Current Psychiatry

Alcohol use disorder (AUD) is a mosaic of psychiatric and medical symptoms. Alcoholic liver disease (ALD) in its acute and chronic forms is a common clinical consequence of long-standing AUD. Patients with ALD require specialized care from pro­fessionals in addiction, gastroenterology, and psychiatry. However, medical specialists treating ALD might not regularly consider medi­cations to treat AUD because of their limited experience with the drugs or the lack of studies in patients with significant liver disease.¹ Similarly, psychiatrists might be reticent to prescribe medications for AUD, fearing that liver disease will be made worse or that they will cause other medical complications. As a result, patients with ALD might not receive care that could help treat their AUD (Box).

Given the high worldwide prevalence and morbidity of ALD,² gen­eral and subspecialized psychiatrists routinely evaluate patients with AUD in and out of the hospital. This article aims to equip a psychia­trist with:
   • a practical understanding of the natural history and categorization of ALD
   • basic skills to detect symptoms of ALD
   • preparation to collaborate with medical colleagues in multidisciplinary management of co-occurring AUD and ALD
   • a summary of the pharmacotherapeutics of AUD, with emphasis on patients with clinically apparent ALD.

Categorization and clinical features
Alcoholic liver damage encompasses a spectrum of disorders, including alcoholic fatty liver, acute alcohol hepatitis (AH), and cirrhosis following varying durations and patterns of alcohol use. Manifestations of ALD vary from asymptomatic fatty liver with minimal liver enzyme eleva­tion to severe acute AH with jaundice, coagulopathy, and high short-term mor­tality (Table 1). Symptoms seen in patients with AH include fever, abdominal pain, anorexia, jaundice, leukocytosis, and coagulopathy.³

All patients who drink heavily or suffer with AUD are at risk of developing AH; women and binge drinkers are particu­larly vulnerable.⁴ Liver dysfunction and malnutrition in ALD patients compromise the immune system, increasing the risk of infection. Patients hospitalized with AH have a 10% to 30% risk of inpatient mor­tality; their 1- and 2-month post-discharge survival is 50% to 65%, largely determined by whether the patient can maintain sobri­ety.⁵ Psychiatrists’ contribution to ALD treatment therefore has the potential to save lives.

Screening and detection of ALD
Because of the high mortality associated with AH and cirrhosis, symptom recogni­tion and collaborative medical and psy­chiatric management are critical (Table 2). A psychiatrist evaluating a jaun­diced patient who continues to drink should arrange urgent medical evaluation. While gathering a history, mental health providers might hear a patient refer to symptoms of gastrointestinal bleeding (vomiting blood, bloody or dark stool), painful abdominal distension, fevers, or confusion that should prompt a referral to a gastroenterologist or the emergency department. Testing for uri­nary ethyl glucuronide—a direct metabolite of ethanol that can be detected for as long as 90 hours after ethanol ingestion—is use­ful in detecting alcohol use in the past 4 or 5 days.

Medical management of ALD
Corticosteroids are a mainstay in pharma­cotherapy for severe AH. There is evidence for improved outcomes in patients with severe AH treated with prednisolone for 4 to 6 weeks.⁵ Prognostic models such as the Maddrey’s Discriminant Function, Lille Model, and the MELD score help determine the need for steroid use and identify high-risk patients. Patients with active infection or bleeding are not a candidate for steroid treatment. An experienced gastroenterolo­gist or hepatologist should initiate medical intervention after thorough evaluation.

Liver transplantation. A select group of patients with refractory liver failure are con­sidered for liver transplantation. Although transplant programs differ in their criteria for organ listing, many require patients to demonstrate at least 6 months of verified abstinence from alcohol and illicit drugs as well as adherence to a formal AUD treat­ment and rehabilitation plan. The patient’s psychological health and prognosis for sus­tained sobriety are central to candidacy for organ listing, which highlights the key role of psychiatrists.

Further considerations. Thiamine and folate often are given to patients with ALD. Abdominal imaging and screening for HIV and viral hepatitis—identified in 10% to 20% of ALD patients—is routine. Alcohol absti­nence remains central to survival because relapse increases the risk of recurrent, severe liver disease. Regrettably, many physical symptoms of liver disease, such as portal hypertension, ascites, and jaundice, can take months to improve with abstinence.

Treating AUD in patients with ALD
Successful treatment is multifaceted and includes more than just medications. Initial management often includes addressing alcohol withdrawal in dependent patients.⁶

Behavioral interventions are effective and indispensable components in prevent­ing relapse,⁷ including a written relapse prevention plan that formally outlines the patient’s commitment to change, identi­fies triggers, and outlines a discrete plan of action. Primary psychiatric pathology, including depression and anxiety, often are comorbid with AUD; concurrent treatment of these disorders could improve patient outcomes.⁸

Benzodiazepines often are used during acute alcohol withdrawal. They should not be used for relapse prevention in ALD because of their additive interactions with alcohol, cognitive and psychomotor side effects, and abuse potential.^9,10 Many of these drugs are cleared by the liver and generally are not recommended for use in patients with ALD.

Other agents, further considerations. Drug trials in AUD largely have been con­ducted in small, heterogeneous populations and revealed modest and, at times, con­flicting drug effect sizes.^6,11,12 The placebo effect among the AUD population is pro­nounced.^6,7,13 Despite these caveats, several agents have been studied and validated by the FDA to treat AUD. Additional agents with promising pilot data are being inves­tigated. Table 3^{1,7,10,11,13-43} summa­rizes drugs used to treat AUD—those with and without FDA approval—with a focus on how they might be used in patients with ALD. Of note, several of these agents do not rely on the liver for metabolism or excretion.

That being said, the AUD treatment liter­ature suggests that specific drugs might be more useful in patients with varying sever­ity of disease and during different phases of recovery:
   • Acamprosate has been found to be effective in supporting abstinence in sober patients.^14,44
   • Naltrexone has been shown to be useful in patients with severe alcohol cravings. By modulating alcohol’s rewarding effects, naltrexone also reduces heavy alcohol consumption in patients who are drinking.^14,15,44
   • Disulfiram generally is not recommended for use in patients with clinically apparent hepatic insufficiency, such as decompensated cirrhosis or preexisting jaundice.

Although alcohol abstinence remains the treatment goal and a requirement for liver transplant, providers must recognize that some patients might not be able to maintain long-term sobriety. Therefore, harm reduc­tion models are important companions to abstinence-only models of AUD treatment.⁴⁵ The array of behavioral, pharmacologi­cal, and philosophical approaches to AUD treatment underlines the need for an indi­vidualized approach to relapse prevention.

Collaboration between medicine and psychiatry
When AUD and ALD are comorbid, psy­chiatrists might worry about making the patient’s medical condition worse by pre­scribing additional psychoactive medica­tions—particularly ones that are cleared by the liver. Remember that AUD confers a substantial mortality rate that is more than 3 times that of the general population, along with severe medical⁴⁶ and psycho­social³¹ effects. Although prescribers must remain vigilant for adverse drug effects, medications easily can be blamed for what might be the natural progression and symp­toms of AUD in patients with ALD.²⁶ This erroneous conclusion can lead to premature medication discontinuation and under-treatment of AUD.

In the end, keeping the patient sober and mentally well might be more beneficial than eliminating the burden of any medica­tion side effects. Collaborative medical and psychiatric management of ALD patients can ensure that clinicians properly weigh the risks, benefits, and duration of treat­ment unique to each patient.

Starting AUD treatment promptly after alcohol relapse is essential and entails a multidisciplinary effort between medicine and psychiatry, both in and out of the hos­pital. Because the relapsing, ill ALD patient most often will be admitted to a medical specialist, AUD might not receive enough attention during the medical admission. Psychiatrists can help in initiating AUD treatment in the acute medical setting, which has been shown to improve the out­patient course.⁶ For medically stable ALD patients admitted for inpatient psychiatric care or presenting a clinic, the mental health clinician should be aware of key laboratory and physical exam findings.

Bottom Line
Patients with alcoholic liver disease (ALD) require collaborative care from specialists in addiction, gastroenterology, and psychiatry. Psychiatrists have a role in identifying signs of ALD, prescribing medication to treat alcohol use disorder, and encouraging abstinence. There is some evidence supporting specific medications for varying severity of disease and different phases of recovery. Pharmacotherapy decisions should be made case by case.

Related Resources
• Khan A, Tansel A, White DL, et al. Efficacy of psychosocial interventions in inducing and maintaining alcohol abstinence in patients with chronic liver disease: a systematic review [published online August 6, 2015]. Clin Gastroenterol Hepatol. doi: 10.1016/j.cgh.2015.07.047.
• Vuittonet CL, Halse M, Leggio L, et al. Pharmacotherapy for alcoholic patients with alcoholic liver disease. Am J Health Syst Pharm. 2014;71(15):1265-1276.

Drug Brand Names
Acamprosate • Campral                       
Baclofen • Lioresal                              
Disulfiram • Antabuse                          
Gabapentin • Neurontin                       
Naltrexone • ReVia, Vivitrol
Pentoxifylline • Trental
Prednisolone • Prelone
Rifaximin • Xifaxan
Topiramate • Topamax

Disclosures
Dr. Winder and Dr. Mellinger report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products. Dr. Fontana receives research funding from Bristol Myers Squibb, Gilead, and Janssen and consults for the Chronic Liver Disease Foundation.

Alcohol use disorder (AUD) is a mosaic of psychiatric and medical symptoms. Alcoholic liver disease (ALD) in its acute and chronic forms is a common clinical consequence of long-standing AUD. Patients with ALD require specialized care from pro­fessionals in addiction, gastroenterology, and psychiatry. However, medical specialists treating ALD might not regularly consider medi­cations to treat AUD because of their limited experience with the drugs or the lack of studies in patients with significant liver disease.¹ Similarly, psychiatrists might be reticent to prescribe medications for AUD, fearing that liver disease will be made worse or that they will cause other medical complications. As a result, patients with ALD might not receive care that could help treat their AUD (Box).

Given the high worldwide prevalence and morbidity of ALD,² gen­eral and subspecialized psychiatrists routinely evaluate patients with AUD in and out of the hospital. This article aims to equip a psychia­trist with:
   • a practical understanding of the natural history and categorization of ALD
   • basic skills to detect symptoms of ALD
   • preparation to collaborate with medical colleagues in multidisciplinary management of co-occurring AUD and ALD
   • a summary of the pharmacotherapeutics of AUD, with emphasis on patients with clinically apparent ALD.

Categorization and clinical features
Alcoholic liver damage encompasses a spectrum of disorders, including alcoholic fatty liver, acute alcohol hepatitis (AH), and cirrhosis following varying durations and patterns of alcohol use. Manifestations of ALD vary from asymptomatic fatty liver with minimal liver enzyme eleva­tion to severe acute AH with jaundice, coagulopathy, and high short-term mor­tality (Table 1). Symptoms seen in patients with AH include fever, abdominal pain, anorexia, jaundice, leukocytosis, and coagulopathy.³

All patients who drink heavily or suffer with AUD are at risk of developing AH; women and binge drinkers are particu­larly vulnerable.⁴ Liver dysfunction and malnutrition in ALD patients compromise the immune system, increasing the risk of infection. Patients hospitalized with AH have a 10% to 30% risk of inpatient mor­tality; their 1- and 2-month post-discharge survival is 50% to 65%, largely determined by whether the patient can maintain sobri­ety.⁵ Psychiatrists’ contribution to ALD treatment therefore has the potential to save lives.

Screening and detection of ALD
Because of the high mortality associated with AH and cirrhosis, symptom recogni­tion and collaborative medical and psy­chiatric management are critical (Table 2). A psychiatrist evaluating a jaun­diced patient who continues to drink should arrange urgent medical evaluation. While gathering a history, mental health providers might hear a patient refer to symptoms of gastrointestinal bleeding (vomiting blood, bloody or dark stool), painful abdominal distension, fevers, or confusion that should prompt a referral to a gastroenterologist or the emergency department. Testing for uri­nary ethyl glucuronide—a direct metabolite of ethanol that can be detected for as long as 90 hours after ethanol ingestion—is use­ful in detecting alcohol use in the past 4 or 5 days.

Medical management of ALD
Corticosteroids are a mainstay in pharma­cotherapy for severe AH. There is evidence for improved outcomes in patients with severe AH treated with prednisolone for 4 to 6 weeks.⁵ Prognostic models such as the Maddrey’s Discriminant Function, Lille Model, and the MELD score help determine the need for steroid use and identify high-risk patients. Patients with active infection or bleeding are not a candidate for steroid treatment. An experienced gastroenterolo­gist or hepatologist should initiate medical intervention after thorough evaluation.

Liver transplantation. A select group of patients with refractory liver failure are con­sidered for liver transplantation. Although transplant programs differ in their criteria for organ listing, many require patients to demonstrate at least 6 months of verified abstinence from alcohol and illicit drugs as well as adherence to a formal AUD treat­ment and rehabilitation plan. The patient’s psychological health and prognosis for sus­tained sobriety are central to candidacy for organ listing, which highlights the key role of psychiatrists.

Further considerations. Thiamine and folate often are given to patients with ALD. Abdominal imaging and screening for HIV and viral hepatitis—identified in 10% to 20% of ALD patients—is routine. Alcohol absti­nence remains central to survival because relapse increases the risk of recurrent, severe liver disease. Regrettably, many physical symptoms of liver disease, such as portal hypertension, ascites, and jaundice, can take months to improve with abstinence.

Treating AUD in patients with ALD
Successful treatment is multifaceted and includes more than just medications. Initial management often includes addressing alcohol withdrawal in dependent patients.⁶

Behavioral interventions are effective and indispensable components in prevent­ing relapse,⁷ including a written relapse prevention plan that formally outlines the patient’s commitment to change, identi­fies triggers, and outlines a discrete plan of action. Primary psychiatric pathology, including depression and anxiety, often are comorbid with AUD; concurrent treatment of these disorders could improve patient outcomes.⁸

Benzodiazepines often are used during acute alcohol withdrawal. They should not be used for relapse prevention in ALD because of their additive interactions with alcohol, cognitive and psychomotor side effects, and abuse potential.^9,10 Many of these drugs are cleared by the liver and generally are not recommended for use in patients with ALD.

Other agents, further considerations. Drug trials in AUD largely have been con­ducted in small, heterogeneous populations and revealed modest and, at times, con­flicting drug effect sizes.^6,11,12 The placebo effect among the AUD population is pro­nounced.^6,7,13 Despite these caveats, several agents have been studied and validated by the FDA to treat AUD. Additional agents with promising pilot data are being inves­tigated. Table 3^{1,7,10,11,13-43} summa­rizes drugs used to treat AUD—those with and without FDA approval—with a focus on how they might be used in patients with ALD. Of note, several of these agents do not rely on the liver for metabolism or excretion.

That being said, the AUD treatment liter­ature suggests that specific drugs might be more useful in patients with varying sever­ity of disease and during different phases of recovery:
   • Acamprosate has been found to be effective in supporting abstinence in sober patients.^14,44
   • Naltrexone has been shown to be useful in patients with severe alcohol cravings. By modulating alcohol’s rewarding effects, naltrexone also reduces heavy alcohol consumption in patients who are drinking.^14,15,44
   • Disulfiram generally is not recommended for use in patients with clinically apparent hepatic insufficiency, such as decompensated cirrhosis or preexisting jaundice.

Although alcohol abstinence remains the treatment goal and a requirement for liver transplant, providers must recognize that some patients might not be able to maintain long-term sobriety. Therefore, harm reduc­tion models are important companions to abstinence-only models of AUD treatment.⁴⁵ The array of behavioral, pharmacologi­cal, and philosophical approaches to AUD treatment underlines the need for an indi­vidualized approach to relapse prevention.

Collaboration between medicine and psychiatry
When AUD and ALD are comorbid, psy­chiatrists might worry about making the patient’s medical condition worse by pre­scribing additional psychoactive medica­tions—particularly ones that are cleared by the liver. Remember that AUD confers a substantial mortality rate that is more than 3 times that of the general population, along with severe medical⁴⁶ and psycho­social³¹ effects. Although prescribers must remain vigilant for adverse drug effects, medications easily can be blamed for what might be the natural progression and symp­toms of AUD in patients with ALD.²⁶ This erroneous conclusion can lead to premature medication discontinuation and under-treatment of AUD.

In the end, keeping the patient sober and mentally well might be more beneficial than eliminating the burden of any medica­tion side effects. Collaborative medical and psychiatric management of ALD patients can ensure that clinicians properly weigh the risks, benefits, and duration of treat­ment unique to each patient.

Starting AUD treatment promptly after alcohol relapse is essential and entails a multidisciplinary effort between medicine and psychiatry, both in and out of the hos­pital. Because the relapsing, ill ALD patient most often will be admitted to a medical specialist, AUD might not receive enough attention during the medical admission. Psychiatrists can help in initiating AUD treatment in the acute medical setting, which has been shown to improve the out­patient course.⁶ For medically stable ALD patients admitted for inpatient psychiatric care or presenting a clinic, the mental health clinician should be aware of key laboratory and physical exam findings.

Bottom Line
Patients with alcoholic liver disease (ALD) require collaborative care from specialists in addiction, gastroenterology, and psychiatry. Psychiatrists have a role in identifying signs of ALD, prescribing medication to treat alcohol use disorder, and encouraging abstinence. There is some evidence supporting specific medications for varying severity of disease and different phases of recovery. Pharmacotherapy decisions should be made case by case.

Related Resources
• Khan A, Tansel A, White DL, et al. Efficacy of psychosocial interventions in inducing and maintaining alcohol abstinence in patients with chronic liver disease: a systematic review [published online August 6, 2015]. Clin Gastroenterol Hepatol. doi: 10.1016/j.cgh.2015.07.047.
• Vuittonet CL, Halse M, Leggio L, et al. Pharmacotherapy for alcoholic patients with alcoholic liver disease. Am J Health Syst Pharm. 2014;71(15):1265-1276.

Drug Brand Names
Acamprosate • Campral                       
Baclofen • Lioresal                              
Disulfiram • Antabuse                          
Gabapentin • Neurontin                       
Naltrexone • ReVia, Vivitrol
Pentoxifylline • Trental
Prednisolone • Prelone
Rifaximin • Xifaxan
Topiramate • Topamax

Disclosures
Dr. Winder and Dr. Mellinger report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products. Dr. Fontana receives research funding from Bristol Myers Squibb, Gilead, and Janssen and consults for the Chronic Liver Disease Foundation.

Alcohol use disorder (AUD) is a mosaic of psychiatric and medical symptoms. Alcoholic liver disease (ALD) in its acute and chronic forms is a common clinical consequence of long-standing AUD. Patients with ALD require specialized care from pro­fessionals in addiction, gastroenterology, and psychiatry. However, medical specialists treating ALD might not regularly consider medi­cations to treat AUD because of their limited experience with the drugs or the lack of studies in patients with significant liver disease.¹ Similarly, psychiatrists might be reticent to prescribe medications for AUD, fearing that liver disease will be made worse or that they will cause other medical complications. As a result, patients with ALD might not receive care that could help treat their AUD (Box).

Given the high worldwide prevalence and morbidity of ALD,² gen­eral and subspecialized psychiatrists routinely evaluate patients with AUD in and out of the hospital. This article aims to equip a psychia­trist with:
   • a practical understanding of the natural history and categorization of ALD
   • basic skills to detect symptoms of ALD
   • preparation to collaborate with medical colleagues in multidisciplinary management of co-occurring AUD and ALD
   • a summary of the pharmacotherapeutics of AUD, with emphasis on patients with clinically apparent ALD.

Categorization and clinical features
Alcoholic liver damage encompasses a spectrum of disorders, including alcoholic fatty liver, acute alcohol hepatitis (AH), and cirrhosis following varying durations and patterns of alcohol use. Manifestations of ALD vary from asymptomatic fatty liver with minimal liver enzyme eleva­tion to severe acute AH with jaundice, coagulopathy, and high short-term mor­tality (Table 1). Symptoms seen in patients with AH include fever, abdominal pain, anorexia, jaundice, leukocytosis, and coagulopathy.³

All patients who drink heavily or suffer with AUD are at risk of developing AH; women and binge drinkers are particu­larly vulnerable.⁴ Liver dysfunction and malnutrition in ALD patients compromise the immune system, increasing the risk of infection. Patients hospitalized with AH have a 10% to 30% risk of inpatient mor­tality; their 1- and 2-month post-discharge survival is 50% to 65%, largely determined by whether the patient can maintain sobri­ety.⁵ Psychiatrists’ contribution to ALD treatment therefore has the potential to save lives.

Screening and detection of ALD
Because of the high mortality associated with AH and cirrhosis, symptom recogni­tion and collaborative medical and psy­chiatric management are critical (Table 2). A psychiatrist evaluating a jaun­diced patient who continues to drink should arrange urgent medical evaluation. While gathering a history, mental health providers might hear a patient refer to symptoms of gastrointestinal bleeding (vomiting blood, bloody or dark stool), painful abdominal distension, fevers, or confusion that should prompt a referral to a gastroenterologist or the emergency department. Testing for uri­nary ethyl glucuronide—a direct metabolite of ethanol that can be detected for as long as 90 hours after ethanol ingestion—is use­ful in detecting alcohol use in the past 4 or 5 days.

Medical management of ALD
Corticosteroids are a mainstay in pharma­cotherapy for severe AH. There is evidence for improved outcomes in patients with severe AH treated with prednisolone for 4 to 6 weeks.⁵ Prognostic models such as the Maddrey’s Discriminant Function, Lille Model, and the MELD score help determine the need for steroid use and identify high-risk patients. Patients with active infection or bleeding are not a candidate for steroid treatment. An experienced gastroenterolo­gist or hepatologist should initiate medical intervention after thorough evaluation.

Liver transplantation. A select group of patients with refractory liver failure are con­sidered for liver transplantation. Although transplant programs differ in their criteria for organ listing, many require patients to demonstrate at least 6 months of verified abstinence from alcohol and illicit drugs as well as adherence to a formal AUD treat­ment and rehabilitation plan. The patient’s psychological health and prognosis for sus­tained sobriety are central to candidacy for organ listing, which highlights the key role of psychiatrists.

Further considerations. Thiamine and folate often are given to patients with ALD. Abdominal imaging and screening for HIV and viral hepatitis—identified in 10% to 20% of ALD patients—is routine. Alcohol absti­nence remains central to survival because relapse increases the risk of recurrent, severe liver disease. Regrettably, many physical symptoms of liver disease, such as portal hypertension, ascites, and jaundice, can take months to improve with abstinence.

Treating AUD in patients with ALD
Successful treatment is multifaceted and includes more than just medications. Initial management often includes addressing alcohol withdrawal in dependent patients.⁶

Behavioral interventions are effective and indispensable components in prevent­ing relapse,⁷ including a written relapse prevention plan that formally outlines the patient’s commitment to change, identi­fies triggers, and outlines a discrete plan of action. Primary psychiatric pathology, including depression and anxiety, often are comorbid with AUD; concurrent treatment of these disorders could improve patient outcomes.⁸

Benzodiazepines often are used during acute alcohol withdrawal. They should not be used for relapse prevention in ALD because of their additive interactions with alcohol, cognitive and psychomotor side effects, and abuse potential.^9,10 Many of these drugs are cleared by the liver and generally are not recommended for use in patients with ALD.

Other agents, further considerations. Drug trials in AUD largely have been con­ducted in small, heterogeneous populations and revealed modest and, at times, con­flicting drug effect sizes.^6,11,12 The placebo effect among the AUD population is pro­nounced.^6,7,13 Despite these caveats, several agents have been studied and validated by the FDA to treat AUD. Additional agents with promising pilot data are being inves­tigated. Table 3^{1,7,10,11,13-43} summa­rizes drugs used to treat AUD—those with and without FDA approval—with a focus on how they might be used in patients with ALD. Of note, several of these agents do not rely on the liver for metabolism or excretion.

That being said, the AUD treatment liter­ature suggests that specific drugs might be more useful in patients with varying sever­ity of disease and during different phases of recovery:
   • Acamprosate has been found to be effective in supporting abstinence in sober patients.^14,44
   • Naltrexone has been shown to be useful in patients with severe alcohol cravings. By modulating alcohol’s rewarding effects, naltrexone also reduces heavy alcohol consumption in patients who are drinking.^14,15,44
   • Disulfiram generally is not recommended for use in patients with clinically apparent hepatic insufficiency, such as decompensated cirrhosis or preexisting jaundice.

Although alcohol abstinence remains the treatment goal and a requirement for liver transplant, providers must recognize that some patients might not be able to maintain long-term sobriety. Therefore, harm reduc­tion models are important companions to abstinence-only models of AUD treatment.⁴⁵ The array of behavioral, pharmacologi­cal, and philosophical approaches to AUD treatment underlines the need for an indi­vidualized approach to relapse prevention.

Collaboration between medicine and psychiatry
When AUD and ALD are comorbid, psy­chiatrists might worry about making the patient’s medical condition worse by pre­scribing additional psychoactive medica­tions—particularly ones that are cleared by the liver. Remember that AUD confers a substantial mortality rate that is more than 3 times that of the general population, along with severe medical⁴⁶ and psycho­social³¹ effects. Although prescribers must remain vigilant for adverse drug effects, medications easily can be blamed for what might be the natural progression and symp­toms of AUD in patients with ALD.²⁶ This erroneous conclusion can lead to premature medication discontinuation and under-treatment of AUD.

In the end, keeping the patient sober and mentally well might be more beneficial than eliminating the burden of any medica­tion side effects. Collaborative medical and psychiatric management of ALD patients can ensure that clinicians properly weigh the risks, benefits, and duration of treat­ment unique to each patient.

Starting AUD treatment promptly after alcohol relapse is essential and entails a multidisciplinary effort between medicine and psychiatry, both in and out of the hos­pital. Because the relapsing, ill ALD patient most often will be admitted to a medical specialist, AUD might not receive enough attention during the medical admission. Psychiatrists can help in initiating AUD treatment in the acute medical setting, which has been shown to improve the out­patient course.⁶ For medically stable ALD patients admitted for inpatient psychiatric care or presenting a clinic, the mental health clinician should be aware of key laboratory and physical exam findings.

Bottom Line
Patients with alcoholic liver disease (ALD) require collaborative care from specialists in addiction, gastroenterology, and psychiatry. Psychiatrists have a role in identifying signs of ALD, prescribing medication to treat alcohol use disorder, and encouraging abstinence. There is some evidence supporting specific medications for varying severity of disease and different phases of recovery. Pharmacotherapy decisions should be made case by case.

Related Resources
• Khan A, Tansel A, White DL, et al. Efficacy of psychosocial interventions in inducing and maintaining alcohol abstinence in patients with chronic liver disease: a systematic review [published online August 6, 2015]. Clin Gastroenterol Hepatol. doi: 10.1016/j.cgh.2015.07.047.
• Vuittonet CL, Halse M, Leggio L, et al. Pharmacotherapy for alcoholic patients with alcoholic liver disease. Am J Health Syst Pharm. 2014;71(15):1265-1276.

Drug Brand Names
Acamprosate • Campral                       
Baclofen • Lioresal                              
Disulfiram • Antabuse                          
Gabapentin • Neurontin                       
Naltrexone • ReVia, Vivitrol
Pentoxifylline • Trental
Prednisolone • Prelone
Rifaximin • Xifaxan
Topiramate • Topamax

Disclosures
Dr. Winder and Dr. Mellinger report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products. Dr. Fontana receives research funding from Bristol Myers Squibb, Gilead, and Janssen and consults for the Chronic Liver Disease Foundation.

Nightmares are a common feature of posttraumatic stress disorder (PTSD) that could lead to fatigue, impaired concentration, and poor work performance. The α-1 antagonist prazosin decreases noradrenergic hyperactivity and reduces nightmares; however, it can cause adverse effects, be contraindicated, or pro­vide no benefit to some patients. Consider these alternative medications to reduce nightmares in PTSD.

Alpha-2 agonists
Clonidine and guanfacine are α-2 ago­nists, used to treat attention-deficit/hyper­activity disorder and high blood pressure, that decrease noradrenergic activity, and either medication might be preferable to prazosin because they are more likely to cause sedation. A review and a case series showed that many patients—some with comorbid traumatic brain injury—reported fewer nightmares after taking 0.2 to 0.6 mg of clonidine.^1,2 Guanfacine might be more beneficial because it has a longer half-life; 2 mg of guanfacine eliminated nightmares in 1 patient.³ However, in a double-blind placebo-controlled study and an extension study, guanfacine did not reduce night­mares or other PTSD symptoms.^4,5

Initiate 0.1 mg of clonidine at bedtime, and titrate to efficacy or to 0.6 mg. Similarly, initiate guanfacine at 1 mg, and titrate to efficacy or to 4 mg. Monitor for hypoten­sion, excess sedation, dry mouth, and rebound hypertension.

Cyproheptadine
Used to treat serotonin syndrome, cypro­heptadine’s antagonism of serotonin 2A receptors has varying efficacy for reducing nightmares. Some patients have reported a decrease in nightmares at dosages rang­ing from 4 to 24 mg.^1,6 Other studies found no reduction in nightmares or diminished quality of sleep.^1,7

Initiate cyproheptadine at 4 mg/d, titrate every 2 or 3 days, and monitor for sedation, confusion, or reduced efficacy of concurrent serotonergic medications. Cyproheptadine might be preferable for its sedating effect and potential to reduce sexual adverse effects from serotonergic medications.

Topiramate
Topiramate is approved for treatment of epilepsy and migraine headache. At 75 to 100 mg/d in a clinical trial, topira­mate partially or completely suppressed nightmares.⁸ Start with 25 mg/d, titrate to efficacy, and monitor for anorexia, paresthesias, and cognitive impairment. Topiramate might be better than prazosin for patients without renal impairment who want sedation, weight loss, or reduced irritability.

Gabapentin
Gabapentin is approved to treat seizures and postherpetic neuralgia and also is used to treat neuropathic pain. When 300 to 3,600 mg/d (mean dosage, 1,300 mg/d) of gabapentin was added to medication regi­mens, most patients reported decreased fre­quency or intensity of nightmares.⁹ Monitor patients for sedation, dizziness, mood changes, and weight gain. Gabapentin might be an option for patients without renal impairment who have comorbid pain, insomnia, or anxiety.

Are these reasonable alternatives?
Despite small sample sizes in published studies and few randomized trials, cloni­dine, guanfacine, cyproheptadine, topi­ramate, and gabapentin are reasonable alternatives to prazosin for reducing night­mares in patients with PTSD.

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

Nightmares are a common feature of posttraumatic stress disorder (PTSD) that could lead to fatigue, impaired concentration, and poor work performance. The α-1 antagonist prazosin decreases noradrenergic hyperactivity and reduces nightmares; however, it can cause adverse effects, be contraindicated, or pro­vide no benefit to some patients. Consider these alternative medications to reduce nightmares in PTSD.

Alpha-2 agonists
Clonidine and guanfacine are α-2 ago­nists, used to treat attention-deficit/hyper­activity disorder and high blood pressure, that decrease noradrenergic activity, and either medication might be preferable to prazosin because they are more likely to cause sedation. A review and a case series showed that many patients—some with comorbid traumatic brain injury—reported fewer nightmares after taking 0.2 to 0.6 mg of clonidine.^1,2 Guanfacine might be more beneficial because it has a longer half-life; 2 mg of guanfacine eliminated nightmares in 1 patient.³ However, in a double-blind placebo-controlled study and an extension study, guanfacine did not reduce night­mares or other PTSD symptoms.^4,5

Initiate 0.1 mg of clonidine at bedtime, and titrate to efficacy or to 0.6 mg. Similarly, initiate guanfacine at 1 mg, and titrate to efficacy or to 4 mg. Monitor for hypoten­sion, excess sedation, dry mouth, and rebound hypertension.

Cyproheptadine
Used to treat serotonin syndrome, cypro­heptadine’s antagonism of serotonin 2A receptors has varying efficacy for reducing nightmares. Some patients have reported a decrease in nightmares at dosages rang­ing from 4 to 24 mg.^1,6 Other studies found no reduction in nightmares or diminished quality of sleep.^1,7

Initiate cyproheptadine at 4 mg/d, titrate every 2 or 3 days, and monitor for sedation, confusion, or reduced efficacy of concurrent serotonergic medications. Cyproheptadine might be preferable for its sedating effect and potential to reduce sexual adverse effects from serotonergic medications.

Topiramate
Topiramate is approved for treatment of epilepsy and migraine headache. At 75 to 100 mg/d in a clinical trial, topira­mate partially or completely suppressed nightmares.⁸ Start with 25 mg/d, titrate to efficacy, and monitor for anorexia, paresthesias, and cognitive impairment. Topiramate might be better than prazosin for patients without renal impairment who want sedation, weight loss, or reduced irritability.

Gabapentin
Gabapentin is approved to treat seizures and postherpetic neuralgia and also is used to treat neuropathic pain. When 300 to 3,600 mg/d (mean dosage, 1,300 mg/d) of gabapentin was added to medication regi­mens, most patients reported decreased fre­quency or intensity of nightmares.⁹ Monitor patients for sedation, dizziness, mood changes, and weight gain. Gabapentin might be an option for patients without renal impairment who have comorbid pain, insomnia, or anxiety.

Are these reasonable alternatives?
Despite small sample sizes in published studies and few randomized trials, cloni­dine, guanfacine, cyproheptadine, topi­ramate, and gabapentin are reasonable alternatives to prazosin for reducing night­mares in patients with PTSD.

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

Nightmares are a common feature of posttraumatic stress disorder (PTSD) that could lead to fatigue, impaired concentration, and poor work performance. The α-1 antagonist prazosin decreases noradrenergic hyperactivity and reduces nightmares; however, it can cause adverse effects, be contraindicated, or pro­vide no benefit to some patients. Consider these alternative medications to reduce nightmares in PTSD.

Alpha-2 agonists
Clonidine and guanfacine are α-2 ago­nists, used to treat attention-deficit/hyper­activity disorder and high blood pressure, that decrease noradrenergic activity, and either medication might be preferable to prazosin because they are more likely to cause sedation. A review and a case series showed that many patients—some with comorbid traumatic brain injury—reported fewer nightmares after taking 0.2 to 0.6 mg of clonidine.^1,2 Guanfacine might be more beneficial because it has a longer half-life; 2 mg of guanfacine eliminated nightmares in 1 patient.³ However, in a double-blind placebo-controlled study and an extension study, guanfacine did not reduce night­mares or other PTSD symptoms.^4,5

Initiate 0.1 mg of clonidine at bedtime, and titrate to efficacy or to 0.6 mg. Similarly, initiate guanfacine at 1 mg, and titrate to efficacy or to 4 mg. Monitor for hypoten­sion, excess sedation, dry mouth, and rebound hypertension.

Cyproheptadine
Used to treat serotonin syndrome, cypro­heptadine’s antagonism of serotonin 2A receptors has varying efficacy for reducing nightmares. Some patients have reported a decrease in nightmares at dosages rang­ing from 4 to 24 mg.^1,6 Other studies found no reduction in nightmares or diminished quality of sleep.^1,7

Initiate cyproheptadine at 4 mg/d, titrate every 2 or 3 days, and monitor for sedation, confusion, or reduced efficacy of concurrent serotonergic medications. Cyproheptadine might be preferable for its sedating effect and potential to reduce sexual adverse effects from serotonergic medications.

Topiramate
Topiramate is approved for treatment of epilepsy and migraine headache. At 75 to 100 mg/d in a clinical trial, topira­mate partially or completely suppressed nightmares.⁸ Start with 25 mg/d, titrate to efficacy, and monitor for anorexia, paresthesias, and cognitive impairment. Topiramate might be better than prazosin for patients without renal impairment who want sedation, weight loss, or reduced irritability.

Gabapentin
Gabapentin is approved to treat seizures and postherpetic neuralgia and also is used to treat neuropathic pain. When 300 to 3,600 mg/d (mean dosage, 1,300 mg/d) of gabapentin was added to medication regi­mens, most patients reported decreased fre­quency or intensity of nightmares.⁹ Monitor patients for sedation, dizziness, mood changes, and weight gain. Gabapentin might be an option for patients without renal impairment who have comorbid pain, insomnia, or anxiety.

Are these reasonable alternatives?
Despite small sample sizes in published studies and few randomized trials, cloni­dine, guanfacine, cyproheptadine, topi­ramate, and gabapentin are reasonable alternatives to prazosin for reducing night­mares in patients with PTSD.

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

Designer drugs are rapidly making inroads with young people, primar­ily because of easier access, lower overall cost, and nebulous legality. These drugs are made as variants of illicit drugs or new formulations and sold as “research chemicals” and labeled as “not for human consumption,” which allows them to fall outside existing laws. The ingredients typi­cally are not detected in a urine drug screen.

Notoriously addictive, these designer drugs, such as bath salts, are known to incorporate synthetic cathinones—namely, methylone, mephedrone or methylenedioxypyrovalerone (MDPV). The stimu­lant, amphetamine-like effects of bath salts make the drug attractive to adolescents with attention-deficit/hyperactivity disorder (ADHD).

Why do teens gravitate toward bath salts?
Adolescents with undiagnosed ADHD might self-medicate with drugs that are suited for addressing restlessness, intra­psychic turmoil, and other symptoms of ADHD. In 2 case studies, using the self-medication hypothesis, people with ADHD were more likely to seek cocaine by means of “self-selection.”¹ These drug-seeking behaviors often led to cocaine dependence, even when other substances, such as alco­hol or Cannabis, were available.

Methylphenidate and other ADHD phar­macotherapies influence the nucleus accum­bens in a manner similar to that of cocaine. These findings suggest that adolescents with ADHD and cocaine dependence might respond to therapeutic interventions that substitute cocaine with psychostimulants.¹

Bath salts fall within the same spectrum of psychostimulant agents as methylpheni­date and cocaine. MDPV approximates the effect of methylphenidate at low doses, and cocaine at higher doses. It often is marketed under the name “Ivory Wave” and could be confused with cocaine. Self-administration of MDPV can induce psychoactive effects that help alleviate ADHD symptoms; adolescents might continue to experience enhanced concentration and overall per­formance.² Also, because of the low cost of “legal” bath salts, they are an appealing alternative to cocaine for self-medication.

Managing the sequelae of bath salt intoxication
Bath salts may produce sympathomimetic effects greater than cocaine, which require a proactive approach to symptom manage­ment. A medley of unknown ingredients in bath salt preparations makes it difficult for clinicians to gauge the pharmacological impact on individual patients; therefore, therapeutic interventions are on a case-by-case basis. However, emergencies con­cerning amphetamines and amphetamine analogues and derivatives often have simi­lar presentations.

Cardiovascular effects. MDPV-specific urine and blood tests conducted on patients admitted to the emergency room showed a 10-fold increase in overall dopamine levels compared with those who took cocaine. As a sympathomimetic, high doses of dopamine are responsible for raising blood pressure and could lead to the development of pro­nounced cardiovascular effects.^3,4

Agitation. Clinicians generally are advised to treat agitation before providing a more comprehensive assessment of symptoms. Endotracheal intubation often is a required for adequate control of agitation. Bath salt-induced agitation often is treated with IV benzodiazepines.^4,5 Monitor patients for excessive sedation or new-onset “paradoxi­cal agitation” as a function of ongoing benzo-diazepine therapy. Clinicians also may choose to co-administer an antipsychotic with benzodiazepines, although the practice is not uni­versally encouraged for agitation control.

Mephedrone produces a delirious state in conjunction with psychotic symptoms. Antipsychotic therapy has been suggested for addressing ongoing agitation.⁶ 

Tachycardia. Symptomatic treatment of tachycardia involves beta blockers, such as labetalol. Nitroglycerine has evidence of effi­cacy for chest pain associated with cocaine intoxication; however, it is unclear whether it is effective for similar drugs of abuse.⁴

Multi-organ collapse caused by MDPV necessitates aggressive intervention, includ­ing prompt dialysis. Carefully evaluate the patient for the presence of organ-specific insults and initiate supportive measures accordingly. Pronounced agitation with hyperthermia might portend severely com­promised renal, hepatic, and/or cardiac function in MDPV users.⁷ Those who present with MDPV intoxication and concomitant renal injury seem to benefit from hemodi­alysis.⁸ Repeat intoxication events may yield a presentation of acute renal injury replete with metabolic derangements, including metabolic acidosis, hyperuricemia, and rhab­domyolysis.⁹ Thorough patient assessments and interventions are useful in determining long-term outcomes, including issues per­taining to mortality.

Confronting an epidemic
Adolescents are quickly adopting designer drugs as a readily accessible form of recre­ational “legal highs.”¹⁰ Public awareness and educational initiatives can bring to light the dangers of these substances that exert pow­erful and, sometimes, unpredictable psycho­active effects on the user.

Self-mutilation and suicidal ideation also have been documented among those who ingested bath salts. These reports appear to be escalating across Europe and the United States. On a national level, U.S. poison cen­ters have reported an almost 20-fold increase in calls regarding bath salts between 2010 and 2011.⁵ It is of utmost importance for clini­cians and emergency personnel to familiar­ize themselves with the sympathomimetic toxidrome and management for bath salt consumption.

Designer drugs are rapidly making inroads with young people, primar­ily because of easier access, lower overall cost, and nebulous legality. These drugs are made as variants of illicit drugs or new formulations and sold as “research chemicals” and labeled as “not for human consumption,” which allows them to fall outside existing laws. The ingredients typi­cally are not detected in a urine drug screen.

Notoriously addictive, these designer drugs, such as bath salts, are known to incorporate synthetic cathinones—namely, methylone, mephedrone or methylenedioxypyrovalerone (MDPV). The stimu­lant, amphetamine-like effects of bath salts make the drug attractive to adolescents with attention-deficit/hyperactivity disorder (ADHD).

Why do teens gravitate toward bath salts?
Adolescents with undiagnosed ADHD might self-medicate with drugs that are suited for addressing restlessness, intra­psychic turmoil, and other symptoms of ADHD. In 2 case studies, using the self-medication hypothesis, people with ADHD were more likely to seek cocaine by means of “self-selection.”¹ These drug-seeking behaviors often led to cocaine dependence, even when other substances, such as alco­hol or Cannabis, were available.

Methylphenidate and other ADHD phar­macotherapies influence the nucleus accum­bens in a manner similar to that of cocaine. These findings suggest that adolescents with ADHD and cocaine dependence might respond to therapeutic interventions that substitute cocaine with psychostimulants.¹

Bath salts fall within the same spectrum of psychostimulant agents as methylpheni­date and cocaine. MDPV approximates the effect of methylphenidate at low doses, and cocaine at higher doses. It often is marketed under the name “Ivory Wave” and could be confused with cocaine. Self-administration of MDPV can induce psychoactive effects that help alleviate ADHD symptoms; adolescents might continue to experience enhanced concentration and overall per­formance.² Also, because of the low cost of “legal” bath salts, they are an appealing alternative to cocaine for self-medication.

Managing the sequelae of bath salt intoxication
Bath salts may produce sympathomimetic effects greater than cocaine, which require a proactive approach to symptom manage­ment. A medley of unknown ingredients in bath salt preparations makes it difficult for clinicians to gauge the pharmacological impact on individual patients; therefore, therapeutic interventions are on a case-by-case basis. However, emergencies con­cerning amphetamines and amphetamine analogues and derivatives often have simi­lar presentations.

Cardiovascular effects. MDPV-specific urine and blood tests conducted on patients admitted to the emergency room showed a 10-fold increase in overall dopamine levels compared with those who took cocaine. As a sympathomimetic, high doses of dopamine are responsible for raising blood pressure and could lead to the development of pro­nounced cardiovascular effects.^3,4

Agitation. Clinicians generally are advised to treat agitation before providing a more comprehensive assessment of symptoms. Endotracheal intubation often is a required for adequate control of agitation. Bath salt-induced agitation often is treated with IV benzodiazepines.^4,5 Monitor patients for excessive sedation or new-onset “paradoxi­cal agitation” as a function of ongoing benzo-diazepine therapy. Clinicians also may choose to co-administer an antipsychotic with benzodiazepines, although the practice is not uni­versally encouraged for agitation control.

Mephedrone produces a delirious state in conjunction with psychotic symptoms. Antipsychotic therapy has been suggested for addressing ongoing agitation.⁶ 

Tachycardia. Symptomatic treatment of tachycardia involves beta blockers, such as labetalol. Nitroglycerine has evidence of effi­cacy for chest pain associated with cocaine intoxication; however, it is unclear whether it is effective for similar drugs of abuse.⁴

Multi-organ collapse caused by MDPV necessitates aggressive intervention, includ­ing prompt dialysis. Carefully evaluate the patient for the presence of organ-specific insults and initiate supportive measures accordingly. Pronounced agitation with hyperthermia might portend severely com­promised renal, hepatic, and/or cardiac function in MDPV users.⁷ Those who present with MDPV intoxication and concomitant renal injury seem to benefit from hemodi­alysis.⁸ Repeat intoxication events may yield a presentation of acute renal injury replete with metabolic derangements, including metabolic acidosis, hyperuricemia, and rhab­domyolysis.⁹ Thorough patient assessments and interventions are useful in determining long-term outcomes, including issues per­taining to mortality.

Confronting an epidemic
Adolescents are quickly adopting designer drugs as a readily accessible form of recre­ational “legal highs.”¹⁰ Public awareness and educational initiatives can bring to light the dangers of these substances that exert pow­erful and, sometimes, unpredictable psycho­active effects on the user.

Self-mutilation and suicidal ideation also have been documented among those who ingested bath salts. These reports appear to be escalating across Europe and the United States. On a national level, U.S. poison cen­ters have reported an almost 20-fold increase in calls regarding bath salts between 2010 and 2011.⁵ It is of utmost importance for clini­cians and emergency personnel to familiar­ize themselves with the sympathomimetic toxidrome and management for bath salt consumption.

Designer drugs are rapidly making inroads with young people, primar­ily because of easier access, lower overall cost, and nebulous legality. These drugs are made as variants of illicit drugs or new formulations and sold as “research chemicals” and labeled as “not for human consumption,” which allows them to fall outside existing laws. The ingredients typi­cally are not detected in a urine drug screen.

Notoriously addictive, these designer drugs, such as bath salts, are known to incorporate synthetic cathinones—namely, methylone, mephedrone or methylenedioxypyrovalerone (MDPV). The stimu­lant, amphetamine-like effects of bath salts make the drug attractive to adolescents with attention-deficit/hyperactivity disorder (ADHD).

Why do teens gravitate toward bath salts?
Adolescents with undiagnosed ADHD might self-medicate with drugs that are suited for addressing restlessness, intra­psychic turmoil, and other symptoms of ADHD. In 2 case studies, using the self-medication hypothesis, people with ADHD were more likely to seek cocaine by means of “self-selection.”¹ These drug-seeking behaviors often led to cocaine dependence, even when other substances, such as alco­hol or Cannabis, were available.

Methylphenidate and other ADHD phar­macotherapies influence the nucleus accum­bens in a manner similar to that of cocaine. These findings suggest that adolescents with ADHD and cocaine dependence might respond to therapeutic interventions that substitute cocaine with psychostimulants.¹

Bath salts fall within the same spectrum of psychostimulant agents as methylpheni­date and cocaine. MDPV approximates the effect of methylphenidate at low doses, and cocaine at higher doses. It often is marketed under the name “Ivory Wave” and could be confused with cocaine. Self-administration of MDPV can induce psychoactive effects that help alleviate ADHD symptoms; adolescents might continue to experience enhanced concentration and overall per­formance.² Also, because of the low cost of “legal” bath salts, they are an appealing alternative to cocaine for self-medication.

Managing the sequelae of bath salt intoxication
Bath salts may produce sympathomimetic effects greater than cocaine, which require a proactive approach to symptom manage­ment. A medley of unknown ingredients in bath salt preparations makes it difficult for clinicians to gauge the pharmacological impact on individual patients; therefore, therapeutic interventions are on a case-by-case basis. However, emergencies con­cerning amphetamines and amphetamine analogues and derivatives often have simi­lar presentations.

Cardiovascular effects. MDPV-specific urine and blood tests conducted on patients admitted to the emergency room showed a 10-fold increase in overall dopamine levels compared with those who took cocaine. As a sympathomimetic, high doses of dopamine are responsible for raising blood pressure and could lead to the development of pro­nounced cardiovascular effects.^3,4

Agitation. Clinicians generally are advised to treat agitation before providing a more comprehensive assessment of symptoms. Endotracheal intubation often is a required for adequate control of agitation. Bath salt-induced agitation often is treated with IV benzodiazepines.^4,5 Monitor patients for excessive sedation or new-onset “paradoxi­cal agitation” as a function of ongoing benzo-diazepine therapy. Clinicians also may choose to co-administer an antipsychotic with benzodiazepines, although the practice is not uni­versally encouraged for agitation control.

Mephedrone produces a delirious state in conjunction with psychotic symptoms. Antipsychotic therapy has been suggested for addressing ongoing agitation.⁶ 

Tachycardia. Symptomatic treatment of tachycardia involves beta blockers, such as labetalol. Nitroglycerine has evidence of effi­cacy for chest pain associated with cocaine intoxication; however, it is unclear whether it is effective for similar drugs of abuse.⁴

Multi-organ collapse caused by MDPV necessitates aggressive intervention, includ­ing prompt dialysis. Carefully evaluate the patient for the presence of organ-specific insults and initiate supportive measures accordingly. Pronounced agitation with hyperthermia might portend severely com­promised renal, hepatic, and/or cardiac function in MDPV users.⁷ Those who present with MDPV intoxication and concomitant renal injury seem to benefit from hemodi­alysis.⁸ Repeat intoxication events may yield a presentation of acute renal injury replete with metabolic derangements, including metabolic acidosis, hyperuricemia, and rhab­domyolysis.⁹ Thorough patient assessments and interventions are useful in determining long-term outcomes, including issues per­taining to mortality.

Confronting an epidemic
Adolescents are quickly adopting designer drugs as a readily accessible form of recre­ational “legal highs.”¹⁰ Public awareness and educational initiatives can bring to light the dangers of these substances that exert pow­erful and, sometimes, unpredictable psycho­active effects on the user.

Self-mutilation and suicidal ideation also have been documented among those who ingested bath salts. These reports appear to be escalating across Europe and the United States. On a national level, U.S. poison cen­ters have reported an almost 20-fold increase in calls regarding bath salts between 2010 and 2011.⁵ It is of utmost importance for clini­cians and emergency personnel to familiar­ize themselves with the sympathomimetic toxidrome and management for bath salt consumption.

Few methods can build your practice and reputation as well as blogging— nor can they give you as much grief. Your opinions can become known to a wide audience; you might influence public think­ing or behavior; and you might become associated with a particular expertise at almost no financial cost. Yet, having regular deadlines to produce creative content can be stressful, and the time required to do it well has its own cost.

What is it?
“Blog” is the collapsed expression of “Web log.” Blogging is posting your thoughts on a Web site for colleagues or consumers, or both, to read. Typically, a blog is written as if you were writing a newspaper column; word count varies, from 250 to 1,000 words. Alternative formats are auditory (podcasts) or visual (vlog) but those media require greater technical proficiency and take more time to produce.

Whether you decide to write or record your blog entry, be guided by this advice:
   • The subject matter can be anything you choose, but will be easiest to write when what you write about is based on your expertise.
   • The format can be stream of consciousness,essay, or bulleted lists or slides; the latter is the most common and often follows a how-to or list format (eg, “Top [number] strategies to XYZ” or “[Number] of things you didn’t know about ABC”).
   • End the blog with a cliffhanger or a call-to-action statement that invites readers to comment (especially if you then comment on their comments), to help drive interest.
   • Generate material at a consistent interval (eg, once a week or twice a month), so your readers can look forward to your soliloquies on a regular basis.

Your professional Web site can serve as a venue for your blog. Using a WordPress^a-based site, for example, offers a user-friendly way to compose your dispatch, add format­ting (headers, bullets, color, images, etc.) as you see fit, and then publish it. It requires little technical expertise and adds no extra expense to your Web site. Alternatively, you might wish to contact editors at magazines or blog aggregators with story ideas, and let them handle the logistics if your content is appealing to them.

^aWordPress is a Web site creation and management tool.

Spreading the word
There is much you can do to publicize your blog.
   • Take advantage of social media. Build up your contacts on LinkedIn and follow other bloggers and large news sites on Twitter. Often, recipients will respond in-kind. Then, for each new piece, post or tweet it in these accounts.
   • Offer an e-mail subscription so that readers can easily follow you (by means of a free WordPress plug-in, for example).
   • Be found in search engines, such as Google, by writing high-quality, original content. Don’t force certain keywords into your article in the hopes that search engines find them—doing so tends to make writing more robotic and can lower your page rank.

Successful strategies
Regularly setting time aside so that the process is enjoyable and not onerously deadline-driven lends satisfaction to the experience and comes through in the quality of the composition. To save time, consider dictating your thoughts to your computer or phone, then outsource transcription.

Don’t overlook the bounty of material in your day-to-day life: stories from sessions; discoveries from your own reading or the latest news; and lectures you give. All of these can serve as inspiration and mate­rial for posts. Jot down these moments in a notebook as soon as they come up, or else the memory will likely slip away.

Just as with other forms of social media, be mindful of appropriate boundaries. Do not disclose identifying patient infor­mation; even revealing facets of your life might not be appropriate for current or future patients to have access to. On the other hand, it might be therapeutic for them to know select personal information, such as how you have handled past dilem­mas, that reveals you are a real person (a “whole object” in psychoanalytic terms), and that models meaningful thoughts or deeds.

You’ll find your voice, in time
Getting started with blogging often is the toughest part. Finding the right for­mat, material, and routine will take time. Eventually, you will find your blogging voice, and will value the unique opportu­nity to brand your practice and yourself, provide valuable content to your readers, and find an outlet for artistic expression.

Disclosure
Dr. Braslow is the founder of Luminello.com.

Few methods can build your practice and reputation as well as blogging— nor can they give you as much grief. Your opinions can become known to a wide audience; you might influence public think­ing or behavior; and you might become associated with a particular expertise at almost no financial cost. Yet, having regular deadlines to produce creative content can be stressful, and the time required to do it well has its own cost.

What is it?
“Blog” is the collapsed expression of “Web log.” Blogging is posting your thoughts on a Web site for colleagues or consumers, or both, to read. Typically, a blog is written as if you were writing a newspaper column; word count varies, from 250 to 1,000 words. Alternative formats are auditory (podcasts) or visual (vlog) but those media require greater technical proficiency and take more time to produce.

Whether you decide to write or record your blog entry, be guided by this advice:
   • The subject matter can be anything you choose, but will be easiest to write when what you write about is based on your expertise.
   • The format can be stream of consciousness,essay, or bulleted lists or slides; the latter is the most common and often follows a how-to or list format (eg, “Top [number] strategies to XYZ” or “[Number] of things you didn’t know about ABC”).
   • End the blog with a cliffhanger or a call-to-action statement that invites readers to comment (especially if you then comment on their comments), to help drive interest.
   • Generate material at a consistent interval (eg, once a week or twice a month), so your readers can look forward to your soliloquies on a regular basis.

Your professional Web site can serve as a venue for your blog. Using a WordPress^a-based site, for example, offers a user-friendly way to compose your dispatch, add format­ting (headers, bullets, color, images, etc.) as you see fit, and then publish it. It requires little technical expertise and adds no extra expense to your Web site. Alternatively, you might wish to contact editors at magazines or blog aggregators with story ideas, and let them handle the logistics if your content is appealing to them.

^aWordPress is a Web site creation and management tool.

Spreading the word
There is much you can do to publicize your blog.
   • Take advantage of social media. Build up your contacts on LinkedIn and follow other bloggers and large news sites on Twitter. Often, recipients will respond in-kind. Then, for each new piece, post or tweet it in these accounts.
   • Offer an e-mail subscription so that readers can easily follow you (by means of a free WordPress plug-in, for example).
   • Be found in search engines, such as Google, by writing high-quality, original content. Don’t force certain keywords into your article in the hopes that search engines find them—doing so tends to make writing more robotic and can lower your page rank.

Successful strategies
Regularly setting time aside so that the process is enjoyable and not onerously deadline-driven lends satisfaction to the experience and comes through in the quality of the composition. To save time, consider dictating your thoughts to your computer or phone, then outsource transcription.

Don’t overlook the bounty of material in your day-to-day life: stories from sessions; discoveries from your own reading or the latest news; and lectures you give. All of these can serve as inspiration and mate­rial for posts. Jot down these moments in a notebook as soon as they come up, or else the memory will likely slip away.

Just as with other forms of social media, be mindful of appropriate boundaries. Do not disclose identifying patient infor­mation; even revealing facets of your life might not be appropriate for current or future patients to have access to. On the other hand, it might be therapeutic for them to know select personal information, such as how you have handled past dilem­mas, that reveals you are a real person (a “whole object” in psychoanalytic terms), and that models meaningful thoughts or deeds.

You’ll find your voice, in time
Getting started with blogging often is the toughest part. Finding the right for­mat, material, and routine will take time. Eventually, you will find your blogging voice, and will value the unique opportu­nity to brand your practice and yourself, provide valuable content to your readers, and find an outlet for artistic expression.

Disclosure
Dr. Braslow is the founder of Luminello.com.

Few methods can build your practice and reputation as well as blogging— nor can they give you as much grief. Your opinions can become known to a wide audience; you might influence public think­ing or behavior; and you might become associated with a particular expertise at almost no financial cost. Yet, having regular deadlines to produce creative content can be stressful, and the time required to do it well has its own cost.

What is it?
“Blog” is the collapsed expression of “Web log.” Blogging is posting your thoughts on a Web site for colleagues or consumers, or both, to read. Typically, a blog is written as if you were writing a newspaper column; word count varies, from 250 to 1,000 words. Alternative formats are auditory (podcasts) or visual (vlog) but those media require greater technical proficiency and take more time to produce.

Whether you decide to write or record your blog entry, be guided by this advice:
   • The subject matter can be anything you choose, but will be easiest to write when what you write about is based on your expertise.
   • The format can be stream of consciousness,essay, or bulleted lists or slides; the latter is the most common and often follows a how-to or list format (eg, “Top [number] strategies to XYZ” or “[Number] of things you didn’t know about ABC”).
   • End the blog with a cliffhanger or a call-to-action statement that invites readers to comment (especially if you then comment on their comments), to help drive interest.
   • Generate material at a consistent interval (eg, once a week or twice a month), so your readers can look forward to your soliloquies on a regular basis.

Your professional Web site can serve as a venue for your blog. Using a WordPress^a-based site, for example, offers a user-friendly way to compose your dispatch, add format­ting (headers, bullets, color, images, etc.) as you see fit, and then publish it. It requires little technical expertise and adds no extra expense to your Web site. Alternatively, you might wish to contact editors at magazines or blog aggregators with story ideas, and let them handle the logistics if your content is appealing to them.

^aWordPress is a Web site creation and management tool.

Spreading the word
There is much you can do to publicize your blog.
   • Take advantage of social media. Build up your contacts on LinkedIn and follow other bloggers and large news sites on Twitter. Often, recipients will respond in-kind. Then, for each new piece, post or tweet it in these accounts.
   • Offer an e-mail subscription so that readers can easily follow you (by means of a free WordPress plug-in, for example).
   • Be found in search engines, such as Google, by writing high-quality, original content. Don’t force certain keywords into your article in the hopes that search engines find them—doing so tends to make writing more robotic and can lower your page rank.

Successful strategies
Regularly setting time aside so that the process is enjoyable and not onerously deadline-driven lends satisfaction to the experience and comes through in the quality of the composition. To save time, consider dictating your thoughts to your computer or phone, then outsource transcription.

Don’t overlook the bounty of material in your day-to-day life: stories from sessions; discoveries from your own reading or the latest news; and lectures you give. All of these can serve as inspiration and mate­rial for posts. Jot down these moments in a notebook as soon as they come up, or else the memory will likely slip away.

Just as with other forms of social media, be mindful of appropriate boundaries. Do not disclose identifying patient infor­mation; even revealing facets of your life might not be appropriate for current or future patients to have access to. On the other hand, it might be therapeutic for them to know select personal information, such as how you have handled past dilem­mas, that reveals you are a real person (a “whole object” in psychoanalytic terms), and that models meaningful thoughts or deeds.

You’ll find your voice, in time
Getting started with blogging often is the toughest part. Finding the right for­mat, material, and routine will take time. Eventually, you will find your blogging voice, and will value the unique opportu­nity to brand your practice and yourself, provide valuable content to your readers, and find an outlet for artistic expression.

Disclosure
Dr. Braslow is the founder of Luminello.com.

When a patient who has a preexisting medical illness seeks prenatal care, the obstetrician asks herself (himself) 2 questions:
   • What impact will the illness have on the pregnancy?
   • What impact will the pregnancy have on the illness?

Depression is both a pregnancy-associated and pregnancy­-independent illness, which, in the setting of a pregnant woman who has a depressive disorder, makes these questions particu­larly difficult to answer. In such a case, coordination of care with a mental health provider is essential.

Awareness of the obstetrical complications associated with depression during pregnancy, as well as their implications for the future health of the mother–infant dyad, is important for the entire care team. This article reviews the associations and interconnectedness of depression with complications of preg­nancy, childbirth, and the neonatal period.

Diagnosis of depression during prenatal care
The American College of Obstetricians and Gynecologists (ACOG) states that evidence is insufficient to support a rec­ommendation for universal screening for depression among prenatal patients, although such screening should be considered.¹ There is considerable variability among obstetrical pro­viders regarding the practice of depression screening; tools to be used if such screening is done; and screening frequency through the pregnancy.

Discernment of depression is difficult. Many somatic symptoms of depression overlap with common prenatal complaints and, consequentially, can be overlooked. Among a sample of 700 pregnant women, for example, 56% complained of lack of energy; 19%, of insomnia; and 19%, of appe­tite changes.² Weight change, of course, is universal.

The 10-question self-rating Edinburgh Postnatal Depression Scale has been vali­dated for use during pregnancy and post­natally. This screening instrument can be helpful for differentiating purely physical complaints from mental distress due to depressive symptoms.^2,3

When an obstetrical provider suspects a depressive disorder, or one has been diagnosed, she (he) faces the problem of what to do with that information. Women of low socioeconomic status and victims of domestic violence are at increased risk of depression during pregnancy, but barri­ers to appropriate referral can seem nearly insurmountable because they lack insur­ance and social support.^4-9

In addition, within the setting of numer­ous tasks that need attending during the relatively short prenatal period, it is com­mon for women newly given a diagnosis of depression to fail to follow up on a refer­ral to a mental health provider.

Although most providers will “check in” with a depressed or at-risk patient at each prenatal visit about her mood, any effort at follow-up can be overshadowed by tangible physical concerns, such as pre­term contractions, fetal growth restriction, and coordination of routine testing that has been delayed because of scant prena­tal care. All these physical concerns and circumstances of care are associated with maternal depression, as we will discuss.

Preterm labor and birth
Preterm labor is defined as uterine contrac­tions that lead to cervical change before 37 weeks gestational age. Preterm labor increases the risk of preterm birth; pre­term labor precedes 50% of preterm births. Preterm birth is the leading cause of neona­tal mortality in the United States, and rates of morbidity and mortality increase as ges­tational age decreases.¹⁰ Common neonatal complications related to prematurity are shown in the Figure.¹¹

Women who suffer from depression have an increased risk of preterm labor and preterm birth, as many studies of treated and untreated depressed pregnant women have shown.^12-20 The causative mechanism is unknown; it has been proposed that the increase in maternal cortisol production asso­ciated with depression and distress triggers overproduction of placental cortisol releasing hormone, which is thought to be involved in initiation of parturition.^21,22 Depression also is associated with other risk factors for preterm birth, such as low socioeconomic status, sub­stance use, and smoking.

Intrauterine growth restriction
Women who have depression during preg­nancy have an increased risk of intrauterine growth restriction (IUGR), which leads to delivery of an infant who is small for ges­tational age (SGA) or of low birth weight (LBW) (weighing <2,500 g at birth), or both.²³ Again, the basis of the association between depression and IUGR and SGA is unknown; it is theorized that increased levels of cortisol and catecholamines associated with maternal distress might, by increasing blood pressure and inducing vasoconstriction, cause placen­tal hypoperfusion.^24,25

It also is possible that the association of depression with other risk factors for IUGR, such as smoking, substance use, obesity, and poor prenatal care, puts the infants of depressed women at risk of growth restric­tion.²⁶ Several large-scale studies showed that the association between LBW and depres­sion is lost when smoking and substance use are accounted for; other studies, however, found a persistent association in untreated depressed women when smokers, substance users, and drinkers were excluded.^17,26,27

IUGR infants are at increased risk of iat­rogenic prematurity and stillbirth. Fetuses that weigh <10th percentile for their ges­tational age are delivered no later than 40 weeks; delivery can be indicated as early as 32 weeks, depending on the results of other antenatal tests. Women who have a growth-restricted infant have a higher risk of cesarean delivery because growth-restricted infants often have less reserve and poorer tolerance of labor.

Preeclampsia and eclampsia
Preeclampsia is defined as blood pressure >140/90 mm HG on at least 2 occasions, with proteinuria, that occurs later than the twentieth week of pregnancy in women who did not have hypertension or renal dysfunction at baseline. Preeclampsia is a progressive disease that can cause severe maternal morbidity, including renal failure, stroke, hepatic rupture, pulmonary edema, and heart failure.

Eclampsia refers to onset of seizures in the setting of preeclampsia. These 2 hyperten­sive disorders are the third leading world wide cause of maternal mortality.²⁸

Depressed women have an elevated risk of preeclampsia. The association between preeclampsia and depression might be caused by the presence of increased levels of inflammatory mediators^29,30; other comorbidities, such as increased body mass index, also might be involved, but the risk for preeclampsia in depressed women still is increased after controlling for obesity.³¹

The presence of preeclampsia is respon­sible for a high percentage of iatrogenic pre­term births, because the cure for the disorder is delivery—even at early or previable gesta­tional age. Complication rates for mother and infant are high.

The presence of preeclampsia is a sig­nificant risk factor for intrauterine fetal demise. Treating the mother after delivery involves administration of IV magnesium for 24 hours; often, the mother is separated from her infant for a day after birth.

Impact on prenatal care
Depression increases odds that women will have fewer prenatal visits.³² During pregnancy, women typically initiate pre­natal care during the first trimester, when pregnancy-dating ultrasonography and early screening tests for chromosomal abnormalities are performed. Prenatal vis­its occur monthly until the third trimes­ter, then every 2 weeks between 32 and 36 weeks’ gestation, increasing to weekly after 36 weeks’ gestation.

The increased number of visits in late pregnancy allows for early detection and treatment of hypertensive disorders; assesses fetal well-being; and decreases the risks of morbidity and mortality for mother and fetus.³³ Because women who suffer from depression are at increased risk of an array of adverse pregnancy outcomes, the impor­tance of regular and timely prenatal care cannot be understated.

In addition, the prenatal visit gives the obstetrician the opportunity to connect women with other specialists for manage­ment of any unmet medical needs. One study showed that, when women have adequate prenatal care (measured by the number of visits), the association between preterm birth and self-reported maternal depression was eliminated.³⁴

Substance use
Substance use and depression often co-exist.^35,36 Unlike screening for depression, screening for substance use is universal dur­ing prenatal care. Studies have shown that women who screen positive for depression are at higher risk of a number of comorbidi­ties, including substance use.^37,38 Conversely, women who use substances are more likely to screen positive for depression.

Evidence suggests that best practice might be to screen for depression in any woman who has a positive drug screen, if a provider is not routinely screening their general patient population.³⁹ Substance use in pregnancy is associated with a number of poor outcomes, including placental abrup­tion (cocaine use); dysmorphic facies and congenital anomalies (alcohol); and neonatal abstinence syndrome (heroin).

Antidepressants in pregnancy
A full discussion of the risks and ben­efits associated with pharmacotherapy for depression in pregnancy is beyond the scope of this article. Generally, antidepressant use is fraught with concerns over teratogenic­ity and adverse fetal outcomes. Although ACOG states that (1) pharmacotherapy for depression should be individualized and (2) most selective serotonin reuptake inhibi­tors (SSRIs) are not considered major terato­genic agents, many obstetricians and patients feel uncomfortable using these medications in pregnancy.⁴⁰ Often, pre-pregnancy antide­pressants are discontinued in the first trimes­ter; one large population-based study found that only 0.9% of women who had depres­sion filled their antidepressant prescription consistently throughout their pregnancy.⁴¹

It is unclear whether antidepressant use in pregnancy contributes to the risk of preterm birth seen in women who have depression. In a large population-based study, use of antidepressants in the second trimester was associated with preterm delivery but severe depression was not.¹⁸ A recent meta-analysis revealed an increased risk of preterm birth in women who used an antidepressant, com­pared with healthy women and untreated depressed women.⁴²

Research limits, unanswered questions. Regrettably, it is difficult to untangle risk factors for preterm birth among depressed women without randomized controlled studies that are not ethically feasible. It can­not be said with certainty whether antide­pressant pharmacotherapy is associated with a higher risk of preterm birth than depression alone.

Likewise, it is difficult to clarify the extent to which antidepressants contribute to infant growth restriction, if at all. Two recent meta-analyses concluded that exposure to antidepressants is associated with a statisti­cally significant risk of LBW.^42,43 However, increased severity of depressive symptoms generally is associated with exposure to anti­depressants during pregnancy, and a ran­domized controlled trial is, again, impossible to conduct for ethical reasons.

Whereas a plausible biological mecha­nism associating IUGR, SGA, and LBW with depression exists, the same cannot be said for antidepressants. In one study, exposure to maternal depression altered the expres­sion of certain placental genes but exposure to SSRIs did not cause further changes. This suggests that, on a cellular level, placental function might differ in depressed women.⁴⁴ Although antidepressants do cross the pla­centa, it remains to be seen whether fetal growth is impacted as a result. One study found decreased fetal head circumference in infants who had been exposed to antidepres­sants during pregnancy, but no increased risk for having a SGA or LWB infant.⁴⁵

Obstetrical management and mental health implications
Treated or not, women who suffer depres­sion are a high-risk group when it comes to preterm birth and a host of other pregnancy comorbidities. Women with serious compli­cations of pregnancy often are hospitalized for observation, and can undergo a pro­longed stay when close proximity to medical services or a surgical suite is required.

For example, hospitalization until deliv­ery is the standard of care for women who have preterm premature rupture of mem­branes or preeclampsia before 34 weeks’ gestation. Prolonged inpatient admis­sions and associated restriction of activity is profoundly deleterious on mood, with depression and anxiety significantly cor­related with length of stay.^46,47 Given the associations between depression and pre­term birth, it might be reasonable to con­sider screening antenatal inpatients at risk of preterm birth for depression on a regu­lar basis, so that treatment can be initiated if needed.

Depression during pregnancy is rela­tively common; an estimated 12.7% of pregnant women are affected at some time between conception and birth.⁴⁸ Not only does depression appear to have deleterious effects on pregnancy outcomes, it also plays a pivotal role in the qualitative experience of pregnancy for the mother.

Bottom Line
Awareness of obstetrical complications associated with depression in pregnancy is important for the entire care team, including the psychiatrist and obstetrician. Depression not only appears to have deleterious effects on pregnancy outcomes, it also plays a pivotal role in the qualitative experience of pregnancy for the mother. Antidepressant use generally is fraught with concerns over teratogenicity and adverse fetal outcomes.

Related Resources
• Freeman MP. Some SSRIs are better than others for pregnant women (audio interview). Current Psychiatry. 2014;13(7). http://www.currentpsychiatry.com/specialty-focus/practice-trends/article/some-ssris-are-better-thanothers-for-pregnant-women/e3adb4704e25492f3e15331fc1cc058d.html.
• Freeman MP, Joffe H, Cohen LS. Postpartum depression: Help patients find the right treatment. Current Psychiatry. 2012;11(11):14-16,19-21.

Disclosures
Dr. Habecker reports no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. Freeman is a member of the advisory board of JDS Therapeutics, Sunovion Pharmaceuticals, Inc., and Takeda Pharmaceutical Co. She receives research grant support from Takeda Pharmaceutical Co.

When a patient who has a preexisting medical illness seeks prenatal care, the obstetrician asks herself (himself) 2 questions:
   • What impact will the illness have on the pregnancy?
   • What impact will the pregnancy have on the illness?

Depression is both a pregnancy-associated and pregnancy­-independent illness, which, in the setting of a pregnant woman who has a depressive disorder, makes these questions particu­larly difficult to answer. In such a case, coordination of care with a mental health provider is essential.

Awareness of the obstetrical complications associated with depression during pregnancy, as well as their implications for the future health of the mother–infant dyad, is important for the entire care team. This article reviews the associations and interconnectedness of depression with complications of preg­nancy, childbirth, and the neonatal period.

Diagnosis of depression during prenatal care
The American College of Obstetricians and Gynecologists (ACOG) states that evidence is insufficient to support a rec­ommendation for universal screening for depression among prenatal patients, although such screening should be considered.¹ There is considerable variability among obstetrical pro­viders regarding the practice of depression screening; tools to be used if such screening is done; and screening frequency through the pregnancy.

Discernment of depression is difficult. Many somatic symptoms of depression overlap with common prenatal complaints and, consequentially, can be overlooked. Among a sample of 700 pregnant women, for example, 56% complained of lack of energy; 19%, of insomnia; and 19%, of appe­tite changes.² Weight change, of course, is universal.

The 10-question self-rating Edinburgh Postnatal Depression Scale has been vali­dated for use during pregnancy and post­natally. This screening instrument can be helpful for differentiating purely physical complaints from mental distress due to depressive symptoms.^2,3

When an obstetrical provider suspects a depressive disorder, or one has been diagnosed, she (he) faces the problem of what to do with that information. Women of low socioeconomic status and victims of domestic violence are at increased risk of depression during pregnancy, but barri­ers to appropriate referral can seem nearly insurmountable because they lack insur­ance and social support.^4-9

In addition, within the setting of numer­ous tasks that need attending during the relatively short prenatal period, it is com­mon for women newly given a diagnosis of depression to fail to follow up on a refer­ral to a mental health provider.

Although most providers will “check in” with a depressed or at-risk patient at each prenatal visit about her mood, any effort at follow-up can be overshadowed by tangible physical concerns, such as pre­term contractions, fetal growth restriction, and coordination of routine testing that has been delayed because of scant prena­tal care. All these physical concerns and circumstances of care are associated with maternal depression, as we will discuss.

Preterm labor and birth
Preterm labor is defined as uterine contrac­tions that lead to cervical change before 37 weeks gestational age. Preterm labor increases the risk of preterm birth; pre­term labor precedes 50% of preterm births. Preterm birth is the leading cause of neona­tal mortality in the United States, and rates of morbidity and mortality increase as ges­tational age decreases.¹⁰ Common neonatal complications related to prematurity are shown in the Figure.¹¹

Women who suffer from depression have an increased risk of preterm labor and preterm birth, as many studies of treated and untreated depressed pregnant women have shown.^12-20 The causative mechanism is unknown; it has been proposed that the increase in maternal cortisol production asso­ciated with depression and distress triggers overproduction of placental cortisol releasing hormone, which is thought to be involved in initiation of parturition.^21,22 Depression also is associated with other risk factors for preterm birth, such as low socioeconomic status, sub­stance use, and smoking.

Intrauterine growth restriction
Women who have depression during preg­nancy have an increased risk of intrauterine growth restriction (IUGR), which leads to delivery of an infant who is small for ges­tational age (SGA) or of low birth weight (LBW) (weighing <2,500 g at birth), or both.²³ Again, the basis of the association between depression and IUGR and SGA is unknown; it is theorized that increased levels of cortisol and catecholamines associated with maternal distress might, by increasing blood pressure and inducing vasoconstriction, cause placen­tal hypoperfusion.^24,25

It also is possible that the association of depression with other risk factors for IUGR, such as smoking, substance use, obesity, and poor prenatal care, puts the infants of depressed women at risk of growth restric­tion.²⁶ Several large-scale studies showed that the association between LBW and depres­sion is lost when smoking and substance use are accounted for; other studies, however, found a persistent association in untreated depressed women when smokers, substance users, and drinkers were excluded.^17,26,27

IUGR infants are at increased risk of iat­rogenic prematurity and stillbirth. Fetuses that weigh <10th percentile for their ges­tational age are delivered no later than 40 weeks; delivery can be indicated as early as 32 weeks, depending on the results of other antenatal tests. Women who have a growth-restricted infant have a higher risk of cesarean delivery because growth-restricted infants often have less reserve and poorer tolerance of labor.

Preeclampsia and eclampsia
Preeclampsia is defined as blood pressure >140/90 mm HG on at least 2 occasions, with proteinuria, that occurs later than the twentieth week of pregnancy in women who did not have hypertension or renal dysfunction at baseline. Preeclampsia is a progressive disease that can cause severe maternal morbidity, including renal failure, stroke, hepatic rupture, pulmonary edema, and heart failure.

Eclampsia refers to onset of seizures in the setting of preeclampsia. These 2 hyperten­sive disorders are the third leading world wide cause of maternal mortality.²⁸

Depressed women have an elevated risk of preeclampsia. The association between preeclampsia and depression might be caused by the presence of increased levels of inflammatory mediators^29,30; other comorbidities, such as increased body mass index, also might be involved, but the risk for preeclampsia in depressed women still is increased after controlling for obesity.³¹

The presence of preeclampsia is respon­sible for a high percentage of iatrogenic pre­term births, because the cure for the disorder is delivery—even at early or previable gesta­tional age. Complication rates for mother and infant are high.

The presence of preeclampsia is a sig­nificant risk factor for intrauterine fetal demise. Treating the mother after delivery involves administration of IV magnesium for 24 hours; often, the mother is separated from her infant for a day after birth.

Impact on prenatal care
Depression increases odds that women will have fewer prenatal visits.³² During pregnancy, women typically initiate pre­natal care during the first trimester, when pregnancy-dating ultrasonography and early screening tests for chromosomal abnormalities are performed. Prenatal vis­its occur monthly until the third trimes­ter, then every 2 weeks between 32 and 36 weeks’ gestation, increasing to weekly after 36 weeks’ gestation.

The increased number of visits in late pregnancy allows for early detection and treatment of hypertensive disorders; assesses fetal well-being; and decreases the risks of morbidity and mortality for mother and fetus.³³ Because women who suffer from depression are at increased risk of an array of adverse pregnancy outcomes, the impor­tance of regular and timely prenatal care cannot be understated.

In addition, the prenatal visit gives the obstetrician the opportunity to connect women with other specialists for manage­ment of any unmet medical needs. One study showed that, when women have adequate prenatal care (measured by the number of visits), the association between preterm birth and self-reported maternal depression was eliminated.³⁴

Substance use
Substance use and depression often co-exist.^35,36 Unlike screening for depression, screening for substance use is universal dur­ing prenatal care. Studies have shown that women who screen positive for depression are at higher risk of a number of comorbidi­ties, including substance use.^37,38 Conversely, women who use substances are more likely to screen positive for depression.

Evidence suggests that best practice might be to screen for depression in any woman who has a positive drug screen, if a provider is not routinely screening their general patient population.³⁹ Substance use in pregnancy is associated with a number of poor outcomes, including placental abrup­tion (cocaine use); dysmorphic facies and congenital anomalies (alcohol); and neonatal abstinence syndrome (heroin).

Antidepressants in pregnancy
A full discussion of the risks and ben­efits associated with pharmacotherapy for depression in pregnancy is beyond the scope of this article. Generally, antidepressant use is fraught with concerns over teratogenic­ity and adverse fetal outcomes. Although ACOG states that (1) pharmacotherapy for depression should be individualized and (2) most selective serotonin reuptake inhibi­tors (SSRIs) are not considered major terato­genic agents, many obstetricians and patients feel uncomfortable using these medications in pregnancy.⁴⁰ Often, pre-pregnancy antide­pressants are discontinued in the first trimes­ter; one large population-based study found that only 0.9% of women who had depres­sion filled their antidepressant prescription consistently throughout their pregnancy.⁴¹

It is unclear whether antidepressant use in pregnancy contributes to the risk of preterm birth seen in women who have depression. In a large population-based study, use of antidepressants in the second trimester was associated with preterm delivery but severe depression was not.¹⁸ A recent meta-analysis revealed an increased risk of preterm birth in women who used an antidepressant, com­pared with healthy women and untreated depressed women.⁴²

Research limits, unanswered questions. Regrettably, it is difficult to untangle risk factors for preterm birth among depressed women without randomized controlled studies that are not ethically feasible. It can­not be said with certainty whether antide­pressant pharmacotherapy is associated with a higher risk of preterm birth than depression alone.

Likewise, it is difficult to clarify the extent to which antidepressants contribute to infant growth restriction, if at all. Two recent meta-analyses concluded that exposure to antidepressants is associated with a statisti­cally significant risk of LBW.^42,43 However, increased severity of depressive symptoms generally is associated with exposure to anti­depressants during pregnancy, and a ran­domized controlled trial is, again, impossible to conduct for ethical reasons.

Whereas a plausible biological mecha­nism associating IUGR, SGA, and LBW with depression exists, the same cannot be said for antidepressants. In one study, exposure to maternal depression altered the expres­sion of certain placental genes but exposure to SSRIs did not cause further changes. This suggests that, on a cellular level, placental function might differ in depressed women.⁴⁴ Although antidepressants do cross the pla­centa, it remains to be seen whether fetal growth is impacted as a result. One study found decreased fetal head circumference in infants who had been exposed to antidepres­sants during pregnancy, but no increased risk for having a SGA or LWB infant.⁴⁵

Obstetrical management and mental health implications
Treated or not, women who suffer depres­sion are a high-risk group when it comes to preterm birth and a host of other pregnancy comorbidities. Women with serious compli­cations of pregnancy often are hospitalized for observation, and can undergo a pro­longed stay when close proximity to medical services or a surgical suite is required.

For example, hospitalization until deliv­ery is the standard of care for women who have preterm premature rupture of mem­branes or preeclampsia before 34 weeks’ gestation. Prolonged inpatient admis­sions and associated restriction of activity is profoundly deleterious on mood, with depression and anxiety significantly cor­related with length of stay.^46,47 Given the associations between depression and pre­term birth, it might be reasonable to con­sider screening antenatal inpatients at risk of preterm birth for depression on a regu­lar basis, so that treatment can be initiated if needed.

Depression during pregnancy is rela­tively common; an estimated 12.7% of pregnant women are affected at some time between conception and birth.⁴⁸ Not only does depression appear to have deleterious effects on pregnancy outcomes, it also plays a pivotal role in the qualitative experience of pregnancy for the mother.

Bottom Line
Awareness of obstetrical complications associated with depression in pregnancy is important for the entire care team, including the psychiatrist and obstetrician. Depression not only appears to have deleterious effects on pregnancy outcomes, it also plays a pivotal role in the qualitative experience of pregnancy for the mother. Antidepressant use generally is fraught with concerns over teratogenicity and adverse fetal outcomes.

Related Resources
• Freeman MP. Some SSRIs are better than others for pregnant women (audio interview). Current Psychiatry. 2014;13(7). http://www.currentpsychiatry.com/specialty-focus/practice-trends/article/some-ssris-are-better-thanothers-for-pregnant-women/e3adb4704e25492f3e15331fc1cc058d.html.
• Freeman MP, Joffe H, Cohen LS. Postpartum depression: Help patients find the right treatment. Current Psychiatry. 2012;11(11):14-16,19-21.

Disclosures
Dr. Habecker reports no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. Freeman is a member of the advisory board of JDS Therapeutics, Sunovion Pharmaceuticals, Inc., and Takeda Pharmaceutical Co. She receives research grant support from Takeda Pharmaceutical Co.

When a patient who has a preexisting medical illness seeks prenatal care, the obstetrician asks herself (himself) 2 questions:
   • What impact will the illness have on the pregnancy?
   • What impact will the pregnancy have on the illness?

Depression is both a pregnancy-associated and pregnancy­-independent illness, which, in the setting of a pregnant woman who has a depressive disorder, makes these questions particu­larly difficult to answer. In such a case, coordination of care with a mental health provider is essential.

Awareness of the obstetrical complications associated with depression during pregnancy, as well as their implications for the future health of the mother–infant dyad, is important for the entire care team. This article reviews the associations and interconnectedness of depression with complications of preg­nancy, childbirth, and the neonatal period.

Diagnosis of depression during prenatal care
The American College of Obstetricians and Gynecologists (ACOG) states that evidence is insufficient to support a rec­ommendation for universal screening for depression among prenatal patients, although such screening should be considered.¹ There is considerable variability among obstetrical pro­viders regarding the practice of depression screening; tools to be used if such screening is done; and screening frequency through the pregnancy.

Discernment of depression is difficult. Many somatic symptoms of depression overlap with common prenatal complaints and, consequentially, can be overlooked. Among a sample of 700 pregnant women, for example, 56% complained of lack of energy; 19%, of insomnia; and 19%, of appe­tite changes.² Weight change, of course, is universal.

The 10-question self-rating Edinburgh Postnatal Depression Scale has been vali­dated for use during pregnancy and post­natally. This screening instrument can be helpful for differentiating purely physical complaints from mental distress due to depressive symptoms.^2,3

When an obstetrical provider suspects a depressive disorder, or one has been diagnosed, she (he) faces the problem of what to do with that information. Women of low socioeconomic status and victims of domestic violence are at increased risk of depression during pregnancy, but barri­ers to appropriate referral can seem nearly insurmountable because they lack insur­ance and social support.^4-9

In addition, within the setting of numer­ous tasks that need attending during the relatively short prenatal period, it is com­mon for women newly given a diagnosis of depression to fail to follow up on a refer­ral to a mental health provider.

Although most providers will “check in” with a depressed or at-risk patient at each prenatal visit about her mood, any effort at follow-up can be overshadowed by tangible physical concerns, such as pre­term contractions, fetal growth restriction, and coordination of routine testing that has been delayed because of scant prena­tal care. All these physical concerns and circumstances of care are associated with maternal depression, as we will discuss.

Preterm labor and birth
Preterm labor is defined as uterine contrac­tions that lead to cervical change before 37 weeks gestational age. Preterm labor increases the risk of preterm birth; pre­term labor precedes 50% of preterm births. Preterm birth is the leading cause of neona­tal mortality in the United States, and rates of morbidity and mortality increase as ges­tational age decreases.¹⁰ Common neonatal complications related to prematurity are shown in the Figure.¹¹

Women who suffer from depression have an increased risk of preterm labor and preterm birth, as many studies of treated and untreated depressed pregnant women have shown.^12-20 The causative mechanism is unknown; it has been proposed that the increase in maternal cortisol production asso­ciated with depression and distress triggers overproduction of placental cortisol releasing hormone, which is thought to be involved in initiation of parturition.^21,22 Depression also is associated with other risk factors for preterm birth, such as low socioeconomic status, sub­stance use, and smoking.

Intrauterine growth restriction
Women who have depression during preg­nancy have an increased risk of intrauterine growth restriction (IUGR), which leads to delivery of an infant who is small for ges­tational age (SGA) or of low birth weight (LBW) (weighing <2,500 g at birth), or both.²³ Again, the basis of the association between depression and IUGR and SGA is unknown; it is theorized that increased levels of cortisol and catecholamines associated with maternal distress might, by increasing blood pressure and inducing vasoconstriction, cause placen­tal hypoperfusion.^24,25

It also is possible that the association of depression with other risk factors for IUGR, such as smoking, substance use, obesity, and poor prenatal care, puts the infants of depressed women at risk of growth restric­tion.²⁶ Several large-scale studies showed that the association between LBW and depres­sion is lost when smoking and substance use are accounted for; other studies, however, found a persistent association in untreated depressed women when smokers, substance users, and drinkers were excluded.^17,26,27

IUGR infants are at increased risk of iat­rogenic prematurity and stillbirth. Fetuses that weigh <10th percentile for their ges­tational age are delivered no later than 40 weeks; delivery can be indicated as early as 32 weeks, depending on the results of other antenatal tests. Women who have a growth-restricted infant have a higher risk of cesarean delivery because growth-restricted infants often have less reserve and poorer tolerance of labor.

Preeclampsia and eclampsia
Preeclampsia is defined as blood pressure >140/90 mm HG on at least 2 occasions, with proteinuria, that occurs later than the twentieth week of pregnancy in women who did not have hypertension or renal dysfunction at baseline. Preeclampsia is a progressive disease that can cause severe maternal morbidity, including renal failure, stroke, hepatic rupture, pulmonary edema, and heart failure.

Eclampsia refers to onset of seizures in the setting of preeclampsia. These 2 hyperten­sive disorders are the third leading world wide cause of maternal mortality.²⁸

Depressed women have an elevated risk of preeclampsia. The association between preeclampsia and depression might be caused by the presence of increased levels of inflammatory mediators^29,30; other comorbidities, such as increased body mass index, also might be involved, but the risk for preeclampsia in depressed women still is increased after controlling for obesity.³¹

The presence of preeclampsia is respon­sible for a high percentage of iatrogenic pre­term births, because the cure for the disorder is delivery—even at early or previable gesta­tional age. Complication rates for mother and infant are high.

The presence of preeclampsia is a sig­nificant risk factor for intrauterine fetal demise. Treating the mother after delivery involves administration of IV magnesium for 24 hours; often, the mother is separated from her infant for a day after birth.

Impact on prenatal care
Depression increases odds that women will have fewer prenatal visits.³² During pregnancy, women typically initiate pre­natal care during the first trimester, when pregnancy-dating ultrasonography and early screening tests for chromosomal abnormalities are performed. Prenatal vis­its occur monthly until the third trimes­ter, then every 2 weeks between 32 and 36 weeks’ gestation, increasing to weekly after 36 weeks’ gestation.

The increased number of visits in late pregnancy allows for early detection and treatment of hypertensive disorders; assesses fetal well-being; and decreases the risks of morbidity and mortality for mother and fetus.³³ Because women who suffer from depression are at increased risk of an array of adverse pregnancy outcomes, the impor­tance of regular and timely prenatal care cannot be understated.

In addition, the prenatal visit gives the obstetrician the opportunity to connect women with other specialists for manage­ment of any unmet medical needs. One study showed that, when women have adequate prenatal care (measured by the number of visits), the association between preterm birth and self-reported maternal depression was eliminated.³⁴

Substance use
Substance use and depression often co-exist.^35,36 Unlike screening for depression, screening for substance use is universal dur­ing prenatal care. Studies have shown that women who screen positive for depression are at higher risk of a number of comorbidi­ties, including substance use.^37,38 Conversely, women who use substances are more likely to screen positive for depression.

Evidence suggests that best practice might be to screen for depression in any woman who has a positive drug screen, if a provider is not routinely screening their general patient population.³⁹ Substance use in pregnancy is associated with a number of poor outcomes, including placental abrup­tion (cocaine use); dysmorphic facies and congenital anomalies (alcohol); and neonatal abstinence syndrome (heroin).

Antidepressants in pregnancy
A full discussion of the risks and ben­efits associated with pharmacotherapy for depression in pregnancy is beyond the scope of this article. Generally, antidepressant use is fraught with concerns over teratogenic­ity and adverse fetal outcomes. Although ACOG states that (1) pharmacotherapy for depression should be individualized and (2) most selective serotonin reuptake inhibi­tors (SSRIs) are not considered major terato­genic agents, many obstetricians and patients feel uncomfortable using these medications in pregnancy.⁴⁰ Often, pre-pregnancy antide­pressants are discontinued in the first trimes­ter; one large population-based study found that only 0.9% of women who had depres­sion filled their antidepressant prescription consistently throughout their pregnancy.⁴¹

It is unclear whether antidepressant use in pregnancy contributes to the risk of preterm birth seen in women who have depression. In a large population-based study, use of antidepressants in the second trimester was associated with preterm delivery but severe depression was not.¹⁸ A recent meta-analysis revealed an increased risk of preterm birth in women who used an antidepressant, com­pared with healthy women and untreated depressed women.⁴²

Research limits, unanswered questions. Regrettably, it is difficult to untangle risk factors for preterm birth among depressed women without randomized controlled studies that are not ethically feasible. It can­not be said with certainty whether antide­pressant pharmacotherapy is associated with a higher risk of preterm birth than depression alone.

Likewise, it is difficult to clarify the extent to which antidepressants contribute to infant growth restriction, if at all. Two recent meta-analyses concluded that exposure to antidepressants is associated with a statisti­cally significant risk of LBW.^42,43 However, increased severity of depressive symptoms generally is associated with exposure to anti­depressants during pregnancy, and a ran­domized controlled trial is, again, impossible to conduct for ethical reasons.

Whereas a plausible biological mecha­nism associating IUGR, SGA, and LBW with depression exists, the same cannot be said for antidepressants. In one study, exposure to maternal depression altered the expres­sion of certain placental genes but exposure to SSRIs did not cause further changes. This suggests that, on a cellular level, placental function might differ in depressed women.⁴⁴ Although antidepressants do cross the pla­centa, it remains to be seen whether fetal growth is impacted as a result. One study found decreased fetal head circumference in infants who had been exposed to antidepres­sants during pregnancy, but no increased risk for having a SGA or LWB infant.⁴⁵

Obstetrical management and mental health implications
Treated or not, women who suffer depres­sion are a high-risk group when it comes to preterm birth and a host of other pregnancy comorbidities. Women with serious compli­cations of pregnancy often are hospitalized for observation, and can undergo a pro­longed stay when close proximity to medical services or a surgical suite is required.

For example, hospitalization until deliv­ery is the standard of care for women who have preterm premature rupture of mem­branes or preeclampsia before 34 weeks’ gestation. Prolonged inpatient admis­sions and associated restriction of activity is profoundly deleterious on mood, with depression and anxiety significantly cor­related with length of stay.^46,47 Given the associations between depression and pre­term birth, it might be reasonable to con­sider screening antenatal inpatients at risk of preterm birth for depression on a regu­lar basis, so that treatment can be initiated if needed.

Depression during pregnancy is rela­tively common; an estimated 12.7% of pregnant women are affected at some time between conception and birth.⁴⁸ Not only does depression appear to have deleterious effects on pregnancy outcomes, it also plays a pivotal role in the qualitative experience of pregnancy for the mother.

Bottom Line
Awareness of obstetrical complications associated with depression in pregnancy is important for the entire care team, including the psychiatrist and obstetrician. Depression not only appears to have deleterious effects on pregnancy outcomes, it also plays a pivotal role in the qualitative experience of pregnancy for the mother. Antidepressant use generally is fraught with concerns over teratogenicity and adverse fetal outcomes.

Related Resources
• Freeman MP. Some SSRIs are better than others for pregnant women (audio interview). Current Psychiatry. 2014;13(7). http://www.currentpsychiatry.com/specialty-focus/practice-trends/article/some-ssris-are-better-thanothers-for-pregnant-women/e3adb4704e25492f3e15331fc1cc058d.html.
• Freeman MP, Joffe H, Cohen LS. Postpartum depression: Help patients find the right treatment. Current Psychiatry. 2012;11(11):14-16,19-21.

Disclosures
Dr. Habecker reports no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. Freeman is a member of the advisory board of JDS Therapeutics, Sunovion Pharmaceuticals, Inc., and Takeda Pharmaceutical Co. She receives research grant support from Takeda Pharmaceutical Co.

CASE Improvement, then decline
Ms. M, age 37, is brought to the hospi­tal after her husband found her at home, after an unknown duration of impaired consciousness. Her husband reports that Ms. M had normal cognitive functioning before this event, with no difficulty complet­ing activities of daily living. Ms. M’s medi­cal and psychiatric histories are notable for type 2 diabetes mellitus, unspecified bipolar disorder, and opioid, cocaine, and alcohol use disorders. Her medications include parox­etine, 40 mg/d, and gabapentin, 1,200 mg/d.

First admission. Poor inspiratory effort and oxygen saturation of 70% leads to emergent intubation. Serum laboratory studies reveal a white blood cell (WBC) count at 10,900/μL and creatinine phos­phokinase level of 25,000 U/L. Urine drug screen is positive for tetrahydrocannabinol, cocaine, and opioids.

Ms. M is admitted to the ICU for manage­ment of rhabdomyolysis and multi-organ system failure, including acute hypoxic kid­ney injury.

By hospital Day 7, the tube is extubated with no recorded physical neurologic defi­cits. Mental status exam is normal, except for impaired memory of events surrounding the admission. Ms. M is discharged home with a recommendation for outpatient follow-up.

2 Weeks later. Ms. M is brought to the emergency department after a progressive decrease in social interaction, limited oral intake, decline in activities of daily living, and urinary incontinence. Results from laboratory studies are within normal limits; brain MRI is negative; EEG shows generalized moderate slowing.

During psychiatric evaluation, Ms. M is mute and staring continuously. Examination reveals oppositional paratonia (gegen­halten), catalepsy, prominent negativism, and waxy flexibility, all suggestive of cata­tonia. IV lorazepam is initiated at 1 mg every 8 hours, titrated to 2 mg, 3 times a day.

Ms. M is transferred to a psychiatric hospi­tal for further treatment of catatonia.

Second admission. Evaluation with the Bush-Francis Catatonia Rating Scale supported a diagnosis of catatonia, with the presence of >3 features from the 14-item screen and a score of 16 on the 23-item rating scale.¹ After titrat­ing lorazepam to 9 mg/d with minimal thera­peutic impact, the psychiatry team consults the electroconvulsive therapy (ECT) service, who deems Ms. M to be an appropriate candidate and petitions for court-ordered ECT.

On hospital Day 8, Ms. M has a fever of 104°F, tachycardia at 180 beats per minute, increased rigidity, and a WBC count of 17,800/μL. She is transferred to the ICU, with a presumptive diagnosis of malignant catatonia.

The medical evaluation, including general laboratory studies, EEG, and spinal fluid anal­ysis, is unremarkable. Because of vital sign instability, 2 ECT treatments are completed in the general hospital before Ms. M resumes psychiatric inpatient care.

By the tenth ECT treatment, Ms. M is no longer febrile and experiences no further autonomic instability or psychomotor fea­tures of catatonia. Despite these improve­ments, she is noted to have persistent word-finding difficulty.

Which test would you order as the next step in your work up?
   a) EEG
   b) lumbar puncture
   c) MRI
   d) CT

The authors’ observations
In approximately 25% of cases, catatonia is caused by a general medical condition²; as such, a comprehensive medical workup is vital for assessment and management of catatonic patients. In Ms. M’s case, we con­sidered several medical causes, including nutritional deficiency, infection, a toxin, renal or hepatic impairment, hypothyroidism, sei­zure, and stroke. Evaluation included measurement of thyroid-stimulating hormone, vitamin B₁₂, and folic acid levels; urinalysis and urine drug screen; chest radiography; lumbar puncture; neuroimaging; and EEG (Table 1).

Several conditions in the differen­tial diagnosis were noteworthy. Ms. M’s severe and sudden neurologic decline, along with a positive urine drug screen for substances of abuse, raised concern about overdose leading to toxic encephalopathy or hypoxic brain injury. Ms. M’s oxygen saturation when she was found was mod­erately hypoxic at 70%, which is not a level associated with hypoxic brain damage.

We also considered posterior reversible encephalopathy syndrome (PRES), which presents variably with nausea, visual impairment, disturbance in conscious­ness, seizures, and focal neurologic signs.³ Although 67% to 80% of patients with PRES also have acute hypertension, blood pressure elevation is not necessary for the diagnosis.⁴ Similar to toxic leukoencepha­lopathy, PRES is diagnosed by brain MRI, with classic signs of posterior white-matter edema.

Case reports also describe an uncom­mon demyelinating syndrome, delayed post-hypoxic leukoencephalopathy (DPHL), which develops several weeks or months after a cerebral anoxic insult.⁵ In Ms. M’s case, brain MRI performed during her sec­ond medical hospitalization, 7 days after the initial neuropsychiatric decline, was unremarkable. Using this result to rule out DPHL would have been premature because pathognomonic abnormalities can appear as long as 40 days after the anoxic insult. Given our differential diagnosis, we ordered a repeat MRI.

Etiology and pathophysiology
First described in 1979, DPHL is rare, pos­ing diagnostic challenges for clinical pro­viders.⁶ Although the exact incidence of DPHL is unknown, the precipitating event typically involves cerebral anoxia, which can occur through carbon monoxide (CO) poisoning, strangulation, cardiac arrest, respiratory failure, and overdose from sed­atives and narcotics (Table 2).⁷ DPHL was first observed in a small percentage (2.75%) of patients suffering from CO poison­ing.^8,9 Progression of the disease generally includes a period of unconsciousness, then a lucid interval that can last 2 to 40 days, followed by the abrupt onset of neuropsy­chiatric symptoms.¹⁰ The specific patho­physiologic mechanism is unknown, but has been hypothesized to involve inferior compensatory response to decreased oxy­genation in the white matter.

Diagnosis and clinical features
DPHL can be divided into 2 clinical varia­tions: parkinsonism and akinetic mutism. The former consists of conventional par­kinsonian features along with agitation, apathy, hallucinations, dystonic postur­ing, and odd behaviors. The latter variant presents with apathy, minimal response to pain, functional bowel and bladder inconti­nence, mutism, and, at times, inappropriate laughter or tearfulness.⁵ Both variants share similar features with hypokinetic forms of catatonia.

DPHL is a diagnosis of exclusion. A careful history is critical to establish the possibility of a recent anoxic event. MRI findings, including hyperintensities in the cerebral white matter on T2-based sequencing, are suggestive of the disease. A choline peak on magnetic resonance spectroscopy also might be present in patients with DPHL, although it is not spe­cific to the diagnosis.

Early reports of DPHL suggested an associated deficiency of arylsulfatase A, an enzyme required in the modulation of myelin; however, more recent case reports are conflicting.¹¹ Familial mutations in the gene for arylsulfatase A also result in meta­chromatic leukodystrophy, and adult onset can present with psychiatric symptoms, including delusions and hallucinations.¹²

Treatment and prognosis
The treatment of DPHL consists primarily of supportive care and rehabilitation with physical, occupational, and speech ther­apy.¹¹ With these measures, most patients improve after 3 to 6 months; however, a large percentage sustain some long-term cognitive deficit, the most prevalent symp­tom being frontal executive dysfunction.⁵

OUTCOME Supportive care
A second MRI shows diffuse hyperintensities in the white matter that spare the cerebel­lum and brainstem (Figure). This finding is pathognomonic for DPHL.

ECT is discontinued because there is no evidence to support ECT-associated improve­ment in DPHL. Moreover, ECT might worsen the clinical course through increased stress and metabolic demand on the brain.¹³

Because the primary treatment of DPHL is early rehabilitation, we consider that Ms. M would benefit most from increased sup­portive care and therapy. She is discharged to a brain injury rehabilitation facility, where metoprolol is prescribed for mild tachycardia, along with thiamine and vitamins B₁₂ and D. Physical, occupational, and speech therapy are continued.

Approximately 3 weeks after admission to the rehabilitation program, Ms. M is dis­charged home. Although she improves in overall activities of daily living, she continues to experience moderate communication def­icits and occasional external distractibility.

Bottom Line
Although delayed post-hypoxic leukoencephalopathy is considered rare, consider it in the differential diagnosis when a patient has a recent history of an anoxic event followed by the abrupt onset of neuropsychiatric symptoms. Keep in mind that the condition can be missed if an MRI is obtained too early, and the clinical signs can mimic hypokinetic catatonia.

Related Resources
• Meyer MA. Delayed post-hypoxic leukoencephalopathy: case report with a review of disease pathophysiology. Neurol Int. 2013;5(3):e13. doi: 10.4081/ni.2013.e13.
• Aljarallah S, Al-Hussain F. Acute fatal posthypoxic leukoencephalopathy following benzodiazepine overdose: a case report and review of the literature. BMC Neurol. 2015;15:69.

Drug Brand Names
Gabapentin • Neurontin
Lorazepam • Ativan
Metoprolol • Lopressor
Paroxetine • Paxil

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

CASE Improvement, then decline
Ms. M, age 37, is brought to the hospi­tal after her husband found her at home, after an unknown duration of impaired consciousness. Her husband reports that Ms. M had normal cognitive functioning before this event, with no difficulty complet­ing activities of daily living. Ms. M’s medi­cal and psychiatric histories are notable for type 2 diabetes mellitus, unspecified bipolar disorder, and opioid, cocaine, and alcohol use disorders. Her medications include parox­etine, 40 mg/d, and gabapentin, 1,200 mg/d.

First admission. Poor inspiratory effort and oxygen saturation of 70% leads to emergent intubation. Serum laboratory studies reveal a white blood cell (WBC) count at 10,900/μL and creatinine phos­phokinase level of 25,000 U/L. Urine drug screen is positive for tetrahydrocannabinol, cocaine, and opioids.

Ms. M is admitted to the ICU for manage­ment of rhabdomyolysis and multi-organ system failure, including acute hypoxic kid­ney injury.

By hospital Day 7, the tube is extubated with no recorded physical neurologic defi­cits. Mental status exam is normal, except for impaired memory of events surrounding the admission. Ms. M is discharged home with a recommendation for outpatient follow-up.

2 Weeks later. Ms. M is brought to the emergency department after a progressive decrease in social interaction, limited oral intake, decline in activities of daily living, and urinary incontinence. Results from laboratory studies are within normal limits; brain MRI is negative; EEG shows generalized moderate slowing.

During psychiatric evaluation, Ms. M is mute and staring continuously. Examination reveals oppositional paratonia (gegen­halten), catalepsy, prominent negativism, and waxy flexibility, all suggestive of cata­tonia. IV lorazepam is initiated at 1 mg every 8 hours, titrated to 2 mg, 3 times a day.

Ms. M is transferred to a psychiatric hospi­tal for further treatment of catatonia.

Second admission. Evaluation with the Bush-Francis Catatonia Rating Scale supported a diagnosis of catatonia, with the presence of >3 features from the 14-item screen and a score of 16 on the 23-item rating scale.¹ After titrat­ing lorazepam to 9 mg/d with minimal thera­peutic impact, the psychiatry team consults the electroconvulsive therapy (ECT) service, who deems Ms. M to be an appropriate candidate and petitions for court-ordered ECT.

On hospital Day 8, Ms. M has a fever of 104°F, tachycardia at 180 beats per minute, increased rigidity, and a WBC count of 17,800/μL. She is transferred to the ICU, with a presumptive diagnosis of malignant catatonia.

The medical evaluation, including general laboratory studies, EEG, and spinal fluid anal­ysis, is unremarkable. Because of vital sign instability, 2 ECT treatments are completed in the general hospital before Ms. M resumes psychiatric inpatient care.

By the tenth ECT treatment, Ms. M is no longer febrile and experiences no further autonomic instability or psychomotor fea­tures of catatonia. Despite these improve­ments, she is noted to have persistent word-finding difficulty.

Which test would you order as the next step in your work up?
   a) EEG
   b) lumbar puncture
   c) MRI
   d) CT

The authors’ observations
In approximately 25% of cases, catatonia is caused by a general medical condition²; as such, a comprehensive medical workup is vital for assessment and management of catatonic patients. In Ms. M’s case, we con­sidered several medical causes, including nutritional deficiency, infection, a toxin, renal or hepatic impairment, hypothyroidism, sei­zure, and stroke. Evaluation included measurement of thyroid-stimulating hormone, vitamin B₁₂, and folic acid levels; urinalysis and urine drug screen; chest radiography; lumbar puncture; neuroimaging; and EEG (Table 1).

Several conditions in the differen­tial diagnosis were noteworthy. Ms. M’s severe and sudden neurologic decline, along with a positive urine drug screen for substances of abuse, raised concern about overdose leading to toxic encephalopathy or hypoxic brain injury. Ms. M’s oxygen saturation when she was found was mod­erately hypoxic at 70%, which is not a level associated with hypoxic brain damage.

We also considered posterior reversible encephalopathy syndrome (PRES), which presents variably with nausea, visual impairment, disturbance in conscious­ness, seizures, and focal neurologic signs.³ Although 67% to 80% of patients with PRES also have acute hypertension, blood pressure elevation is not necessary for the diagnosis.⁴ Similar to toxic leukoencepha­lopathy, PRES is diagnosed by brain MRI, with classic signs of posterior white-matter edema.

Case reports also describe an uncom­mon demyelinating syndrome, delayed post-hypoxic leukoencephalopathy (DPHL), which develops several weeks or months after a cerebral anoxic insult.⁵ In Ms. M’s case, brain MRI performed during her sec­ond medical hospitalization, 7 days after the initial neuropsychiatric decline, was unremarkable. Using this result to rule out DPHL would have been premature because pathognomonic abnormalities can appear as long as 40 days after the anoxic insult. Given our differential diagnosis, we ordered a repeat MRI.

Etiology and pathophysiology
First described in 1979, DPHL is rare, pos­ing diagnostic challenges for clinical pro­viders.⁶ Although the exact incidence of DPHL is unknown, the precipitating event typically involves cerebral anoxia, which can occur through carbon monoxide (CO) poisoning, strangulation, cardiac arrest, respiratory failure, and overdose from sed­atives and narcotics (Table 2).⁷ DPHL was first observed in a small percentage (2.75%) of patients suffering from CO poison­ing.^8,9 Progression of the disease generally includes a period of unconsciousness, then a lucid interval that can last 2 to 40 days, followed by the abrupt onset of neuropsy­chiatric symptoms.¹⁰ The specific patho­physiologic mechanism is unknown, but has been hypothesized to involve inferior compensatory response to decreased oxy­genation in the white matter.

Diagnosis and clinical features
DPHL can be divided into 2 clinical varia­tions: parkinsonism and akinetic mutism. The former consists of conventional par­kinsonian features along with agitation, apathy, hallucinations, dystonic postur­ing, and odd behaviors. The latter variant presents with apathy, minimal response to pain, functional bowel and bladder inconti­nence, mutism, and, at times, inappropriate laughter or tearfulness.⁵ Both variants share similar features with hypokinetic forms of catatonia.

DPHL is a diagnosis of exclusion. A careful history is critical to establish the possibility of a recent anoxic event. MRI findings, including hyperintensities in the cerebral white matter on T2-based sequencing, are suggestive of the disease. A choline peak on magnetic resonance spectroscopy also might be present in patients with DPHL, although it is not spe­cific to the diagnosis.

Early reports of DPHL suggested an associated deficiency of arylsulfatase A, an enzyme required in the modulation of myelin; however, more recent case reports are conflicting.¹¹ Familial mutations in the gene for arylsulfatase A also result in meta­chromatic leukodystrophy, and adult onset can present with psychiatric symptoms, including delusions and hallucinations.¹²

Treatment and prognosis
The treatment of DPHL consists primarily of supportive care and rehabilitation with physical, occupational, and speech ther­apy.¹¹ With these measures, most patients improve after 3 to 6 months; however, a large percentage sustain some long-term cognitive deficit, the most prevalent symp­tom being frontal executive dysfunction.⁵

OUTCOME Supportive care
A second MRI shows diffuse hyperintensities in the white matter that spare the cerebel­lum and brainstem (Figure). This finding is pathognomonic for DPHL.

ECT is discontinued because there is no evidence to support ECT-associated improve­ment in DPHL. Moreover, ECT might worsen the clinical course through increased stress and metabolic demand on the brain.¹³

Because the primary treatment of DPHL is early rehabilitation, we consider that Ms. M would benefit most from increased sup­portive care and therapy. She is discharged to a brain injury rehabilitation facility, where metoprolol is prescribed for mild tachycardia, along with thiamine and vitamins B₁₂ and D. Physical, occupational, and speech therapy are continued.

Approximately 3 weeks after admission to the rehabilitation program, Ms. M is dis­charged home. Although she improves in overall activities of daily living, she continues to experience moderate communication def­icits and occasional external distractibility.

Bottom Line
Although delayed post-hypoxic leukoencephalopathy is considered rare, consider it in the differential diagnosis when a patient has a recent history of an anoxic event followed by the abrupt onset of neuropsychiatric symptoms. Keep in mind that the condition can be missed if an MRI is obtained too early, and the clinical signs can mimic hypokinetic catatonia.

Related Resources
• Meyer MA. Delayed post-hypoxic leukoencephalopathy: case report with a review of disease pathophysiology. Neurol Int. 2013;5(3):e13. doi: 10.4081/ni.2013.e13.
• Aljarallah S, Al-Hussain F. Acute fatal posthypoxic leukoencephalopathy following benzodiazepine overdose: a case report and review of the literature. BMC Neurol. 2015;15:69.

Drug Brand Names
Gabapentin • Neurontin
Lorazepam • Ativan
Metoprolol • Lopressor
Paroxetine • Paxil

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

CASE Improvement, then decline
Ms. M, age 37, is brought to the hospi­tal after her husband found her at home, after an unknown duration of impaired consciousness. Her husband reports that Ms. M had normal cognitive functioning before this event, with no difficulty complet­ing activities of daily living. Ms. M’s medi­cal and psychiatric histories are notable for type 2 diabetes mellitus, unspecified bipolar disorder, and opioid, cocaine, and alcohol use disorders. Her medications include parox­etine, 40 mg/d, and gabapentin, 1,200 mg/d.

First admission. Poor inspiratory effort and oxygen saturation of 70% leads to emergent intubation. Serum laboratory studies reveal a white blood cell (WBC) count at 10,900/μL and creatinine phos­phokinase level of 25,000 U/L. Urine drug screen is positive for tetrahydrocannabinol, cocaine, and opioids.

Ms. M is admitted to the ICU for manage­ment of rhabdomyolysis and multi-organ system failure, including acute hypoxic kid­ney injury.

By hospital Day 7, the tube is extubated with no recorded physical neurologic defi­cits. Mental status exam is normal, except for impaired memory of events surrounding the admission. Ms. M is discharged home with a recommendation for outpatient follow-up.

2 Weeks later. Ms. M is brought to the emergency department after a progressive decrease in social interaction, limited oral intake, decline in activities of daily living, and urinary incontinence. Results from laboratory studies are within normal limits; brain MRI is negative; EEG shows generalized moderate slowing.

During psychiatric evaluation, Ms. M is mute and staring continuously. Examination reveals oppositional paratonia (gegen­halten), catalepsy, prominent negativism, and waxy flexibility, all suggestive of cata­tonia. IV lorazepam is initiated at 1 mg every 8 hours, titrated to 2 mg, 3 times a day.

Ms. M is transferred to a psychiatric hospi­tal for further treatment of catatonia.

Second admission. Evaluation with the Bush-Francis Catatonia Rating Scale supported a diagnosis of catatonia, with the presence of >3 features from the 14-item screen and a score of 16 on the 23-item rating scale.¹ After titrat­ing lorazepam to 9 mg/d with minimal thera­peutic impact, the psychiatry team consults the electroconvulsive therapy (ECT) service, who deems Ms. M to be an appropriate candidate and petitions for court-ordered ECT.

On hospital Day 8, Ms. M has a fever of 104°F, tachycardia at 180 beats per minute, increased rigidity, and a WBC count of 17,800/μL. She is transferred to the ICU, with a presumptive diagnosis of malignant catatonia.

The medical evaluation, including general laboratory studies, EEG, and spinal fluid anal­ysis, is unremarkable. Because of vital sign instability, 2 ECT treatments are completed in the general hospital before Ms. M resumes psychiatric inpatient care.

By the tenth ECT treatment, Ms. M is no longer febrile and experiences no further autonomic instability or psychomotor fea­tures of catatonia. Despite these improve­ments, she is noted to have persistent word-finding difficulty.

Which test would you order as the next step in your work up?
   a) EEG
   b) lumbar puncture
   c) MRI
   d) CT

The authors’ observations
In approximately 25% of cases, catatonia is caused by a general medical condition²; as such, a comprehensive medical workup is vital for assessment and management of catatonic patients. In Ms. M’s case, we con­sidered several medical causes, including nutritional deficiency, infection, a toxin, renal or hepatic impairment, hypothyroidism, sei­zure, and stroke. Evaluation included measurement of thyroid-stimulating hormone, vitamin B₁₂, and folic acid levels; urinalysis and urine drug screen; chest radiography; lumbar puncture; neuroimaging; and EEG (Table 1).

Several conditions in the differen­tial diagnosis were noteworthy. Ms. M’s severe and sudden neurologic decline, along with a positive urine drug screen for substances of abuse, raised concern about overdose leading to toxic encephalopathy or hypoxic brain injury. Ms. M’s oxygen saturation when she was found was mod­erately hypoxic at 70%, which is not a level associated with hypoxic brain damage.

We also considered posterior reversible encephalopathy syndrome (PRES), which presents variably with nausea, visual impairment, disturbance in conscious­ness, seizures, and focal neurologic signs.³ Although 67% to 80% of patients with PRES also have acute hypertension, blood pressure elevation is not necessary for the diagnosis.⁴ Similar to toxic leukoencepha­lopathy, PRES is diagnosed by brain MRI, with classic signs of posterior white-matter edema.

Case reports also describe an uncom­mon demyelinating syndrome, delayed post-hypoxic leukoencephalopathy (DPHL), which develops several weeks or months after a cerebral anoxic insult.⁵ In Ms. M’s case, brain MRI performed during her sec­ond medical hospitalization, 7 days after the initial neuropsychiatric decline, was unremarkable. Using this result to rule out DPHL would have been premature because pathognomonic abnormalities can appear as long as 40 days after the anoxic insult. Given our differential diagnosis, we ordered a repeat MRI.

Etiology and pathophysiology
First described in 1979, DPHL is rare, pos­ing diagnostic challenges for clinical pro­viders.⁶ Although the exact incidence of DPHL is unknown, the precipitating event typically involves cerebral anoxia, which can occur through carbon monoxide (CO) poisoning, strangulation, cardiac arrest, respiratory failure, and overdose from sed­atives and narcotics (Table 2).⁷ DPHL was first observed in a small percentage (2.75%) of patients suffering from CO poison­ing.^8,9 Progression of the disease generally includes a period of unconsciousness, then a lucid interval that can last 2 to 40 days, followed by the abrupt onset of neuropsy­chiatric symptoms.¹⁰ The specific patho­physiologic mechanism is unknown, but has been hypothesized to involve inferior compensatory response to decreased oxy­genation in the white matter.

Diagnosis and clinical features
DPHL can be divided into 2 clinical varia­tions: parkinsonism and akinetic mutism. The former consists of conventional par­kinsonian features along with agitation, apathy, hallucinations, dystonic postur­ing, and odd behaviors. The latter variant presents with apathy, minimal response to pain, functional bowel and bladder inconti­nence, mutism, and, at times, inappropriate laughter or tearfulness.⁵ Both variants share similar features with hypokinetic forms of catatonia.

DPHL is a diagnosis of exclusion. A careful history is critical to establish the possibility of a recent anoxic event. MRI findings, including hyperintensities in the cerebral white matter on T2-based sequencing, are suggestive of the disease. A choline peak on magnetic resonance spectroscopy also might be present in patients with DPHL, although it is not spe­cific to the diagnosis.

Early reports of DPHL suggested an associated deficiency of arylsulfatase A, an enzyme required in the modulation of myelin; however, more recent case reports are conflicting.¹¹ Familial mutations in the gene for arylsulfatase A also result in meta­chromatic leukodystrophy, and adult onset can present with psychiatric symptoms, including delusions and hallucinations.¹²

Treatment and prognosis
The treatment of DPHL consists primarily of supportive care and rehabilitation with physical, occupational, and speech ther­apy.¹¹ With these measures, most patients improve after 3 to 6 months; however, a large percentage sustain some long-term cognitive deficit, the most prevalent symp­tom being frontal executive dysfunction.⁵

OUTCOME Supportive care
A second MRI shows diffuse hyperintensities in the white matter that spare the cerebel­lum and brainstem (Figure). This finding is pathognomonic for DPHL.

ECT is discontinued because there is no evidence to support ECT-associated improve­ment in DPHL. Moreover, ECT might worsen the clinical course through increased stress and metabolic demand on the brain.¹³

Because the primary treatment of DPHL is early rehabilitation, we consider that Ms. M would benefit most from increased sup­portive care and therapy. She is discharged to a brain injury rehabilitation facility, where metoprolol is prescribed for mild tachycardia, along with thiamine and vitamins B₁₂ and D. Physical, occupational, and speech therapy are continued.

Approximately 3 weeks after admission to the rehabilitation program, Ms. M is dis­charged home. Although she improves in overall activities of daily living, she continues to experience moderate communication def­icits and occasional external distractibility.

Bottom Line
Although delayed post-hypoxic leukoencephalopathy is considered rare, consider it in the differential diagnosis when a patient has a recent history of an anoxic event followed by the abrupt onset of neuropsychiatric symptoms. Keep in mind that the condition can be missed if an MRI is obtained too early, and the clinical signs can mimic hypokinetic catatonia.

Related Resources
• Meyer MA. Delayed post-hypoxic leukoencephalopathy: case report with a review of disease pathophysiology. Neurol Int. 2013;5(3):e13. doi: 10.4081/ni.2013.e13.
• Aljarallah S, Al-Hussain F. Acute fatal posthypoxic leukoencephalopathy following benzodiazepine overdose: a case report and review of the literature. BMC Neurol. 2015;15:69.

Drug Brand Names
Gabapentin • Neurontin
Lorazepam • Ativan
Metoprolol • Lopressor
Paroxetine • Paxil

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

This past September, exactly 10 years after publication of the primary findings of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study¹—namely, that effectiveness (defined as all-cause discontinuation) was not different across first-generation antipsychotics (FGAs) and second generation antipsychotics (SGAs)— a new meta-analysis by Vita et al2 of differences in cortical gray-matter change between those 2 classes of antipsychotics offers a reminder: The clinical focus of the CATIE study overlooked impor­tant neurobiological and neuropro­tective differences between FGAs and SGAs.

How drastically 1 decade can change the scientific perspective! Vita et al’s meta-analysis and meta-regression encompassed all 18 MRI studies of cortical gray matter in patients with schizophrenia.² Earlier studies (published between 1983 and 2014) had lumped together patients who were receiving an FGA and those receiving an SGA, and authors reported overall reduction in cortical gray matter with prolonged antipsy­chotic treatment.

Remarkable findings emerge
When Vita et al² analyzed FGA- and SGA-treated patients separately, how­ever, they found a significant reduc­tion in cortical gray matter in the FGA group but not in the SGA group. In fact, while higher daily dosages of FGAs were associated with greater reduction in cortical gray matter, higher dosages of SGAs were associated with lower cortical gray matter reduction and, in some samples, with an increase in vol­ume of cortical gray matter.

The researchers hypothesized that the differential effects of FGAs and SGAs might be attributable to the neu­rotoxicity of typical FGAs and the neu­roprotective effect of atypical SGAs.

Hindsight
The key neurobiological difference between FGAs and SGAs reported by Vita et al² was not addressed in the CATIE study, leading, at that time, to a rush to judgment that all antipsy­chotics are the same. This conclusion emboldened managed-care organi­zations to mandate use of older (and cheaper) generic FGAs instead of newer (and more expensive) SGAs— most of which have become available as generic equivalents since the CATIE study was completed.

Investigators in the CATIE study— of which I was one—cannot be blamed for not focusing on neurotoxicity and neuroprotection; those data were not on the psychiatry’s radar when the CATIE study was designed in 1998. The major focus was on whether SGAs (new on the scene in the late 1990s) were more efficacious, safe, and tol­erable (that is, more effective) than FGAs.

In fact, the first study reporting that SGAs stimulated neurogenesis (in ani­mals) was published in 2002,³ when the CATIE study was more than half complete. Research into the neuropro­tective properties of SGAs then grew rapidly. In fact, the principal investi­gator of the CATIE study conducted a head-to-head comparison of FGA haloperidol and SGA olanzapine in a sample of first-episode schizophrenia patients⁴; over 1 year of follow-up, it was determined that patients in the haloperidol-treated group exhibited significant brain volume loss on MRI but those in the olanzapine-treated group did not. This study was pub­lished in 2005—the same year the CATIE study was published!

SGAs offer neuroprotection
Over the past decade, the neuroprotec­tive effects of SGAs5 and the neurotoxic effects of FGAs⁶ have been studied intensively, revealing that SGAs have multiple neuroprotective effects. These effects include:
   • stimulation of the production of new brain cells (neurons and glia), known as neurogenesis^5,7,8
   • an increase in neurotrophic factors, such as nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF),⁹ which are found at a significantly low level in patients with psychosis¹⁰
   • reversal of phencyclidine (PCP)-induced changes in gene expression¹¹
   • neuroprotection against ischemic stroke^12-14
   • reversal of PCP-induced loss of dendritic spines in the frontal cortex¹⁵
   • prevention of oligodendrocyte damage caused by interferon gamma-stimulated microglia^16,17
   • reversal of loss of dendritic spines in the prefrontal cortex induced by dopamine depletion¹⁸
   • an anti-inflammatory effect^19,20
   • protection against β-amyloid and hydrogen peroxide-induced cell death²¹
   • protection against prefrontal cortical neuronal damage caused by dizocilpine (MK-801)²²
   • reversal of a PCP-induced decrease in the glutathione level and alteration of antioxidant defenses²³
   • protection of cortical neurons from glutamate neurotoxicity.²⁴

One reason why SGAs are neuro­protective, but FGAs are not, can be attributed to their receptor profiles. FGAs block dopamine D2 receptors far more than serotonin 2A recep­tors, whereas SGAs do the opposite: They block 5-HT2A receptors 500% to 1,000% more than they block D2 recep­tors. This difference is associated in turn with a different neurobiological and neuroprotective profiles, such as a decrease or an increase in BDNF.^25,26
 

Neither similar nor interchangeable
Since publication of the findings of the CATIE study, the primary investiga­tor has proposed that neuroprotection can be a therapeutic strategy to prevent neurodegeneration and neurodeterio­ration associated with schizophrenia.²⁷ Given the preponderance of data show­ing that SGAs have numerous neuro­protective properties but FGAs have many neurotoxic effects,⁶ the message to psychiatric practitioners, a decade after the CATIE study, is that the 2 gen­erations of antipsychotic agents are not really similar or interchangeable. They might have similar clinical effective­ness but they exert very different neu­robiological effects.

The proof of the pudding is in the eating: Despite the findings of the CATIE study, the vast majority of psy­chiatrists would prefer to treat their own family members with an SGA, not an FGA, if the need for antipsychotic medication arises.

This past September, exactly 10 years after publication of the primary findings of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study¹—namely, that effectiveness (defined as all-cause discontinuation) was not different across first-generation antipsychotics (FGAs) and second generation antipsychotics (SGAs)— a new meta-analysis by Vita et al2 of differences in cortical gray-matter change between those 2 classes of antipsychotics offers a reminder: The clinical focus of the CATIE study overlooked impor­tant neurobiological and neuropro­tective differences between FGAs and SGAs.

How drastically 1 decade can change the scientific perspective! Vita et al’s meta-analysis and meta-regression encompassed all 18 MRI studies of cortical gray matter in patients with schizophrenia.² Earlier studies (published between 1983 and 2014) had lumped together patients who were receiving an FGA and those receiving an SGA, and authors reported overall reduction in cortical gray matter with prolonged antipsy­chotic treatment.

Remarkable findings emerge
When Vita et al² analyzed FGA- and SGA-treated patients separately, how­ever, they found a significant reduc­tion in cortical gray matter in the FGA group but not in the SGA group. In fact, while higher daily dosages of FGAs were associated with greater reduction in cortical gray matter, higher dosages of SGAs were associated with lower cortical gray matter reduction and, in some samples, with an increase in vol­ume of cortical gray matter.

The researchers hypothesized that the differential effects of FGAs and SGAs might be attributable to the neu­rotoxicity of typical FGAs and the neu­roprotective effect of atypical SGAs.

Hindsight
The key neurobiological difference between FGAs and SGAs reported by Vita et al² was not addressed in the CATIE study, leading, at that time, to a rush to judgment that all antipsy­chotics are the same. This conclusion emboldened managed-care organi­zations to mandate use of older (and cheaper) generic FGAs instead of newer (and more expensive) SGAs— most of which have become available as generic equivalents since the CATIE study was completed.

Investigators in the CATIE study— of which I was one—cannot be blamed for not focusing on neurotoxicity and neuroprotection; those data were not on the psychiatry’s radar when the CATIE study was designed in 1998. The major focus was on whether SGAs (new on the scene in the late 1990s) were more efficacious, safe, and tol­erable (that is, more effective) than FGAs.

In fact, the first study reporting that SGAs stimulated neurogenesis (in ani­mals) was published in 2002,³ when the CATIE study was more than half complete. Research into the neuropro­tective properties of SGAs then grew rapidly. In fact, the principal investi­gator of the CATIE study conducted a head-to-head comparison of FGA haloperidol and SGA olanzapine in a sample of first-episode schizophrenia patients⁴; over 1 year of follow-up, it was determined that patients in the haloperidol-treated group exhibited significant brain volume loss on MRI but those in the olanzapine-treated group did not. This study was pub­lished in 2005—the same year the CATIE study was published!

SGAs offer neuroprotection
Over the past decade, the neuroprotec­tive effects of SGAs5 and the neurotoxic effects of FGAs⁶ have been studied intensively, revealing that SGAs have multiple neuroprotective effects. These effects include:
   • stimulation of the production of new brain cells (neurons and glia), known as neurogenesis^5,7,8
   • an increase in neurotrophic factors, such as nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF),⁹ which are found at a significantly low level in patients with psychosis¹⁰
   • reversal of phencyclidine (PCP)-induced changes in gene expression¹¹
   • neuroprotection against ischemic stroke^12-14
   • reversal of PCP-induced loss of dendritic spines in the frontal cortex¹⁵
   • prevention of oligodendrocyte damage caused by interferon gamma-stimulated microglia^16,17
   • reversal of loss of dendritic spines in the prefrontal cortex induced by dopamine depletion¹⁸
   • an anti-inflammatory effect^19,20
   • protection against β-amyloid and hydrogen peroxide-induced cell death²¹
   • protection against prefrontal cortical neuronal damage caused by dizocilpine (MK-801)²²
   • reversal of a PCP-induced decrease in the glutathione level and alteration of antioxidant defenses²³
   • protection of cortical neurons from glutamate neurotoxicity.²⁴

One reason why SGAs are neuro­protective, but FGAs are not, can be attributed to their receptor profiles. FGAs block dopamine D2 receptors far more than serotonin 2A recep­tors, whereas SGAs do the opposite: They block 5-HT2A receptors 500% to 1,000% more than they block D2 recep­tors. This difference is associated in turn with a different neurobiological and neuroprotective profiles, such as a decrease or an increase in BDNF.^25,26
 

Neither similar nor interchangeable
Since publication of the findings of the CATIE study, the primary investiga­tor has proposed that neuroprotection can be a therapeutic strategy to prevent neurodegeneration and neurodeterio­ration associated with schizophrenia.²⁷ Given the preponderance of data show­ing that SGAs have numerous neuro­protective properties but FGAs have many neurotoxic effects,⁶ the message to psychiatric practitioners, a decade after the CATIE study, is that the 2 gen­erations of antipsychotic agents are not really similar or interchangeable. They might have similar clinical effective­ness but they exert very different neu­robiological effects.

The proof of the pudding is in the eating: Despite the findings of the CATIE study, the vast majority of psy­chiatrists would prefer to treat their own family members with an SGA, not an FGA, if the need for antipsychotic medication arises.

This past September, exactly 10 years after publication of the primary findings of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study¹—namely, that effectiveness (defined as all-cause discontinuation) was not different across first-generation antipsychotics (FGAs) and second generation antipsychotics (SGAs)— a new meta-analysis by Vita et al2 of differences in cortical gray-matter change between those 2 classes of antipsychotics offers a reminder: The clinical focus of the CATIE study overlooked impor­tant neurobiological and neuropro­tective differences between FGAs and SGAs.

How drastically 1 decade can change the scientific perspective! Vita et al’s meta-analysis and meta-regression encompassed all 18 MRI studies of cortical gray matter in patients with schizophrenia.² Earlier studies (published between 1983 and 2014) had lumped together patients who were receiving an FGA and those receiving an SGA, and authors reported overall reduction in cortical gray matter with prolonged antipsy­chotic treatment.

Remarkable findings emerge
When Vita et al² analyzed FGA- and SGA-treated patients separately, how­ever, they found a significant reduc­tion in cortical gray matter in the FGA group but not in the SGA group. In fact, while higher daily dosages of FGAs were associated with greater reduction in cortical gray matter, higher dosages of SGAs were associated with lower cortical gray matter reduction and, in some samples, with an increase in vol­ume of cortical gray matter.

The researchers hypothesized that the differential effects of FGAs and SGAs might be attributable to the neu­rotoxicity of typical FGAs and the neu­roprotective effect of atypical SGAs.

Hindsight
The key neurobiological difference between FGAs and SGAs reported by Vita et al² was not addressed in the CATIE study, leading, at that time, to a rush to judgment that all antipsy­chotics are the same. This conclusion emboldened managed-care organi­zations to mandate use of older (and cheaper) generic FGAs instead of newer (and more expensive) SGAs— most of which have become available as generic equivalents since the CATIE study was completed.

Investigators in the CATIE study— of which I was one—cannot be blamed for not focusing on neurotoxicity and neuroprotection; those data were not on the psychiatry’s radar when the CATIE study was designed in 1998. The major focus was on whether SGAs (new on the scene in the late 1990s) were more efficacious, safe, and tol­erable (that is, more effective) than FGAs.

In fact, the first study reporting that SGAs stimulated neurogenesis (in ani­mals) was published in 2002,³ when the CATIE study was more than half complete. Research into the neuropro­tective properties of SGAs then grew rapidly. In fact, the principal investi­gator of the CATIE study conducted a head-to-head comparison of FGA haloperidol and SGA olanzapine in a sample of first-episode schizophrenia patients⁴; over 1 year of follow-up, it was determined that patients in the haloperidol-treated group exhibited significant brain volume loss on MRI but those in the olanzapine-treated group did not. This study was pub­lished in 2005—the same year the CATIE study was published!

SGAs offer neuroprotection
Over the past decade, the neuroprotec­tive effects of SGAs5 and the neurotoxic effects of FGAs⁶ have been studied intensively, revealing that SGAs have multiple neuroprotective effects. These effects include:
   • stimulation of the production of new brain cells (neurons and glia), known as neurogenesis^5,7,8
   • an increase in neurotrophic factors, such as nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF),⁹ which are found at a significantly low level in patients with psychosis¹⁰
   • reversal of phencyclidine (PCP)-induced changes in gene expression¹¹
   • neuroprotection against ischemic stroke^12-14
   • reversal of PCP-induced loss of dendritic spines in the frontal cortex¹⁵
   • prevention of oligodendrocyte damage caused by interferon gamma-stimulated microglia^16,17
   • reversal of loss of dendritic spines in the prefrontal cortex induced by dopamine depletion¹⁸
   • an anti-inflammatory effect^19,20
   • protection against β-amyloid and hydrogen peroxide-induced cell death²¹
   • protection against prefrontal cortical neuronal damage caused by dizocilpine (MK-801)²²
   • reversal of a PCP-induced decrease in the glutathione level and alteration of antioxidant defenses²³
   • protection of cortical neurons from glutamate neurotoxicity.²⁴

One reason why SGAs are neuro­protective, but FGAs are not, can be attributed to their receptor profiles. FGAs block dopamine D2 receptors far more than serotonin 2A recep­tors, whereas SGAs do the opposite: They block 5-HT2A receptors 500% to 1,000% more than they block D2 recep­tors. This difference is associated in turn with a different neurobiological and neuroprotective profiles, such as a decrease or an increase in BDNF.^25,26
 

Neither similar nor interchangeable
Since publication of the findings of the CATIE study, the primary investiga­tor has proposed that neuroprotection can be a therapeutic strategy to prevent neurodegeneration and neurodeterio­ration associated with schizophrenia.²⁷ Given the preponderance of data show­ing that SGAs have numerous neuro­protective properties but FGAs have many neurotoxic effects,⁶ the message to psychiatric practitioners, a decade after the CATIE study, is that the 2 gen­erations of antipsychotic agents are not really similar or interchangeable. They might have similar clinical effective­ness but they exert very different neu­robiological effects.

The proof of the pudding is in the eating: Despite the findings of the CATIE study, the vast majority of psy­chiatrists would prefer to treat their own family members with an SGA, not an FGA, if the need for antipsychotic medication arises.

Dear Dr. Mossman,

Psychiatrists should not reveal what their patients say except to avert a threat to health or safety or to report abuse. So, how can psy­chiatrists be subpoenaed to provide informa­tion for a trial? If I receive a subpoena, how can I comply without violating patient privacy? If I have to go to court, can I “plead the Fifth”?

Submitted by “Dr. S”

Physicians who are served with a sub­poena feel upset for the reason Dr. S described: Complying with a sub­poena seems to violate the obligation to pro­tect patients’ privacy. But physicians can’t “plead the Fifth” under these circumstances, because the Fifth Amendment to the U.S. Constitution only bars forcing someone to give self-incriminating testimony.¹

If you receive a subpoena for information gleaned during patient care, you should not ignore it. Failing to respond might place you in contempt of court and subject you to a fine or even jail time. Yet simply comply­ing could have legal and professional impli­cations, too.

Often, a psychiatrist who receives a sub­poena should seek an attorney’s advice on how to best respond. But understanding what subpoenas are and how they work might let you feel less anxious as you go through the process of responding. With this goal in mind, this article covers:
   • what a subpoena is and isn’t
   • 2 types of privacy obligations
   • legal options
   • avoiding potential embarrassment (Box).²

What is a subpoena?
All citizens have a legal obligation to fur­nish courts with the information needed to decide legal issues.³ Statutes and legal rules dictate how such material comes to court.

Issuing a subpoena (from the Latin sub poena, “under penalty”) is one way of obtaining information needed for a legal proceeding. A subpoena ad testificandum directs the recipient to appear at a legal pro­ceeding and provide testimony. A subpoena duces tecum (“you shall bring with you”) directs the recipient to produce specific records or to appear at a legal proceeding with the records.

Usually, subpoenas are issued by attor­neys or court clerks, not by judges. As such, they are not court orders. If you receive a subpoena, you should make a timely response of some sort. But, ultimately, you might not have to release the information. Although physicians have to follow the same rules as other citizens, courts recog­nize that doctors also have professional obligations to their patients.

Confidentiality: Your reason to hesitate
Receiving a subpoena doesn’t change your obligation to protect your patient’s con­fidentiality. From the law’s standpoint, patient confidentiality is a function of the rules that govern use of information in legal proceedings.

The Privacy Rule⁴ that arose from the Health Insurance Portability and Accountability Act (HIPAA) of 1996⁵ pro­vides guidance on acceptable responses to subpoenas by “covered entities,” which includes most physicians’ practices. HIPAA permits disclosure of the minimum amount of personal information needed to fulfill the demands of a subpoena. The Table^6,7 explains HIPAA’s rules about specific responses to subpoenas, depending on their source.
 

Many states have patient privacy laws that are stricter than HIPAA rules. If you practice in one of those states, you have to follow the more stringent rule.⁸ For example, Ohio law does not let subpoenaed provid­ers tender medical records for use in a grand jury proceeding without a release signed by the patient, although HIPAA would allow this (Table).^6,7 Out of concern that “giving law enforcement unbridled access to medi­cal records could discourage patients from seeking medical treatment,” Ohio protects patient records more than HIPAA does.⁹ New York State’s privilege rules also are stricter than HIPAA¹⁰ and contain specific provisions about releasing certain types of information (eg, HIV status¹¹). State courts expect physicians to follow their laws about patient privacy and to consult attorneys to make sure that releasing information is done properly.¹²

Releasing information improperly could become grounds for legal action against you, even if you released the information in response to a subpoena. Legal action could take the form of a lawsuit for breach of con­fidentiality, a HIPAA-based complaint, a complaint to the state medical board, or all 3 of these.

Must you turn over information?
Before you testify or turn over documents, you need to verify that the legal and ethi­cal requirements for the disclosure are met—as you would for any release of patient information. You can do this by obtaining your patient’s formal, writ­ten consent for the disclosure. Before you accept the patient’s agreement, however, you might—and in most cases should— consider discussing how the disclosure could affect the patient’s well-being or your treatment relationship.

If the patient will not agree to the disclo­sure, the patient or the patient’s attorney can seek to have the subpoena modified or quashed (declared void). One tactic for doing this is by asserting doctor–patient privilege, a legal doctrine codified in most state’s laws. The privilege recognizes that, because privacy is important in medical care, stopping clinical information from automatically coming in court serves an important social purpose.¹³

The doctor–patient privilege belongs to the litigant—here, your patient—not to you, so your patient has to raise the objection to releasing information.¹⁴ Also, the privilege is not absolute. If having the clinical information is necessary, the judge may issue a court order denying the patient’s motion to quash. Unless the judge later modifies or vacates the order, you risk being found in contempt of court if you still refuse to turn over documents demanded by the subpoena.

Fact witness or expert witness?
If the subpoena demands your testimony, the issuing party might want you to serve as a fact witness or expert witness. Persons with relevant personal knowledge to a legal proceeding can serve as fact witnesses, and testify about things they did or perceived.¹⁵ For example, a psychiatrist serving as a fact witness could recount having heard or seen a patient talking aloud as if arguing with someone when no real interlocutor was present.

A witness whom the court deems an “expert” by virtue of special knowledge, skill, experience, training, or education may offer opinions based on specific sets of facts. Courts hear such testimony when the expert’s specialized knowledge will help the jury understand the evidence or reach a verdict in a case.¹⁶ To return to the example above: a psychiatric expert witness might tell jurors that the patient’s “arguing” was evidence that she was hallucinating and suffered from schizophrenia.

If you receive a subpoena to testify about someone you have treated, you should notify the issuing party that you will pro­vide fact testimony if required to do so. You cannot be compelled to serve as an expert witness, however. In many situations, attempting to provide objective expert testi­mony about one’s own patient could create unresolvable conflicts between the obliga­tion to tell the truth and your obligation to serve your patient’s interests.¹⁷

If the subpoena requests deposition tes­timony about a patient, you probably will be able to schedule the deposition at a time that is convenient for you and the attor­neys involved. Yet you should not agree to be deposed unless (a) you have received the patient’s authorization, (b) a court has ordered you to testify despite the patient’s objection, or (c) your attorney (whom you have consulted about the situation) has advised you that providing testimony is appropriate.

If you are called as a fact witness for a trial, the attorney or court that has subpoe­naed you often will try to schedule things to minimize the time taken away from your other duties. Once in court, you can ask the judge (on the record) whether you must answer if you are asked questions about a patient who has not previously autho­rized you to release treatment information. A judge’s explicit command to respond absolves you of any further ethical obliga­tion to withhold confidential information about the patient’s care.

Bottom Line
If you receive a subpoena for records or testimony, obtaining the patient’s written authorization should allow you to release the information without violating confidentiality obligations. If your patient won’t agree to the release, if turning over information might adversely affect the patient, or if you’re not sure what to do, seek advice from an attorney who knows about medical privacy rules. That way, you can be sure you are meeting all legal and professional standards that apply.

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

Dear Dr. Mossman,

Psychiatrists should not reveal what their patients say except to avert a threat to health or safety or to report abuse. So, how can psy­chiatrists be subpoenaed to provide informa­tion for a trial? If I receive a subpoena, how can I comply without violating patient privacy? If I have to go to court, can I “plead the Fifth”?

Submitted by “Dr. S”

Physicians who are served with a sub­poena feel upset for the reason Dr. S described: Complying with a sub­poena seems to violate the obligation to pro­tect patients’ privacy. But physicians can’t “plead the Fifth” under these circumstances, because the Fifth Amendment to the U.S. Constitution only bars forcing someone to give self-incriminating testimony.¹

If you receive a subpoena for information gleaned during patient care, you should not ignore it. Failing to respond might place you in contempt of court and subject you to a fine or even jail time. Yet simply comply­ing could have legal and professional impli­cations, too.

Often, a psychiatrist who receives a sub­poena should seek an attorney’s advice on how to best respond. But understanding what subpoenas are and how they work might let you feel less anxious as you go through the process of responding. With this goal in mind, this article covers:
   • what a subpoena is and isn’t
   • 2 types of privacy obligations
   • legal options
   • avoiding potential embarrassment (Box).²

What is a subpoena?
All citizens have a legal obligation to fur­nish courts with the information needed to decide legal issues.³ Statutes and legal rules dictate how such material comes to court.

Issuing a subpoena (from the Latin sub poena, “under penalty”) is one way of obtaining information needed for a legal proceeding. A subpoena ad testificandum directs the recipient to appear at a legal pro­ceeding and provide testimony. A subpoena duces tecum (“you shall bring with you”) directs the recipient to produce specific records or to appear at a legal proceeding with the records.

Usually, subpoenas are issued by attor­neys or court clerks, not by judges. As such, they are not court orders. If you receive a subpoena, you should make a timely response of some sort. But, ultimately, you might not have to release the information. Although physicians have to follow the same rules as other citizens, courts recog­nize that doctors also have professional obligations to their patients.

Confidentiality: Your reason to hesitate
Receiving a subpoena doesn’t change your obligation to protect your patient’s con­fidentiality. From the law’s standpoint, patient confidentiality is a function of the rules that govern use of information in legal proceedings.

The Privacy Rule⁴ that arose from the Health Insurance Portability and Accountability Act (HIPAA) of 1996⁵ pro­vides guidance on acceptable responses to subpoenas by “covered entities,” which includes most physicians’ practices. HIPAA permits disclosure of the minimum amount of personal information needed to fulfill the demands of a subpoena. The Table^6,7 explains HIPAA’s rules about specific responses to subpoenas, depending on their source.
 

Many states have patient privacy laws that are stricter than HIPAA rules. If you practice in one of those states, you have to follow the more stringent rule.⁸ For example, Ohio law does not let subpoenaed provid­ers tender medical records for use in a grand jury proceeding without a release signed by the patient, although HIPAA would allow this (Table).^6,7 Out of concern that “giving law enforcement unbridled access to medi­cal records could discourage patients from seeking medical treatment,” Ohio protects patient records more than HIPAA does.⁹ New York State’s privilege rules also are stricter than HIPAA¹⁰ and contain specific provisions about releasing certain types of information (eg, HIV status¹¹). State courts expect physicians to follow their laws about patient privacy and to consult attorneys to make sure that releasing information is done properly.¹²

Releasing information improperly could become grounds for legal action against you, even if you released the information in response to a subpoena. Legal action could take the form of a lawsuit for breach of con­fidentiality, a HIPAA-based complaint, a complaint to the state medical board, or all 3 of these.

Must you turn over information?
Before you testify or turn over documents, you need to verify that the legal and ethi­cal requirements for the disclosure are met—as you would for any release of patient information. You can do this by obtaining your patient’s formal, writ­ten consent for the disclosure. Before you accept the patient’s agreement, however, you might—and in most cases should— consider discussing how the disclosure could affect the patient’s well-being or your treatment relationship.

If the patient will not agree to the disclo­sure, the patient or the patient’s attorney can seek to have the subpoena modified or quashed (declared void). One tactic for doing this is by asserting doctor–patient privilege, a legal doctrine codified in most state’s laws. The privilege recognizes that, because privacy is important in medical care, stopping clinical information from automatically coming in court serves an important social purpose.¹³

The doctor–patient privilege belongs to the litigant—here, your patient—not to you, so your patient has to raise the objection to releasing information.¹⁴ Also, the privilege is not absolute. If having the clinical information is necessary, the judge may issue a court order denying the patient’s motion to quash. Unless the judge later modifies or vacates the order, you risk being found in contempt of court if you still refuse to turn over documents demanded by the subpoena.

Fact witness or expert witness?
If the subpoena demands your testimony, the issuing party might want you to serve as a fact witness or expert witness. Persons with relevant personal knowledge to a legal proceeding can serve as fact witnesses, and testify about things they did or perceived.¹⁵ For example, a psychiatrist serving as a fact witness could recount having heard or seen a patient talking aloud as if arguing with someone when no real interlocutor was present.

A witness whom the court deems an “expert” by virtue of special knowledge, skill, experience, training, or education may offer opinions based on specific sets of facts. Courts hear such testimony when the expert’s specialized knowledge will help the jury understand the evidence or reach a verdict in a case.¹⁶ To return to the example above: a psychiatric expert witness might tell jurors that the patient’s “arguing” was evidence that she was hallucinating and suffered from schizophrenia.

If you receive a subpoena to testify about someone you have treated, you should notify the issuing party that you will pro­vide fact testimony if required to do so. You cannot be compelled to serve as an expert witness, however. In many situations, attempting to provide objective expert testi­mony about one’s own patient could create unresolvable conflicts between the obliga­tion to tell the truth and your obligation to serve your patient’s interests.¹⁷

If the subpoena requests deposition tes­timony about a patient, you probably will be able to schedule the deposition at a time that is convenient for you and the attor­neys involved. Yet you should not agree to be deposed unless (a) you have received the patient’s authorization, (b) a court has ordered you to testify despite the patient’s objection, or (c) your attorney (whom you have consulted about the situation) has advised you that providing testimony is appropriate.

If you are called as a fact witness for a trial, the attorney or court that has subpoe­naed you often will try to schedule things to minimize the time taken away from your other duties. Once in court, you can ask the judge (on the record) whether you must answer if you are asked questions about a patient who has not previously autho­rized you to release treatment information. A judge’s explicit command to respond absolves you of any further ethical obliga­tion to withhold confidential information about the patient’s care.

Bottom Line
If you receive a subpoena for records or testimony, obtaining the patient’s written authorization should allow you to release the information without violating confidentiality obligations. If your patient won’t agree to the release, if turning over information might adversely affect the patient, or if you’re not sure what to do, seek advice from an attorney who knows about medical privacy rules. That way, you can be sure you are meeting all legal and professional standards that apply.

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

Dear Dr. Mossman,

Psychiatrists should not reveal what their patients say except to avert a threat to health or safety or to report abuse. So, how can psy­chiatrists be subpoenaed to provide informa­tion for a trial? If I receive a subpoena, how can I comply without violating patient privacy? If I have to go to court, can I “plead the Fifth”?

Submitted by “Dr. S”

Physicians who are served with a sub­poena feel upset for the reason Dr. S described: Complying with a sub­poena seems to violate the obligation to pro­tect patients’ privacy. But physicians can’t “plead the Fifth” under these circumstances, because the Fifth Amendment to the U.S. Constitution only bars forcing someone to give self-incriminating testimony.¹

If you receive a subpoena for information gleaned during patient care, you should not ignore it. Failing to respond might place you in contempt of court and subject you to a fine or even jail time. Yet simply comply­ing could have legal and professional impli­cations, too.

Often, a psychiatrist who receives a sub­poena should seek an attorney’s advice on how to best respond. But understanding what subpoenas are and how they work might let you feel less anxious as you go through the process of responding. With this goal in mind, this article covers:
   • what a subpoena is and isn’t
   • 2 types of privacy obligations
   • legal options
   • avoiding potential embarrassment (Box).²

What is a subpoena?
All citizens have a legal obligation to fur­nish courts with the information needed to decide legal issues.³ Statutes and legal rules dictate how such material comes to court.

Issuing a subpoena (from the Latin sub poena, “under penalty”) is one way of obtaining information needed for a legal proceeding. A subpoena ad testificandum directs the recipient to appear at a legal pro­ceeding and provide testimony. A subpoena duces tecum (“you shall bring with you”) directs the recipient to produce specific records or to appear at a legal proceeding with the records.

Usually, subpoenas are issued by attor­neys or court clerks, not by judges. As such, they are not court orders. If you receive a subpoena, you should make a timely response of some sort. But, ultimately, you might not have to release the information. Although physicians have to follow the same rules as other citizens, courts recog­nize that doctors also have professional obligations to their patients.

Confidentiality: Your reason to hesitate
Receiving a subpoena doesn’t change your obligation to protect your patient’s con­fidentiality. From the law’s standpoint, patient confidentiality is a function of the rules that govern use of information in legal proceedings.

The Privacy Rule⁴ that arose from the Health Insurance Portability and Accountability Act (HIPAA) of 1996⁵ pro­vides guidance on acceptable responses to subpoenas by “covered entities,” which includes most physicians’ practices. HIPAA permits disclosure of the minimum amount of personal information needed to fulfill the demands of a subpoena. The Table^6,7 explains HIPAA’s rules about specific responses to subpoenas, depending on their source.
 

Many states have patient privacy laws that are stricter than HIPAA rules. If you practice in one of those states, you have to follow the more stringent rule.⁸ For example, Ohio law does not let subpoenaed provid­ers tender medical records for use in a grand jury proceeding without a release signed by the patient, although HIPAA would allow this (Table).^6,7 Out of concern that “giving law enforcement unbridled access to medi­cal records could discourage patients from seeking medical treatment,” Ohio protects patient records more than HIPAA does.⁹ New York State’s privilege rules also are stricter than HIPAA¹⁰ and contain specific provisions about releasing certain types of information (eg, HIV status¹¹). State courts expect physicians to follow their laws about patient privacy and to consult attorneys to make sure that releasing information is done properly.¹²

Releasing information improperly could become grounds for legal action against you, even if you released the information in response to a subpoena. Legal action could take the form of a lawsuit for breach of con­fidentiality, a HIPAA-based complaint, a complaint to the state medical board, or all 3 of these.

Must you turn over information?
Before you testify or turn over documents, you need to verify that the legal and ethi­cal requirements for the disclosure are met—as you would for any release of patient information. You can do this by obtaining your patient’s formal, writ­ten consent for the disclosure. Before you accept the patient’s agreement, however, you might—and in most cases should— consider discussing how the disclosure could affect the patient’s well-being or your treatment relationship.

If the patient will not agree to the disclo­sure, the patient or the patient’s attorney can seek to have the subpoena modified or quashed (declared void). One tactic for doing this is by asserting doctor–patient privilege, a legal doctrine codified in most state’s laws. The privilege recognizes that, because privacy is important in medical care, stopping clinical information from automatically coming in court serves an important social purpose.¹³

The doctor–patient privilege belongs to the litigant—here, your patient—not to you, so your patient has to raise the objection to releasing information.¹⁴ Also, the privilege is not absolute. If having the clinical information is necessary, the judge may issue a court order denying the patient’s motion to quash. Unless the judge later modifies or vacates the order, you risk being found in contempt of court if you still refuse to turn over documents demanded by the subpoena.

Fact witness or expert witness?
If the subpoena demands your testimony, the issuing party might want you to serve as a fact witness or expert witness. Persons with relevant personal knowledge to a legal proceeding can serve as fact witnesses, and testify about things they did or perceived.¹⁵ For example, a psychiatrist serving as a fact witness could recount having heard or seen a patient talking aloud as if arguing with someone when no real interlocutor was present.

A witness whom the court deems an “expert” by virtue of special knowledge, skill, experience, training, or education may offer opinions based on specific sets of facts. Courts hear such testimony when the expert’s specialized knowledge will help the jury understand the evidence or reach a verdict in a case.¹⁶ To return to the example above: a psychiatric expert witness might tell jurors that the patient’s “arguing” was evidence that she was hallucinating and suffered from schizophrenia.

If you receive a subpoena to testify about someone you have treated, you should notify the issuing party that you will pro­vide fact testimony if required to do so. You cannot be compelled to serve as an expert witness, however. In many situations, attempting to provide objective expert testi­mony about one’s own patient could create unresolvable conflicts between the obliga­tion to tell the truth and your obligation to serve your patient’s interests.¹⁷

If the subpoena requests deposition tes­timony about a patient, you probably will be able to schedule the deposition at a time that is convenient for you and the attor­neys involved. Yet you should not agree to be deposed unless (a) you have received the patient’s authorization, (b) a court has ordered you to testify despite the patient’s objection, or (c) your attorney (whom you have consulted about the situation) has advised you that providing testimony is appropriate.

If you are called as a fact witness for a trial, the attorney or court that has subpoe­naed you often will try to schedule things to minimize the time taken away from your other duties. Once in court, you can ask the judge (on the record) whether you must answer if you are asked questions about a patient who has not previously autho­rized you to release treatment information. A judge’s explicit command to respond absolves you of any further ethical obliga­tion to withhold confidential information about the patient’s care.

Bottom Line
If you receive a subpoena for records or testimony, obtaining the patient’s written authorization should allow you to release the information without violating confidentiality obligations. If your patient won’t agree to the release, if turning over information might adversely affect the patient, or if you’re not sure what to do, seek advice from an attorney who knows about medical privacy rules. That way, you can be sure you are meeting all legal and professional standards that apply.

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