Current Psychiatry

Historically and recently, leaders within psychiatry have expressed disdain over the public’s misunderstanding of the specialty.¹ There are many factors—cultural and sociopolitical influences, for example—that contribute to a generalized suspicion of the intent and the abilities of psychiatry. Few observers, however, have focused on how a lack of cohesion within the discipline might be an important, underappreciated influence in the misconceptions and mistrust.

One way to view the recent publication of the DSM-5 is as further positive application of evidence-based medicine and an indicator of the flexible, progressive adaptability of psychiatry. Indeed, Gawande has demonstrated the benefit of implementing a high degree of standardization in terms of maximizing economic efficiency and minimizing medical error.²

Yet critics of psychiatry use the DSM-5 to substantiate their claim that the field is still murky and unsure of itself. Major changes in classification and diagnostic criteria might support a Szaszian fallacy that we somehow create mental illness and simply fit individuals into the framework at our whim. In the midst of what is, at best, lateral movement in psychiatry, the extremism of critics of the specialty, such as Peter Breggin, might gain undeserved credence. Furthermore, the merits of these critics’ arguments remain largely unchallenged in the public arena.

It is worth noting 2 additional factors within psychiatry that contribute to its stagnation:

• Knowledge and practice are grossly misaligned. What practitioners know and what they do are quite different, and the best way to treat mental illness often takes a back seat to tradition or convenience. Consider neuroimaging, which has illustrated structural and functional changes in the brain that have contributed to the phenomenology of schizophrenia. Schizophrenia is considered a clinical diagnosis, but the value of imaging in predicting prognosis, progression, response to treatment, etc. is well known. Yet neuroimaging is underutilized and the cost-benefit analysis of this modality remains unexplored. Likewise, cognitive testing, an important tool in the diagnosis and prognosis of schizophrenia, is not standard practice. These are good reasons why psychiatry shouldn’t shy from the push toward medicalization: Incorporating imaging and genetic analysis into practice will go a long way toward building legitimacy.
• Mental illness is stigmatized within. The stigma of mental illness that psychiatry must overcome is rooted in ignorance and misunderstanding. However, psychiatry itself has done little to eliminate the stigma of mental illness among its practitioners. This is apparent in the punitive, non-progressive nature of most state programs for impaired physicians.³ This type of “individual discrimination” described by Carl Hart⁴ undoubtedly permeates the residency match and ranking process, even in psychiatry. How can any headway be made in curbing societal intolerance of, say, addiction when it thrives in the academic environment? 

A marriage that will dispel ignorance

In light of the continued undervaluation and ignorance of psychiatry, we can start by heeding the Buddhist teaching that change must come from within. To undertake change means to consolidate information and begin to change the inner workings, practices, and structure of the field itself. It means taking seriously the Research Domain Criteria outlined by Thomas Insel, MD, Director of the National Institute of Mental Health.⁵

 It is increasingly apparent that psychiatry and neurology are inseparable.⁶ Why is there still reluctance to collaborate between the specialties? Why are these 2 fields’ research efforts still relatively distinct from one another, and not being built upon what is already known?

Based on current knowledge, sophisticated proponents of neuropsychiatry aren’t being unreasonable in their desire to push for an elevated status. If the field is to move in the most constructive direction, we should encourage a marriage—a fusion—of psychiatry and neurology. We shouldn’t be satisfied with connecting the specialties in theory and discussion; we should seek a structural unison of departments, journals, teaching, texts, research efforts, and fellowship options and accreditations.

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

Historically and recently, leaders within psychiatry have expressed disdain over the public’s misunderstanding of the specialty.¹ There are many factors—cultural and sociopolitical influences, for example—that contribute to a generalized suspicion of the intent and the abilities of psychiatry. Few observers, however, have focused on how a lack of cohesion within the discipline might be an important, underappreciated influence in the misconceptions and mistrust.

One way to view the recent publication of the DSM-5 is as further positive application of evidence-based medicine and an indicator of the flexible, progressive adaptability of psychiatry. Indeed, Gawande has demonstrated the benefit of implementing a high degree of standardization in terms of maximizing economic efficiency and minimizing medical error.²

Yet critics of psychiatry use the DSM-5 to substantiate their claim that the field is still murky and unsure of itself. Major changes in classification and diagnostic criteria might support a Szaszian fallacy that we somehow create mental illness and simply fit individuals into the framework at our whim. In the midst of what is, at best, lateral movement in psychiatry, the extremism of critics of the specialty, such as Peter Breggin, might gain undeserved credence. Furthermore, the merits of these critics’ arguments remain largely unchallenged in the public arena.

It is worth noting 2 additional factors within psychiatry that contribute to its stagnation:

• Knowledge and practice are grossly misaligned. What practitioners know and what they do are quite different, and the best way to treat mental illness often takes a back seat to tradition or convenience. Consider neuroimaging, which has illustrated structural and functional changes in the brain that have contributed to the phenomenology of schizophrenia. Schizophrenia is considered a clinical diagnosis, but the value of imaging in predicting prognosis, progression, response to treatment, etc. is well known. Yet neuroimaging is underutilized and the cost-benefit analysis of this modality remains unexplored. Likewise, cognitive testing, an important tool in the diagnosis and prognosis of schizophrenia, is not standard practice. These are good reasons why psychiatry shouldn’t shy from the push toward medicalization: Incorporating imaging and genetic analysis into practice will go a long way toward building legitimacy.
• Mental illness is stigmatized within. The stigma of mental illness that psychiatry must overcome is rooted in ignorance and misunderstanding. However, psychiatry itself has done little to eliminate the stigma of mental illness among its practitioners. This is apparent in the punitive, non-progressive nature of most state programs for impaired physicians.³ This type of “individual discrimination” described by Carl Hart⁴ undoubtedly permeates the residency match and ranking process, even in psychiatry. How can any headway be made in curbing societal intolerance of, say, addiction when it thrives in the academic environment? 

A marriage that will dispel ignorance

In light of the continued undervaluation and ignorance of psychiatry, we can start by heeding the Buddhist teaching that change must come from within. To undertake change means to consolidate information and begin to change the inner workings, practices, and structure of the field itself. It means taking seriously the Research Domain Criteria outlined by Thomas Insel, MD, Director of the National Institute of Mental Health.⁵

 It is increasingly apparent that psychiatry and neurology are inseparable.⁶ Why is there still reluctance to collaborate between the specialties? Why are these 2 fields’ research efforts still relatively distinct from one another, and not being built upon what is already known?

Based on current knowledge, sophisticated proponents of neuropsychiatry aren’t being unreasonable in their desire to push for an elevated status. If the field is to move in the most constructive direction, we should encourage a marriage—a fusion—of psychiatry and neurology. We shouldn’t be satisfied with connecting the specialties in theory and discussion; we should seek a structural unison of departments, journals, teaching, texts, research efforts, and fellowship options and accreditations.

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

Historically and recently, leaders within psychiatry have expressed disdain over the public’s misunderstanding of the specialty.¹ There are many factors—cultural and sociopolitical influences, for example—that contribute to a generalized suspicion of the intent and the abilities of psychiatry. Few observers, however, have focused on how a lack of cohesion within the discipline might be an important, underappreciated influence in the misconceptions and mistrust.

One way to view the recent publication of the DSM-5 is as further positive application of evidence-based medicine and an indicator of the flexible, progressive adaptability of psychiatry. Indeed, Gawande has demonstrated the benefit of implementing a high degree of standardization in terms of maximizing economic efficiency and minimizing medical error.²

Yet critics of psychiatry use the DSM-5 to substantiate their claim that the field is still murky and unsure of itself. Major changes in classification and diagnostic criteria might support a Szaszian fallacy that we somehow create mental illness and simply fit individuals into the framework at our whim. In the midst of what is, at best, lateral movement in psychiatry, the extremism of critics of the specialty, such as Peter Breggin, might gain undeserved credence. Furthermore, the merits of these critics’ arguments remain largely unchallenged in the public arena.

It is worth noting 2 additional factors within psychiatry that contribute to its stagnation:

• Knowledge and practice are grossly misaligned. What practitioners know and what they do are quite different, and the best way to treat mental illness often takes a back seat to tradition or convenience. Consider neuroimaging, which has illustrated structural and functional changes in the brain that have contributed to the phenomenology of schizophrenia. Schizophrenia is considered a clinical diagnosis, but the value of imaging in predicting prognosis, progression, response to treatment, etc. is well known. Yet neuroimaging is underutilized and the cost-benefit analysis of this modality remains unexplored. Likewise, cognitive testing, an important tool in the diagnosis and prognosis of schizophrenia, is not standard practice. These are good reasons why psychiatry shouldn’t shy from the push toward medicalization: Incorporating imaging and genetic analysis into practice will go a long way toward building legitimacy.
• Mental illness is stigmatized within. The stigma of mental illness that psychiatry must overcome is rooted in ignorance and misunderstanding. However, psychiatry itself has done little to eliminate the stigma of mental illness among its practitioners. This is apparent in the punitive, non-progressive nature of most state programs for impaired physicians.³ This type of “individual discrimination” described by Carl Hart⁴ undoubtedly permeates the residency match and ranking process, even in psychiatry. How can any headway be made in curbing societal intolerance of, say, addiction when it thrives in the academic environment? 

A marriage that will dispel ignorance

In light of the continued undervaluation and ignorance of psychiatry, we can start by heeding the Buddhist teaching that change must come from within. To undertake change means to consolidate information and begin to change the inner workings, practices, and structure of the field itself. It means taking seriously the Research Domain Criteria outlined by Thomas Insel, MD, Director of the National Institute of Mental Health.⁵

 It is increasingly apparent that psychiatry and neurology are inseparable.⁶ Why is there still reluctance to collaborate between the specialties? Why are these 2 fields’ research efforts still relatively distinct from one another, and not being built upon what is already known?

Based on current knowledge, sophisticated proponents of neuropsychiatry aren’t being unreasonable in their desire to push for an elevated status. If the field is to move in the most constructive direction, we should encourage a marriage—a fusion—of psychiatry and neurology. We shouldn’t be satisfied with connecting the specialties in theory and discussion; we should seek a structural unison of departments, journals, teaching, texts, research efforts, and fellowship options and accreditations.

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

Discharging patients from a hospital or emergency department despite his (her) ongoing suicidal ideation is a clinical dilemma. Typically, these patients do not respond to hospital care and do not follow up after discharge. They often have a poorly treated illness and many unmet psychosocial and interpersonal needs.¹ These patients may communicate their suicidality as conditional, aimed at satisfying unmet needs; secondary gain; dependency needs; or remaining in the sick role. Faced with impending discharge, such a patient might increase the intensity of his suicidal statements or engage in behaviors that subvert discharge. Some go as far as to engage in behaviors with apparent suicidal intent soon after discharge.

A complicated decision

Such patients often are at a chronically elevated risk for suicide because of mood disorders, personality pathology, substance use disorder, or a history of serious suicide attempt.² Do not dismiss a patient’s suicidal statements; he is ill and may end his own life.

Managing these situations can put you under a variety of pressures: your own negative emotional and psychological reactions to the patient; pressure from staff to avoid admission or expedite discharge of the patient; and administrative pressure to efficiently manage resources.³ You’re faced with a difficult decision: Discharge a patient who might self-harm or commit suicide, or continue care that may be counterproductive.

We propose 6 steps that have helped us promote good clinical care while documenting the necessary information to manage risk in these complex situations.

1. Define and document the clinical situation. Summarize the clinical dilemma.

2. Assess and document current suicide risk.⁴ Conduct a formal suicide risk assessment; if necessary, reassess throughout care. Focus on dynamic risk factors; protective risk factors (static and dynamic); acute stressors (or lack thereof) that would increase their risk of suicide above their chronically elevated baseline; and access to lethal means—firearms, stockpiled medication, etc.

3. Document modified dynamic or protective factors. Review the dynamic risk and protective factors you have identified and how they have been modified by treatment to date. If dynamic factors have not been modified, indicate why and document the recommended plan to address these matters. You might not be able to provide relief, but you should be able to outline a plan for eventual relief.

4. Document the reasons continued care in the acute setting is not indicated. Reasons might include: the patient isn’t participating in recommended care or treatment; the patient isn’t improving, or is becoming worse, in the care environment; continued care is preventing or interfering with access to more effective care options; is counterproductive to the patient’s stated goals; or compromising the safety benefit of the structured care environment because the patient is not collaborating with his care team.

5. Document your discussion of discharge with the patient. Highlight attempts to engage the patient in adaptive problem solving. Work out a crisis or suicide safety plan and give the patient a copy and keep a copy in his (her) chart.

      If the patient refuses to engage in safety planning, document it in the chart. Note the absence of any conditions that might impair the patient’s volitional capacity to not end their life—intoxication, delirium, acute psychosis, etc. Explicitly frame the patient’s responsibility for his life. Discuss and document a follow-up plan and make direct contact with providers and social supports, documenting whether contacting these providers was successful.

6. Consult with a colleague. An informal non-visit consultation with a colleague demonstrates your recognition of the complexity of the situation and your due diligence in arriving at a discharge decision. Consultation often will result in useful additional strategies for managing or engaging the patient. A colleague’s agreement helps demonstrate that “average practitioner” and “prudent practitioner” standards of care have been met with respect to clinical decision-making.

Disclosure

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

Discharging patients from a hospital or emergency department despite his (her) ongoing suicidal ideation is a clinical dilemma. Typically, these patients do not respond to hospital care and do not follow up after discharge. They often have a poorly treated illness and many unmet psychosocial and interpersonal needs.¹ These patients may communicate their suicidality as conditional, aimed at satisfying unmet needs; secondary gain; dependency needs; or remaining in the sick role. Faced with impending discharge, such a patient might increase the intensity of his suicidal statements or engage in behaviors that subvert discharge. Some go as far as to engage in behaviors with apparent suicidal intent soon after discharge.

A complicated decision

Such patients often are at a chronically elevated risk for suicide because of mood disorders, personality pathology, substance use disorder, or a history of serious suicide attempt.² Do not dismiss a patient’s suicidal statements; he is ill and may end his own life.

Managing these situations can put you under a variety of pressures: your own negative emotional and psychological reactions to the patient; pressure from staff to avoid admission or expedite discharge of the patient; and administrative pressure to efficiently manage resources.³ You’re faced with a difficult decision: Discharge a patient who might self-harm or commit suicide, or continue care that may be counterproductive.

We propose 6 steps that have helped us promote good clinical care while documenting the necessary information to manage risk in these complex situations.

1. Define and document the clinical situation. Summarize the clinical dilemma.

2. Assess and document current suicide risk.⁴ Conduct a formal suicide risk assessment; if necessary, reassess throughout care. Focus on dynamic risk factors; protective risk factors (static and dynamic); acute stressors (or lack thereof) that would increase their risk of suicide above their chronically elevated baseline; and access to lethal means—firearms, stockpiled medication, etc.

3. Document modified dynamic or protective factors. Review the dynamic risk and protective factors you have identified and how they have been modified by treatment to date. If dynamic factors have not been modified, indicate why and document the recommended plan to address these matters. You might not be able to provide relief, but you should be able to outline a plan for eventual relief.

4. Document the reasons continued care in the acute setting is not indicated. Reasons might include: the patient isn’t participating in recommended care or treatment; the patient isn’t improving, or is becoming worse, in the care environment; continued care is preventing or interfering with access to more effective care options; is counterproductive to the patient’s stated goals; or compromising the safety benefit of the structured care environment because the patient is not collaborating with his care team.

5. Document your discussion of discharge with the patient. Highlight attempts to engage the patient in adaptive problem solving. Work out a crisis or suicide safety plan and give the patient a copy and keep a copy in his (her) chart.

      If the patient refuses to engage in safety planning, document it in the chart. Note the absence of any conditions that might impair the patient’s volitional capacity to not end their life—intoxication, delirium, acute psychosis, etc. Explicitly frame the patient’s responsibility for his life. Discuss and document a follow-up plan and make direct contact with providers and social supports, documenting whether contacting these providers was successful.

6. Consult with a colleague. An informal non-visit consultation with a colleague demonstrates your recognition of the complexity of the situation and your due diligence in arriving at a discharge decision. Consultation often will result in useful additional strategies for managing or engaging the patient. A colleague’s agreement helps demonstrate that “average practitioner” and “prudent practitioner” standards of care have been met with respect to clinical decision-making.

Disclosure

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

Discharging patients from a hospital or emergency department despite his (her) ongoing suicidal ideation is a clinical dilemma. Typically, these patients do not respond to hospital care and do not follow up after discharge. They often have a poorly treated illness and many unmet psychosocial and interpersonal needs.¹ These patients may communicate their suicidality as conditional, aimed at satisfying unmet needs; secondary gain; dependency needs; or remaining in the sick role. Faced with impending discharge, such a patient might increase the intensity of his suicidal statements or engage in behaviors that subvert discharge. Some go as far as to engage in behaviors with apparent suicidal intent soon after discharge.

A complicated decision

Such patients often are at a chronically elevated risk for suicide because of mood disorders, personality pathology, substance use disorder, or a history of serious suicide attempt.² Do not dismiss a patient’s suicidal statements; he is ill and may end his own life.

Managing these situations can put you under a variety of pressures: your own negative emotional and psychological reactions to the patient; pressure from staff to avoid admission or expedite discharge of the patient; and administrative pressure to efficiently manage resources.³ You’re faced with a difficult decision: Discharge a patient who might self-harm or commit suicide, or continue care that may be counterproductive.

We propose 6 steps that have helped us promote good clinical care while documenting the necessary information to manage risk in these complex situations.

1. Define and document the clinical situation. Summarize the clinical dilemma.

2. Assess and document current suicide risk.⁴ Conduct a formal suicide risk assessment; if necessary, reassess throughout care. Focus on dynamic risk factors; protective risk factors (static and dynamic); acute stressors (or lack thereof) that would increase their risk of suicide above their chronically elevated baseline; and access to lethal means—firearms, stockpiled medication, etc.

3. Document modified dynamic or protective factors. Review the dynamic risk and protective factors you have identified and how they have been modified by treatment to date. If dynamic factors have not been modified, indicate why and document the recommended plan to address these matters. You might not be able to provide relief, but you should be able to outline a plan for eventual relief.

4. Document the reasons continued care in the acute setting is not indicated. Reasons might include: the patient isn’t participating in recommended care or treatment; the patient isn’t improving, or is becoming worse, in the care environment; continued care is preventing or interfering with access to more effective care options; is counterproductive to the patient’s stated goals; or compromising the safety benefit of the structured care environment because the patient is not collaborating with his care team.

5. Document your discussion of discharge with the patient. Highlight attempts to engage the patient in adaptive problem solving. Work out a crisis or suicide safety plan and give the patient a copy and keep a copy in his (her) chart.

      If the patient refuses to engage in safety planning, document it in the chart. Note the absence of any conditions that might impair the patient’s volitional capacity to not end their life—intoxication, delirium, acute psychosis, etc. Explicitly frame the patient’s responsibility for his life. Discuss and document a follow-up plan and make direct contact with providers and social supports, documenting whether contacting these providers was successful.

6. Consult with a colleague. An informal non-visit consultation with a colleague demonstrates your recognition of the complexity of the situation and your due diligence in arriving at a discharge decision. Consultation often will result in useful additional strategies for managing or engaging the patient. A colleague’s agreement helps demonstrate that “average practitioner” and “prudent practitioner” standards of care have been met with respect to clinical decision-making.

Disclosure

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

Historically, alcohol use disorder (AUD; classified as alcohol abuse or dependence in DSM-IV-TR) has been treated with psychosocial therapies, but many patients treated this way relapse into heavy drinking patterns and are unable to sustain sobriety (Box 1¹). Although vital for treating AUD, psychosocial methods have, to date, a modest success rate. Research has demonstrated that combining pharmacotherapy with psychosocial programs is effective for treating AUD.²

Patients and clinicians might associate AUD medications with so-called aversion therapy because, for many years, the only treatment was disulfiram, which causes unpleasant physical effects when consumed with alcohol. However, newer medications help patients maintain abstinence by targeting brain neurotransmitters relevant to addiction neurocircuitry, such as dopamine, serotonin, _ϒ-aminobutyric acid (GABA), glutamate, and opioid.³ These medications may help patients with AUD achieve sobriety, avoid relapse, decrease heavy drinking days, and delay time to recurrent drinking.

    In this article, we review FDA-approved medications (Table 1)^4-6 and off-label agents (Table 2)^3,7-18 and provide recommendations for treating patients with AUD (Box 2).^19-21

FDA-approved treatments

Naltrexone is an opiate antagonist that blocks the mu receptor and is believed to interrupt the dopamine reward pathway in the brain for alcohol. A meta-analysis of 2,861 patients in 24 combined randomized controlled trials (RCTs) demonstrated naltrexone to be an effective short-term (12 weeks) treatment for alcoholism, significantly decreasing relapses.²² The large multisite COMBINE study (N = 1,383) showed that naltrexone, 100 mg/d, and medical treatment without behavioral treatment over 16 weeks was more effective than placebo in increasing percentage of days abstinent (80.6% vs 75.1%, respectively) and reducing the percentage of patients experiencing heavy drinking days (66.2% vs 73.1%, respectively).² Patients who have a family history of AUD or strong cravings, or both, may benefit most from naltrexone.^3,7,23 Despite evidence of the effectiveness of naltrexone for AUD, not all studies have yielded positive results.²⁴

Common side effects of naltrexone, if present, appear early in treatment and include GI upset (eg, nausea, vomiting, abdominal pain), headache, and fatigue.^2,3,22,23 Hepatotoxicity has been reported with dosages of 100 to 300 mg/d, but lab values typically normalize when naltrexone is discontinued.^2,3,23 Monitor markers of liver function including _ϒ-glutamyltransferase, aspartate aminotransferase, alanine aminotransferase, and bilirubin before and during naltrexone treatment (we check patients 1 to 3 months after starting treatment and yearly thereafter). Obtain a negative urine drug screen for opioids before administering naltrexone, because if opioids were consumed recently naltrexone could precipitate withdrawal. Because of the unknown teratogenicity of naltrexone, women of childbearing age should undergo pregnancy testing before and periodically during naltrexone therapy.

Naltrexone also is available in a once-monthly, 380-mg injectable formulation. Studies show that, similar to its oral counterpart, injectable naltrexone effectively reduces heavy drinking days and number of drinks a day compared with placebo.^25,26 Advantages of injectable naltrexone are its extended steady release of medication and its efficacy for patients who do not adhere to oral dosing.^7,27 Side effects are similar to oral naltrexone, except for injection site reactions and pain.

Contraindications to naltrexone include current opioid use because its antagonistic effects on opioid receptors render opioid analgesia ineffective. Patients who have used opioids within 7 to 10 days or who may be surreptitiously using opioids should not take naltrexone because it may cause opioid withdrawal. Some patients may try to override the opioid receptor blockade of naltrexone with higher opioid doses, which could result in overdose.

Naltrexone is approved for treating opioid use disorder and may be useful for persons with comorbid opioid use disorder and AUD, if the patient has been adequately detoxified from opioids and intends to abstain from these drugs. Patients who have extensive liver damage secondary to acute hepatitis or uncompensated cirrhosis would not be good candidates for naltrexone because of a risk of hepatotoxicity.^2,3,22

Because of ease of dosing, we recommend naltrexone as a first-line treatment for AUD, unless the patient requires opioids or has severe liver disease. We recommend increasing naltrexone from 50 mg to 100 mg before switching to acamprosate, based on European studies.

Acamprosate is a glutamate antagonist that is thought to modulate overactive glutamatergic brain activity that occurs after stopping chronic heavy alcohol use. In a meta-analysis of 17 studies (N = 4,087), continuous abstinence rates at 6 months were significantly higher in acamprosate-treated patients (36.1%) than in patients receiving placebo (23.4%).²⁸ In a review of European studies, acamprosate benefited patients who have increased anxiety, physiological dependence, negative family history of AUD, and late age of onset (age >25) of alcohol dependence.⁷ However, in the COMBINE trial acamprosate was no more effective than placebo.²

We consider acamprosate an effective option for patients who do not respond to naltrexone or have a contraindication. Dosages of 333 mg to 666 mg, 3 times a day, are recommended, although dosages up to 3 g/d have been studied; titration is not required.^2,7,28 We recommend advising patients to continue treatment even if they relapse, because these medications may mitigate relapse severity. Adherence to multiple daily doses can be problematic for some patients, but pairing medications with meals or bedtime may improve adherence.

Diarrhea is the most common side effect of acamprosate; nervousness, fatigue, insomnia, and depression have been reported with high dosages.^2,3,7,28 Acamprosate is excreted through the kidney and is safe for patients with liver disorders such as acute hepatitis or cirrhosis. The drug is contraindicated in patients with acute or chronic renal failure with creatinine clearance <30 mL/min; those with less severe renal insufficiency might need a lower dosage. Obtain baseline renal function before starting acamprosate; women of childbearing age should undergo a pregnancy test.

Disulfiram inhibits alcohol metabolism, resulting in acetaldehyde accumulation, which causes unpleasant physical effects such as nausea, vomiting, and hypotension. This creates a negative rather than a positive experience with drinking. A US Veterans Administration Cooperative Study randomized 605 participants to riboflavin, disulfiram, 1 mg/d (an inactive dose), or disulfiram, 250 mg/d (standard dose). There was no difference in percentage of patients remaining abstinent or time to first drink.⁸ Participants receiving disulfiram, 250 mg/d, had fewer drinking days after relapse compared with the other groups.⁸

Adverse physical effects produced when disulfiram and alcohol interact include tremor, diaphoresis, unstable blood pressure, and severe diarrhea and vomiting. Disulfiram can cause medically serious reactions in a small percentage of patients, especially those with significant medical comorbidity or advanced age. Patients with severe hypertension, diabetes mellitus, heart disease, a history of stroke, peripheral neuropathy, epilepsy, or renal or hepatic insufficiency should not use disulfiram.³ Patients taking disulfiram should avoid casual exposures to food, aftershave, mouthwash, and hand sanitizer that might contain alcohol. Disulfiram has no significant effect on alcohol craving. Social support to help oversee dosing may enhance adherence.⁷

Off-label medications

Topiramate is FDA-approved to treat migraine headaches and some seizure disorders. Topiramate facilitates GABA-mediated neuronal inhibition and antagonizes certain glutamate receptor subtypes. In an RCT (N = 150), topiramate, up to 300 mg/d, was more effective than placebo at reducing heavy drinking days and number of drinks per day, increasing days abstinent, and alleviating cravings.⁹ In a 12-week, double-blind RCT (N = 150), topiramate increased “safe drinking”—defined as ≤1 standard drink per day for women and ≤2 per day for men—vs placebo.¹⁰ Dosages were 75 mg to 300 mg/d in twice daily divided doses. Dosing starts at 25 mg/d and increases by 25 to 50 mg a day at weekly intervals. We recommend reserving topiramate for persons who do not respond to or cannot tolerate naltrexone and acamprosate because of the slow titration needed to prevent side effects. Although not studied, it may seem that topiramate’s antiepileptic actions could prevent seizures during alcohol withdrawal, but the protracted titration would limit its utility.

Side effects of topiramate include impaired memory and concentration, paresthesia, and anorexia and are more likely to present during rapid titration or with a high dosage.^7,8 Rare reports of spontaneous myopia, angle-closure glaucoma, increased intraocular pressure, ocular pain, and blurry vision have been reported, but these complications often resolve with discontinuation of topiramate.^7,8

Topiramate primarily is excreted through the kidney, and its action in the renal tubules can lead to metabolic acidosis or nephrolithiasis.⁸ Relative contraindications include acute or chronic kidney disease, including kidney stones. Consider slower titration and a 50% reduction in dosing if creatinine clearance is <70 mL/min. Obtain renal function tests before starting topiramate and consider monitoring serum bicarbonate for metabolic acidosis (we test at 3 and 6 months, then every 6 months). Because of teratogenic effects of topiramate (eg, cleft lip and palate), rule out pregnancy in all women of childbearing age.

Baclofen is a GABA_b receptor agonist that is FDA approved for treating spasticity. Because GABA transmission is down-regulated in chronic AUD, it is a commonly targeted neurotransmitter when developing medications for AUD. GABA_a receptors are fast-acting inhibitory ion channels, and its agonists (eg, benzodiazepines) have a significant abuse and cross-addiction liability. GABA_b receptors, however, are slow-acting through a complex cascade of intracellular signals, and therefore GABA_b agonists such as baclofen have been studied for treating addiction.

In a randomized double-blind, placebo-controlled trial (N = 39), baclofen was superior to placebo in suppressing obsessive aspects of cravings and decreasing state anxiety.¹¹ Baclofen, 10 mg 3 times daily, in another randomized double-blind, placebo-controlled trial (n = 42) reduced the number of drinks per day by 53% vs placebo; 20 mg 3 times a day resulted in a 68% reduction in drinks per day vs placebo.¹² However, a placebo-controlled RCT (n = 80) reported that baclofen, 10 mg 3 times daily, was not superior to placebo for primary outcomes related to alcohol consumption, although it did significantly decrease cravings and anxiety among persons with AUD.¹³ Evidence suggests that baclofen might be effective for promoting abstinence, reducing the risk of relapse, and alleviating cravings and anxiety in persons with AUD, although further investigation is needed.

In studies for AUD, the side-effect profile for baclofen was relatively benign.^11-13 Nausea, fatigue, sleepiness, vertigo, and abdominal pain were reported; overall, baclofen was found to be safe and to have no abuse liability.^7,10,12 The addictive potential of other muscle relaxers may have dissuaded providers from using baclofen for AUD, but we consider it a reasonable alternative when FDA-approved treatments fail.

Because baclofen is primarily eliminated by the kidneys, it may be safe for people with cirrhosis or severe liver disease.¹² Baseline renal labs should be performed before administering baclofen and a negative pregnancy test obtained for women of childbearing age.

Ondansetron is a serotonin receptor type 3 (5-HT3) antagonist that has shown promising results for AUD.^3,7 Research suggests that 5-HT3 receptors are an action site for alcohol in the brain and are thought to play a role in its rewarding effects.⁷ Ondansetron may be more effective for early-onset alcoholism (EOA) than late-onset alcoholism (LOA).^14,15 EOA (age ≤25) is characterized by strong family history of AUD and prominent antisocial traits. A randomized double-blind, placebo-controlled trial (n = 271) reported that ondansetron, 4 mcg/kg twice daily, was superior to placebo in reducing number of drinks per day, increasing days abstinent, and reducing cravings in patients with EOA.¹⁴ Among persons with EOA, ondansetron, 16 mcg/kg twice daily, significantly reduced the severity of symptoms of fatigue, confusion, and overall mood disturbance such as depression, anxiety, and hostility compared with placebo in an RCT (n = 321).¹⁵ The lowest available oral dosage of ondansetron is 4 mg tablets or 4 mg/5 mL solution. We have used 4 mg twice daily for patients who have failed naltrexone and acamprosate or when these agents are contraindicated.

Common side effects of ondansetron include constipation, diarrhea, elevated liver enzymes, tachycardia, headache, and fatigue. Contraindications include congenital long QT syndrome, QTc prolongation risk, or significant hepatic impairment. We suggest evaluating baseline electrocardiogram and liver function tests. Women should undergo a pregnancy test before receiving medications.

Gabapentin is an anticonvulsant that is FDA-approved for treating epilepsy and postherpetic neuralgia. Gabapentin is related structurally to GABA and may potentiate central nervous system GABA activity, inhibit glutamate activity, and reduce norepinephrine and dopamine release.¹⁶ Gabapentin is thought to balance the GABA/glutamate dysregulation found in early alcohol abstinence and reduce risk for alcohol relapse.¹⁶A randomized, double-blind, placebo-controlled trial (N = 60) demonstrated that gabapentin, 600 mg/d, significantly reduced number of drinks per day and heavy drinking days and increased days of abstinence compared with placebo over 28 days.¹⁷ Another double-blind, randomized, placebo-controlled trial of 150 people used gabapentin, 900 or 1,800 mg/d; there was a linear dose response for increased days abstinent and no heavy drinking days in favor of gabapentin.¹⁸

An RCT (N = 150) evaluated adding gabapentin, up to 1200 mg/d, to naltrexone, 50 mg/d, vs naltrexone with placebo or double placebo over 6 weeks of treatment. The combined gabapentin-naltrexone group outperformed the other 2 groups on time to heavy drinking, number of heavy drinking days, and number of drinks per day. Gabapentin’s positive effects on sleep may have mediated some of its beneficial effects.²⁹ In an open-label pilot study, gabapentin was more effective than trazodone for insomnia during early alcohol abstinence.³⁰ Of note, gabapentin is a safe alternative to benzodiazepines for alcohol detoxification in patients with severe hepatic disease or those at risk of interacting with alcohol (eg, outpatients at high risk to drink during detoxification).³¹ Gabapentin, 400 mg/d to 1,600 mg/d, generally is safe and well tolerated and has some support for improving cravings, reducing alcohol consumption, delaying relapse, and improving sleep in patients with AUD.

Side effects of gabapentin include daytime sedation, dizziness, ataxia, fatigue, and dyspepsia. Using 3 divided doses might enhance tolerability. To reduce daytime sedation, we recommend administering most of the dose at night, which also may relieve insomnia. Gabapentin is excreted through the kidney; baseline renal function tests should be performed before initiating treatment, because the dosage might need to be adjusted in people with renal insufficiency. 

Bottom Line

FDA-approved (acamprosate, naltrexone, and disulfiram) and off-label (baclofen, gabapentin, ondansetron, and topiramate) agents can help patients with alcohol use disorder achieve abstinence, reduce heavy drinking days, prevent relapse, and maintain sobriety. Research supports the use of pharmacotherapy combined with psychosocial modalities, such as 12-step programs, motivational interviewing, and cognitive-behavioral therapy.

Related Resources

• National Institute on Drug Abuse. Principles of drug addiction treatment: A research-based guide (third edition). www.drugabuse.gov/publications/principles-drug-addiction-treatment-research-based-guide-third-edition/evidence-based-approaches-to-drug-addiction-treatment/pharmacotherapi-1.
• Substance Abuse and Mental Health Services Administration. Incorporating alcohol pharmacotherapies into medical practice. http://162.99.3.213/products/manuals/tips/pdf/TIP49.pdf.
• Pettinati HM, Mattson ME. Medical management treatment manual: A clinical guide for researchers and clinicians providing pharmacotherapy for alcohol dependence. http://pubs.niaaa.nih.gov/publications/MedicalManual/MMManual.pdf.

Drug Brand Names

Acamprosate • Campral                        Naltrexone • Vivitrol, ReVia

Baclofen • Lioresal                                Ondansetron • Zofran

Disulfiram • Antabuse                           Topiramate • Topamax

Gabapentin • Neurontin                         Trazodone • Desyrel, Oleptro

Metronidazole • Flagyl

Disclosure

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

Historically, alcohol use disorder (AUD; classified as alcohol abuse or dependence in DSM-IV-TR) has been treated with psychosocial therapies, but many patients treated this way relapse into heavy drinking patterns and are unable to sustain sobriety (Box 1¹). Although vital for treating AUD, psychosocial methods have, to date, a modest success rate. Research has demonstrated that combining pharmacotherapy with psychosocial programs is effective for treating AUD.²

Patients and clinicians might associate AUD medications with so-called aversion therapy because, for many years, the only treatment was disulfiram, which causes unpleasant physical effects when consumed with alcohol. However, newer medications help patients maintain abstinence by targeting brain neurotransmitters relevant to addiction neurocircuitry, such as dopamine, serotonin, _ϒ-aminobutyric acid (GABA), glutamate, and opioid.³ These medications may help patients with AUD achieve sobriety, avoid relapse, decrease heavy drinking days, and delay time to recurrent drinking.

    In this article, we review FDA-approved medications (Table 1)^4-6 and off-label agents (Table 2)^3,7-18 and provide recommendations for treating patients with AUD (Box 2).^19-21

FDA-approved treatments

Naltrexone is an opiate antagonist that blocks the mu receptor and is believed to interrupt the dopamine reward pathway in the brain for alcohol. A meta-analysis of 2,861 patients in 24 combined randomized controlled trials (RCTs) demonstrated naltrexone to be an effective short-term (12 weeks) treatment for alcoholism, significantly decreasing relapses.²² The large multisite COMBINE study (N = 1,383) showed that naltrexone, 100 mg/d, and medical treatment without behavioral treatment over 16 weeks was more effective than placebo in increasing percentage of days abstinent (80.6% vs 75.1%, respectively) and reducing the percentage of patients experiencing heavy drinking days (66.2% vs 73.1%, respectively).² Patients who have a family history of AUD or strong cravings, or both, may benefit most from naltrexone.^3,7,23 Despite evidence of the effectiveness of naltrexone for AUD, not all studies have yielded positive results.²⁴

Common side effects of naltrexone, if present, appear early in treatment and include GI upset (eg, nausea, vomiting, abdominal pain), headache, and fatigue.^2,3,22,23 Hepatotoxicity has been reported with dosages of 100 to 300 mg/d, but lab values typically normalize when naltrexone is discontinued.^2,3,23 Monitor markers of liver function including _ϒ-glutamyltransferase, aspartate aminotransferase, alanine aminotransferase, and bilirubin before and during naltrexone treatment (we check patients 1 to 3 months after starting treatment and yearly thereafter). Obtain a negative urine drug screen for opioids before administering naltrexone, because if opioids were consumed recently naltrexone could precipitate withdrawal. Because of the unknown teratogenicity of naltrexone, women of childbearing age should undergo pregnancy testing before and periodically during naltrexone therapy.

Naltrexone also is available in a once-monthly, 380-mg injectable formulation. Studies show that, similar to its oral counterpart, injectable naltrexone effectively reduces heavy drinking days and number of drinks a day compared with placebo.^25,26 Advantages of injectable naltrexone are its extended steady release of medication and its efficacy for patients who do not adhere to oral dosing.^7,27 Side effects are similar to oral naltrexone, except for injection site reactions and pain.

Contraindications to naltrexone include current opioid use because its antagonistic effects on opioid receptors render opioid analgesia ineffective. Patients who have used opioids within 7 to 10 days or who may be surreptitiously using opioids should not take naltrexone because it may cause opioid withdrawal. Some patients may try to override the opioid receptor blockade of naltrexone with higher opioid doses, which could result in overdose.

Naltrexone is approved for treating opioid use disorder and may be useful for persons with comorbid opioid use disorder and AUD, if the patient has been adequately detoxified from opioids and intends to abstain from these drugs. Patients who have extensive liver damage secondary to acute hepatitis or uncompensated cirrhosis would not be good candidates for naltrexone because of a risk of hepatotoxicity.^2,3,22

Because of ease of dosing, we recommend naltrexone as a first-line treatment for AUD, unless the patient requires opioids or has severe liver disease. We recommend increasing naltrexone from 50 mg to 100 mg before switching to acamprosate, based on European studies.

Acamprosate is a glutamate antagonist that is thought to modulate overactive glutamatergic brain activity that occurs after stopping chronic heavy alcohol use. In a meta-analysis of 17 studies (N = 4,087), continuous abstinence rates at 6 months were significantly higher in acamprosate-treated patients (36.1%) than in patients receiving placebo (23.4%).²⁸ In a review of European studies, acamprosate benefited patients who have increased anxiety, physiological dependence, negative family history of AUD, and late age of onset (age >25) of alcohol dependence.⁷ However, in the COMBINE trial acamprosate was no more effective than placebo.²

We consider acamprosate an effective option for patients who do not respond to naltrexone or have a contraindication. Dosages of 333 mg to 666 mg, 3 times a day, are recommended, although dosages up to 3 g/d have been studied; titration is not required.^2,7,28 We recommend advising patients to continue treatment even if they relapse, because these medications may mitigate relapse severity. Adherence to multiple daily doses can be problematic for some patients, but pairing medications with meals or bedtime may improve adherence.

Diarrhea is the most common side effect of acamprosate; nervousness, fatigue, insomnia, and depression have been reported with high dosages.^2,3,7,28 Acamprosate is excreted through the kidney and is safe for patients with liver disorders such as acute hepatitis or cirrhosis. The drug is contraindicated in patients with acute or chronic renal failure with creatinine clearance <30 mL/min; those with less severe renal insufficiency might need a lower dosage. Obtain baseline renal function before starting acamprosate; women of childbearing age should undergo a pregnancy test.

Disulfiram inhibits alcohol metabolism, resulting in acetaldehyde accumulation, which causes unpleasant physical effects such as nausea, vomiting, and hypotension. This creates a negative rather than a positive experience with drinking. A US Veterans Administration Cooperative Study randomized 605 participants to riboflavin, disulfiram, 1 mg/d (an inactive dose), or disulfiram, 250 mg/d (standard dose). There was no difference in percentage of patients remaining abstinent or time to first drink.⁸ Participants receiving disulfiram, 250 mg/d, had fewer drinking days after relapse compared with the other groups.⁸

Adverse physical effects produced when disulfiram and alcohol interact include tremor, diaphoresis, unstable blood pressure, and severe diarrhea and vomiting. Disulfiram can cause medically serious reactions in a small percentage of patients, especially those with significant medical comorbidity or advanced age. Patients with severe hypertension, diabetes mellitus, heart disease, a history of stroke, peripheral neuropathy, epilepsy, or renal or hepatic insufficiency should not use disulfiram.³ Patients taking disulfiram should avoid casual exposures to food, aftershave, mouthwash, and hand sanitizer that might contain alcohol. Disulfiram has no significant effect on alcohol craving. Social support to help oversee dosing may enhance adherence.⁷

Off-label medications

Topiramate is FDA-approved to treat migraine headaches and some seizure disorders. Topiramate facilitates GABA-mediated neuronal inhibition and antagonizes certain glutamate receptor subtypes. In an RCT (N = 150), topiramate, up to 300 mg/d, was more effective than placebo at reducing heavy drinking days and number of drinks per day, increasing days abstinent, and alleviating cravings.⁹ In a 12-week, double-blind RCT (N = 150), topiramate increased “safe drinking”—defined as ≤1 standard drink per day for women and ≤2 per day for men—vs placebo.¹⁰ Dosages were 75 mg to 300 mg/d in twice daily divided doses. Dosing starts at 25 mg/d and increases by 25 to 50 mg a day at weekly intervals. We recommend reserving topiramate for persons who do not respond to or cannot tolerate naltrexone and acamprosate because of the slow titration needed to prevent side effects. Although not studied, it may seem that topiramate’s antiepileptic actions could prevent seizures during alcohol withdrawal, but the protracted titration would limit its utility.

Side effects of topiramate include impaired memory and concentration, paresthesia, and anorexia and are more likely to present during rapid titration or with a high dosage.^7,8 Rare reports of spontaneous myopia, angle-closure glaucoma, increased intraocular pressure, ocular pain, and blurry vision have been reported, but these complications often resolve with discontinuation of topiramate.^7,8

Topiramate primarily is excreted through the kidney, and its action in the renal tubules can lead to metabolic acidosis or nephrolithiasis.⁸ Relative contraindications include acute or chronic kidney disease, including kidney stones. Consider slower titration and a 50% reduction in dosing if creatinine clearance is <70 mL/min. Obtain renal function tests before starting topiramate and consider monitoring serum bicarbonate for metabolic acidosis (we test at 3 and 6 months, then every 6 months). Because of teratogenic effects of topiramate (eg, cleft lip and palate), rule out pregnancy in all women of childbearing age.

Baclofen is a GABA_b receptor agonist that is FDA approved for treating spasticity. Because GABA transmission is down-regulated in chronic AUD, it is a commonly targeted neurotransmitter when developing medications for AUD. GABA_a receptors are fast-acting inhibitory ion channels, and its agonists (eg, benzodiazepines) have a significant abuse and cross-addiction liability. GABA_b receptors, however, are slow-acting through a complex cascade of intracellular signals, and therefore GABA_b agonists such as baclofen have been studied for treating addiction.

In a randomized double-blind, placebo-controlled trial (N = 39), baclofen was superior to placebo in suppressing obsessive aspects of cravings and decreasing state anxiety.¹¹ Baclofen, 10 mg 3 times daily, in another randomized double-blind, placebo-controlled trial (n = 42) reduced the number of drinks per day by 53% vs placebo; 20 mg 3 times a day resulted in a 68% reduction in drinks per day vs placebo.¹² However, a placebo-controlled RCT (n = 80) reported that baclofen, 10 mg 3 times daily, was not superior to placebo for primary outcomes related to alcohol consumption, although it did significantly decrease cravings and anxiety among persons with AUD.¹³ Evidence suggests that baclofen might be effective for promoting abstinence, reducing the risk of relapse, and alleviating cravings and anxiety in persons with AUD, although further investigation is needed.

In studies for AUD, the side-effect profile for baclofen was relatively benign.^11-13 Nausea, fatigue, sleepiness, vertigo, and abdominal pain were reported; overall, baclofen was found to be safe and to have no abuse liability.^7,10,12 The addictive potential of other muscle relaxers may have dissuaded providers from using baclofen for AUD, but we consider it a reasonable alternative when FDA-approved treatments fail.

Because baclofen is primarily eliminated by the kidneys, it may be safe for people with cirrhosis or severe liver disease.¹² Baseline renal labs should be performed before administering baclofen and a negative pregnancy test obtained for women of childbearing age.

Ondansetron is a serotonin receptor type 3 (5-HT3) antagonist that has shown promising results for AUD.^3,7 Research suggests that 5-HT3 receptors are an action site for alcohol in the brain and are thought to play a role in its rewarding effects.⁷ Ondansetron may be more effective for early-onset alcoholism (EOA) than late-onset alcoholism (LOA).^14,15 EOA (age ≤25) is characterized by strong family history of AUD and prominent antisocial traits. A randomized double-blind, placebo-controlled trial (n = 271) reported that ondansetron, 4 mcg/kg twice daily, was superior to placebo in reducing number of drinks per day, increasing days abstinent, and reducing cravings in patients with EOA.¹⁴ Among persons with EOA, ondansetron, 16 mcg/kg twice daily, significantly reduced the severity of symptoms of fatigue, confusion, and overall mood disturbance such as depression, anxiety, and hostility compared with placebo in an RCT (n = 321).¹⁵ The lowest available oral dosage of ondansetron is 4 mg tablets or 4 mg/5 mL solution. We have used 4 mg twice daily for patients who have failed naltrexone and acamprosate or when these agents are contraindicated.

Common side effects of ondansetron include constipation, diarrhea, elevated liver enzymes, tachycardia, headache, and fatigue. Contraindications include congenital long QT syndrome, QTc prolongation risk, or significant hepatic impairment. We suggest evaluating baseline electrocardiogram and liver function tests. Women should undergo a pregnancy test before receiving medications.

Gabapentin is an anticonvulsant that is FDA-approved for treating epilepsy and postherpetic neuralgia. Gabapentin is related structurally to GABA and may potentiate central nervous system GABA activity, inhibit glutamate activity, and reduce norepinephrine and dopamine release.¹⁶ Gabapentin is thought to balance the GABA/glutamate dysregulation found in early alcohol abstinence and reduce risk for alcohol relapse.¹⁶A randomized, double-blind, placebo-controlled trial (N = 60) demonstrated that gabapentin, 600 mg/d, significantly reduced number of drinks per day and heavy drinking days and increased days of abstinence compared with placebo over 28 days.¹⁷ Another double-blind, randomized, placebo-controlled trial of 150 people used gabapentin, 900 or 1,800 mg/d; there was a linear dose response for increased days abstinent and no heavy drinking days in favor of gabapentin.¹⁸

An RCT (N = 150) evaluated adding gabapentin, up to 1200 mg/d, to naltrexone, 50 mg/d, vs naltrexone with placebo or double placebo over 6 weeks of treatment. The combined gabapentin-naltrexone group outperformed the other 2 groups on time to heavy drinking, number of heavy drinking days, and number of drinks per day. Gabapentin’s positive effects on sleep may have mediated some of its beneficial effects.²⁹ In an open-label pilot study, gabapentin was more effective than trazodone for insomnia during early alcohol abstinence.³⁰ Of note, gabapentin is a safe alternative to benzodiazepines for alcohol detoxification in patients with severe hepatic disease or those at risk of interacting with alcohol (eg, outpatients at high risk to drink during detoxification).³¹ Gabapentin, 400 mg/d to 1,600 mg/d, generally is safe and well tolerated and has some support for improving cravings, reducing alcohol consumption, delaying relapse, and improving sleep in patients with AUD.

Side effects of gabapentin include daytime sedation, dizziness, ataxia, fatigue, and dyspepsia. Using 3 divided doses might enhance tolerability. To reduce daytime sedation, we recommend administering most of the dose at night, which also may relieve insomnia. Gabapentin is excreted through the kidney; baseline renal function tests should be performed before initiating treatment, because the dosage might need to be adjusted in people with renal insufficiency. 

Bottom Line

FDA-approved (acamprosate, naltrexone, and disulfiram) and off-label (baclofen, gabapentin, ondansetron, and topiramate) agents can help patients with alcohol use disorder achieve abstinence, reduce heavy drinking days, prevent relapse, and maintain sobriety. Research supports the use of pharmacotherapy combined with psychosocial modalities, such as 12-step programs, motivational interviewing, and cognitive-behavioral therapy.

Related Resources

• National Institute on Drug Abuse. Principles of drug addiction treatment: A research-based guide (third edition). www.drugabuse.gov/publications/principles-drug-addiction-treatment-research-based-guide-third-edition/evidence-based-approaches-to-drug-addiction-treatment/pharmacotherapi-1.
• Substance Abuse and Mental Health Services Administration. Incorporating alcohol pharmacotherapies into medical practice. http://162.99.3.213/products/manuals/tips/pdf/TIP49.pdf.
• Pettinati HM, Mattson ME. Medical management treatment manual: A clinical guide for researchers and clinicians providing pharmacotherapy for alcohol dependence. http://pubs.niaaa.nih.gov/publications/MedicalManual/MMManual.pdf.

Drug Brand Names

Acamprosate • Campral                        Naltrexone • Vivitrol, ReVia

Baclofen • Lioresal                                Ondansetron • Zofran

Disulfiram • Antabuse                           Topiramate • Topamax

Gabapentin • Neurontin                         Trazodone • Desyrel, Oleptro

Metronidazole • Flagyl

Disclosure

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

Historically, alcohol use disorder (AUD; classified as alcohol abuse or dependence in DSM-IV-TR) has been treated with psychosocial therapies, but many patients treated this way relapse into heavy drinking patterns and are unable to sustain sobriety (Box 1¹). Although vital for treating AUD, psychosocial methods have, to date, a modest success rate. Research has demonstrated that combining pharmacotherapy with psychosocial programs is effective for treating AUD.²

Patients and clinicians might associate AUD medications with so-called aversion therapy because, for many years, the only treatment was disulfiram, which causes unpleasant physical effects when consumed with alcohol. However, newer medications help patients maintain abstinence by targeting brain neurotransmitters relevant to addiction neurocircuitry, such as dopamine, serotonin, _ϒ-aminobutyric acid (GABA), glutamate, and opioid.³ These medications may help patients with AUD achieve sobriety, avoid relapse, decrease heavy drinking days, and delay time to recurrent drinking.

    In this article, we review FDA-approved medications (Table 1)^4-6 and off-label agents (Table 2)^3,7-18 and provide recommendations for treating patients with AUD (Box 2).^19-21

FDA-approved treatments

Naltrexone is an opiate antagonist that blocks the mu receptor and is believed to interrupt the dopamine reward pathway in the brain for alcohol. A meta-analysis of 2,861 patients in 24 combined randomized controlled trials (RCTs) demonstrated naltrexone to be an effective short-term (12 weeks) treatment for alcoholism, significantly decreasing relapses.²² The large multisite COMBINE study (N = 1,383) showed that naltrexone, 100 mg/d, and medical treatment without behavioral treatment over 16 weeks was more effective than placebo in increasing percentage of days abstinent (80.6% vs 75.1%, respectively) and reducing the percentage of patients experiencing heavy drinking days (66.2% vs 73.1%, respectively).² Patients who have a family history of AUD or strong cravings, or both, may benefit most from naltrexone.^3,7,23 Despite evidence of the effectiveness of naltrexone for AUD, not all studies have yielded positive results.²⁴

Common side effects of naltrexone, if present, appear early in treatment and include GI upset (eg, nausea, vomiting, abdominal pain), headache, and fatigue.^2,3,22,23 Hepatotoxicity has been reported with dosages of 100 to 300 mg/d, but lab values typically normalize when naltrexone is discontinued.^2,3,23 Monitor markers of liver function including _ϒ-glutamyltransferase, aspartate aminotransferase, alanine aminotransferase, and bilirubin before and during naltrexone treatment (we check patients 1 to 3 months after starting treatment and yearly thereafter). Obtain a negative urine drug screen for opioids before administering naltrexone, because if opioids were consumed recently naltrexone could precipitate withdrawal. Because of the unknown teratogenicity of naltrexone, women of childbearing age should undergo pregnancy testing before and periodically during naltrexone therapy.

Naltrexone also is available in a once-monthly, 380-mg injectable formulation. Studies show that, similar to its oral counterpart, injectable naltrexone effectively reduces heavy drinking days and number of drinks a day compared with placebo.^25,26 Advantages of injectable naltrexone are its extended steady release of medication and its efficacy for patients who do not adhere to oral dosing.^7,27 Side effects are similar to oral naltrexone, except for injection site reactions and pain.

Contraindications to naltrexone include current opioid use because its antagonistic effects on opioid receptors render opioid analgesia ineffective. Patients who have used opioids within 7 to 10 days or who may be surreptitiously using opioids should not take naltrexone because it may cause opioid withdrawal. Some patients may try to override the opioid receptor blockade of naltrexone with higher opioid doses, which could result in overdose.

Naltrexone is approved for treating opioid use disorder and may be useful for persons with comorbid opioid use disorder and AUD, if the patient has been adequately detoxified from opioids and intends to abstain from these drugs. Patients who have extensive liver damage secondary to acute hepatitis or uncompensated cirrhosis would not be good candidates for naltrexone because of a risk of hepatotoxicity.^2,3,22

Because of ease of dosing, we recommend naltrexone as a first-line treatment for AUD, unless the patient requires opioids or has severe liver disease. We recommend increasing naltrexone from 50 mg to 100 mg before switching to acamprosate, based on European studies.

Acamprosate is a glutamate antagonist that is thought to modulate overactive glutamatergic brain activity that occurs after stopping chronic heavy alcohol use. In a meta-analysis of 17 studies (N = 4,087), continuous abstinence rates at 6 months were significantly higher in acamprosate-treated patients (36.1%) than in patients receiving placebo (23.4%).²⁸ In a review of European studies, acamprosate benefited patients who have increased anxiety, physiological dependence, negative family history of AUD, and late age of onset (age >25) of alcohol dependence.⁷ However, in the COMBINE trial acamprosate was no more effective than placebo.²

We consider acamprosate an effective option for patients who do not respond to naltrexone or have a contraindication. Dosages of 333 mg to 666 mg, 3 times a day, are recommended, although dosages up to 3 g/d have been studied; titration is not required.^2,7,28 We recommend advising patients to continue treatment even if they relapse, because these medications may mitigate relapse severity. Adherence to multiple daily doses can be problematic for some patients, but pairing medications with meals or bedtime may improve adherence.

Diarrhea is the most common side effect of acamprosate; nervousness, fatigue, insomnia, and depression have been reported with high dosages.^2,3,7,28 Acamprosate is excreted through the kidney and is safe for patients with liver disorders such as acute hepatitis or cirrhosis. The drug is contraindicated in patients with acute or chronic renal failure with creatinine clearance <30 mL/min; those with less severe renal insufficiency might need a lower dosage. Obtain baseline renal function before starting acamprosate; women of childbearing age should undergo a pregnancy test.

Disulfiram inhibits alcohol metabolism, resulting in acetaldehyde accumulation, which causes unpleasant physical effects such as nausea, vomiting, and hypotension. This creates a negative rather than a positive experience with drinking. A US Veterans Administration Cooperative Study randomized 605 participants to riboflavin, disulfiram, 1 mg/d (an inactive dose), or disulfiram, 250 mg/d (standard dose). There was no difference in percentage of patients remaining abstinent or time to first drink.⁸ Participants receiving disulfiram, 250 mg/d, had fewer drinking days after relapse compared with the other groups.⁸

Adverse physical effects produced when disulfiram and alcohol interact include tremor, diaphoresis, unstable blood pressure, and severe diarrhea and vomiting. Disulfiram can cause medically serious reactions in a small percentage of patients, especially those with significant medical comorbidity or advanced age. Patients with severe hypertension, diabetes mellitus, heart disease, a history of stroke, peripheral neuropathy, epilepsy, or renal or hepatic insufficiency should not use disulfiram.³ Patients taking disulfiram should avoid casual exposures to food, aftershave, mouthwash, and hand sanitizer that might contain alcohol. Disulfiram has no significant effect on alcohol craving. Social support to help oversee dosing may enhance adherence.⁷

Off-label medications

Topiramate is FDA-approved to treat migraine headaches and some seizure disorders. Topiramate facilitates GABA-mediated neuronal inhibition and antagonizes certain glutamate receptor subtypes. In an RCT (N = 150), topiramate, up to 300 mg/d, was more effective than placebo at reducing heavy drinking days and number of drinks per day, increasing days abstinent, and alleviating cravings.⁹ In a 12-week, double-blind RCT (N = 150), topiramate increased “safe drinking”—defined as ≤1 standard drink per day for women and ≤2 per day for men—vs placebo.¹⁰ Dosages were 75 mg to 300 mg/d in twice daily divided doses. Dosing starts at 25 mg/d and increases by 25 to 50 mg a day at weekly intervals. We recommend reserving topiramate for persons who do not respond to or cannot tolerate naltrexone and acamprosate because of the slow titration needed to prevent side effects. Although not studied, it may seem that topiramate’s antiepileptic actions could prevent seizures during alcohol withdrawal, but the protracted titration would limit its utility.

Side effects of topiramate include impaired memory and concentration, paresthesia, and anorexia and are more likely to present during rapid titration or with a high dosage.^7,8 Rare reports of spontaneous myopia, angle-closure glaucoma, increased intraocular pressure, ocular pain, and blurry vision have been reported, but these complications often resolve with discontinuation of topiramate.^7,8

Topiramate primarily is excreted through the kidney, and its action in the renal tubules can lead to metabolic acidosis or nephrolithiasis.⁸ Relative contraindications include acute or chronic kidney disease, including kidney stones. Consider slower titration and a 50% reduction in dosing if creatinine clearance is <70 mL/min. Obtain renal function tests before starting topiramate and consider monitoring serum bicarbonate for metabolic acidosis (we test at 3 and 6 months, then every 6 months). Because of teratogenic effects of topiramate (eg, cleft lip and palate), rule out pregnancy in all women of childbearing age.

Baclofen is a GABA_b receptor agonist that is FDA approved for treating spasticity. Because GABA transmission is down-regulated in chronic AUD, it is a commonly targeted neurotransmitter when developing medications for AUD. GABA_a receptors are fast-acting inhibitory ion channels, and its agonists (eg, benzodiazepines) have a significant abuse and cross-addiction liability. GABA_b receptors, however, are slow-acting through a complex cascade of intracellular signals, and therefore GABA_b agonists such as baclofen have been studied for treating addiction.

In a randomized double-blind, placebo-controlled trial (N = 39), baclofen was superior to placebo in suppressing obsessive aspects of cravings and decreasing state anxiety.¹¹ Baclofen, 10 mg 3 times daily, in another randomized double-blind, placebo-controlled trial (n = 42) reduced the number of drinks per day by 53% vs placebo; 20 mg 3 times a day resulted in a 68% reduction in drinks per day vs placebo.¹² However, a placebo-controlled RCT (n = 80) reported that baclofen, 10 mg 3 times daily, was not superior to placebo for primary outcomes related to alcohol consumption, although it did significantly decrease cravings and anxiety among persons with AUD.¹³ Evidence suggests that baclofen might be effective for promoting abstinence, reducing the risk of relapse, and alleviating cravings and anxiety in persons with AUD, although further investigation is needed.

In studies for AUD, the side-effect profile for baclofen was relatively benign.^11-13 Nausea, fatigue, sleepiness, vertigo, and abdominal pain were reported; overall, baclofen was found to be safe and to have no abuse liability.^7,10,12 The addictive potential of other muscle relaxers may have dissuaded providers from using baclofen for AUD, but we consider it a reasonable alternative when FDA-approved treatments fail.

Because baclofen is primarily eliminated by the kidneys, it may be safe for people with cirrhosis or severe liver disease.¹² Baseline renal labs should be performed before administering baclofen and a negative pregnancy test obtained for women of childbearing age.

Ondansetron is a serotonin receptor type 3 (5-HT3) antagonist that has shown promising results for AUD.^3,7 Research suggests that 5-HT3 receptors are an action site for alcohol in the brain and are thought to play a role in its rewarding effects.⁷ Ondansetron may be more effective for early-onset alcoholism (EOA) than late-onset alcoholism (LOA).^14,15 EOA (age ≤25) is characterized by strong family history of AUD and prominent antisocial traits. A randomized double-blind, placebo-controlled trial (n = 271) reported that ondansetron, 4 mcg/kg twice daily, was superior to placebo in reducing number of drinks per day, increasing days abstinent, and reducing cravings in patients with EOA.¹⁴ Among persons with EOA, ondansetron, 16 mcg/kg twice daily, significantly reduced the severity of symptoms of fatigue, confusion, and overall mood disturbance such as depression, anxiety, and hostility compared with placebo in an RCT (n = 321).¹⁵ The lowest available oral dosage of ondansetron is 4 mg tablets or 4 mg/5 mL solution. We have used 4 mg twice daily for patients who have failed naltrexone and acamprosate or when these agents are contraindicated.

Common side effects of ondansetron include constipation, diarrhea, elevated liver enzymes, tachycardia, headache, and fatigue. Contraindications include congenital long QT syndrome, QTc prolongation risk, or significant hepatic impairment. We suggest evaluating baseline electrocardiogram and liver function tests. Women should undergo a pregnancy test before receiving medications.

Gabapentin is an anticonvulsant that is FDA-approved for treating epilepsy and postherpetic neuralgia. Gabapentin is related structurally to GABA and may potentiate central nervous system GABA activity, inhibit glutamate activity, and reduce norepinephrine and dopamine release.¹⁶ Gabapentin is thought to balance the GABA/glutamate dysregulation found in early alcohol abstinence and reduce risk for alcohol relapse.¹⁶A randomized, double-blind, placebo-controlled trial (N = 60) demonstrated that gabapentin, 600 mg/d, significantly reduced number of drinks per day and heavy drinking days and increased days of abstinence compared with placebo over 28 days.¹⁷ Another double-blind, randomized, placebo-controlled trial of 150 people used gabapentin, 900 or 1,800 mg/d; there was a linear dose response for increased days abstinent and no heavy drinking days in favor of gabapentin.¹⁸

An RCT (N = 150) evaluated adding gabapentin, up to 1200 mg/d, to naltrexone, 50 mg/d, vs naltrexone with placebo or double placebo over 6 weeks of treatment. The combined gabapentin-naltrexone group outperformed the other 2 groups on time to heavy drinking, number of heavy drinking days, and number of drinks per day. Gabapentin’s positive effects on sleep may have mediated some of its beneficial effects.²⁹ In an open-label pilot study, gabapentin was more effective than trazodone for insomnia during early alcohol abstinence.³⁰ Of note, gabapentin is a safe alternative to benzodiazepines for alcohol detoxification in patients with severe hepatic disease or those at risk of interacting with alcohol (eg, outpatients at high risk to drink during detoxification).³¹ Gabapentin, 400 mg/d to 1,600 mg/d, generally is safe and well tolerated and has some support for improving cravings, reducing alcohol consumption, delaying relapse, and improving sleep in patients with AUD.

Side effects of gabapentin include daytime sedation, dizziness, ataxia, fatigue, and dyspepsia. Using 3 divided doses might enhance tolerability. To reduce daytime sedation, we recommend administering most of the dose at night, which also may relieve insomnia. Gabapentin is excreted through the kidney; baseline renal function tests should be performed before initiating treatment, because the dosage might need to be adjusted in people with renal insufficiency. 

Bottom Line

FDA-approved (acamprosate, naltrexone, and disulfiram) and off-label (baclofen, gabapentin, ondansetron, and topiramate) agents can help patients with alcohol use disorder achieve abstinence, reduce heavy drinking days, prevent relapse, and maintain sobriety. Research supports the use of pharmacotherapy combined with psychosocial modalities, such as 12-step programs, motivational interviewing, and cognitive-behavioral therapy.

Related Resources

• National Institute on Drug Abuse. Principles of drug addiction treatment: A research-based guide (third edition). www.drugabuse.gov/publications/principles-drug-addiction-treatment-research-based-guide-third-edition/evidence-based-approaches-to-drug-addiction-treatment/pharmacotherapi-1.
• Substance Abuse and Mental Health Services Administration. Incorporating alcohol pharmacotherapies into medical practice. http://162.99.3.213/products/manuals/tips/pdf/TIP49.pdf.
• Pettinati HM, Mattson ME. Medical management treatment manual: A clinical guide for researchers and clinicians providing pharmacotherapy for alcohol dependence. http://pubs.niaaa.nih.gov/publications/MedicalManual/MMManual.pdf.

Drug Brand Names

Acamprosate • Campral                        Naltrexone • Vivitrol, ReVia

Baclofen • Lioresal                                Ondansetron • Zofran

Disulfiram • Antabuse                           Topiramate • Topamax

Gabapentin • Neurontin                         Trazodone • Desyrel, Oleptro

Metronidazole • Flagyl

Disclosure

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

One of the most common reasons medical colleagues seek consultation with a psychiatrist is to address the question of capacity. Indeed, this referral question often is posed as, “Is the patient competent?”

This referral question is incomplete and incorrectly phrased. The question should include the domain in which capacity is being questioned—for example, “Is the patient competent to refuse surgery?” Specifically identifying the area in which competency is questioned is necessary because a person might be competent in one area and incompetent in another (Box 1).

The question of competency should be modified as follows: “Does the patient have capacity to refuse surgery?” Competency is the degree of mental soundness necessary to make decisions about a specific issue or to carry out a specific act. Capacity is a person’s ability to make an informed decision. A determination of competency is a judicial finding made by the court. A physician can opine about a patient’s capacity, but cannot determine competency.

Adults are presumed to have capacity unless determined otherwise by the court. A person who lacks capacity to make an informed decision or give consent might need to be referred for a competency hearing or have a guardian appointed. Psychiatrists often are called on to provide an opinion to the court regarding a person’s capacity. Psychiatrists are particularly skilled at accessing a person’s mental status and gauging its potential for interfering with specific areas of functioning, but, in fact, any physician can make a determination of capacity.¹

In this article, I:

• outline the components of a capacity evaluation
• describe the tools used in the determination of capacity
• review the typical features of patients and psychiatrists who perform capacity evaluations.

What constitutes a capacity evaluation?

The components of a capacity evaluation are comprehension, free choice, and reliability.

Comprehension refers to a patient’s factual understanding of his (her) medical condition—for example, including the risks and benefits of treatment and reasonable alternatives. The patient should show an understanding of 1) the situation as it relates to his condition, and 2) the consequences of his decisions. He also should demonstrate a rational manipulation of the information presented, applying a coherent and logical thought process to analyze possible courses of action.²

To determine if the patient has the requisite knowledge regarding his condition, the physician must be familiar with the patient’s clinical status. This might require consultation with the treating physician. Communication is a key component of capacity evaluations. Barriers to good communication can lead to the evaluating physician’s perception that the patient lacks capacity. If a patient does not understand his condition or the proposed treatments, the psychiatrist should educate him. It might be useful to arrange a meeting with the treating physician to facilitate communication.

Free choice. The patient’s decision to accept or reject a proposed treatment should be voluntary and free of coercion. In assessing a patient’s capacity, the psychiatrist should determine whether choices have been rendered impossible because of unrealistic fears or expectations about treatment, or because of impaired mental processes.

Reliability refers to a patient’s ability to provide a consistent choice over time. A patient who vacillates or is inconsistent does not have capacity to make decisions.

Features of patients referred for evaluation, and their evaluators

The most common reason for a capacity evaluation is a patient’s refusal of medical treatment. Between 3% and 25% of requests for psychiatric consultation in hospital settings involve questions about patients’ competence to make a treatment-related decision.³ Approximately 25% of adult medicine inpatients lack capacity for medical decision-making.⁴

Decision-making capacity is a functional evaluation. Decision-making capacity does not relate specifically to a person’s psychiatric diagnosis. In other words, the presence of a mental disorder does not render a person incapable of making decisions. However, people with Alzheimer’s disease or dementia have a high rate of impaired capacity for making treatment decisions.

Schizophrenia has been found to have the highest rate of impaired decision-making among psychiatric disorders; depression is second and bipolar disorder, third. The strongest predictor of incapacity in psychiatric patients is lack of insight.⁵ Positive symptoms, negative symptoms, severity of symptoms, involuntary admission, lack of insight, and treatment refusal were strong predictors of incapacity in a sample of psychiatric patients.⁶

The neuronal basis of decision-making is unknown. Studies have implicated functioning of the medial and lateral prefrontal cortex as an important correlate of decision-making capacity.⁷ As a result of these findings, a brain-based criterion could be added to the conceptual criteria of capacity. The specific neuropsychological components necessary for decision-making capacity are unknown. Some studies suggest that poor executive functioning and limited learning ability correlate with impaired decision-making capacity.⁸ Little is known about the relationship between emotion and capacity. Supady et al demonstrated that higher cognitive empathy and good emotion recognition were associated with increased decision-making capacity and higher rates of refusal to give informed consent.⁹

Physician bias has been identified in capacity evaluations. See Box 2.^4,10-12

Tools used in capacity evaluations

Most capacity evaluations are conducted by clinical interview (Box 3). The reliability of physicians’ unstructured judgments of capacity has been poor.¹³ In a study of 5 physicians who made a determination of capacity after watching a videotape of capacity assessments, the rate of agreement among the subjects was no better than that of chance.¹⁴

There is no specific, simple, quick test to assess capacity.

Folstein Mini-Mental State Examination. The MMSE has not been found to be predictive of decision-making capacity. It has been found to correlate with clinical judgments of incapacity, and may be used to identify patients at the high and low ends of the range of capacity, especially among older persons who exhibit cognitive impairment.¹⁵ Patients who have severe dementia (MMSE score <16) have a high likelihood of being unable to consent to treatment.¹⁶

MacArthur Competence Assessment Tool-Treatment. The MacCAT-T is a structured interviewing tool used to evaluate a patient’s decision-making ability. It is the most commonly used screening tool to evaluate decision-making capacity. Advantages of the MacCAT-T include a higher inter-rater agreement and—unlike other assessment instruments—its ability to incorporate information specific to a patient’s decision-making situation.¹⁷ The MacCAT-T requires training and experience to administer.

Bottom Line

Physicians make decisions about a patient’s decision-making capacity. Courts determine competence by a formal judicial proceeding. The psychiatric consultant’s role in capacity evaluations is to determine if the patient 1) possesses the requisite knowledge about the specific referral issue and 2) demonstrates a voluntary and reliable decision.

Related Resources

• The MacArthur Treatment Competence Study. www.macarthur.virginia.edu/treatment.html.
• Resnick P, Sorrentino R: Forensic considerations (chapter. 8). In: Psychosomatic medicine. Blumenfield M, Strain JJ, eds. Baltimore, MD: Lippincott Williams & Wilkins; 2006:91-106.
• Appelbaum PS. Assessment of patients’ competence to consent to treatment. N Engl J Med. 2007;357(18):1834-1840. 

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

One of the most common reasons medical colleagues seek consultation with a psychiatrist is to address the question of capacity. Indeed, this referral question often is posed as, “Is the patient competent?”

This referral question is incomplete and incorrectly phrased. The question should include the domain in which capacity is being questioned—for example, “Is the patient competent to refuse surgery?” Specifically identifying the area in which competency is questioned is necessary because a person might be competent in one area and incompetent in another (Box 1).

The question of competency should be modified as follows: “Does the patient have capacity to refuse surgery?” Competency is the degree of mental soundness necessary to make decisions about a specific issue or to carry out a specific act. Capacity is a person’s ability to make an informed decision. A determination of competency is a judicial finding made by the court. A physician can opine about a patient’s capacity, but cannot determine competency.

Adults are presumed to have capacity unless determined otherwise by the court. A person who lacks capacity to make an informed decision or give consent might need to be referred for a competency hearing or have a guardian appointed. Psychiatrists often are called on to provide an opinion to the court regarding a person’s capacity. Psychiatrists are particularly skilled at accessing a person’s mental status and gauging its potential for interfering with specific areas of functioning, but, in fact, any physician can make a determination of capacity.¹

In this article, I:

• outline the components of a capacity evaluation
• describe the tools used in the determination of capacity
• review the typical features of patients and psychiatrists who perform capacity evaluations.

What constitutes a capacity evaluation?

The components of a capacity evaluation are comprehension, free choice, and reliability.

Comprehension refers to a patient’s factual understanding of his (her) medical condition—for example, including the risks and benefits of treatment and reasonable alternatives. The patient should show an understanding of 1) the situation as it relates to his condition, and 2) the consequences of his decisions. He also should demonstrate a rational manipulation of the information presented, applying a coherent and logical thought process to analyze possible courses of action.²

To determine if the patient has the requisite knowledge regarding his condition, the physician must be familiar with the patient’s clinical status. This might require consultation with the treating physician. Communication is a key component of capacity evaluations. Barriers to good communication can lead to the evaluating physician’s perception that the patient lacks capacity. If a patient does not understand his condition or the proposed treatments, the psychiatrist should educate him. It might be useful to arrange a meeting with the treating physician to facilitate communication.

Free choice. The patient’s decision to accept or reject a proposed treatment should be voluntary and free of coercion. In assessing a patient’s capacity, the psychiatrist should determine whether choices have been rendered impossible because of unrealistic fears or expectations about treatment, or because of impaired mental processes.

Reliability refers to a patient’s ability to provide a consistent choice over time. A patient who vacillates or is inconsistent does not have capacity to make decisions.

Features of patients referred for evaluation, and their evaluators

The most common reason for a capacity evaluation is a patient’s refusal of medical treatment. Between 3% and 25% of requests for psychiatric consultation in hospital settings involve questions about patients’ competence to make a treatment-related decision.³ Approximately 25% of adult medicine inpatients lack capacity for medical decision-making.⁴

Decision-making capacity is a functional evaluation. Decision-making capacity does not relate specifically to a person’s psychiatric diagnosis. In other words, the presence of a mental disorder does not render a person incapable of making decisions. However, people with Alzheimer’s disease or dementia have a high rate of impaired capacity for making treatment decisions.

Schizophrenia has been found to have the highest rate of impaired decision-making among psychiatric disorders; depression is second and bipolar disorder, third. The strongest predictor of incapacity in psychiatric patients is lack of insight.⁵ Positive symptoms, negative symptoms, severity of symptoms, involuntary admission, lack of insight, and treatment refusal were strong predictors of incapacity in a sample of psychiatric patients.⁶

The neuronal basis of decision-making is unknown. Studies have implicated functioning of the medial and lateral prefrontal cortex as an important correlate of decision-making capacity.⁷ As a result of these findings, a brain-based criterion could be added to the conceptual criteria of capacity. The specific neuropsychological components necessary for decision-making capacity are unknown. Some studies suggest that poor executive functioning and limited learning ability correlate with impaired decision-making capacity.⁸ Little is known about the relationship between emotion and capacity. Supady et al demonstrated that higher cognitive empathy and good emotion recognition were associated with increased decision-making capacity and higher rates of refusal to give informed consent.⁹

Physician bias has been identified in capacity evaluations. See Box 2.^4,10-12

Tools used in capacity evaluations

Most capacity evaluations are conducted by clinical interview (Box 3). The reliability of physicians’ unstructured judgments of capacity has been poor.¹³ In a study of 5 physicians who made a determination of capacity after watching a videotape of capacity assessments, the rate of agreement among the subjects was no better than that of chance.¹⁴

There is no specific, simple, quick test to assess capacity.

Folstein Mini-Mental State Examination. The MMSE has not been found to be predictive of decision-making capacity. It has been found to correlate with clinical judgments of incapacity, and may be used to identify patients at the high and low ends of the range of capacity, especially among older persons who exhibit cognitive impairment.¹⁵ Patients who have severe dementia (MMSE score <16) have a high likelihood of being unable to consent to treatment.¹⁶

MacArthur Competence Assessment Tool-Treatment. The MacCAT-T is a structured interviewing tool used to evaluate a patient’s decision-making ability. It is the most commonly used screening tool to evaluate decision-making capacity. Advantages of the MacCAT-T include a higher inter-rater agreement and—unlike other assessment instruments—its ability to incorporate information specific to a patient’s decision-making situation.¹⁷ The MacCAT-T requires training and experience to administer.

Bottom Line

Physicians make decisions about a patient’s decision-making capacity. Courts determine competence by a formal judicial proceeding. The psychiatric consultant’s role in capacity evaluations is to determine if the patient 1) possesses the requisite knowledge about the specific referral issue and 2) demonstrates a voluntary and reliable decision.

Related Resources

• The MacArthur Treatment Competence Study. www.macarthur.virginia.edu/treatment.html.
• Resnick P, Sorrentino R: Forensic considerations (chapter. 8). In: Psychosomatic medicine. Blumenfield M, Strain JJ, eds. Baltimore, MD: Lippincott Williams & Wilkins; 2006:91-106.
• Appelbaum PS. Assessment of patients’ competence to consent to treatment. N Engl J Med. 2007;357(18):1834-1840. 

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

One of the most common reasons medical colleagues seek consultation with a psychiatrist is to address the question of capacity. Indeed, this referral question often is posed as, “Is the patient competent?”

This referral question is incomplete and incorrectly phrased. The question should include the domain in which capacity is being questioned—for example, “Is the patient competent to refuse surgery?” Specifically identifying the area in which competency is questioned is necessary because a person might be competent in one area and incompetent in another (Box 1).

The question of competency should be modified as follows: “Does the patient have capacity to refuse surgery?” Competency is the degree of mental soundness necessary to make decisions about a specific issue or to carry out a specific act. Capacity is a person’s ability to make an informed decision. A determination of competency is a judicial finding made by the court. A physician can opine about a patient’s capacity, but cannot determine competency.

Adults are presumed to have capacity unless determined otherwise by the court. A person who lacks capacity to make an informed decision or give consent might need to be referred for a competency hearing or have a guardian appointed. Psychiatrists often are called on to provide an opinion to the court regarding a person’s capacity. Psychiatrists are particularly skilled at accessing a person’s mental status and gauging its potential for interfering with specific areas of functioning, but, in fact, any physician can make a determination of capacity.¹

In this article, I:

• outline the components of a capacity evaluation
• describe the tools used in the determination of capacity
• review the typical features of patients and psychiatrists who perform capacity evaluations.

What constitutes a capacity evaluation?

The components of a capacity evaluation are comprehension, free choice, and reliability.

Comprehension refers to a patient’s factual understanding of his (her) medical condition—for example, including the risks and benefits of treatment and reasonable alternatives. The patient should show an understanding of 1) the situation as it relates to his condition, and 2) the consequences of his decisions. He also should demonstrate a rational manipulation of the information presented, applying a coherent and logical thought process to analyze possible courses of action.²

To determine if the patient has the requisite knowledge regarding his condition, the physician must be familiar with the patient’s clinical status. This might require consultation with the treating physician. Communication is a key component of capacity evaluations. Barriers to good communication can lead to the evaluating physician’s perception that the patient lacks capacity. If a patient does not understand his condition or the proposed treatments, the psychiatrist should educate him. It might be useful to arrange a meeting with the treating physician to facilitate communication.

Free choice. The patient’s decision to accept or reject a proposed treatment should be voluntary and free of coercion. In assessing a patient’s capacity, the psychiatrist should determine whether choices have been rendered impossible because of unrealistic fears or expectations about treatment, or because of impaired mental processes.

Reliability refers to a patient’s ability to provide a consistent choice over time. A patient who vacillates or is inconsistent does not have capacity to make decisions.

Features of patients referred for evaluation, and their evaluators

The most common reason for a capacity evaluation is a patient’s refusal of medical treatment. Between 3% and 25% of requests for psychiatric consultation in hospital settings involve questions about patients’ competence to make a treatment-related decision.³ Approximately 25% of adult medicine inpatients lack capacity for medical decision-making.⁴

Decision-making capacity is a functional evaluation. Decision-making capacity does not relate specifically to a person’s psychiatric diagnosis. In other words, the presence of a mental disorder does not render a person incapable of making decisions. However, people with Alzheimer’s disease or dementia have a high rate of impaired capacity for making treatment decisions.

Schizophrenia has been found to have the highest rate of impaired decision-making among psychiatric disorders; depression is second and bipolar disorder, third. The strongest predictor of incapacity in psychiatric patients is lack of insight.⁵ Positive symptoms, negative symptoms, severity of symptoms, involuntary admission, lack of insight, and treatment refusal were strong predictors of incapacity in a sample of psychiatric patients.⁶

The neuronal basis of decision-making is unknown. Studies have implicated functioning of the medial and lateral prefrontal cortex as an important correlate of decision-making capacity.⁷ As a result of these findings, a brain-based criterion could be added to the conceptual criteria of capacity. The specific neuropsychological components necessary for decision-making capacity are unknown. Some studies suggest that poor executive functioning and limited learning ability correlate with impaired decision-making capacity.⁸ Little is known about the relationship between emotion and capacity. Supady et al demonstrated that higher cognitive empathy and good emotion recognition were associated with increased decision-making capacity and higher rates of refusal to give informed consent.⁹

Physician bias has been identified in capacity evaluations. See Box 2.^4,10-12

Tools used in capacity evaluations

Most capacity evaluations are conducted by clinical interview (Box 3). The reliability of physicians’ unstructured judgments of capacity has been poor.¹³ In a study of 5 physicians who made a determination of capacity after watching a videotape of capacity assessments, the rate of agreement among the subjects was no better than that of chance.¹⁴

There is no specific, simple, quick test to assess capacity.

Folstein Mini-Mental State Examination. The MMSE has not been found to be predictive of decision-making capacity. It has been found to correlate with clinical judgments of incapacity, and may be used to identify patients at the high and low ends of the range of capacity, especially among older persons who exhibit cognitive impairment.¹⁵ Patients who have severe dementia (MMSE score <16) have a high likelihood of being unable to consent to treatment.¹⁶

MacArthur Competence Assessment Tool-Treatment. The MacCAT-T is a structured interviewing tool used to evaluate a patient’s decision-making ability. It is the most commonly used screening tool to evaluate decision-making capacity. Advantages of the MacCAT-T include a higher inter-rater agreement and—unlike other assessment instruments—its ability to incorporate information specific to a patient’s decision-making situation.¹⁷ The MacCAT-T requires training and experience to administer.

Bottom Line

Physicians make decisions about a patient’s decision-making capacity. Courts determine competence by a formal judicial proceeding. The psychiatric consultant’s role in capacity evaluations is to determine if the patient 1) possesses the requisite knowledge about the specific referral issue and 2) demonstrates a voluntary and reliable decision.

Related Resources

• The MacArthur Treatment Competence Study. www.macarthur.virginia.edu/treatment.html.
• Resnick P, Sorrentino R: Forensic considerations (chapter. 8). In: Psychosomatic medicine. Blumenfield M, Strain JJ, eds. Baltimore, MD: Lippincott Williams & Wilkins; 2006:91-106.
• Appelbaum PS. Assessment of patients’ competence to consent to treatment. N Engl J Med. 2007;357(18):1834-1840. 

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

Mr. M, age 28, was given a diagnosis of schizophrenia 6 years ago after experiencing a psychotic break involving auditory hallucinations and paranoia. Olanzapine, 10 mg/d, relieved his symptoms, but he stopped taking the drug after gaining 40 pounds and developing diabetes mellitus. He had 2 other hospital admissions for acute psychosis and has taken at least 1 other medication, the name of which he can’t recall. Recently, Mr. M was involuntarily admitted to the psychiatric ward of his local hospital. His psychiatrist started aripiprazole, 10 mg/d, which was titrated to 30 mg/d. After 2 weeks he reports only a slight decrease in hallucinations. His mother is growing concerned about the effectiveness of this medication and wants to know if it’s time to consider another drug.

Time to onset of action of antipsychotic agents has been debated since at least 1970.¹ Supporters of the delayed-onset hypothesis assert that antipsychotics take weeks or months to show significant improvement of symptoms because of the need for depolarization block for efficacy.² Trials of 4 to 6 weeks often are recommended for patients before failure is declared,^3,4 and trials of this length or longer have proved useful for first-episode patients.^5-7 Recent studies suggest, however, that response is cumulative for chronically ill Practice Points

• Chronically ill and first-episode patients may respond differently to antipsychotics.
• In chronically ill patients with schizophrenia, early non-response accurately predicts non-response at weeks 4 to 12 in 75% to 85% of patients. Early response accurately predicts sustained response at weeks 4 to 12 in approximately 50% to 70% of patients.
• In first-episode patients with schizophrenia, early non-response predicts non-response at weeks 12 to 16 in approximately 60% to 65% of patients. Early response predicts response at weeks 12 to 16 in approximately 60% to 75% of patients.triglyceride, and LDL levels, and a decrease in the HDL level.² These effects may be seen without an increase in BMI, and should be considered a direct effect of the antipsychotic.⁵ Although the mechanism by which dyslipidemia occurs is poorly understood, an increase in the blood glucose level is thought to be, in part, mediated by antagonism of M3 muscarinic receptors on pancreatic âpatients with most improvement occurring during weeks 1 and 2.^1,8

Two meta-analyses found the greatest rate of cumulative improvement in symptoms during the first 2 weeks.^1,8 These analyses included chronically ill patients with mean duration of illness of 15.5 and 10.4 years, respectively. Patients reported 21.9% and 20.5% reductions in symptoms from baseline at 2 weeks, with total responses between 30% at 4 weeks and 40% at 1 year, respectively. These meta-analyses indicate that most of the benefit from antipsychotics in this patient population occurs in the first 2 weeks, which supports the early-response hypothesis.

These observations led to questions about the predictive value of early response and minimum time to determine treatment failure. This article discusses the significance of early response and non-response to antipsychotics and their impact on treating patients with schizophrenia.

What are the predictive factors? How can they guide treatment?

Of the 8 studies in our literature review, only 2 reported early response rates >50%.^9,10 (see this article at CurrentPsychiatry.com for a Box describing the literature review.) Positive predictive value (PPV) ranged from 0.51 to 0.81, meaning that 51% to 81% of early responders continued to respond. Six of the 8 studies reported PPV of 50% to 70%. ^9,11-15 This appears to be true for chronic and first-episode patients, suggesting that 30% to 50% of early responders will fail to have a sustained response (Table 1,^9-16Table 2,^9-16 and Figure).

Compared with early response, early non-response is a more consistent predictor of final non-response. In every study of chronically ill patients, negative predictive value (NPV) was greater than PPV (Table 1).^9-16 NPVs in the literature suggest that 58% to 91% of early non-responders will continue to be non-responders. This seems to be true of chronically ill patients for whom NPVs consistently were between 75% and 85%. By comparison, in first-episode patients NPVs of 58% and 66% were calculated (Table 1^9-16 and Figure).^14,15

These observations suggest that reassessing drug therapy is indicated early in treatment for early non-responders, particularly in chronically ill patients. However, early non-response in a first-episode patient is not as strong a predictor of eventual treatment failure, supporting the idea that first-episode patients may experience a delayed response to therapy. Researchers studying onset of antipsychotic effect report that median time to response onset in first-episode patients may be ≥8 weeks.^6,8 In patients who do not achieve modest early response, assess dose, adherence, substance abuse, and psychosocial stressors.³ For patients without dose, adherence, substance use, or stress issues, switching drug therapy in chronically ill early non-responders is reasonable because the probability of a late response is small.

Individual patient characteristics determine how much these data aid clinical decision-making. If a patient has a good response to an antipsychotic in the first 2 weeks, continue the drug, but observe the patient closely because response may not be sustained. In first-episode patients who fail to respond within 2 weeks of starting an antipsychotic, it is reasonable to continue the drug for several weeks because these patients may be more likely to respond later in therapy.

Clinicians treating chronically ill patients who have failed several antipsychotics and demonstrate a poor response after 2 weeks of an appropriate antipsychotic dose are justified in changing medications because later significant response is unlikely. If a patient has a poor early response but has failed several other antipsychotics with few remaining alternatives, it is reasonable to continue the maximum tolerated dose of the current therapy because the patient may be a late responder. However, early non-response predicts future non-response in many patients.

Case continued

In the case described here, Mr. M is failing his current treatment regimen with a reasonable antipsychotic dose after 2 weeks. Because Mr. M has been on 2 antipsychotics and demonstrated a good response to olanzapine, changing medications should be considered.

Related Resource

• Correll CU, Hauser M. The year in psychosis and bipolar disorder: predicting response to schizophrenia treatment. www.medscape.com/viewarticle/735211_7.

Drug Brand Names

Aripiprazole • Abilify                Quetiapine • Seroquel

Haloperidol • Haldol                 Risperidone • Risperdal

Olanzapine • Zyprexa               Ziprasidone • Geodon

Paliperidone • Invega

Disclosures
Dr. Straley owns stock in Johnson & Johnson. Dr. Webster reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Mr. M, age 28, was given a diagnosis of schizophrenia 6 years ago after experiencing a psychotic break involving auditory hallucinations and paranoia. Olanzapine, 10 mg/d, relieved his symptoms, but he stopped taking the drug after gaining 40 pounds and developing diabetes mellitus. He had 2 other hospital admissions for acute psychosis and has taken at least 1 other medication, the name of which he can’t recall. Recently, Mr. M was involuntarily admitted to the psychiatric ward of his local hospital. His psychiatrist started aripiprazole, 10 mg/d, which was titrated to 30 mg/d. After 2 weeks he reports only a slight decrease in hallucinations. His mother is growing concerned about the effectiveness of this medication and wants to know if it’s time to consider another drug.

Time to onset of action of antipsychotic agents has been debated since at least 1970.¹ Supporters of the delayed-onset hypothesis assert that antipsychotics take weeks or months to show significant improvement of symptoms because of the need for depolarization block for efficacy.² Trials of 4 to 6 weeks often are recommended for patients before failure is declared,^3,4 and trials of this length or longer have proved useful for first-episode patients.^5-7 Recent studies suggest, however, that response is cumulative for chronically ill Practice Points

• Chronically ill and first-episode patients may respond differently to antipsychotics.
• In chronically ill patients with schizophrenia, early non-response accurately predicts non-response at weeks 4 to 12 in 75% to 85% of patients. Early response accurately predicts sustained response at weeks 4 to 12 in approximately 50% to 70% of patients.
• In first-episode patients with schizophrenia, early non-response predicts non-response at weeks 12 to 16 in approximately 60% to 65% of patients. Early response predicts response at weeks 12 to 16 in approximately 60% to 75% of patients.triglyceride, and LDL levels, and a decrease in the HDL level.² These effects may be seen without an increase in BMI, and should be considered a direct effect of the antipsychotic.⁵ Although the mechanism by which dyslipidemia occurs is poorly understood, an increase in the blood glucose level is thought to be, in part, mediated by antagonism of M3 muscarinic receptors on pancreatic âpatients with most improvement occurring during weeks 1 and 2.^1,8

Two meta-analyses found the greatest rate of cumulative improvement in symptoms during the first 2 weeks.^1,8 These analyses included chronically ill patients with mean duration of illness of 15.5 and 10.4 years, respectively. Patients reported 21.9% and 20.5% reductions in symptoms from baseline at 2 weeks, with total responses between 30% at 4 weeks and 40% at 1 year, respectively. These meta-analyses indicate that most of the benefit from antipsychotics in this patient population occurs in the first 2 weeks, which supports the early-response hypothesis.

These observations led to questions about the predictive value of early response and minimum time to determine treatment failure. This article discusses the significance of early response and non-response to antipsychotics and their impact on treating patients with schizophrenia.

What are the predictive factors? How can they guide treatment?

Of the 8 studies in our literature review, only 2 reported early response rates >50%.^9,10 (see this article at CurrentPsychiatry.com for a Box describing the literature review.) Positive predictive value (PPV) ranged from 0.51 to 0.81, meaning that 51% to 81% of early responders continued to respond. Six of the 8 studies reported PPV of 50% to 70%. ^9,11-15 This appears to be true for chronic and first-episode patients, suggesting that 30% to 50% of early responders will fail to have a sustained response (Table 1,^9-16Table 2,^9-16 and Figure).

Compared with early response, early non-response is a more consistent predictor of final non-response. In every study of chronically ill patients, negative predictive value (NPV) was greater than PPV (Table 1).^9-16 NPVs in the literature suggest that 58% to 91% of early non-responders will continue to be non-responders. This seems to be true of chronically ill patients for whom NPVs consistently were between 75% and 85%. By comparison, in first-episode patients NPVs of 58% and 66% were calculated (Table 1^9-16 and Figure).^14,15

These observations suggest that reassessing drug therapy is indicated early in treatment for early non-responders, particularly in chronically ill patients. However, early non-response in a first-episode patient is not as strong a predictor of eventual treatment failure, supporting the idea that first-episode patients may experience a delayed response to therapy. Researchers studying onset of antipsychotic effect report that median time to response onset in first-episode patients may be ≥8 weeks.^6,8 In patients who do not achieve modest early response, assess dose, adherence, substance abuse, and psychosocial stressors.³ For patients without dose, adherence, substance use, or stress issues, switching drug therapy in chronically ill early non-responders is reasonable because the probability of a late response is small.

Individual patient characteristics determine how much these data aid clinical decision-making. If a patient has a good response to an antipsychotic in the first 2 weeks, continue the drug, but observe the patient closely because response may not be sustained. In first-episode patients who fail to respond within 2 weeks of starting an antipsychotic, it is reasonable to continue the drug for several weeks because these patients may be more likely to respond later in therapy.

Clinicians treating chronically ill patients who have failed several antipsychotics and demonstrate a poor response after 2 weeks of an appropriate antipsychotic dose are justified in changing medications because later significant response is unlikely. If a patient has a poor early response but has failed several other antipsychotics with few remaining alternatives, it is reasonable to continue the maximum tolerated dose of the current therapy because the patient may be a late responder. However, early non-response predicts future non-response in many patients.

Case continued

In the case described here, Mr. M is failing his current treatment regimen with a reasonable antipsychotic dose after 2 weeks. Because Mr. M has been on 2 antipsychotics and demonstrated a good response to olanzapine, changing medications should be considered.

Related Resource

• Correll CU, Hauser M. The year in psychosis and bipolar disorder: predicting response to schizophrenia treatment. www.medscape.com/viewarticle/735211_7.

Drug Brand Names

Aripiprazole • Abilify                Quetiapine • Seroquel

Haloperidol • Haldol                 Risperidone • Risperdal

Olanzapine • Zyprexa               Ziprasidone • Geodon

Paliperidone • Invega

Disclosures
Dr. Straley owns stock in Johnson & Johnson. Dr. Webster reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Mr. M, age 28, was given a diagnosis of schizophrenia 6 years ago after experiencing a psychotic break involving auditory hallucinations and paranoia. Olanzapine, 10 mg/d, relieved his symptoms, but he stopped taking the drug after gaining 40 pounds and developing diabetes mellitus. He had 2 other hospital admissions for acute psychosis and has taken at least 1 other medication, the name of which he can’t recall. Recently, Mr. M was involuntarily admitted to the psychiatric ward of his local hospital. His psychiatrist started aripiprazole, 10 mg/d, which was titrated to 30 mg/d. After 2 weeks he reports only a slight decrease in hallucinations. His mother is growing concerned about the effectiveness of this medication and wants to know if it’s time to consider another drug.

Time to onset of action of antipsychotic agents has been debated since at least 1970.¹ Supporters of the delayed-onset hypothesis assert that antipsychotics take weeks or months to show significant improvement of symptoms because of the need for depolarization block for efficacy.² Trials of 4 to 6 weeks often are recommended for patients before failure is declared,^3,4 and trials of this length or longer have proved useful for first-episode patients.^5-7 Recent studies suggest, however, that response is cumulative for chronically ill Practice Points

• Chronically ill and first-episode patients may respond differently to antipsychotics.
• In chronically ill patients with schizophrenia, early non-response accurately predicts non-response at weeks 4 to 12 in 75% to 85% of patients. Early response accurately predicts sustained response at weeks 4 to 12 in approximately 50% to 70% of patients.
• In first-episode patients with schizophrenia, early non-response predicts non-response at weeks 12 to 16 in approximately 60% to 65% of patients. Early response predicts response at weeks 12 to 16 in approximately 60% to 75% of patients.triglyceride, and LDL levels, and a decrease in the HDL level.² These effects may be seen without an increase in BMI, and should be considered a direct effect of the antipsychotic.⁵ Although the mechanism by which dyslipidemia occurs is poorly understood, an increase in the blood glucose level is thought to be, in part, mediated by antagonism of M3 muscarinic receptors on pancreatic âpatients with most improvement occurring during weeks 1 and 2.^1,8

Two meta-analyses found the greatest rate of cumulative improvement in symptoms during the first 2 weeks.^1,8 These analyses included chronically ill patients with mean duration of illness of 15.5 and 10.4 years, respectively. Patients reported 21.9% and 20.5% reductions in symptoms from baseline at 2 weeks, with total responses between 30% at 4 weeks and 40% at 1 year, respectively. These meta-analyses indicate that most of the benefit from antipsychotics in this patient population occurs in the first 2 weeks, which supports the early-response hypothesis.

These observations led to questions about the predictive value of early response and minimum time to determine treatment failure. This article discusses the significance of early response and non-response to antipsychotics and their impact on treating patients with schizophrenia.

What are the predictive factors? How can they guide treatment?

Of the 8 studies in our literature review, only 2 reported early response rates >50%.^9,10 (see this article at CurrentPsychiatry.com for a Box describing the literature review.) Positive predictive value (PPV) ranged from 0.51 to 0.81, meaning that 51% to 81% of early responders continued to respond. Six of the 8 studies reported PPV of 50% to 70%. ^9,11-15 This appears to be true for chronic and first-episode patients, suggesting that 30% to 50% of early responders will fail to have a sustained response (Table 1,^9-16Table 2,^9-16 and Figure).

Compared with early response, early non-response is a more consistent predictor of final non-response. In every study of chronically ill patients, negative predictive value (NPV) was greater than PPV (Table 1).^9-16 NPVs in the literature suggest that 58% to 91% of early non-responders will continue to be non-responders. This seems to be true of chronically ill patients for whom NPVs consistently were between 75% and 85%. By comparison, in first-episode patients NPVs of 58% and 66% were calculated (Table 1^9-16 and Figure).^14,15

These observations suggest that reassessing drug therapy is indicated early in treatment for early non-responders, particularly in chronically ill patients. However, early non-response in a first-episode patient is not as strong a predictor of eventual treatment failure, supporting the idea that first-episode patients may experience a delayed response to therapy. Researchers studying onset of antipsychotic effect report that median time to response onset in first-episode patients may be ≥8 weeks.^6,8 In patients who do not achieve modest early response, assess dose, adherence, substance abuse, and psychosocial stressors.³ For patients without dose, adherence, substance use, or stress issues, switching drug therapy in chronically ill early non-responders is reasonable because the probability of a late response is small.

Individual patient characteristics determine how much these data aid clinical decision-making. If a patient has a good response to an antipsychotic in the first 2 weeks, continue the drug, but observe the patient closely because response may not be sustained. In first-episode patients who fail to respond within 2 weeks of starting an antipsychotic, it is reasonable to continue the drug for several weeks because these patients may be more likely to respond later in therapy.

Clinicians treating chronically ill patients who have failed several antipsychotics and demonstrate a poor response after 2 weeks of an appropriate antipsychotic dose are justified in changing medications because later significant response is unlikely. If a patient has a poor early response but has failed several other antipsychotics with few remaining alternatives, it is reasonable to continue the maximum tolerated dose of the current therapy because the patient may be a late responder. However, early non-response predicts future non-response in many patients.

Case continued

In the case described here, Mr. M is failing his current treatment regimen with a reasonable antipsychotic dose after 2 weeks. Because Mr. M has been on 2 antipsychotics and demonstrated a good response to olanzapine, changing medications should be considered.

Related Resource

• Correll CU, Hauser M. The year in psychosis and bipolar disorder: predicting response to schizophrenia treatment. www.medscape.com/viewarticle/735211_7.

Drug Brand Names

Aripiprazole • Abilify                Quetiapine • Seroquel

Haloperidol • Haldol                 Risperidone • Risperdal

Olanzapine • Zyprexa               Ziprasidone • Geodon

Paliperidone • Invega

Disclosures
Dr. Straley owns stock in Johnson & Johnson. Dr. Webster reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Staggering disparities and lack of parity mark many aspects of mental health care, at huge cost to the 25% of Americans who suffer a mental disorder. It’s time to correct this unconscionable discrepancy.

Imagine a world in which aortic stenosis is fully covered by health insurance but coverage for atrial fibrillation is carved out and assigned partial coverage, with a high copayment, a limit on physician visits and hospital days, and a lifetime cap on coverage. If it strikes you as outrageous that disorders of the same organ could be treated so differently, with irrational discrimination, think again! Such an egregious injustice has been going on for a long time against disorders of the brain.

Care provided for stroke, brain tumor, and epilepsy is given full coverage—but not so for depression, psychosis, and panic disorder. To make the matter more bizarre, depression is a known complication of certain types of stroke; some brain tumors are associated with psychosis; and panic attacks can occur with complex partial seizures—demonstrating that the pathways of so-called “mental” illnesses are as “physical” as any neurological disorder of the brain.

Welcome to the absurd world of lack of parity for psychiatric brain disorders!

Senseless, unethical discrimination against mental illness goes on unabated, despite lip service by politicians and policy-makers. The lack of parity adds insult to injury for psychiatric patients, inflicting a financial burden atop unbearable suffering and functional disability.

How long will this injustice endure?

For a civilized society, in which discrimination based on skin color, sex, sexual orientation, and religious belief is prohibited, discrimination by medical illness seems to be tolerated with impunity. This is a blind spot of unimaginable magnitude in the conscience of society and a cancerous lesion on its ethical standards.

The lack of parity in health-care coverage for psychiatric disorders is compounded by several other disparities. Consider this array of discriminatory actions and conditions directed at psychiatrists and their patients:

• The mentally ill endure a stigma that deprives them of the compassion and sympathy that people who have other medical disorders routinely receive.

• Managed-care organizations and some health-maintenance organizations are reluctant to allow the use of newer, more tolerable, and less neurotoxic psychoactive medications by psychiatrists and nurse practitioners; instead, they impose a fail-first policy with decades-old generic drugs to save money—although newer drugs are readily available for oncologists, cardiologists, and neurologists to use.

• Behavioral health is always “carved out”—that obscene word—in insurance contracts. This is overt discrimination against the mentally ill and mental health professionals that the government should not allow, in its role as a watchdog of human rights.

• Psychiatric wards usually are the most poorly renovated and oldest section of hospitals, while obstetrics, oncology, cardiology, and orthopedics units have state-of-the-art facilities. Many inner-city community mental health centers look tad better than a war zone, with dilapidated buildings, stained and broken furniture, and peeling walls. Where are the funds that were supposed to be recovered by shuttering asylums and to flow into community care for outpatient mental health care?

• It’s the height of discrimination that the relapsed mentally ill have no place to go but jail or prison. Isn’t it the worst injustice to transform medical illness into a felony? Why are there few long-term facilities for severe mental illness any more—the equivalent of refractory patients? In a civilized nation, why is homelessness among people who have a brain disorder tolerated?

• The medical records of psychiatric patients are segregated and set aside, perpetuating the unfair shame and guilt associated with mental illness. When will a history of depression and a broken spirit be no more secretive than having a broken leg?

• The lack of regard for psychiatry as a vital medical specialty reflects medieval-like ignorance and discrimination in an age when the neurobiology of psychiatric brain disorders is unfolding with dazzling scientific elegance. When will those who treat mood, thought, behavior, and cognition receive the same respect as a surgeon who transplants a liver or a cardiologist who manages heart failure?

• The disparity in access by the seriously mentally ill to primary, secondary, and tertiary care has, literally, fatal consequences. Despite the high prevalence of serious cardio-metabolic, pulmonary, infectious, and gastrointestinal disorders among the mentally ill, a large percentage do not receive the most basic primary care to manage their ailments—let alone undergo special procedures or advanced surgical interventions. This shameful neglect and health-care disparity contribute to early mortality (by 20 to 25 years) among people who suffer a serious mental disorder. This is a deadly disparity, yet it goes unaddressed.

• Last, a disparity exists in funding for research to find the causes of, and cures for, disorders of the brain’s mind. Psychiatric disorders and substance use cost society more than  $300 billion annually in the United States, yet investment in research on those disorders pales compared with the support provided to the study of other medical disorders.

It’s time society closed this ugly gap

Lack of parity extends across a broad swath of issues related to mental illness, with a huge personal and material cost to the 25% of the US population that suffers a mental disorder. It’s time to close the shameful gap and end this harmful discrimination. Let’s hope that ongoing changes in health care will, finally, reverse the injustice. Given the broken promises of the past, however, let’s not count our chickens before they hatch….

Staggering disparities and lack of parity mark many aspects of mental health care, at huge cost to the 25% of Americans who suffer a mental disorder. It’s time to correct this unconscionable discrepancy.

Imagine a world in which aortic stenosis is fully covered by health insurance but coverage for atrial fibrillation is carved out and assigned partial coverage, with a high copayment, a limit on physician visits and hospital days, and a lifetime cap on coverage. If it strikes you as outrageous that disorders of the same organ could be treated so differently, with irrational discrimination, think again! Such an egregious injustice has been going on for a long time against disorders of the brain.

Care provided for stroke, brain tumor, and epilepsy is given full coverage—but not so for depression, psychosis, and panic disorder. To make the matter more bizarre, depression is a known complication of certain types of stroke; some brain tumors are associated with psychosis; and panic attacks can occur with complex partial seizures—demonstrating that the pathways of so-called “mental” illnesses are as “physical” as any neurological disorder of the brain.

Welcome to the absurd world of lack of parity for psychiatric brain disorders!

Senseless, unethical discrimination against mental illness goes on unabated, despite lip service by politicians and policy-makers. The lack of parity adds insult to injury for psychiatric patients, inflicting a financial burden atop unbearable suffering and functional disability.

How long will this injustice endure?

For a civilized society, in which discrimination based on skin color, sex, sexual orientation, and religious belief is prohibited, discrimination by medical illness seems to be tolerated with impunity. This is a blind spot of unimaginable magnitude in the conscience of society and a cancerous lesion on its ethical standards.

The lack of parity in health-care coverage for psychiatric disorders is compounded by several other disparities. Consider this array of discriminatory actions and conditions directed at psychiatrists and their patients:

• The mentally ill endure a stigma that deprives them of the compassion and sympathy that people who have other medical disorders routinely receive.

• Managed-care organizations and some health-maintenance organizations are reluctant to allow the use of newer, more tolerable, and less neurotoxic psychoactive medications by psychiatrists and nurse practitioners; instead, they impose a fail-first policy with decades-old generic drugs to save money—although newer drugs are readily available for oncologists, cardiologists, and neurologists to use.

• Behavioral health is always “carved out”—that obscene word—in insurance contracts. This is overt discrimination against the mentally ill and mental health professionals that the government should not allow, in its role as a watchdog of human rights.

• Psychiatric wards usually are the most poorly renovated and oldest section of hospitals, while obstetrics, oncology, cardiology, and orthopedics units have state-of-the-art facilities. Many inner-city community mental health centers look tad better than a war zone, with dilapidated buildings, stained and broken furniture, and peeling walls. Where are the funds that were supposed to be recovered by shuttering asylums and to flow into community care for outpatient mental health care?

• It’s the height of discrimination that the relapsed mentally ill have no place to go but jail or prison. Isn’t it the worst injustice to transform medical illness into a felony? Why are there few long-term facilities for severe mental illness any more—the equivalent of refractory patients? In a civilized nation, why is homelessness among people who have a brain disorder tolerated?

• The medical records of psychiatric patients are segregated and set aside, perpetuating the unfair shame and guilt associated with mental illness. When will a history of depression and a broken spirit be no more secretive than having a broken leg?

• The lack of regard for psychiatry as a vital medical specialty reflects medieval-like ignorance and discrimination in an age when the neurobiology of psychiatric brain disorders is unfolding with dazzling scientific elegance. When will those who treat mood, thought, behavior, and cognition receive the same respect as a surgeon who transplants a liver or a cardiologist who manages heart failure?

• The disparity in access by the seriously mentally ill to primary, secondary, and tertiary care has, literally, fatal consequences. Despite the high prevalence of serious cardio-metabolic, pulmonary, infectious, and gastrointestinal disorders among the mentally ill, a large percentage do not receive the most basic primary care to manage their ailments—let alone undergo special procedures or advanced surgical interventions. This shameful neglect and health-care disparity contribute to early mortality (by 20 to 25 years) among people who suffer a serious mental disorder. This is a deadly disparity, yet it goes unaddressed.

• Last, a disparity exists in funding for research to find the causes of, and cures for, disorders of the brain’s mind. Psychiatric disorders and substance use cost society more than  $300 billion annually in the United States, yet investment in research on those disorders pales compared with the support provided to the study of other medical disorders.

It’s time society closed this ugly gap

Lack of parity extends across a broad swath of issues related to mental illness, with a huge personal and material cost to the 25% of the US population that suffers a mental disorder. It’s time to close the shameful gap and end this harmful discrimination. Let’s hope that ongoing changes in health care will, finally, reverse the injustice. Given the broken promises of the past, however, let’s not count our chickens before they hatch….

Staggering disparities and lack of parity mark many aspects of mental health care, at huge cost to the 25% of Americans who suffer a mental disorder. It’s time to correct this unconscionable discrepancy.

Imagine a world in which aortic stenosis is fully covered by health insurance but coverage for atrial fibrillation is carved out and assigned partial coverage, with a high copayment, a limit on physician visits and hospital days, and a lifetime cap on coverage. If it strikes you as outrageous that disorders of the same organ could be treated so differently, with irrational discrimination, think again! Such an egregious injustice has been going on for a long time against disorders of the brain.

Care provided for stroke, brain tumor, and epilepsy is given full coverage—but not so for depression, psychosis, and panic disorder. To make the matter more bizarre, depression is a known complication of certain types of stroke; some brain tumors are associated with psychosis; and panic attacks can occur with complex partial seizures—demonstrating that the pathways of so-called “mental” illnesses are as “physical” as any neurological disorder of the brain.

Welcome to the absurd world of lack of parity for psychiatric brain disorders!

Senseless, unethical discrimination against mental illness goes on unabated, despite lip service by politicians and policy-makers. The lack of parity adds insult to injury for psychiatric patients, inflicting a financial burden atop unbearable suffering and functional disability.

How long will this injustice endure?

For a civilized society, in which discrimination based on skin color, sex, sexual orientation, and religious belief is prohibited, discrimination by medical illness seems to be tolerated with impunity. This is a blind spot of unimaginable magnitude in the conscience of society and a cancerous lesion on its ethical standards.

The lack of parity in health-care coverage for psychiatric disorders is compounded by several other disparities. Consider this array of discriminatory actions and conditions directed at psychiatrists and their patients:

• The mentally ill endure a stigma that deprives them of the compassion and sympathy that people who have other medical disorders routinely receive.

• Managed-care organizations and some health-maintenance organizations are reluctant to allow the use of newer, more tolerable, and less neurotoxic psychoactive medications by psychiatrists and nurse practitioners; instead, they impose a fail-first policy with decades-old generic drugs to save money—although newer drugs are readily available for oncologists, cardiologists, and neurologists to use.

• Behavioral health is always “carved out”—that obscene word—in insurance contracts. This is overt discrimination against the mentally ill and mental health professionals that the government should not allow, in its role as a watchdog of human rights.

• Psychiatric wards usually are the most poorly renovated and oldest section of hospitals, while obstetrics, oncology, cardiology, and orthopedics units have state-of-the-art facilities. Many inner-city community mental health centers look tad better than a war zone, with dilapidated buildings, stained and broken furniture, and peeling walls. Where are the funds that were supposed to be recovered by shuttering asylums and to flow into community care for outpatient mental health care?

• It’s the height of discrimination that the relapsed mentally ill have no place to go but jail or prison. Isn’t it the worst injustice to transform medical illness into a felony? Why are there few long-term facilities for severe mental illness any more—the equivalent of refractory patients? In a civilized nation, why is homelessness among people who have a brain disorder tolerated?

• The medical records of psychiatric patients are segregated and set aside, perpetuating the unfair shame and guilt associated with mental illness. When will a history of depression and a broken spirit be no more secretive than having a broken leg?

• The lack of regard for psychiatry as a vital medical specialty reflects medieval-like ignorance and discrimination in an age when the neurobiology of psychiatric brain disorders is unfolding with dazzling scientific elegance. When will those who treat mood, thought, behavior, and cognition receive the same respect as a surgeon who transplants a liver or a cardiologist who manages heart failure?

• The disparity in access by the seriously mentally ill to primary, secondary, and tertiary care has, literally, fatal consequences. Despite the high prevalence of serious cardio-metabolic, pulmonary, infectious, and gastrointestinal disorders among the mentally ill, a large percentage do not receive the most basic primary care to manage their ailments—let alone undergo special procedures or advanced surgical interventions. This shameful neglect and health-care disparity contribute to early mortality (by 20 to 25 years) among people who suffer a serious mental disorder. This is a deadly disparity, yet it goes unaddressed.

• Last, a disparity exists in funding for research to find the causes of, and cures for, disorders of the brain’s mind. Psychiatric disorders and substance use cost society more than  $300 billion annually in the United States, yet investment in research on those disorders pales compared with the support provided to the study of other medical disorders.

It’s time society closed this ugly gap

Lack of parity extends across a broad swath of issues related to mental illness, with a huge personal and material cost to the 25% of the US population that suffers a mental disorder. It’s time to close the shameful gap and end this harmful discrimination. Let’s hope that ongoing changes in health care will, finally, reverse the injustice. Given the broken promises of the past, however, let’s not count our chickens before they hatch….

We read with interest Dr. Henry A. Nasrallah’s call to unify psychiatry and neurology into 1 specialty (Current Psychiatry, From the Editor, August 2013, p. 8-9; http://bit.ly/16wImL3). Trends in this direction already are evident. Medical schools, including New York University School of Medicine, the University of Massachusetts Medical School, and the Medical University of South Carolina, have 6-year combined psychiatry and neurology residency programs that prepare students for board exams in either specialty or both specialties. We offer considerations that we hope will energize and inform the discussion, in turn moving us toward discovery of an optimal framework for all stakeholders.

In support of unification, Dr. Nasrallah’s editorial points to research advances in pharmacology, neuroimaging, and genetics. He writes that a “neuropharmacological revolution” is occurring, and it includes the discovery of medications that control symptoms of mood and anxiety disorders. The use of psychotropic medications certainly is escalating; >1 in every 10 Americans currently takes an antidepressant,^1,2 reflecting a >400% increase over the past 2 decades.²

However, increasing use does not prove efficacy or establish causal mechanisms. Controversy persists regarding antidepressant efficacy, particularly for mild-to-moderate depression. The Sequenced Treatment Alternatives to Relieve Depression trial³ was the largest study to evaluate antidepressant effectiveness.³ Summarizing the findings, Thomas Insel, MD, Director of the National Institute of Mental Health stated, “Most important, this study demonstrates that for at least 70% of patients, appropriate treatment with an SSRI [selective serotonin reuptake inhibitor] is not enough.”⁴ What is clear is that the benefits of antidepressants are smaller than originally thought, and may be limited to patients with particular types of (severe) depression.

We agree that developments in neuroimaging and genetics of mental illness are exciting and some day may change the relationship between neurology and psychiatry. However, advanced neuroimaging technologies such as functional magnetic resonance imaging (fMRI) and diffusion tensor imaging (or diffusion MRI) have shown abnormalities involving brain-wide networks in psychiatric disorders⁵—not distinct regional abnormalities. In other words, psychiatry deals with mental phenomena that are modular in nature and not always reducible to their molecular origins, whereas in neurologic disorders, research linear cause-effect relationships and regional abnormalities are more common.

Genome-wide association studies have shown that few polymorphisms can be associated with numerous mental disorders⁶ (ie, multifinality), and that several genes may be associated with a particular disorder (ie, equifinality). Multifinality and equfinality are characteristics of complex disorders, with nonlinear gene × gene and gene × environment interactions. In contrast, most heritable neurologic disorders follow a Mendelian pattern of inheritance and predictable cause-effect neuropathology. Furthermore, recent advances in epigenetics—in which environmental and social factors modify gene expression and affect patterns of inheritance⁷—have further complicated our understanding of genetic contributions to psychiatric illness, and have revealed limitations in reductionist models.

Although neurologic and psychiatric disorders ultimately reflect cerebral pathology, the former commonly result from circumscribed lesions, and the latter are more complexly determined, resulting from disruptions in brain circuitry influenced by genetic, epigenetic, environmental, and social factors.⁷ As much as we might like it, research in psychiatry has not progressed to the point of fully explaining the brain-based processes underlying complex psychiatric disorders, decipher complex gene × gene and gene × environment interactions, or associate certain genes and biological pathways with specific disorders. A move to formally combine neurology and psychiatry may be prescient but premature because different sets of skills and methodologies might be required of clinicians and researchers in either specialty. More research is needed to shape and refine our disease and training models, and inform evidence-based practice.

Patrick J. Lustman, PhD
St. Louis VA Medical Center
John Cochran Hospital Division
Department of Psychiatry
Washington University School of Medicine

John M. Ray, MA
St. Louis VA Medical Center
John Cochran Hospital Division

Andrea L. Taylor, PhD
St. Louis VA Medical Center
John Cochran Hospital Division

Kenneth E. Freedland, PhD
Department of Psychiatry
Washington University School of Medicine

Dragan M. Svrakic, MD
St. Louis VA Medical Center
John Cochran Hospital Division
Department of Psychiatry
Washington University School of Medicine

St. Louis, Missouri

We read with interest Dr. Henry A. Nasrallah’s call to unify psychiatry and neurology into 1 specialty (Current Psychiatry, From the Editor, August 2013, p. 8-9; http://bit.ly/16wImL3). Trends in this direction already are evident. Medical schools, including New York University School of Medicine, the University of Massachusetts Medical School, and the Medical University of South Carolina, have 6-year combined psychiatry and neurology residency programs that prepare students for board exams in either specialty or both specialties. We offer considerations that we hope will energize and inform the discussion, in turn moving us toward discovery of an optimal framework for all stakeholders.

In support of unification, Dr. Nasrallah’s editorial points to research advances in pharmacology, neuroimaging, and genetics. He writes that a “neuropharmacological revolution” is occurring, and it includes the discovery of medications that control symptoms of mood and anxiety disorders. The use of psychotropic medications certainly is escalating; >1 in every 10 Americans currently takes an antidepressant,^1,2 reflecting a >400% increase over the past 2 decades.²

However, increasing use does not prove efficacy or establish causal mechanisms. Controversy persists regarding antidepressant efficacy, particularly for mild-to-moderate depression. The Sequenced Treatment Alternatives to Relieve Depression trial³ was the largest study to evaluate antidepressant effectiveness.³ Summarizing the findings, Thomas Insel, MD, Director of the National Institute of Mental Health stated, “Most important, this study demonstrates that for at least 70% of patients, appropriate treatment with an SSRI [selective serotonin reuptake inhibitor] is not enough.”⁴ What is clear is that the benefits of antidepressants are smaller than originally thought, and may be limited to patients with particular types of (severe) depression.

We agree that developments in neuroimaging and genetics of mental illness are exciting and some day may change the relationship between neurology and psychiatry. However, advanced neuroimaging technologies such as functional magnetic resonance imaging (fMRI) and diffusion tensor imaging (or diffusion MRI) have shown abnormalities involving brain-wide networks in psychiatric disorders⁵—not distinct regional abnormalities. In other words, psychiatry deals with mental phenomena that are modular in nature and not always reducible to their molecular origins, whereas in neurologic disorders, research linear cause-effect relationships and regional abnormalities are more common.

Genome-wide association studies have shown that few polymorphisms can be associated with numerous mental disorders⁶ (ie, multifinality), and that several genes may be associated with a particular disorder (ie, equifinality). Multifinality and equfinality are characteristics of complex disorders, with nonlinear gene × gene and gene × environment interactions. In contrast, most heritable neurologic disorders follow a Mendelian pattern of inheritance and predictable cause-effect neuropathology. Furthermore, recent advances in epigenetics—in which environmental and social factors modify gene expression and affect patterns of inheritance⁷—have further complicated our understanding of genetic contributions to psychiatric illness, and have revealed limitations in reductionist models.

Although neurologic and psychiatric disorders ultimately reflect cerebral pathology, the former commonly result from circumscribed lesions, and the latter are more complexly determined, resulting from disruptions in brain circuitry influenced by genetic, epigenetic, environmental, and social factors.⁷ As much as we might like it, research in psychiatry has not progressed to the point of fully explaining the brain-based processes underlying complex psychiatric disorders, decipher complex gene × gene and gene × environment interactions, or associate certain genes and biological pathways with specific disorders. A move to formally combine neurology and psychiatry may be prescient but premature because different sets of skills and methodologies might be required of clinicians and researchers in either specialty. More research is needed to shape and refine our disease and training models, and inform evidence-based practice.

Patrick J. Lustman, PhD
St. Louis VA Medical Center
John Cochran Hospital Division
Department of Psychiatry
Washington University School of Medicine

John M. Ray, MA
St. Louis VA Medical Center
John Cochran Hospital Division

Andrea L. Taylor, PhD
St. Louis VA Medical Center
John Cochran Hospital Division

Kenneth E. Freedland, PhD
Department of Psychiatry
Washington University School of Medicine

Dragan M. Svrakic, MD
St. Louis VA Medical Center
John Cochran Hospital Division
Department of Psychiatry
Washington University School of Medicine

St. Louis, Missouri

We read with interest Dr. Henry A. Nasrallah’s call to unify psychiatry and neurology into 1 specialty (Current Psychiatry, From the Editor, August 2013, p. 8-9; http://bit.ly/16wImL3). Trends in this direction already are evident. Medical schools, including New York University School of Medicine, the University of Massachusetts Medical School, and the Medical University of South Carolina, have 6-year combined psychiatry and neurology residency programs that prepare students for board exams in either specialty or both specialties. We offer considerations that we hope will energize and inform the discussion, in turn moving us toward discovery of an optimal framework for all stakeholders.

In support of unification, Dr. Nasrallah’s editorial points to research advances in pharmacology, neuroimaging, and genetics. He writes that a “neuropharmacological revolution” is occurring, and it includes the discovery of medications that control symptoms of mood and anxiety disorders. The use of psychotropic medications certainly is escalating; >1 in every 10 Americans currently takes an antidepressant,^1,2 reflecting a >400% increase over the past 2 decades.²

However, increasing use does not prove efficacy or establish causal mechanisms. Controversy persists regarding antidepressant efficacy, particularly for mild-to-moderate depression. The Sequenced Treatment Alternatives to Relieve Depression trial³ was the largest study to evaluate antidepressant effectiveness.³ Summarizing the findings, Thomas Insel, MD, Director of the National Institute of Mental Health stated, “Most important, this study demonstrates that for at least 70% of patients, appropriate treatment with an SSRI [selective serotonin reuptake inhibitor] is not enough.”⁴ What is clear is that the benefits of antidepressants are smaller than originally thought, and may be limited to patients with particular types of (severe) depression.

We agree that developments in neuroimaging and genetics of mental illness are exciting and some day may change the relationship between neurology and psychiatry. However, advanced neuroimaging technologies such as functional magnetic resonance imaging (fMRI) and diffusion tensor imaging (or diffusion MRI) have shown abnormalities involving brain-wide networks in psychiatric disorders⁵—not distinct regional abnormalities. In other words, psychiatry deals with mental phenomena that are modular in nature and not always reducible to their molecular origins, whereas in neurologic disorders, research linear cause-effect relationships and regional abnormalities are more common.

Genome-wide association studies have shown that few polymorphisms can be associated with numerous mental disorders⁶ (ie, multifinality), and that several genes may be associated with a particular disorder (ie, equifinality). Multifinality and equfinality are characteristics of complex disorders, with nonlinear gene × gene and gene × environment interactions. In contrast, most heritable neurologic disorders follow a Mendelian pattern of inheritance and predictable cause-effect neuropathology. Furthermore, recent advances in epigenetics—in which environmental and social factors modify gene expression and affect patterns of inheritance⁷—have further complicated our understanding of genetic contributions to psychiatric illness, and have revealed limitations in reductionist models.

Although neurologic and psychiatric disorders ultimately reflect cerebral pathology, the former commonly result from circumscribed lesions, and the latter are more complexly determined, resulting from disruptions in brain circuitry influenced by genetic, epigenetic, environmental, and social factors.⁷ As much as we might like it, research in psychiatry has not progressed to the point of fully explaining the brain-based processes underlying complex psychiatric disorders, decipher complex gene × gene and gene × environment interactions, or associate certain genes and biological pathways with specific disorders. A move to formally combine neurology and psychiatry may be prescient but premature because different sets of skills and methodologies might be required of clinicians and researchers in either specialty. More research is needed to shape and refine our disease and training models, and inform evidence-based practice.

Patrick J. Lustman, PhD
St. Louis VA Medical Center
John Cochran Hospital Division
Department of Psychiatry
Washington University School of Medicine

John M. Ray, MA
St. Louis VA Medical Center
John Cochran Hospital Division

Andrea L. Taylor, PhD
St. Louis VA Medical Center
John Cochran Hospital Division

Kenneth E. Freedland, PhD
Department of Psychiatry
Washington University School of Medicine

Dragan M. Svrakic, MD
St. Louis VA Medical Center
John Cochran Hospital Division
Department of Psychiatry
Washington University School of Medicine

St. Louis, Missouri

I enjoyed reading “New ‘legal’ highs: Kratom and methoxetamine” (Current Psychiatry, Pearls, August 2013, p.54-55; http://bit.ly/1gmPVFB), which discussed legal substances of abuse with adverse effects. I appreciate Dr. Julianna Troy’s recommendation to be familiar with “legal” drugs given their prevalence and potential for adverse effects when taken alone or with psychotropics.

Another legal substance, Bromo-DragonFLY—so named for the resemblance of its chemical structure to the insect—is illegal in many European countries and is being abused in the United States, notably in New Orleans, Louisiana.¹ Available as a white or off-white powder, or as paper “blotters,” the drug exerts serotonergic and noradrenergic receptor agonism.¹ It is characterized by slow onset but long duration of action.

Intoxication with Bromo-Dragon-FLY beyond the usual dose of 800 to 1,300 µg can result in dystonia, tachycardia, hypertension, psychosis, tachypnea, vasoconstriction with necrosis, seizures, hepatic or renal dysfunction, and death.^1-5 Treatment comprises hydration, respiratory support, and benzodiazepines, muscle relaxants, or antipsychotics.^1-4

Jonathan R. Scarff, MD
VA Outpatient Clinic
Spartanburg, South Carolina

I enjoyed reading “New ‘legal’ highs: Kratom and methoxetamine” (Current Psychiatry, Pearls, August 2013, p.54-55; http://bit.ly/1gmPVFB), which discussed legal substances of abuse with adverse effects. I appreciate Dr. Julianna Troy’s recommendation to be familiar with “legal” drugs given their prevalence and potential for adverse effects when taken alone or with psychotropics.

Another legal substance, Bromo-DragonFLY—so named for the resemblance of its chemical structure to the insect—is illegal in many European countries and is being abused in the United States, notably in New Orleans, Louisiana.¹ Available as a white or off-white powder, or as paper “blotters,” the drug exerts serotonergic and noradrenergic receptor agonism.¹ It is characterized by slow onset but long duration of action.

Intoxication with Bromo-Dragon-FLY beyond the usual dose of 800 to 1,300 µg can result in dystonia, tachycardia, hypertension, psychosis, tachypnea, vasoconstriction with necrosis, seizures, hepatic or renal dysfunction, and death.^1-5 Treatment comprises hydration, respiratory support, and benzodiazepines, muscle relaxants, or antipsychotics.^1-4

Jonathan R. Scarff, MD
VA Outpatient Clinic
Spartanburg, South Carolina

I enjoyed reading “New ‘legal’ highs: Kratom and methoxetamine” (Current Psychiatry, Pearls, August 2013, p.54-55; http://bit.ly/1gmPVFB), which discussed legal substances of abuse with adverse effects. I appreciate Dr. Julianna Troy’s recommendation to be familiar with “legal” drugs given their prevalence and potential for adverse effects when taken alone or with psychotropics.

Another legal substance, Bromo-DragonFLY—so named for the resemblance of its chemical structure to the insect—is illegal in many European countries and is being abused in the United States, notably in New Orleans, Louisiana.¹ Available as a white or off-white powder, or as paper “blotters,” the drug exerts serotonergic and noradrenergic receptor agonism.¹ It is characterized by slow onset but long duration of action.

Intoxication with Bromo-Dragon-FLY beyond the usual dose of 800 to 1,300 µg can result in dystonia, tachycardia, hypertension, psychosis, tachypnea, vasoconstriction with necrosis, seizures, hepatic or renal dysfunction, and death.^1-5 Treatment comprises hydration, respiratory support, and benzodiazepines, muscle relaxants, or antipsychotics.^1-4

Jonathan R. Scarff, MD
VA Outpatient Clinic
Spartanburg, South Carolina