 to 50 sexual encounters over 4 years, ranging from fondling to indecent exposure to rape. Vinson asserted that she never reported these events for fear of losing her job. The Supreme Court, in a 9-to-0 decision, recognized sexual harassment as a violation of Title VII of the Civil Rights Act of 1964.

Continue to: Harris v Forklift Systems, Inc. (1993)

Harris v Forklift Systems, Inc. (1993).⁹ Teresa Harris, a manager at Forklift Systems, Inc., claimed that the company’s president frequently directed offensive remarks at her that were sexual and discriminatory. The Supreme Court clarified the definition of a “hostile” or “abusive” work environment under Title VII of the Civil Rights Act of 1964. Associate Justice Sandra Day O’Connor was joined by a unanimous majority opinion in agreement with Harris.

Physicians are not immune

Clinicians are affected by sexual harassment, too. We have a duty to protect our patients, colleagues, and ourselves. Psychiatrists in particular often are on the frontlines of helping victims process their trauma.¹⁰

But will the field of medicine also face a reckoning when it comes to perpetrating harassment? It seems likely that the medical field would be ripe with harassment when you consider its history of male domination and a hierarchical structure with strong power differentials—not to mention the late nights, exhaustion, easy access to beds, and late-night encounters where inhibitions may be lowered.¹¹

A shocking number of female doctors are sexually harassed. Thirty percent of the top female clinician-researchers have experienced blatant sexual harassment on the job, according to a survey of 573 men and 493 women who received career development awards from the National Institutes of Health in 2006 to 2009.¹² In this survey, harassment covered the scope of sexist remarks or behavior, unwanted sexual advances, bribery, threats, and coercion. The majority of those affected said the experience undermined their confidence as professionals, and many said the harassment negatively affected their career advancement.¹²

Continue to: But what about the progress women have made...

But what about the progress women have made in medicine? Women are surpassing men in terms of admittance to medical school. Last year, for the first time, women accounted for more than half of the enrollees in U.S. medical schools, according to the Association of American Medical Colleges.¹³ Yet there has been a stalling in terms of change when it comes to harassment.¹² Women may be more vulnerable to harassment, both when they’re perceived as weak and when they’re so strong that they challenge traditional hierarchies.

Perpetuating the problem is the trouble with reporting sexual harassment. Victims do not fare well in our society. Even in the #MeToo era, reporting such behavior is far from straightforward.¹¹ Women fear that reporting any harassment will make them a target. Think of Anita Hill—her testimony against Clarence Thomas during his confirmation hearings for the Supreme Court showed that women who report sexual harassment experience marginalization, retaliation, stigmatization, and worse.

The result is that medical professionals tend to suppress the recognition of harassment. We make excuses for it, blame ourselves, or just take it on the chin and move on. There’s also confusion regarding what constitutes harassment. As doctors, especially psychiatrists, we hear harrowing stories. It’s reasonable to downplay our own experiences. Turning everyone into a victim of sexual harassment could detract from the stories of women who were raped, molested, and severely taken advantage of. There is a reasonable fear that diluting their message could be further damaging.¹⁴

Time for action

The field of medicine needs to do better in terms of education, support, anticipation, prevention, and reaction to harassment. We have the awareness. Now, we need action.

Continue to: One way to change any culture...

One way to change any culture of harassment or discrimination would be the advancement of more female physicians into leadership positions. The Association of American Medical Colleges has reported that fewer women than men hold faculty positions and full professorships.^15,16 There’s also a striking imbalance among fields of medicine practiced by men and women, with more women seen in pediatrics, obstetrics, and gynecology as opposed to surgery. Advancement into policy-setting echelons of medicine is essential for change. Sexual harassment can be a silent problem that will be corrected only when institutions and leaders put it on the forefront of discussions.¹⁷

Another possible solution would be to shift problem-solving from punishment to prevention. Many institutions set expectations about intolerance of sexual harassment and conduct occasional lectures about it. However, enforcing protocols and safeguards that support and enforce policy are difficult on the ground level. In any event, punishment alone won’t change a culture.¹⁷

Working with students until they are comfortable disclosing details of incidents can be helpful. For example, the University of Wisconsin-Madison employs an ombuds to help with this process.¹⁸ All institutions should encourage reporting along confidential pathways and have multiple ways to report.¹⁷ Tracking complaints, even seemingly minor infractions, can help identify patterns of behavior and anticipate future incidents.

Some solutions seem obvious, such as informal and retaliation-free reporting that allows institutions to track perpetrators’ behavior; mandatory training that includes bystander training; and disciplining and monitoring transgressors and terminating their employment when appropriate—something along the lines of a zero-tolerance policy. There needs to be more research on the prevalence, severity, and outcomes of sexual harassment, and subsequent investigations, along with research into evidence-based prevention and intervention strategies.¹⁷

Continue to: Although this article focuses...

Although this article focuses on harassment of women, men are equally important to this conversation because they, too, can be victims. Men also can serve a pivotal role in mentoring and championing their female counterparts as they strive for advancement, equality, and respect.

The task ahead is large, and this discussion is not over.

Sexual harassment hit a peak of cultural awareness over the past year. Will medicine be the next field to experience a reckoning?

In 2017, Time magazine’s Person of the Year Award went to the Silence Breakers who spoke out against sexual assault and harassment.¹ The exposure of predatory behavior exhibited by once-celebrated movie producers, newscasters, and actors has given rise to a powerful change. The #MeToo movement has risen to support survivors and end sexual violence.

Just like show business, other industries have rich histories of discrimination and power. Think Wall Street, Silicon Valley, hospitality services, and the list goes on and on.² But what about medicine? To answer this question, this article aims to:

• review the dilemma
• explore our duty to our patients and each other
• discuss solutions to address the problem.

Sexual harassment: A brief history

Decades ago, Anita Hill accused U.S. Supreme Court nominee Clarence Thomas, her boss at the U.S. Department of Education and the Equal Employment Opportunity Commission (EEOC), of sexual harassment.³

The year was 1991, and President George H. W. Bush had nominated Thomas, a federal Circuit Judge, to succeed retiring Associate Supreme Court Justice Thurgood Marshall. With Thomas’s good character presented as a primary qualification, he appeared to be a sure thing.

Continue to: That was until an FBI interview...

That was until an FBI interview of Hill was leaked to the press. Hill asserted that Thomas had sexually harassed her while he was her supervisor at the Department of Education and the EEOC.⁴ Heavily scrutinized for her choice to follow Thomas to a second job after he had already allegedly harassed her, Hill was in a conundrum shared by many women—putting up with abuse in exchange for a reputable position and the opportunity to fulfill a career ambition.

Hill is a trailblazer for women yearning to speak the truth, and she brought national attention to sexual harassment in the early 1990s. On December 16, 2017, the Commission on Sexual Harassment and Advancing Equality in the Workplace was formed. Hill was selected to lead the charge against sexual harassment in the entertainment industry.⁵

A forensic assessment of harassment

Hill’s courageous story is one of many touched upon in the 2016 book Because of Sex.⁶ Author Gillian Thomas, a senior staff attorney with the American Civil Liberties Union’s Women’s Rights Project, explores how Title VII of the Civil Rights Act of 1964 made it illegal to discriminate “because of sex.”

The field of forensic psychiatry has long been attentive to themes of sexual harassment and discrimination. The American Academy of Psychiatry and Law has a robust list of landmark cases thought to be especially important and significant for forensic psychiatry.⁷ This list includes cases brought forth by tenacious, yet ordinary women who used the law to advocate, and some have taken their fight all the way to the Supreme Court. Let’s consider 2 such cases:

Meritor Savings Bank, FSB v Vinson (1986).⁸ This was a U.S. labor law case. Michelle Vinson rose through the ranks at Meritor Savings Bank, only to be fired for excessive sick leave. She filed a Title VII suit against the bank. Vinson alleged that the bank was liable for sexual harassment perpetrated by its employee and vice president, Sidney Taylor. Vinson claimed that there had been 40 to 50 sexual encounters over 4 years, ranging from fondling to indecent exposure to rape. Vinson asserted that she never reported these events for fear of losing her job. The Supreme Court, in a 9-to-0 decision, recognized sexual harassment as a violation of Title VII of the Civil Rights Act of 1964.

Continue to: Harris v Forklift Systems, Inc. (1993)

Harris v Forklift Systems, Inc. (1993).⁹ Teresa Harris, a manager at Forklift Systems, Inc., claimed that the company’s president frequently directed offensive remarks at her that were sexual and discriminatory. The Supreme Court clarified the definition of a “hostile” or “abusive” work environment under Title VII of the Civil Rights Act of 1964. Associate Justice Sandra Day O’Connor was joined by a unanimous majority opinion in agreement with Harris.

Physicians are not immune

Clinicians are affected by sexual harassment, too. We have a duty to protect our patients, colleagues, and ourselves. Psychiatrists in particular often are on the frontlines of helping victims process their trauma.¹⁰

But will the field of medicine also face a reckoning when it comes to perpetrating harassment? It seems likely that the medical field would be ripe with harassment when you consider its history of male domination and a hierarchical structure with strong power differentials—not to mention the late nights, exhaustion, easy access to beds, and late-night encounters where inhibitions may be lowered.¹¹

A shocking number of female doctors are sexually harassed. Thirty percent of the top female clinician-researchers have experienced blatant sexual harassment on the job, according to a survey of 573 men and 493 women who received career development awards from the National Institutes of Health in 2006 to 2009.¹² In this survey, harassment covered the scope of sexist remarks or behavior, unwanted sexual advances, bribery, threats, and coercion. The majority of those affected said the experience undermined their confidence as professionals, and many said the harassment negatively affected their career advancement.¹²

Continue to: But what about the progress women have made...

But what about the progress women have made in medicine? Women are surpassing men in terms of admittance to medical school. Last year, for the first time, women accounted for more than half of the enrollees in U.S. medical schools, according to the Association of American Medical Colleges.¹³ Yet there has been a stalling in terms of change when it comes to harassment.¹² Women may be more vulnerable to harassment, both when they’re perceived as weak and when they’re so strong that they challenge traditional hierarchies.

Perpetuating the problem is the trouble with reporting sexual harassment. Victims do not fare well in our society. Even in the #MeToo era, reporting such behavior is far from straightforward.¹¹ Women fear that reporting any harassment will make them a target. Think of Anita Hill—her testimony against Clarence Thomas during his confirmation hearings for the Supreme Court showed that women who report sexual harassment experience marginalization, retaliation, stigmatization, and worse.

The result is that medical professionals tend to suppress the recognition of harassment. We make excuses for it, blame ourselves, or just take it on the chin and move on. There’s also confusion regarding what constitutes harassment. As doctors, especially psychiatrists, we hear harrowing stories. It’s reasonable to downplay our own experiences. Turning everyone into a victim of sexual harassment could detract from the stories of women who were raped, molested, and severely taken advantage of. There is a reasonable fear that diluting their message could be further damaging.¹⁴

Time for action

The field of medicine needs to do better in terms of education, support, anticipation, prevention, and reaction to harassment. We have the awareness. Now, we need action.

Continue to: One way to change any culture...

One way to change any culture of harassment or discrimination would be the advancement of more female physicians into leadership positions. The Association of American Medical Colleges has reported that fewer women than men hold faculty positions and full professorships.^15,16 There’s also a striking imbalance among fields of medicine practiced by men and women, with more women seen in pediatrics, obstetrics, and gynecology as opposed to surgery. Advancement into policy-setting echelons of medicine is essential for change. Sexual harassment can be a silent problem that will be corrected only when institutions and leaders put it on the forefront of discussions.¹⁷

Another possible solution would be to shift problem-solving from punishment to prevention. Many institutions set expectations about intolerance of sexual harassment and conduct occasional lectures about it. However, enforcing protocols and safeguards that support and enforce policy are difficult on the ground level. In any event, punishment alone won’t change a culture.¹⁷

Working with students until they are comfortable disclosing details of incidents can be helpful. For example, the University of Wisconsin-Madison employs an ombuds to help with this process.¹⁸ All institutions should encourage reporting along confidential pathways and have multiple ways to report.¹⁷ Tracking complaints, even seemingly minor infractions, can help identify patterns of behavior and anticipate future incidents.

Some solutions seem obvious, such as informal and retaliation-free reporting that allows institutions to track perpetrators’ behavior; mandatory training that includes bystander training; and disciplining and monitoring transgressors and terminating their employment when appropriate—something along the lines of a zero-tolerance policy. There needs to be more research on the prevalence, severity, and outcomes of sexual harassment, and subsequent investigations, along with research into evidence-based prevention and intervention strategies.¹⁷

Continue to: Although this article focuses...

Although this article focuses on harassment of women, men are equally important to this conversation because they, too, can be victims. Men also can serve a pivotal role in mentoring and championing their female counterparts as they strive for advancement, equality, and respect.

The task ahead is large, and this discussion is not over.

Sexual harassment hit a peak of cultural awareness over the past year. Will medicine be the next field to experience a reckoning?

In 2017, Time magazine’s Person of the Year Award went to the Silence Breakers who spoke out against sexual assault and harassment.¹ The exposure of predatory behavior exhibited by once-celebrated movie producers, newscasters, and actors has given rise to a powerful change. The #MeToo movement has risen to support survivors and end sexual violence.

Just like show business, other industries have rich histories of discrimination and power. Think Wall Street, Silicon Valley, hospitality services, and the list goes on and on.² But what about medicine? To answer this question, this article aims to:

• review the dilemma
• explore our duty to our patients and each other
• discuss solutions to address the problem.

Sexual harassment: A brief history

Decades ago, Anita Hill accused U.S. Supreme Court nominee Clarence Thomas, her boss at the U.S. Department of Education and the Equal Employment Opportunity Commission (EEOC), of sexual harassment.³

The year was 1991, and President George H. W. Bush had nominated Thomas, a federal Circuit Judge, to succeed retiring Associate Supreme Court Justice Thurgood Marshall. With Thomas’s good character presented as a primary qualification, he appeared to be a sure thing.

Continue to: That was until an FBI interview...

That was until an FBI interview of Hill was leaked to the press. Hill asserted that Thomas had sexually harassed her while he was her supervisor at the Department of Education and the EEOC.⁴ Heavily scrutinized for her choice to follow Thomas to a second job after he had already allegedly harassed her, Hill was in a conundrum shared by many women—putting up with abuse in exchange for a reputable position and the opportunity to fulfill a career ambition.

Hill is a trailblazer for women yearning to speak the truth, and she brought national attention to sexual harassment in the early 1990s. On December 16, 2017, the Commission on Sexual Harassment and Advancing Equality in the Workplace was formed. Hill was selected to lead the charge against sexual harassment in the entertainment industry.⁵

A forensic assessment of harassment

Hill’s courageous story is one of many touched upon in the 2016 book Because of Sex.⁶ Author Gillian Thomas, a senior staff attorney with the American Civil Liberties Union’s Women’s Rights Project, explores how Title VII of the Civil Rights Act of 1964 made it illegal to discriminate “because of sex.”

The field of forensic psychiatry has long been attentive to themes of sexual harassment and discrimination. The American Academy of Psychiatry and Law has a robust list of landmark cases thought to be especially important and significant for forensic psychiatry.⁷ This list includes cases brought forth by tenacious, yet ordinary women who used the law to advocate, and some have taken their fight all the way to the Supreme Court. Let’s consider 2 such cases:

Meritor Savings Bank, FSB v Vinson (1986).⁸ This was a U.S. labor law case. Michelle Vinson rose through the ranks at Meritor Savings Bank, only to be fired for excessive sick leave. She filed a Title VII suit against the bank. Vinson alleged that the bank was liable for sexual harassment perpetrated by its employee and vice president, Sidney Taylor. Vinson claimed that there had been 40 to 50 sexual encounters over 4 years, ranging from fondling to indecent exposure to rape. Vinson asserted that she never reported these events for fear of losing her job. The Supreme Court, in a 9-to-0 decision, recognized sexual harassment as a violation of Title VII of the Civil Rights Act of 1964.

Continue to: Harris v Forklift Systems, Inc. (1993)

Harris v Forklift Systems, Inc. (1993).⁹ Teresa Harris, a manager at Forklift Systems, Inc., claimed that the company’s president frequently directed offensive remarks at her that were sexual and discriminatory. The Supreme Court clarified the definition of a “hostile” or “abusive” work environment under Title VII of the Civil Rights Act of 1964. Associate Justice Sandra Day O’Connor was joined by a unanimous majority opinion in agreement with Harris.

Physicians are not immune

Clinicians are affected by sexual harassment, too. We have a duty to protect our patients, colleagues, and ourselves. Psychiatrists in particular often are on the frontlines of helping victims process their trauma.¹⁰

But will the field of medicine also face a reckoning when it comes to perpetrating harassment? It seems likely that the medical field would be ripe with harassment when you consider its history of male domination and a hierarchical structure with strong power differentials—not to mention the late nights, exhaustion, easy access to beds, and late-night encounters where inhibitions may be lowered.¹¹

A shocking number of female doctors are sexually harassed. Thirty percent of the top female clinician-researchers have experienced blatant sexual harassment on the job, according to a survey of 573 men and 493 women who received career development awards from the National Institutes of Health in 2006 to 2009.¹² In this survey, harassment covered the scope of sexist remarks or behavior, unwanted sexual advances, bribery, threats, and coercion. The majority of those affected said the experience undermined their confidence as professionals, and many said the harassment negatively affected their career advancement.¹²

Continue to: But what about the progress women have made...

But what about the progress women have made in medicine? Women are surpassing men in terms of admittance to medical school. Last year, for the first time, women accounted for more than half of the enrollees in U.S. medical schools, according to the Association of American Medical Colleges.¹³ Yet there has been a stalling in terms of change when it comes to harassment.¹² Women may be more vulnerable to harassment, both when they’re perceived as weak and when they’re so strong that they challenge traditional hierarchies.

Perpetuating the problem is the trouble with reporting sexual harassment. Victims do not fare well in our society. Even in the #MeToo era, reporting such behavior is far from straightforward.¹¹ Women fear that reporting any harassment will make them a target. Think of Anita Hill—her testimony against Clarence Thomas during his confirmation hearings for the Supreme Court showed that women who report sexual harassment experience marginalization, retaliation, stigmatization, and worse.

The result is that medical professionals tend to suppress the recognition of harassment. We make excuses for it, blame ourselves, or just take it on the chin and move on. There’s also confusion regarding what constitutes harassment. As doctors, especially psychiatrists, we hear harrowing stories. It’s reasonable to downplay our own experiences. Turning everyone into a victim of sexual harassment could detract from the stories of women who were raped, molested, and severely taken advantage of. There is a reasonable fear that diluting their message could be further damaging.¹⁴

Time for action

The field of medicine needs to do better in terms of education, support, anticipation, prevention, and reaction to harassment. We have the awareness. Now, we need action.

Continue to: One way to change any culture...

One way to change any culture of harassment or discrimination would be the advancement of more female physicians into leadership positions. The Association of American Medical Colleges has reported that fewer women than men hold faculty positions and full professorships.^15,16 There’s also a striking imbalance among fields of medicine practiced by men and women, with more women seen in pediatrics, obstetrics, and gynecology as opposed to surgery. Advancement into policy-setting echelons of medicine is essential for change. Sexual harassment can be a silent problem that will be corrected only when institutions and leaders put it on the forefront of discussions.¹⁷

Another possible solution would be to shift problem-solving from punishment to prevention. Many institutions set expectations about intolerance of sexual harassment and conduct occasional lectures about it. However, enforcing protocols and safeguards that support and enforce policy are difficult on the ground level. In any event, punishment alone won’t change a culture.¹⁷

Working with students until they are comfortable disclosing details of incidents can be helpful. For example, the University of Wisconsin-Madison employs an ombuds to help with this process.¹⁸ All institutions should encourage reporting along confidential pathways and have multiple ways to report.¹⁷ Tracking complaints, even seemingly minor infractions, can help identify patterns of behavior and anticipate future incidents.

Some solutions seem obvious, such as informal and retaliation-free reporting that allows institutions to track perpetrators’ behavior; mandatory training that includes bystander training; and disciplining and monitoring transgressors and terminating their employment when appropriate—something along the lines of a zero-tolerance policy. There needs to be more research on the prevalence, severity, and outcomes of sexual harassment, and subsequent investigations, along with research into evidence-based prevention and intervention strategies.¹⁷

Continue to: Although this article focuses...

Although this article focuses on harassment of women, men are equally important to this conversation because they, too, can be victims. Men also can serve a pivotal role in mentoring and championing their female counterparts as they strive for advancement, equality, and respect.

The task ahead is large, and this discussion is not over.

Pharmacologic treatment options for many substance use disorders (SUDs) are limited. This is especially true for cocaine use disorder and cannabis use disorder, for which there are no FDA-approved medications. FDA-approved medications for other SUDs often take the form of replacement or agonist therapies (eg, nicotine replacement therapy) that substitute the effects of the substance to aid in cessation. Other pharmacotherapies treat symptoms of withdrawal, reduce craving, or provide aversive counter-conditioning if the patient consumes the substance while on the medication (eg, disulfiram).

The over-the-counter (OTC) antioxidant N-acetylcysteine (NAC) may be a potential treatment for SUDs. Although NAC is not approved by the FDA for treating SUDs, its proposed mechanism of action differs from that of current FDA-approved medications for SUDs. NAC’s potential for broad applicability, favorable adverse-effect profile, accessibility, and low cost make it an intriguing option for patients with multiple comorbidities, and potentially for individuals with polysubstance use. This article reviews the current evidence supporting NAC for treating SUDs, to provide insight about which patients may benefit from NAC and under which circumstances they are most likely to benefit.

NAC may correct glutamate dysregulation

Approximately 85% of individuals with an SUD do not seek treatment for it, and those who do are older, have a longer history of use, have more severe dependence, and have sought treatment numerous times before.¹ By the time most people seek treatment, years of chronic substance use have likely led to significant brain-related adaptations. Individuals with SUDs often indicate that their substance use began as a pleasurable activity—the effects of the drug were enjoyable and they were motivated to use it again. With repeated substance use, they may begin to develop a stronger urge to use the drug, driven not necessarily by a desire for pleasure, but by compulsion.²

Numerous neural adaptations underlie the transition from “liking” a substance to engaging in the compulsive use that is characteristic of an SUD.² For example, repeated use of an addictive substance may result in excess glutamate in the nucleus accumbens,^3,4 an area of the brain that plays a critical role in motivation and learning. As a result, it has been proposed that pharmacotherapies that help correct glutamate dysregulation may be effective in promoting abstinence or preventing relapse to a substance.^5,6

NAC may reverse the neural dysfunction seen in SUDs. As an OTC antioxidant that impacts glutamatergic functioning in the brain, NAC has long been used to treat acetaminophen overdose; however, in recent years, researchers have begun to tap its potential for treating substance use and psychiatric disorders. NAC is thought to upregulate the glutamate transporter (GLT-1) that removes excess glutamate from the nucleus accumbens.⁶ Several published reviews provide more in-depth information about the neurobiology of NAC.^6-10

The adverse-effect profile of NAC is relatively benign. Nausea, vomiting, diarrhea, and sleepiness are relatively infrequent and mild.^11,12 The bioavailability of NAC is about 4% to 9%, with an approximate half-life of 6.25 hours when orally administered.¹³ Because NAC is classified as an OTC supplement, the potency and preparation may vary by supplier. To maximize consistency, NAC should be obtained from a supplier that meets United States Pharmacopeia (USP) standards.

NAC for SUDs: Emerging evidence

Several recent reviews have described the efficacy of NAC for SUDs and other psychiatric disorders. Here we summarize the current research examining the efficacy of NAC for stimulant (ie, cocaine and methamphetamine), cannabis, tobacco, and alcohol use disorders.

Continue to: Stimulant use disorders

Stimulant use disorders. The United Nations Office for Drugs and Crime estimates that worldwide, more than 18 million people use cocaine and more than 35 million use amphetamines.¹⁴ There are currently no FDA-approved treatments for stimulant use disorders, and clinicians treating patients with cocaine or amphetamine dependence often are at a loss for how best to promote abstinence. Recent studies suggest that NAC may decrease drug-seeking behavior and cravings in adults who seek treatment. The results of studies examining NAC for treating cocaine use and methamphetamine use are summarized in Table 1^15-17 and Table 2,^18,19 respectively.

Cocaine cessation and relapse prevention. Several small pilot projects^15,16 found that compared with placebo, various doses of NAC reduced craving (as measured with a visual analog scale). However, in a double-blind, placebo-controlled study, NAC did not decrease cravings or use after 8 weeks of treatment in individuals with cocaine use disorder who were still using cocaine (ie, they had not yet become abstinent). Interestingly, those who were abstinent when treatment began reported lower craving and remained abstinent longer if they received NAC (vs placebo), which suggests that NAC may be useful for preventing relapse.¹⁷

Methamphetamine cessation and relapse prevention. One study (N = 32) that evaluated the use of NAC, 1,200 mg/d for 4 weeks, vs placebo found reduced cravings among methamphetamine users who were seeking treatment.¹⁸ In contrast, a study of 31 methamphetamine users who were not seeking treatment evaluated the use of NAC, 2,400 mg/d, plus naltrexone, 200 mg/d, vs placebo for 8 weeks.¹⁹ It found no significant differences in craving or use patterns. Further research is needed to optimize the use of NAC for stimulant use disorders, and to better understand the role that abstinence plays.

Appropriate populations. The most support for use of NAC has been as an anti-relapse agent in treatment-seeking adults.

Continue to: Safety and dosing

Safety and dosing. Suggested dosages for the treatment of cocaine use disorder range from 1,200 to 3,600 mg/d (typically 600 to 1,800 mg twice daily, due to NAC’s short half-life), with higher retention rates noted in individuals who received 2,400 mg/d and 3,600 mg/d.¹⁶

Clinical implications. NAC is thought to act as an anti-relapse agent, rather than an agent that can help someone who is actively using stimulants to stop. Consequently, NAC will likely be most helpful for patients who are motivated to quit and are abstinent when they start taking NAC; however, this hypothesis needs further testing.

Cannabis use disorder

There are no FDA-approved treatments for cannabis use disorder. Individuals who use marijuana or other forms of cannabis may be less likely to report negative consequences or seek treatment compared with those who use other substances. Approximately 9% of individuals who use marijuana develop cannabis use disorder²⁰; those who begin using marijuana earlier in adolescence are at increased risk.²¹ Commonly reported reasons for wanting to stop using marijuana include being concerned about health consequences, regaining or demonstrating self-control, saving money, avoiding legal consequences, obtaining or keeping employment, and reducing interpersonal conflict.^22,23 Table 3^24-27 summarizes initial evidence that suggests NAC may be particularly useful in reducing marijuana use among adolescents (age 15 to 21).^24,25

Cessation. An open-label, pilot clinical trial found significant reductions in self-reported marijuana use and craving—but not in biomarkers of use—among 24 adolescents after 4 weeks of NAC, 1,200 mg twice daily.²⁴ In an 8-week, double-blind, randomized controlled trial of 116 adolescents, NAC, 1,200 mg twice daily, plus contingency management doubled the odds of abstinence, but had no effect on self-reported craving or use.^25,26 In a sample of 302 adults, a 12-week trial of NAC, 1,200 mg twice daily, plus contingency management was no more effective than contingency management alone in promoting abstinence.²⁷

Continue to: Appropriate populations

Appropriate populations. Evidence is stronger for use of NAC among adolescents (age 15 to 21) than for individuals older than age 21.^25,27 Further research is needed to explore potential reasons for age-specific effects.

Safety and dosing. A safe and potentially efficacious dosage for the treatment of cannabis use disorder is 2,400 mg/d (1,200 mg twice daily).^24,25,27

Clinical implications. Combined with contingency management, NAC might be efficacious for adolescents with cannabis use disorder, with treatment gains evident by the fourth week of treatment.^24,25 To date, no clinical trials have examined the efficacy of NAC for treating cannabis use disorder without adjunctive contingency management, and research is needed to isolate the clinical effect of NAC among adolescents.

Tobacco use disorder

Cigarette smoking remains a leading cause of preventable death in the United States,²⁸ and nearly 70% of people who start using tobacco become dependent.²⁰ Existing FDA-approved treatments include nicotine replacement products, varenicline, and bupropion. Even though efficacious treatments exist, successful and sustained quit attempts are infrequent.²⁹ NAC may exert a complementary effect to existing tobacco cessation interventions, such as varenicline.³⁰ While these medications promote abstinence, NAC may be particularly beneficial in preventing relapse after abstinence has been achieved (Table 4^30-36).

Continue to: Cessation and relapse prevention

Cessation and relapse prevention. Several pilot studies found that adult smokers who received NAC (alone or in combination with another treatment) had lower carbon monoxide levels,^31,32 smoked fewer cigarettes,^32,33 and had fewer self-reported symptoms of nicotine dependence³⁴ and/or less craving for cigarettes.³¹ However, one study of 33 smokers did not find a reduction in craving or carbon monoxide for NAC compared with placebo.³³ Another pilot study of 22 young adult smokers found that those who received NAC rated their first cigarette after treatment (smoked in the laboratory) as less rewarding, relative to smokers who received a placebo.³⁵

Secondary analyses of adults with bipolar disorder³⁶ and adolescents with cannabis use disorder³⁷ found no decreases in tobacco use among those who received NAC compared with placebo. However, the studies in these analyses did not specifically recruit tobacco users, and participants who were tobacco users were not necessarily interested in quitting. This may partially explain discrepant findings.

Appropriate populations. NAC has been studied mostly in adult cigarette smokers.

Safety and dosing. Suggested dosages for treating tobacco use disorder range from 1,200 to 3,600 mg/d (600 to 1,800 mg twice daily).

Continue to: Clinical implications

Clinical implications. Data on NAC’s efficacy for tobacco use disorder come from small, pilot trials. Although initial evidence is promising, it is premature to suggest NAC for smoking cessation until a fully powered, randomized clinical trial provides evidence of efficacy.

Alcohol use disorder

Alcohol use disorders are widely prevalent; 13.9% of U.S. adults met criteria in the past year, and 29.1% of U.S. adults meet criteria in their lifetime.³⁸ Alcohol use disorders can result in significant negative consequences, including relationship problems, violent behavior, medical problems, and death. Existing FDA-approved medications for alcohol use disorder include naltrexone, acamprosate, and disulfiram.

Due to the severe potential health consequences of alcohol, NAC has been examined as a possible aid in preventing relapse. However, most studies have been conducted using animals. Three studies have examined alcohol use in humans (Table 5^36,39,40). One was a pilot study,³⁹ and the other 2 were secondary data analyses.^36,40 None of them specifically focused on alcohol use disorders. A pilot study of 35 veterans with co-occurring posttraumautic stress disorder (PTSD) and SUDs (82% of whom had an alcohol use disorder) found that compared with placebo, NAC significantly decreased PTSD symptoms, craving, and depression.³⁹ In a study of 75 adults with bipolar disorder, secondary alcohol use was not significantly reduced.³⁶ However, one study suggested that NAC may decrease adolescent alcohol and marijuana co-use.⁴⁰ Future work is needed to examine the potential clinical utility of NAC in individuals with alcohol use disorders.

Findings from animal studies indicate that NAC may:

• reduce alcohol-seeking⁴¹
• reduce withdrawal symptoms⁴²
• reduce the teratogenic effects of alcohol⁴³
• prevent alcohol toxicity⁴⁴
• reduce health-related consequences of alcohol (eg, myocardial oxidative stress⁴⁵ and alcohol-related steatohepatitis⁴⁶).

Continue to: Appropriate populations

Appropriate populations. Pilot studies have suggested that appropriate populations may include veterans with SUD and PTSD³⁹ and adolescents with marijuana dependence who use alcohol.⁴⁰

Safety and dosing. Suggested dosages for the treatment of alcohol use disorder based on these studies range from 1,000 to 2,400 mg/d (500 to 1,200 mg twice daily).

Clinical implications. Future work is needed to determine if NAC is effective for treating alcohol use disorders. Ongoing randomized clinical trials are examining the efficacy of NAC in reducing alcohol use among individuals with alcohol use disorder. It is premature to recommend NAC for treatment of alcohol use disorders.

Other psychiatric uses

Although we have highlighted NAC’s effect on glutamatergic transmission, evidence suggests that NAC may have multiple mechanisms of action that could impact psychiatric functioning. For example, NAC may also reverse oxidative stress, which is frequently observed in psychiatric disorders such as schizophrenia and bipolar disorder.^10,12 NAC also has anti-inflammatory properties. When inflammatory pathways of the CNS are dysregulated, production of neurotransmitters may be impaired, resulting in depression-like symptoms.^10,12,47 Preliminary evidence suggests that NAC may be effective in treating mood-related symptoms (eg, irritability, depression) in individuals with psychiatric disorders (eg, bipolar and depressive disorders, PTSD, and SUDs) and general symptoms of schizophrenia, obsessive-compulsive disorder, and trichotillomania, although mixed findings in controlled studies suggest a need for further research.^12,39

Continue to: NAC: A promising candidate

Initial evidence suggests NAC may be helpful for treating patients with SUDs. A patient seeking SUD treatment who is treated with NAC may experience a decreased drive, craving, or compulsion to use. Notably, NAC may be particularly useful in preventing relapse after an individual has achieved abstinence. Evidence suggests that NAC may be useful in the treatment of adults with cocaine use disorders who have achieved abstinence, and adolescents with cannabis use disorders. Preliminary results for adult tobacco use disorder are also promising. Human data examining the efficacy of NAC for alcohol use disorder is limited. Researchers’ ongoing challenge is to identify which patients with which SUDs are most likely to benefit from NAC, and to create clear clinical guidelines for the provider.

Bottom Line

N-acetylcysteine is likely to have modest effects for some patients who have a substance use disorder, particularly adults who use cocaine and adolescents who use marijuana. It may be useful in preventing relapse to substance use after an individual has achieved abstinence.

Related Resources

• Deepmala, Slattery J, Kumar N, et al. Clinical trials of N-acetylcysteine in psychiatry and neurology: a systematic review. Neurosci Biobehav Rev. 2015;55:294-321.
• Roberts-Wolfe D, Kalivas P. Glutamate transporter GLT-1 as a therapeutic target for substance use disorders. CNS Neurol Disord Drug Targets. 2015;14(6):745-756.
• National Institute on Drug Abuse. Treatment approaches for drug addiction. https://www.drugabuse.gov/publications/drugfacts/treatment-approaches-drug-addiction.

Drug Brand Names

Acamprosate • Campral
Acetaminophen • Tylenol
Baclofen • Lioresal
Bupropion • Zyban
Disulfiram • Antabuse
Naltrexone • Revia,Vivitrol
Varenicline • Chantix

Pharmacologic treatment options for many substance use disorders (SUDs) are limited. This is especially true for cocaine use disorder and cannabis use disorder, for which there are no FDA-approved medications. FDA-approved medications for other SUDs often take the form of replacement or agonist therapies (eg, nicotine replacement therapy) that substitute the effects of the substance to aid in cessation. Other pharmacotherapies treat symptoms of withdrawal, reduce craving, or provide aversive counter-conditioning if the patient consumes the substance while on the medication (eg, disulfiram).

The over-the-counter (OTC) antioxidant N-acetylcysteine (NAC) may be a potential treatment for SUDs. Although NAC is not approved by the FDA for treating SUDs, its proposed mechanism of action differs from that of current FDA-approved medications for SUDs. NAC’s potential for broad applicability, favorable adverse-effect profile, accessibility, and low cost make it an intriguing option for patients with multiple comorbidities, and potentially for individuals with polysubstance use. This article reviews the current evidence supporting NAC for treating SUDs, to provide insight about which patients may benefit from NAC and under which circumstances they are most likely to benefit.

NAC may correct glutamate dysregulation

Approximately 85% of individuals with an SUD do not seek treatment for it, and those who do are older, have a longer history of use, have more severe dependence, and have sought treatment numerous times before.¹ By the time most people seek treatment, years of chronic substance use have likely led to significant brain-related adaptations. Individuals with SUDs often indicate that their substance use began as a pleasurable activity—the effects of the drug were enjoyable and they were motivated to use it again. With repeated substance use, they may begin to develop a stronger urge to use the drug, driven not necessarily by a desire for pleasure, but by compulsion.²

Numerous neural adaptations underlie the transition from “liking” a substance to engaging in the compulsive use that is characteristic of an SUD.² For example, repeated use of an addictive substance may result in excess glutamate in the nucleus accumbens,^3,4 an area of the brain that plays a critical role in motivation and learning. As a result, it has been proposed that pharmacotherapies that help correct glutamate dysregulation may be effective in promoting abstinence or preventing relapse to a substance.^5,6

NAC may reverse the neural dysfunction seen in SUDs. As an OTC antioxidant that impacts glutamatergic functioning in the brain, NAC has long been used to treat acetaminophen overdose; however, in recent years, researchers have begun to tap its potential for treating substance use and psychiatric disorders. NAC is thought to upregulate the glutamate transporter (GLT-1) that removes excess glutamate from the nucleus accumbens.⁶ Several published reviews provide more in-depth information about the neurobiology of NAC.^6-10

The adverse-effect profile of NAC is relatively benign. Nausea, vomiting, diarrhea, and sleepiness are relatively infrequent and mild.^11,12 The bioavailability of NAC is about 4% to 9%, with an approximate half-life of 6.25 hours when orally administered.¹³ Because NAC is classified as an OTC supplement, the potency and preparation may vary by supplier. To maximize consistency, NAC should be obtained from a supplier that meets United States Pharmacopeia (USP) standards.

NAC for SUDs: Emerging evidence

Several recent reviews have described the efficacy of NAC for SUDs and other psychiatric disorders. Here we summarize the current research examining the efficacy of NAC for stimulant (ie, cocaine and methamphetamine), cannabis, tobacco, and alcohol use disorders.

Continue to: Stimulant use disorders

Stimulant use disorders. The United Nations Office for Drugs and Crime estimates that worldwide, more than 18 million people use cocaine and more than 35 million use amphetamines.¹⁴ There are currently no FDA-approved treatments for stimulant use disorders, and clinicians treating patients with cocaine or amphetamine dependence often are at a loss for how best to promote abstinence. Recent studies suggest that NAC may decrease drug-seeking behavior and cravings in adults who seek treatment. The results of studies examining NAC for treating cocaine use and methamphetamine use are summarized in Table 1^15-17 and Table 2,^18,19 respectively.

Cocaine cessation and relapse prevention. Several small pilot projects^15,16 found that compared with placebo, various doses of NAC reduced craving (as measured with a visual analog scale). However, in a double-blind, placebo-controlled study, NAC did not decrease cravings or use after 8 weeks of treatment in individuals with cocaine use disorder who were still using cocaine (ie, they had not yet become abstinent). Interestingly, those who were abstinent when treatment began reported lower craving and remained abstinent longer if they received NAC (vs placebo), which suggests that NAC may be useful for preventing relapse.¹⁷

Methamphetamine cessation and relapse prevention. One study (N = 32) that evaluated the use of NAC, 1,200 mg/d for 4 weeks, vs placebo found reduced cravings among methamphetamine users who were seeking treatment.¹⁸ In contrast, a study of 31 methamphetamine users who were not seeking treatment evaluated the use of NAC, 2,400 mg/d, plus naltrexone, 200 mg/d, vs placebo for 8 weeks.¹⁹ It found no significant differences in craving or use patterns. Further research is needed to optimize the use of NAC for stimulant use disorders, and to better understand the role that abstinence plays.

Appropriate populations. The most support for use of NAC has been as an anti-relapse agent in treatment-seeking adults.

Continue to: Safety and dosing

Safety and dosing. Suggested dosages for the treatment of cocaine use disorder range from 1,200 to 3,600 mg/d (typically 600 to 1,800 mg twice daily, due to NAC’s short half-life), with higher retention rates noted in individuals who received 2,400 mg/d and 3,600 mg/d.¹⁶

Clinical implications. NAC is thought to act as an anti-relapse agent, rather than an agent that can help someone who is actively using stimulants to stop. Consequently, NAC will likely be most helpful for patients who are motivated to quit and are abstinent when they start taking NAC; however, this hypothesis needs further testing.

Cannabis use disorder

There are no FDA-approved treatments for cannabis use disorder. Individuals who use marijuana or other forms of cannabis may be less likely to report negative consequences or seek treatment compared with those who use other substances. Approximately 9% of individuals who use marijuana develop cannabis use disorder²⁰; those who begin using marijuana earlier in adolescence are at increased risk.²¹ Commonly reported reasons for wanting to stop using marijuana include being concerned about health consequences, regaining or demonstrating self-control, saving money, avoiding legal consequences, obtaining or keeping employment, and reducing interpersonal conflict.^22,23 Table 3^24-27 summarizes initial evidence that suggests NAC may be particularly useful in reducing marijuana use among adolescents (age 15 to 21).^24,25

Cessation. An open-label, pilot clinical trial found significant reductions in self-reported marijuana use and craving—but not in biomarkers of use—among 24 adolescents after 4 weeks of NAC, 1,200 mg twice daily.²⁴ In an 8-week, double-blind, randomized controlled trial of 116 adolescents, NAC, 1,200 mg twice daily, plus contingency management doubled the odds of abstinence, but had no effect on self-reported craving or use.^25,26 In a sample of 302 adults, a 12-week trial of NAC, 1,200 mg twice daily, plus contingency management was no more effective than contingency management alone in promoting abstinence.²⁷

Continue to: Appropriate populations

Appropriate populations. Evidence is stronger for use of NAC among adolescents (age 15 to 21) than for individuals older than age 21.^25,27 Further research is needed to explore potential reasons for age-specific effects.

Safety and dosing. A safe and potentially efficacious dosage for the treatment of cannabis use disorder is 2,400 mg/d (1,200 mg twice daily).^24,25,27

Clinical implications. Combined with contingency management, NAC might be efficacious for adolescents with cannabis use disorder, with treatment gains evident by the fourth week of treatment.^24,25 To date, no clinical trials have examined the efficacy of NAC for treating cannabis use disorder without adjunctive contingency management, and research is needed to isolate the clinical effect of NAC among adolescents.

Tobacco use disorder

Cigarette smoking remains a leading cause of preventable death in the United States,²⁸ and nearly 70% of people who start using tobacco become dependent.²⁰ Existing FDA-approved treatments include nicotine replacement products, varenicline, and bupropion. Even though efficacious treatments exist, successful and sustained quit attempts are infrequent.²⁹ NAC may exert a complementary effect to existing tobacco cessation interventions, such as varenicline.³⁰ While these medications promote abstinence, NAC may be particularly beneficial in preventing relapse after abstinence has been achieved (Table 4^30-36).

Continue to: Cessation and relapse prevention

Cessation and relapse prevention. Several pilot studies found that adult smokers who received NAC (alone or in combination with another treatment) had lower carbon monoxide levels,^31,32 smoked fewer cigarettes,^32,33 and had fewer self-reported symptoms of nicotine dependence³⁴ and/or less craving for cigarettes.³¹ However, one study of 33 smokers did not find a reduction in craving or carbon monoxide for NAC compared with placebo.³³ Another pilot study of 22 young adult smokers found that those who received NAC rated their first cigarette after treatment (smoked in the laboratory) as less rewarding, relative to smokers who received a placebo.³⁵

Secondary analyses of adults with bipolar disorder³⁶ and adolescents with cannabis use disorder³⁷ found no decreases in tobacco use among those who received NAC compared with placebo. However, the studies in these analyses did not specifically recruit tobacco users, and participants who were tobacco users were not necessarily interested in quitting. This may partially explain discrepant findings.

Appropriate populations. NAC has been studied mostly in adult cigarette smokers.

Safety and dosing. Suggested dosages for treating tobacco use disorder range from 1,200 to 3,600 mg/d (600 to 1,800 mg twice daily).

Continue to: Clinical implications

Clinical implications. Data on NAC’s efficacy for tobacco use disorder come from small, pilot trials. Although initial evidence is promising, it is premature to suggest NAC for smoking cessation until a fully powered, randomized clinical trial provides evidence of efficacy.

Alcohol use disorder

Alcohol use disorders are widely prevalent; 13.9% of U.S. adults met criteria in the past year, and 29.1% of U.S. adults meet criteria in their lifetime.³⁸ Alcohol use disorders can result in significant negative consequences, including relationship problems, violent behavior, medical problems, and death. Existing FDA-approved medications for alcohol use disorder include naltrexone, acamprosate, and disulfiram.

Due to the severe potential health consequences of alcohol, NAC has been examined as a possible aid in preventing relapse. However, most studies have been conducted using animals. Three studies have examined alcohol use in humans (Table 5^36,39,40). One was a pilot study,³⁹ and the other 2 were secondary data analyses.^36,40 None of them specifically focused on alcohol use disorders. A pilot study of 35 veterans with co-occurring posttraumautic stress disorder (PTSD) and SUDs (82% of whom had an alcohol use disorder) found that compared with placebo, NAC significantly decreased PTSD symptoms, craving, and depression.³⁹ In a study of 75 adults with bipolar disorder, secondary alcohol use was not significantly reduced.³⁶ However, one study suggested that NAC may decrease adolescent alcohol and marijuana co-use.⁴⁰ Future work is needed to examine the potential clinical utility of NAC in individuals with alcohol use disorders.

Findings from animal studies indicate that NAC may:

• reduce alcohol-seeking⁴¹
• reduce withdrawal symptoms⁴²
• reduce the teratogenic effects of alcohol⁴³
• prevent alcohol toxicity⁴⁴
• reduce health-related consequences of alcohol (eg, myocardial oxidative stress⁴⁵ and alcohol-related steatohepatitis⁴⁶).

Continue to: Appropriate populations

Appropriate populations. Pilot studies have suggested that appropriate populations may include veterans with SUD and PTSD³⁹ and adolescents with marijuana dependence who use alcohol.⁴⁰

Safety and dosing. Suggested dosages for the treatment of alcohol use disorder based on these studies range from 1,000 to 2,400 mg/d (500 to 1,200 mg twice daily).

Clinical implications. Future work is needed to determine if NAC is effective for treating alcohol use disorders. Ongoing randomized clinical trials are examining the efficacy of NAC in reducing alcohol use among individuals with alcohol use disorder. It is premature to recommend NAC for treatment of alcohol use disorders.

Other psychiatric uses

Although we have highlighted NAC’s effect on glutamatergic transmission, evidence suggests that NAC may have multiple mechanisms of action that could impact psychiatric functioning. For example, NAC may also reverse oxidative stress, which is frequently observed in psychiatric disorders such as schizophrenia and bipolar disorder.^10,12 NAC also has anti-inflammatory properties. When inflammatory pathways of the CNS are dysregulated, production of neurotransmitters may be impaired, resulting in depression-like symptoms.^10,12,47 Preliminary evidence suggests that NAC may be effective in treating mood-related symptoms (eg, irritability, depression) in individuals with psychiatric disorders (eg, bipolar and depressive disorders, PTSD, and SUDs) and general symptoms of schizophrenia, obsessive-compulsive disorder, and trichotillomania, although mixed findings in controlled studies suggest a need for further research.^12,39

Continue to: NAC: A promising candidate

Initial evidence suggests NAC may be helpful for treating patients with SUDs. A patient seeking SUD treatment who is treated with NAC may experience a decreased drive, craving, or compulsion to use. Notably, NAC may be particularly useful in preventing relapse after an individual has achieved abstinence. Evidence suggests that NAC may be useful in the treatment of adults with cocaine use disorders who have achieved abstinence, and adolescents with cannabis use disorders. Preliminary results for adult tobacco use disorder are also promising. Human data examining the efficacy of NAC for alcohol use disorder is limited. Researchers’ ongoing challenge is to identify which patients with which SUDs are most likely to benefit from NAC, and to create clear clinical guidelines for the provider.

Bottom Line

N-acetylcysteine is likely to have modest effects for some patients who have a substance use disorder, particularly adults who use cocaine and adolescents who use marijuana. It may be useful in preventing relapse to substance use after an individual has achieved abstinence.

Related Resources

• Deepmala, Slattery J, Kumar N, et al. Clinical trials of N-acetylcysteine in psychiatry and neurology: a systematic review. Neurosci Biobehav Rev. 2015;55:294-321.
• Roberts-Wolfe D, Kalivas P. Glutamate transporter GLT-1 as a therapeutic target for substance use disorders. CNS Neurol Disord Drug Targets. 2015;14(6):745-756.
• National Institute on Drug Abuse. Treatment approaches for drug addiction. https://www.drugabuse.gov/publications/drugfacts/treatment-approaches-drug-addiction.

Drug Brand Names

Acamprosate • Campral
Acetaminophen • Tylenol
Baclofen • Lioresal
Bupropion • Zyban
Disulfiram • Antabuse
Naltrexone • Revia,Vivitrol
Varenicline • Chantix

Pharmacologic treatment options for many substance use disorders (SUDs) are limited. This is especially true for cocaine use disorder and cannabis use disorder, for which there are no FDA-approved medications. FDA-approved medications for other SUDs often take the form of replacement or agonist therapies (eg, nicotine replacement therapy) that substitute the effects of the substance to aid in cessation. Other pharmacotherapies treat symptoms of withdrawal, reduce craving, or provide aversive counter-conditioning if the patient consumes the substance while on the medication (eg, disulfiram).

The over-the-counter (OTC) antioxidant N-acetylcysteine (NAC) may be a potential treatment for SUDs. Although NAC is not approved by the FDA for treating SUDs, its proposed mechanism of action differs from that of current FDA-approved medications for SUDs. NAC’s potential for broad applicability, favorable adverse-effect profile, accessibility, and low cost make it an intriguing option for patients with multiple comorbidities, and potentially for individuals with polysubstance use. This article reviews the current evidence supporting NAC for treating SUDs, to provide insight about which patients may benefit from NAC and under which circumstances they are most likely to benefit.

NAC may correct glutamate dysregulation

Approximately 85% of individuals with an SUD do not seek treatment for it, and those who do are older, have a longer history of use, have more severe dependence, and have sought treatment numerous times before.¹ By the time most people seek treatment, years of chronic substance use have likely led to significant brain-related adaptations. Individuals with SUDs often indicate that their substance use began as a pleasurable activity—the effects of the drug were enjoyable and they were motivated to use it again. With repeated substance use, they may begin to develop a stronger urge to use the drug, driven not necessarily by a desire for pleasure, but by compulsion.²

Numerous neural adaptations underlie the transition from “liking” a substance to engaging in the compulsive use that is characteristic of an SUD.² For example, repeated use of an addictive substance may result in excess glutamate in the nucleus accumbens,^3,4 an area of the brain that plays a critical role in motivation and learning. As a result, it has been proposed that pharmacotherapies that help correct glutamate dysregulation may be effective in promoting abstinence or preventing relapse to a substance.^5,6

NAC may reverse the neural dysfunction seen in SUDs. As an OTC antioxidant that impacts glutamatergic functioning in the brain, NAC has long been used to treat acetaminophen overdose; however, in recent years, researchers have begun to tap its potential for treating substance use and psychiatric disorders. NAC is thought to upregulate the glutamate transporter (GLT-1) that removes excess glutamate from the nucleus accumbens.⁶ Several published reviews provide more in-depth information about the neurobiology of NAC.^6-10

The adverse-effect profile of NAC is relatively benign. Nausea, vomiting, diarrhea, and sleepiness are relatively infrequent and mild.^11,12 The bioavailability of NAC is about 4% to 9%, with an approximate half-life of 6.25 hours when orally administered.¹³ Because NAC is classified as an OTC supplement, the potency and preparation may vary by supplier. To maximize consistency, NAC should be obtained from a supplier that meets United States Pharmacopeia (USP) standards.

NAC for SUDs: Emerging evidence

Several recent reviews have described the efficacy of NAC for SUDs and other psychiatric disorders. Here we summarize the current research examining the efficacy of NAC for stimulant (ie, cocaine and methamphetamine), cannabis, tobacco, and alcohol use disorders.

Continue to: Stimulant use disorders

Stimulant use disorders. The United Nations Office for Drugs and Crime estimates that worldwide, more than 18 million people use cocaine and more than 35 million use amphetamines.¹⁴ There are currently no FDA-approved treatments for stimulant use disorders, and clinicians treating patients with cocaine or amphetamine dependence often are at a loss for how best to promote abstinence. Recent studies suggest that NAC may decrease drug-seeking behavior and cravings in adults who seek treatment. The results of studies examining NAC for treating cocaine use and methamphetamine use are summarized in Table 1^15-17 and Table 2,^18,19 respectively.

Cocaine cessation and relapse prevention. Several small pilot projects^15,16 found that compared with placebo, various doses of NAC reduced craving (as measured with a visual analog scale). However, in a double-blind, placebo-controlled study, NAC did not decrease cravings or use after 8 weeks of treatment in individuals with cocaine use disorder who were still using cocaine (ie, they had not yet become abstinent). Interestingly, those who were abstinent when treatment began reported lower craving and remained abstinent longer if they received NAC (vs placebo), which suggests that NAC may be useful for preventing relapse.¹⁷

Methamphetamine cessation and relapse prevention. One study (N = 32) that evaluated the use of NAC, 1,200 mg/d for 4 weeks, vs placebo found reduced cravings among methamphetamine users who were seeking treatment.¹⁸ In contrast, a study of 31 methamphetamine users who were not seeking treatment evaluated the use of NAC, 2,400 mg/d, plus naltrexone, 200 mg/d, vs placebo for 8 weeks.¹⁹ It found no significant differences in craving or use patterns. Further research is needed to optimize the use of NAC for stimulant use disorders, and to better understand the role that abstinence plays.

Appropriate populations. The most support for use of NAC has been as an anti-relapse agent in treatment-seeking adults.

Continue to: Safety and dosing

Safety and dosing. Suggested dosages for the treatment of cocaine use disorder range from 1,200 to 3,600 mg/d (typically 600 to 1,800 mg twice daily, due to NAC’s short half-life), with higher retention rates noted in individuals who received 2,400 mg/d and 3,600 mg/d.¹⁶

Clinical implications. NAC is thought to act as an anti-relapse agent, rather than an agent that can help someone who is actively using stimulants to stop. Consequently, NAC will likely be most helpful for patients who are motivated to quit and are abstinent when they start taking NAC; however, this hypothesis needs further testing.

Cannabis use disorder

There are no FDA-approved treatments for cannabis use disorder. Individuals who use marijuana or other forms of cannabis may be less likely to report negative consequences or seek treatment compared with those who use other substances. Approximately 9% of individuals who use marijuana develop cannabis use disorder²⁰; those who begin using marijuana earlier in adolescence are at increased risk.²¹ Commonly reported reasons for wanting to stop using marijuana include being concerned about health consequences, regaining or demonstrating self-control, saving money, avoiding legal consequences, obtaining or keeping employment, and reducing interpersonal conflict.^22,23 Table 3^24-27 summarizes initial evidence that suggests NAC may be particularly useful in reducing marijuana use among adolescents (age 15 to 21).^24,25

Cessation. An open-label, pilot clinical trial found significant reductions in self-reported marijuana use and craving—but not in biomarkers of use—among 24 adolescents after 4 weeks of NAC, 1,200 mg twice daily.²⁴ In an 8-week, double-blind, randomized controlled trial of 116 adolescents, NAC, 1,200 mg twice daily, plus contingency management doubled the odds of abstinence, but had no effect on self-reported craving or use.^25,26 In a sample of 302 adults, a 12-week trial of NAC, 1,200 mg twice daily, plus contingency management was no more effective than contingency management alone in promoting abstinence.²⁷

Continue to: Appropriate populations

Appropriate populations. Evidence is stronger for use of NAC among adolescents (age 15 to 21) than for individuals older than age 21.^25,27 Further research is needed to explore potential reasons for age-specific effects.

Safety and dosing. A safe and potentially efficacious dosage for the treatment of cannabis use disorder is 2,400 mg/d (1,200 mg twice daily).^24,25,27

Clinical implications. Combined with contingency management, NAC might be efficacious for adolescents with cannabis use disorder, with treatment gains evident by the fourth week of treatment.^24,25 To date, no clinical trials have examined the efficacy of NAC for treating cannabis use disorder without adjunctive contingency management, and research is needed to isolate the clinical effect of NAC among adolescents.

Tobacco use disorder

Cigarette smoking remains a leading cause of preventable death in the United States,²⁸ and nearly 70% of people who start using tobacco become dependent.²⁰ Existing FDA-approved treatments include nicotine replacement products, varenicline, and bupropion. Even though efficacious treatments exist, successful and sustained quit attempts are infrequent.²⁹ NAC may exert a complementary effect to existing tobacco cessation interventions, such as varenicline.³⁰ While these medications promote abstinence, NAC may be particularly beneficial in preventing relapse after abstinence has been achieved (Table 4^30-36).

Continue to: Cessation and relapse prevention

Cessation and relapse prevention. Several pilot studies found that adult smokers who received NAC (alone or in combination with another treatment) had lower carbon monoxide levels,^31,32 smoked fewer cigarettes,^32,33 and had fewer self-reported symptoms of nicotine dependence³⁴ and/or less craving for cigarettes.³¹ However, one study of 33 smokers did not find a reduction in craving or carbon monoxide for NAC compared with placebo.³³ Another pilot study of 22 young adult smokers found that those who received NAC rated their first cigarette after treatment (smoked in the laboratory) as less rewarding, relative to smokers who received a placebo.³⁵

Secondary analyses of adults with bipolar disorder³⁶ and adolescents with cannabis use disorder³⁷ found no decreases in tobacco use among those who received NAC compared with placebo. However, the studies in these analyses did not specifically recruit tobacco users, and participants who were tobacco users were not necessarily interested in quitting. This may partially explain discrepant findings.

Appropriate populations. NAC has been studied mostly in adult cigarette smokers.

Safety and dosing. Suggested dosages for treating tobacco use disorder range from 1,200 to 3,600 mg/d (600 to 1,800 mg twice daily).

Continue to: Clinical implications

Clinical implications. Data on NAC’s efficacy for tobacco use disorder come from small, pilot trials. Although initial evidence is promising, it is premature to suggest NAC for smoking cessation until a fully powered, randomized clinical trial provides evidence of efficacy.

Alcohol use disorder

Alcohol use disorders are widely prevalent; 13.9% of U.S. adults met criteria in the past year, and 29.1% of U.S. adults meet criteria in their lifetime.³⁸ Alcohol use disorders can result in significant negative consequences, including relationship problems, violent behavior, medical problems, and death. Existing FDA-approved medications for alcohol use disorder include naltrexone, acamprosate, and disulfiram.

Due to the severe potential health consequences of alcohol, NAC has been examined as a possible aid in preventing relapse. However, most studies have been conducted using animals. Three studies have examined alcohol use in humans (Table 5^36,39,40). One was a pilot study,³⁹ and the other 2 were secondary data analyses.^36,40 None of them specifically focused on alcohol use disorders. A pilot study of 35 veterans with co-occurring posttraumautic stress disorder (PTSD) and SUDs (82% of whom had an alcohol use disorder) found that compared with placebo, NAC significantly decreased PTSD symptoms, craving, and depression.³⁹ In a study of 75 adults with bipolar disorder, secondary alcohol use was not significantly reduced.³⁶ However, one study suggested that NAC may decrease adolescent alcohol and marijuana co-use.⁴⁰ Future work is needed to examine the potential clinical utility of NAC in individuals with alcohol use disorders.

Findings from animal studies indicate that NAC may:

• reduce alcohol-seeking⁴¹
• reduce withdrawal symptoms⁴²
• reduce the teratogenic effects of alcohol⁴³
• prevent alcohol toxicity⁴⁴
• reduce health-related consequences of alcohol (eg, myocardial oxidative stress⁴⁵ and alcohol-related steatohepatitis⁴⁶).

Continue to: Appropriate populations

Appropriate populations. Pilot studies have suggested that appropriate populations may include veterans with SUD and PTSD³⁹ and adolescents with marijuana dependence who use alcohol.⁴⁰

Safety and dosing. Suggested dosages for the treatment of alcohol use disorder based on these studies range from 1,000 to 2,400 mg/d (500 to 1,200 mg twice daily).

Clinical implications. Future work is needed to determine if NAC is effective for treating alcohol use disorders. Ongoing randomized clinical trials are examining the efficacy of NAC in reducing alcohol use among individuals with alcohol use disorder. It is premature to recommend NAC for treatment of alcohol use disorders.

Other psychiatric uses

Although we have highlighted NAC’s effect on glutamatergic transmission, evidence suggests that NAC may have multiple mechanisms of action that could impact psychiatric functioning. For example, NAC may also reverse oxidative stress, which is frequently observed in psychiatric disorders such as schizophrenia and bipolar disorder.^10,12 NAC also has anti-inflammatory properties. When inflammatory pathways of the CNS are dysregulated, production of neurotransmitters may be impaired, resulting in depression-like symptoms.^10,12,47 Preliminary evidence suggests that NAC may be effective in treating mood-related symptoms (eg, irritability, depression) in individuals with psychiatric disorders (eg, bipolar and depressive disorders, PTSD, and SUDs) and general symptoms of schizophrenia, obsessive-compulsive disorder, and trichotillomania, although mixed findings in controlled studies suggest a need for further research.^12,39

Continue to: NAC: A promising candidate

Initial evidence suggests NAC may be helpful for treating patients with SUDs. A patient seeking SUD treatment who is treated with NAC may experience a decreased drive, craving, or compulsion to use. Notably, NAC may be particularly useful in preventing relapse after an individual has achieved abstinence. Evidence suggests that NAC may be useful in the treatment of adults with cocaine use disorders who have achieved abstinence, and adolescents with cannabis use disorders. Preliminary results for adult tobacco use disorder are also promising. Human data examining the efficacy of NAC for alcohol use disorder is limited. Researchers’ ongoing challenge is to identify which patients with which SUDs are most likely to benefit from NAC, and to create clear clinical guidelines for the provider.

Bottom Line

N-acetylcysteine is likely to have modest effects for some patients who have a substance use disorder, particularly adults who use cocaine and adolescents who use marijuana. It may be useful in preventing relapse to substance use after an individual has achieved abstinence.

Related Resources

• Deepmala, Slattery J, Kumar N, et al. Clinical trials of N-acetylcysteine in psychiatry and neurology: a systematic review. Neurosci Biobehav Rev. 2015;55:294-321.
• Roberts-Wolfe D, Kalivas P. Glutamate transporter GLT-1 as a therapeutic target for substance use disorders. CNS Neurol Disord Drug Targets. 2015;14(6):745-756.
• National Institute on Drug Abuse. Treatment approaches for drug addiction. https://www.drugabuse.gov/publications/drugfacts/treatment-approaches-drug-addiction.

Drug Brand Names

Acamprosate • Campral
Acetaminophen • Tylenol
Baclofen • Lioresal
Bupropion • Zyban
Disulfiram • Antabuse
Naltrexone • Revia,Vivitrol
Varenicline • Chantix

Tourette syndrome (TS) is a chronic neuropsychiatric disorder occurring in early childhood or adolescence that’s characterized by multiple motor and vocal tics that are usually preceded by premonitory urges.^1,2 Usually, the tics are repetitive, sudden, stereotypical, non-rhythmic movements and/or vocalizations.^3,4 Individuals with TS and other tic disorders often experience impulsivity, aggression, obsessive-compulsive disorder (OCD), attention-deficit/hyperactivity disorder, and various mood and anxiety disorders.³ Psychosocial issues may include having low self-esteem, increased family conflict, and poor social skills. Males are affected 3 to 5 times more often than females.³ For most patients, the tics get less severe in late adolescence and early adulthood. However, approximately 10% to 15% of patients continue to experience chronic tics that are associated with significant disability.^2,5-7

There is no definitive treatment for TS. Commonly used interventions are pharmacotherapy and/or behavioral therapy, which includes supportive psychotherapy, habit reversal training, exposure with response prevention, relaxation therapy, cognitive-behavioral therapy, and self-monitoring. Pharmacotherapy for TS and other tic disorders consists mainly of antipsychotics such as haloperidol, pimozide, and aripiprazole, and alpha-2 agonists (guanfacine and clonidine).^4,8-10 Unfortunately, not all children respond to these medications, and these agents are associated with multiple adverse effects.¹¹ Therefore, there is a need for additional treatment options for patients with TS and other tic disorders, especially those who are not helped by conventional treatments.

Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive therapeutic technique in which high-intensity magnetic impulses are delivered through an electromagnetic coil placed on the patient’s scalp to stimulate cortical neurons. The effect is determined by various parameters, including the intensity, frequency, pulse number, duration, coil location, and type of coil.^3,8

rTMS is FDA-approved for treating depression, and has been used to treat anxiety disorders, Parkinson’s disease, chronic pain syndromes, and dystonia.^12,13 Researchers have begun to evaluate the usefulness of rTMS for patients with TS or other tic disorders. In this article, we review the findings of 11 studies—9 clinical trials and 2 case studies—that evaluated rTMS as a treatment option for patients with tic disorders.

A proposed mechanism of action

TS is believed to be caused by multiple factors, including neurotransmitter imbalances and genetic, environmental, and psychosocial factors.¹⁴ Evidence strongly suggests the involvement of the motor cortex, basal ganglia, and reticular activating system in the expression of TS.^2,15-17

Researchers have consistently identified networks of regions in the brain, including the supplementary motor area (SMA), that are active in the seconds before tics occur in patients with these disorders.^6,18-22 The SMA modulates the way information is channeled between motor circuits, the limbic system, and the cognitive processes.^3,23-26 The SMA can be used as a target for focal brain stimulation to modulate activity in those circuits and improve symptoms in resistant patients. Recent rTMS studies that targeted the SMA have found that stimulation to this area may be an effective way to treat TS.^19,20,23,27

Continue to: rTMS for tics: Mixed evidence

We reviewed the results of 11 studies that described the use of rTMS for TS and other tic disorders (Table 1^{1,24-26,28,29} and Table 2^{3,8,23,27,30,31}). They included:

• 2 double-blind, randomized controlled trials^28,29
• 2 single-blind trials^24-26
• 1 double-blind trial with an open-label extension¹
• 4 open-label studies^3,8,23,30
• 1 case series²⁷ and 1 case report.³¹

Study characteristics. In the 11 studies we reviewed, the duration of rTMS treatment varied from 2 days to 4 weeks. The pulses used were 900, 1,200, 1,800, and 2,400 per day, and the frequencies were 1 Hz, 4 Hz, 15 Hz and 30 Hz. Seven studies did not use placebo- or sham-controlled arms.^{1,3,8,23,27,30,31}Although several different scales were used to measure outcomes, many of the studies employed the Yale Global Tic Severity Scale (YGTSS), and effectiveness of rTMS was defined as a significant reduction in the YGTSS score.

Efficacy. Two double-blind trials^28,29 found no significant improvement in tic severity in patients treated with rTMS (P = .066 and P = .43, respectively). In addition, the 2 single-blind studies showed no beneficial effects of rTMS for patients with tics (P > .05).^24-26 However, 3 of the 4 open-label studies found a significant improvement in tics.^3,23,30 In one of the double-blind trials, researchers added an open-label extension phase.¹ They found no significant results in the double-blind phase of the study (P = .27), but in the open-label phase, patients experienced a significant improvement in tic severity (P = .04).¹ Lastly, the case series and case report found an improvement in tic severity and improvement in TS symptoms, respectively, with rTMS treatment.

rTMS might also improve symptoms of OCD that may co-occur with TS.^8,23,28 Two studies found significant improvement in tic severity in a subgroup of patients suffering from comorbid OCD.^8,28

Continue to: Safety profile and adverse effects

Safety profile and adverse effects. In the studies we reviewed, the adverse effects associated with rTMS included headache (45%),^{1,8,24,26,28,29} scalp pain (18%),^8,30 self-injurious crisis (9%),³¹ abdominal pain (9%),²⁹ red eyes (9%),²⁹ neck pain (9%),¹ muscle sprain (9%),¹ tiredness (9%),^24,26 and increase in motor excitability (9%).²⁸ There were no severe adverse effects reported in any of the studies. The self-injurious crisis reported by a patient early in one study as a seizure was later ruled out after careful clinical and electroencephalographic evaluation. This patient demonstrated self-injurious behaviors prior to the treatment, and overall there was a reduction in frequency and intensity of self-injurious behavior as well as an improvement in tics.³¹

Dissimilar studies

There was great heterogeneity among the 11 studies we reviewed. One case series²⁷ and one case report³¹ found significant improvement in tics, but these studies did not have control groups. Both studies employed rTMS with a frequency of 1 Hz and between 900 to 1,200 pulses per day. Three open-label studies that found significant improvement in tic severity used the same frequency of stimulation (1 Hz with 1,200 pulses per day).^3,23,30 All studies we analyzed differed in the total number of rTMS sessions and number of trains per stimulation.

The studies also differed in terms of the age of the participants. Some studies focused primarily on pediatric patients,^3,30 but many of them also included adults. The main limitations of the 11 studies included a small sample size,^{1,3,8,23-25,28-30} no placebo or controlled arm,^{1,3,8,23,27,30,31} concomitant psychiatric comorbidities^8,28,29 or medications,^1,3,23,29,30 low stimulation intensity,^24-26 and use of short trains^24,26 or unilateral cerebral stimulation.^24,26 Among the blinded studies, limitations included a small sample size, prior medications used, comorbidities, low stimulation intensity, and high rTMS dose.^{1,24-26,28,29}

A possible option for treatment-resistant tics

We cannot offer a definitive conclusion on the safety and effectiveness of rTMS for the treatment of TS and other tic disorders because of the inconsistent results, heterogeneity, and small sample sizes of the studies we analyzed. Higher-quality studies failed to find evidence supporting the use of rTMS for treating TS and other tics disorders, but open-label studies and case reports found significant improvements. In light of this evidence and the treatment’s relatively favorable adverse-effects profile, rTMS might be an option for certain patients with treatment-resistant tics, particularly those with comorbid OCD symptoms.

Continue to: Bottom Line

The evidence for using repetitive transcranial stimulation (rTMS) to treat patients with Tourette syndrome and other tic disorders is mixed. Higher-quality studies have found no significant improvements, whereas open-label studies and case studies have. Although not recommended for the routine treatment of tic disorders, rTMS may be an option for patients with treatment-resistant tics, particularly those with comorbid obsessive-compulsive symptoms.

Related Resources

• Tourette Association of America. https://www.tourette.org/.
• Harris E. Children with tic disorders: How to match treatment with symptoms. Current Psychiatry. 2010;9(3):29-36.

Drug Brand Names

Aripiprazole • Abilify  
Clonidine • Catapres, Duraclon
Guanfacine • Intuniv, Tenex
Haloperidol • Haldol
Pimozide • Orap

Tourette syndrome (TS) is a chronic neuropsychiatric disorder occurring in early childhood or adolescence that’s characterized by multiple motor and vocal tics that are usually preceded by premonitory urges.^1,2 Usually, the tics are repetitive, sudden, stereotypical, non-rhythmic movements and/or vocalizations.^3,4 Individuals with TS and other tic disorders often experience impulsivity, aggression, obsessive-compulsive disorder (OCD), attention-deficit/hyperactivity disorder, and various mood and anxiety disorders.³ Psychosocial issues may include having low self-esteem, increased family conflict, and poor social skills. Males are affected 3 to 5 times more often than females.³ For most patients, the tics get less severe in late adolescence and early adulthood. However, approximately 10% to 15% of patients continue to experience chronic tics that are associated with significant disability.^2,5-7

There is no definitive treatment for TS. Commonly used interventions are pharmacotherapy and/or behavioral therapy, which includes supportive psychotherapy, habit reversal training, exposure with response prevention, relaxation therapy, cognitive-behavioral therapy, and self-monitoring. Pharmacotherapy for TS and other tic disorders consists mainly of antipsychotics such as haloperidol, pimozide, and aripiprazole, and alpha-2 agonists (guanfacine and clonidine).^4,8-10 Unfortunately, not all children respond to these medications, and these agents are associated with multiple adverse effects.¹¹ Therefore, there is a need for additional treatment options for patients with TS and other tic disorders, especially those who are not helped by conventional treatments.

Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive therapeutic technique in which high-intensity magnetic impulses are delivered through an electromagnetic coil placed on the patient’s scalp to stimulate cortical neurons. The effect is determined by various parameters, including the intensity, frequency, pulse number, duration, coil location, and type of coil.^3,8

rTMS is FDA-approved for treating depression, and has been used to treat anxiety disorders, Parkinson’s disease, chronic pain syndromes, and dystonia.^12,13 Researchers have begun to evaluate the usefulness of rTMS for patients with TS or other tic disorders. In this article, we review the findings of 11 studies—9 clinical trials and 2 case studies—that evaluated rTMS as a treatment option for patients with tic disorders.

A proposed mechanism of action

TS is believed to be caused by multiple factors, including neurotransmitter imbalances and genetic, environmental, and psychosocial factors.¹⁴ Evidence strongly suggests the involvement of the motor cortex, basal ganglia, and reticular activating system in the expression of TS.^2,15-17

Researchers have consistently identified networks of regions in the brain, including the supplementary motor area (SMA), that are active in the seconds before tics occur in patients with these disorders.^6,18-22 The SMA modulates the way information is channeled between motor circuits, the limbic system, and the cognitive processes.^3,23-26 The SMA can be used as a target for focal brain stimulation to modulate activity in those circuits and improve symptoms in resistant patients. Recent rTMS studies that targeted the SMA have found that stimulation to this area may be an effective way to treat TS.^19,20,23,27

Continue to: rTMS for tics: Mixed evidence

We reviewed the results of 11 studies that described the use of rTMS for TS and other tic disorders (Table 1^{1,24-26,28,29} and Table 2^{3,8,23,27,30,31}). They included:

• 2 double-blind, randomized controlled trials^28,29
• 2 single-blind trials^24-26
• 1 double-blind trial with an open-label extension¹
• 4 open-label studies^3,8,23,30
• 1 case series²⁷ and 1 case report.³¹

Study characteristics. In the 11 studies we reviewed, the duration of rTMS treatment varied from 2 days to 4 weeks. The pulses used were 900, 1,200, 1,800, and 2,400 per day, and the frequencies were 1 Hz, 4 Hz, 15 Hz and 30 Hz. Seven studies did not use placebo- or sham-controlled arms.^{1,3,8,23,27,30,31}Although several different scales were used to measure outcomes, many of the studies employed the Yale Global Tic Severity Scale (YGTSS), and effectiveness of rTMS was defined as a significant reduction in the YGTSS score.

Efficacy. Two double-blind trials^28,29 found no significant improvement in tic severity in patients treated with rTMS (P = .066 and P = .43, respectively). In addition, the 2 single-blind studies showed no beneficial effects of rTMS for patients with tics (P > .05).^24-26 However, 3 of the 4 open-label studies found a significant improvement in tics.^3,23,30 In one of the double-blind trials, researchers added an open-label extension phase.¹ They found no significant results in the double-blind phase of the study (P = .27), but in the open-label phase, patients experienced a significant improvement in tic severity (P = .04).¹ Lastly, the case series and case report found an improvement in tic severity and improvement in TS symptoms, respectively, with rTMS treatment.

rTMS might also improve symptoms of OCD that may co-occur with TS.^8,23,28 Two studies found significant improvement in tic severity in a subgroup of patients suffering from comorbid OCD.^8,28

Continue to: Safety profile and adverse effects

Safety profile and adverse effects. In the studies we reviewed, the adverse effects associated with rTMS included headache (45%),^{1,8,24,26,28,29} scalp pain (18%),^8,30 self-injurious crisis (9%),³¹ abdominal pain (9%),²⁹ red eyes (9%),²⁹ neck pain (9%),¹ muscle sprain (9%),¹ tiredness (9%),^24,26 and increase in motor excitability (9%).²⁸ There were no severe adverse effects reported in any of the studies. The self-injurious crisis reported by a patient early in one study as a seizure was later ruled out after careful clinical and electroencephalographic evaluation. This patient demonstrated self-injurious behaviors prior to the treatment, and overall there was a reduction in frequency and intensity of self-injurious behavior as well as an improvement in tics.³¹

Dissimilar studies

There was great heterogeneity among the 11 studies we reviewed. One case series²⁷ and one case report³¹ found significant improvement in tics, but these studies did not have control groups. Both studies employed rTMS with a frequency of 1 Hz and between 900 to 1,200 pulses per day. Three open-label studies that found significant improvement in tic severity used the same frequency of stimulation (1 Hz with 1,200 pulses per day).^3,23,30 All studies we analyzed differed in the total number of rTMS sessions and number of trains per stimulation.

The studies also differed in terms of the age of the participants. Some studies focused primarily on pediatric patients,^3,30 but many of them also included adults. The main limitations of the 11 studies included a small sample size,^{1,3,8,23-25,28-30} no placebo or controlled arm,^{1,3,8,23,27,30,31} concomitant psychiatric comorbidities^8,28,29 or medications,^1,3,23,29,30 low stimulation intensity,^24-26 and use of short trains^24,26 or unilateral cerebral stimulation.^24,26 Among the blinded studies, limitations included a small sample size, prior medications used, comorbidities, low stimulation intensity, and high rTMS dose.^{1,24-26,28,29}

A possible option for treatment-resistant tics

We cannot offer a definitive conclusion on the safety and effectiveness of rTMS for the treatment of TS and other tic disorders because of the inconsistent results, heterogeneity, and small sample sizes of the studies we analyzed. Higher-quality studies failed to find evidence supporting the use of rTMS for treating TS and other tics disorders, but open-label studies and case reports found significant improvements. In light of this evidence and the treatment’s relatively favorable adverse-effects profile, rTMS might be an option for certain patients with treatment-resistant tics, particularly those with comorbid OCD symptoms.

Continue to: Bottom Line

The evidence for using repetitive transcranial stimulation (rTMS) to treat patients with Tourette syndrome and other tic disorders is mixed. Higher-quality studies have found no significant improvements, whereas open-label studies and case studies have. Although not recommended for the routine treatment of tic disorders, rTMS may be an option for patients with treatment-resistant tics, particularly those with comorbid obsessive-compulsive symptoms.

Related Resources

• Tourette Association of America. https://www.tourette.org/.
• Harris E. Children with tic disorders: How to match treatment with symptoms. Current Psychiatry. 2010;9(3):29-36.

Drug Brand Names

Aripiprazole • Abilify  
Clonidine • Catapres, Duraclon
Guanfacine • Intuniv, Tenex
Haloperidol • Haldol
Pimozide • Orap

Tourette syndrome (TS) is a chronic neuropsychiatric disorder occurring in early childhood or adolescence that’s characterized by multiple motor and vocal tics that are usually preceded by premonitory urges.^1,2 Usually, the tics are repetitive, sudden, stereotypical, non-rhythmic movements and/or vocalizations.^3,4 Individuals with TS and other tic disorders often experience impulsivity, aggression, obsessive-compulsive disorder (OCD), attention-deficit/hyperactivity disorder, and various mood and anxiety disorders.³ Psychosocial issues may include having low self-esteem, increased family conflict, and poor social skills. Males are affected 3 to 5 times more often than females.³ For most patients, the tics get less severe in late adolescence and early adulthood. However, approximately 10% to 15% of patients continue to experience chronic tics that are associated with significant disability.^2,5-7

There is no definitive treatment for TS. Commonly used interventions are pharmacotherapy and/or behavioral therapy, which includes supportive psychotherapy, habit reversal training, exposure with response prevention, relaxation therapy, cognitive-behavioral therapy, and self-monitoring. Pharmacotherapy for TS and other tic disorders consists mainly of antipsychotics such as haloperidol, pimozide, and aripiprazole, and alpha-2 agonists (guanfacine and clonidine).^4,8-10 Unfortunately, not all children respond to these medications, and these agents are associated with multiple adverse effects.¹¹ Therefore, there is a need for additional treatment options for patients with TS and other tic disorders, especially those who are not helped by conventional treatments.

Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive therapeutic technique in which high-intensity magnetic impulses are delivered through an electromagnetic coil placed on the patient’s scalp to stimulate cortical neurons. The effect is determined by various parameters, including the intensity, frequency, pulse number, duration, coil location, and type of coil.^3,8

rTMS is FDA-approved for treating depression, and has been used to treat anxiety disorders, Parkinson’s disease, chronic pain syndromes, and dystonia.^12,13 Researchers have begun to evaluate the usefulness of rTMS for patients with TS or other tic disorders. In this article, we review the findings of 11 studies—9 clinical trials and 2 case studies—that evaluated rTMS as a treatment option for patients with tic disorders.

A proposed mechanism of action

TS is believed to be caused by multiple factors, including neurotransmitter imbalances and genetic, environmental, and psychosocial factors.¹⁴ Evidence strongly suggests the involvement of the motor cortex, basal ganglia, and reticular activating system in the expression of TS.^2,15-17

Researchers have consistently identified networks of regions in the brain, including the supplementary motor area (SMA), that are active in the seconds before tics occur in patients with these disorders.^6,18-22 The SMA modulates the way information is channeled between motor circuits, the limbic system, and the cognitive processes.^3,23-26 The SMA can be used as a target for focal brain stimulation to modulate activity in those circuits and improve symptoms in resistant patients. Recent rTMS studies that targeted the SMA have found that stimulation to this area may be an effective way to treat TS.^19,20,23,27

Continue to: rTMS for tics: Mixed evidence

We reviewed the results of 11 studies that described the use of rTMS for TS and other tic disorders (Table 1^{1,24-26,28,29} and Table 2^{3,8,23,27,30,31}). They included:

• 2 double-blind, randomized controlled trials^28,29
• 2 single-blind trials^24-26
• 1 double-blind trial with an open-label extension¹
• 4 open-label studies^3,8,23,30
• 1 case series²⁷ and 1 case report.³¹

Study characteristics. In the 11 studies we reviewed, the duration of rTMS treatment varied from 2 days to 4 weeks. The pulses used were 900, 1,200, 1,800, and 2,400 per day, and the frequencies were 1 Hz, 4 Hz, 15 Hz and 30 Hz. Seven studies did not use placebo- or sham-controlled arms.^{1,3,8,23,27,30,31}Although several different scales were used to measure outcomes, many of the studies employed the Yale Global Tic Severity Scale (YGTSS), and effectiveness of rTMS was defined as a significant reduction in the YGTSS score.

Efficacy. Two double-blind trials^28,29 found no significant improvement in tic severity in patients treated with rTMS (P = .066 and P = .43, respectively). In addition, the 2 single-blind studies showed no beneficial effects of rTMS for patients with tics (P > .05).^24-26 However, 3 of the 4 open-label studies found a significant improvement in tics.^3,23,30 In one of the double-blind trials, researchers added an open-label extension phase.¹ They found no significant results in the double-blind phase of the study (P = .27), but in the open-label phase, patients experienced a significant improvement in tic severity (P = .04).¹ Lastly, the case series and case report found an improvement in tic severity and improvement in TS symptoms, respectively, with rTMS treatment.

rTMS might also improve symptoms of OCD that may co-occur with TS.^8,23,28 Two studies found significant improvement in tic severity in a subgroup of patients suffering from comorbid OCD.^8,28

Continue to: Safety profile and adverse effects

Safety profile and adverse effects. In the studies we reviewed, the adverse effects associated with rTMS included headache (45%),^{1,8,24,26,28,29} scalp pain (18%),^8,30 self-injurious crisis (9%),³¹ abdominal pain (9%),²⁹ red eyes (9%),²⁹ neck pain (9%),¹ muscle sprain (9%),¹ tiredness (9%),^24,26 and increase in motor excitability (9%).²⁸ There were no severe adverse effects reported in any of the studies. The self-injurious crisis reported by a patient early in one study as a seizure was later ruled out after careful clinical and electroencephalographic evaluation. This patient demonstrated self-injurious behaviors prior to the treatment, and overall there was a reduction in frequency and intensity of self-injurious behavior as well as an improvement in tics.³¹

Dissimilar studies

There was great heterogeneity among the 11 studies we reviewed. One case series²⁷ and one case report³¹ found significant improvement in tics, but these studies did not have control groups. Both studies employed rTMS with a frequency of 1 Hz and between 900 to 1,200 pulses per day. Three open-label studies that found significant improvement in tic severity used the same frequency of stimulation (1 Hz with 1,200 pulses per day).^3,23,30 All studies we analyzed differed in the total number of rTMS sessions and number of trains per stimulation.

The studies also differed in terms of the age of the participants. Some studies focused primarily on pediatric patients,^3,30 but many of them also included adults. The main limitations of the 11 studies included a small sample size,^{1,3,8,23-25,28-30} no placebo or controlled arm,^{1,3,8,23,27,30,31} concomitant psychiatric comorbidities^8,28,29 or medications,^1,3,23,29,30 low stimulation intensity,^24-26 and use of short trains^24,26 or unilateral cerebral stimulation.^24,26 Among the blinded studies, limitations included a small sample size, prior medications used, comorbidities, low stimulation intensity, and high rTMS dose.^{1,24-26,28,29}

A possible option for treatment-resistant tics

We cannot offer a definitive conclusion on the safety and effectiveness of rTMS for the treatment of TS and other tic disorders because of the inconsistent results, heterogeneity, and small sample sizes of the studies we analyzed. Higher-quality studies failed to find evidence supporting the use of rTMS for treating TS and other tics disorders, but open-label studies and case reports found significant improvements. In light of this evidence and the treatment’s relatively favorable adverse-effects profile, rTMS might be an option for certain patients with treatment-resistant tics, particularly those with comorbid OCD symptoms.

Continue to: Bottom Line

The evidence for using repetitive transcranial stimulation (rTMS) to treat patients with Tourette syndrome and other tic disorders is mixed. Higher-quality studies have found no significant improvements, whereas open-label studies and case studies have. Although not recommended for the routine treatment of tic disorders, rTMS may be an option for patients with treatment-resistant tics, particularly those with comorbid obsessive-compulsive symptoms.

Related Resources

• Tourette Association of America. https://www.tourette.org/.
• Harris E. Children with tic disorders: How to match treatment with symptoms. Current Psychiatry. 2010;9(3):29-36.

Drug Brand Names

Aripiprazole • Abilify  
Clonidine • Catapres, Duraclon
Guanfacine • Intuniv, Tenex
Haloperidol • Haldol
Pimozide • Orap