Evidence-Based Reviews

Major depressive disorder (MDD) frequently is recur­rent, with new episodes causing substantial social and economic impairment¹ and increasing the like­lihood of future episodes.² For this reason, contemporary psychiatric practitioners think of depression treatment as long-term and plan thoughtfully for maintenance therapy.

Recognizing the importance of engaging depressed indi­viduals beyond the initial response,³ American Psychiatric Association practice guidelines conceptualize depression treatment as 3 phases:
   • acute treatment, with the aim of remission (symptom removal)
   • continuation treatment, with the aim of preventing re­lapse (symptom return)
   • maintenance treatment, with the aim of preventing re­currence (new episodes).⁴
Interpersonal psychotherapy (IPT) is an evidence-based psychosocial treatment that adheres to this model.⁵ As a time-limited, manual-driven^6,7 approach, IPT focuses on interpersonal distresses as precipitating and perpetuating factors of depression.⁸

Acute IPT’s efficacy is well-established across >200 empirical studies—making it an evidence-based, first-line treatment for adult depression.^4,9,10 Meta-analyses show that acute IPT is superior to placebo and no-treatment con­trols, and largely comparable to antidepressant medication and other active, first-line psychotherapies, such as cogni­tive-behavioral therapy (CBT).^11,12

Although this review, as well as the liter­ature, focuses largely on adult outpatients with depression, evidence of IPT’s general efficacy exists for adolescents,¹³ chronically depressed patients,¹¹ and depressed inpa­tients.¹⁴ This article presents a case study to describe the structure of IPT when used to treat depressed adults. We also present evidence of IPT’s acute and long-term ef­ficacy in preventing depression recurrence and data to guide its use in practice.

CASE REPORT

‘Safe’ but depressed
Timothy, age 18, is a first-year college student who presents for outpatient psychotherapy to address recurrent depression. He reports general unhappiness, loss of interest in things, low energy, sleep problems, poor academic and work functioning, and low self-esteem. He experienced at least 3 similar depressive episodes while in high school.

The therapist’s diagnostic and interper­sonal assessment suggests that Timothy’s depression is interpersonally driven. Timothy longs for relational intimacy but fears he will fail or burden people with his needs. He has difficulty gauging appropriate lev­els of enmeshment with others and either becomes overdependent or stays at a dis­tance. This “safe” approach to relationships contributes to boredom, loneliness, and isolation. His recent transition to college away from home and the failure of a roman­tic relationship have compounded these experiences.

Interpersonal model of IPT
IPT conceptualizes depression as involving predisposing, precipitating, and perpetu­ating biopsychosocial factors, including:
   • underlying biological and social vul­nerability, such as insecure attach­ ment (ie, tenuous and often negative views of self and others)
   • current interpersonal life stressors
   • inadequate social supports.^15,16

For example, poor early attachment to caregivers can give rise to despair, isolation, and low mood. In turn, this can be exacerbated by poor social and commu­nication skills that promote further rejec­tion and withdrawal of social support and thus, intensified despair, isolation, and low mood. As in Timothy’s case, this vicious cycle underscores psychosocial stressors as a causal factor, maintaining factor, and result of depression. Specifically, IPT con­ceptualizes 4 main biopsychosocial problem domains:
   • grief and loss
   • interpersonal disputes
   • role transitions
   • interpersonal/communication deficits (often connected to isolation).

Working within 1 or 2 of the most salient problem domains, IPT centers on strategies for helping patients solve interpersonal problems based on the notion that modi­fied relationships, revised interpersonal expectations, improved communications, and increased social support will lead to symptom reduction.^15-17

Many techniques are utilized in IPT (Table 1) to help patients modify their interpersonal relationships as a mechanism for decreasing their distress. IPT is prob­lem-focused, aiming to improve patients’ relationships by drawing on their assets and helping to build skills around short­comings. Therefore, IPT focuses on observ­able interpersonal patterns, as opposed to latent personality dynamics.

CASE CONTINUED

Setting goals
When the clinical explains in the non-technical terms the data supporting IPT’s efficacy for depression, including with young adults, Timothy agrees to teeatment with acute IPT. The therapist behins with consciousness-raising techniques to help Timothy adopt the “sick role” by viewing depressing as an illness to be cured. Collaboratively, they establish treatment goals that fit the IPT formulation of depression— ie, revising current relationships and expectations of them, increasing social support, improving communication skills, and solving problems within 1 or 2 of the IPT prob­lem domains.

For Timothy, the most pressing psy­chosocial problems seem to be interper­sonal deficits and role transitions. He ap­pears to be insecurely attached to others, which is a risk factor for poor facilitation of, and boundaries around, good relation­ships. A transition to a new and intimidat­ing interpersonal context—living on a college campus—compounded his vulnerabilities and increased his depression.

Acute treatment. The acute phase of IPT is time-limited—often, 12 to 16 sessions with gradual tapering toward the end (akin to a continuation phase). The time limit’s pur­pose is to focus both patient and therapist on the specific goal of removing the acute “illness” of depression. The IPT clinician takes an interpersonal inventory to learn about the patient’s most important rela­tionships and hones in on the IPT domain foci. Working collaboratively, the thera­pist might help the patient mourn a loss, reconstruct a narrative with a deceased loved one, consider ways to increase social contact, develop assertiveness, label feel­ings and needs, resolve an impasse with a significant other, and so forth.

The IPT therapist is an advocate for the patient and adopts an active stance laced with empathy and warmth. However, the therapist is more than unconditionally ac­cepting as depression is viewed as a prob­lem to be actively resolved.

CASE CONTINUED

Creating new patterns
The therapist uses various IPT strategies to work collaboratively with Timothy. She at­tempts to develop a strong working alliance by building interpersonal safety and trust— which take time with an insecurely attached patient. She tries to provide a new model for how close relationships can develop, while also focusing on current relationships. She and Timothy address his romantic desire for a coworker and work on developing realistic ex­pectations and effective methods for convey­ing his interest.

When Timothy approaches his coworker, she does not reject him—as he expected— but wants to pursue friendship before pos­sibly dating. The therapist then works with Timothy’s emotional reaction and explores ways to effectively convey his emotions to this young woman. Drawing on communica­tion analysis and problem-solving strategies, Timothy is able to sustain this friendship—a shift from his typical retreat when relation­ships have not gone as hoped or expected.

Timothy develops confidence to take more risks in initiating social encounters and starts to confide in his roommates when he feels upset. After 3 months of treatment, his expanded social network and improved in­terpersonal skills result in decreased depres­sion. When Timothy suggests termination, he and the therapist agree to end acute IPT but—given his history of depression—to continue maintenance sessions.

Limited data exist on variables that relate to IPT’s acute success or conditions under which it works best. Although process re­search lags behind acute IPT outcome re­search, some findings can help guide the IPT practitioner. For example, variables shown to predict outcomes of acute IPT for depression include a positive therapeutic alliance, therapist warmth, and psycho­ psycho­therapist use of exploratory techniques (Table 2).

Similarly, IPT has been shown to be more effective in some patients than oth­ers, depending on various moderators of depression. For example:
   • For patients with high cognitive dys­function, IPT outperforms CBT.
   • For patients with higher need for medical reassurance, IPT outperforms selective serotonin reuptake inhibitor (SSRI) pharmacotherapy.
   • For patients with severe depression, CBT outperforms IPT.
   • For patients with low psychomotor activation, response is more rapid with an SSRI than with IPT (Table 3).¹⁸

Durability of acute IPT
One way to understand recurrence pre­vention is to examine the durability of a treatment’s acute effect in the absence of a specific maintenance plan. In theory, patients will continue to apply the skills learned in acute IPT to maintain gains and prevent recurrences, even after they stop seeing the psychotherapist.

Initial findings.  Some research speaks to IPT’s acute-phase durability. The inaugural clinical trial of IPT by Weissman et al¹⁹ included 4 months of acute treatment and a 1-year uncontrolled naturalistic follow-up assessment. At follow-up, depression and global clinical symptoms were the same, whether patients had been acutely treated with IPT alone, pharmacotherapy alone (amitriptyline), combined IPT and pharmacotherapy, or nonscheduled treat­ment with a psychiatrist.

Some patients continued to function well, whereas others did not fully main­tain acute treatment gains. Patients who received IPT acutely, either singly or with medication, showed better social function­ing at follow-up compared with patients who did not receive IPT. This long-term durability of social improvements was an obvious target of IPT.

Support from TDCRP. In the National Institute of Mental Health Treatment of Depression Collaborative Research Project (TDCRP),²⁰ patients in the acute phase of depression were assigned to 16 weeks of IPT, CBT, pharmacotherapy (imipramine) and clinical management (CM), or placebo plus CM. Among those who recovered by acute treatment’s end, MDD relapse rates at 18-month naturalistic follow-up were 33% for IPT, 36% for CBT, 50% for imipramine, and 33% for placebo. Between-group differ­ences were not statistically significant.

Because acute responders to different types of treatment might have different inherent relapse tendencies, these data do not support causal attributions about the enduring effects of acute-phase treatment. The relapse rates do suggest, however, that 16 weeks of acute treatment, irrespec­tive of kind, was insufficient for some pa­tients to achieve full recovery and lasting remission. Consistent with the initial IPT trial,¹⁹ IPT (and CBT) outperformed medi cation and placebo in maintaining rela­tionship quality.²¹

Long-term benefits. A more recent trial by Zobel et al²² examined the durabil­ity of benefits from 5 weeks of acute IPT plus pharmacotherapy and pharmaco­therapy plus CM for inpatients with MDD. Although caution is required in interpret­ing naturalistic follow-up studies, patients in both groups showed decreased depres­sion from baseline to 5-year follow-up. Early symptom reduction was more rapid for patients in the IPT plus pharmacother­apy group, but no significant difference ex­isted at 5 years. More IPT patients than CM patients showed sustained remission (28% vs 11%, respectively). These rates demon­strate a need for longer-term potency of acute treatments and more targeted main­tenance treatments.

IPT-M for preventing recurrence
A second way to understand recurrence prevention is to examine the efficacy of a treatment’s maintenance protocol add­ed to an acute treatment phase. IPT has been adapted as a maintenance treatment (IPT-M), with emphasis on keeping pa­tients well. With this revised focus, IPT-M differs somewhat from acute IPT. Although treatment continues to center on interper­sonal functioning, IPT-M favors:
   • vigilance for possible triggers of new depressive episodes
   • longer-term contact with a therapist
   • reinforcing skills learned
   • addressing an expanded number of interpersonal problem areas (given that such problems can be addressed more ef­ficiently relative to acute treatment).

Efficacy of IPT-M. In the initial trial, Frank et al²³ compared the efficacy of IPT-M with that of pharmacotherapy (imipramine) in preventing depressive relapse among pa­tients with recurrent depression who had responded to ≥16 sessions of acute IPT and imipramine and remained well during a 17- week continuation phase. For maintenance, patients were assigned to IPT-M alone, imipramine alone, placebo alone, IPT-M plus imipramine, or IPT-M plus placebo. Maintenance imipramine was continued at the acute dosage (target 200 mg/d; up to 400 mg/d was allowed). Maintenance IPT was monthly sessions. Patients remained in the trial for 3 years or until depression recurred.

On its own, IPT-M showed some efficacy in preventing recurrence, as the mean time to recurrence was 82 weeks for IPT-M alone and 74 weeks for IPT-M plus placebo. The prophylactic effect of imipramine was stron­ger, however. The mean time to recurrence for imipramine with IPT was 131 weeks, and the mean time to recurrence for imipra­mine without IPT was 124 weeks. Therefore, whereas monthly IPT-M can certainly help prolong wellness and delay recurrence, IPT maintenance treatment with acute doses of imipramine might be even more effective— if the patient is willing to take medication. These findings must be considered with caution because of the inherent inequity be­tween imipramine and IPT-M in regard to maintenance dosage strength.

Frequency of treatment. In another trial, Frank et al²⁴ examined whether the fre­quency of maintenance IPT sessions played a role in its prophylactic effect. Adult wom­en who had achieved depression remission with acute IPT (alone or in combination with SSRI pharmacotherapy) were ran­domized to weekly, bi-weekly, or monthly IPT-M alone for 2 years or until recurrence. Depression recurred during IPT-M in:
   • 26% of patients who had received acute IPT alone
   • 50% of those who had received acute IPT plus an SSRI.

Frequency of IPT-M sessions did not af­fect time to recurrence. Thus, for women who can achieve remission with IPT alone, varied frequencies of IPT-M can be good prophylaxis. For women who need an SSRI to augment acute IPT, IPT-M alone at varied dosages is less effective in pre­venting depression recurrence. Therefore, acute treatment response patterns can in­form maintenance plans, with the most prudent maintenance strategy being to maintain the acute treatment strategy over a longer period.

IPT-M for late-life depression. A trial by Reynolds et al25 examined the efficacy of maintenance nortriptyline and IPT-M in preventing depression recurrence in pa­tients age ≥59 who initially recovered after combined acute and continuation IPT plus nortriptyline. The 4 conditions (with their recurrence rates) were:
   • monthly IPT-M with nortriptyline (20%)
   • monthly IPT-M with placebo (64%)
   • nortriptyline plus medication visits (43%)
   • placebo plus medication visits (90%).

Clearly, the combined active treat­ments outperformed placebo and anti­depressant alone in terms of delaying or preventing recurrence, which suggests an optimal maintenance strategy with this population.

IPT-M for later life. Another trial by the same group²⁶ enrolled patients age ≥70 with MDD that responded to acute IPT plus paroxetine. The maintenance treat­ments to which they were randomly as­signed (and recurrence rates within 2 years) were:
   • paroxetine plus IPT-M (35%)
   • placebo plus IPT-M (68%)
   • paroxetine plus clinical management (37%)
   • placebo plus clinical management (58%).

Recurrence rates were the same for pa­tients receiving medication plus IPT-M and medication plus clinical management, and depression was 2.4 times more likely to recur in patients receiving placebo vs active medication. Therefore, for later life depression, the optimal maintenance strat­egy was the SSRI.

Secondary analyses of data from these seminal trials of IPT-M point to other predictors of how and for whom mainte­nance IPT may work (Table 4). For example:
   • Greater variability of depression symptoms during all forms of mainte­nance treatment is related to a greater risk of recurrence.
   • Persistent insomnia is related to greater risk of recurrent depression.
   • High interpersonal focus in IPT-M sessions is related to longer time to recurrence.

Bottom Line
Interpersonal psychotherapy (IPT) is efficacious for acute depression and for preventing recurrences. Patients treated successfully with acute IPT alone benefit from varied doses of maintenance IPT. Combining IPT-M with antidepressant medication can be more potent than IPT-M alone. For late-life depression, medication appears to be most effective for maintenance treatment.

Related Resources

Media
• Video demonstration, role-play transcripts, lesson plans, and quizzes. In: Appendices in and DVD companion to Ravitz P, Watson P, Grigoriadas S. Interpersonal psychother­apy for depression. New York, NY: Norton; 2013.
• Video demonstration of IPT sessions. In: DVD companion to Dewan, M, Steenbarger, B, Greenberg, R, eds. The art and science of brief psychotherapies: An illustrated guide. 2nd ed. Arlington, VA: American Psychiatric Publishing; 2012.

Text
• Stuart S, Robertson M. Interpersonal psychotherapy: a cli­nician’s guide. London, United Kingdom: Taylor & Francis; 2012.
• Weissman MM, Markowitz JC, Klerman GL. Comprehensive guide to interpersonal psychotherapy. New York, NY: Basic Books; 2000.
• Weissman M, Markowitz J, Klerman GL. Clinician’s quick guide to interpersonal psychotherapy. New York, NY: Oxford University Press; 2007.

Websites
• Interpersonal Psychotherapy Institute. http://iptinstitute.com.
• International Society for Interpersonal Psychotherapy. http://interpersonalpsychotherapy.org.

Drug Brand Names
Amitriptyline • Elavil       Nortriptyline • Pamelor
Imipramine • Tofranil     Paroxetine • Paxil

Acknowledgments
The authors are grateful to Samantha L. Bernecker, MS, and Nicholas R. Morrison for their assistance with the research review.

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

Major depressive disorder (MDD) frequently is recur­rent, with new episodes causing substantial social and economic impairment¹ and increasing the like­lihood of future episodes.² For this reason, contemporary psychiatric practitioners think of depression treatment as long-term and plan thoughtfully for maintenance therapy.

Recognizing the importance of engaging depressed indi­viduals beyond the initial response,³ American Psychiatric Association practice guidelines conceptualize depression treatment as 3 phases:
   • acute treatment, with the aim of remission (symptom removal)
   • continuation treatment, with the aim of preventing re­lapse (symptom return)
   • maintenance treatment, with the aim of preventing re­currence (new episodes).⁴
Interpersonal psychotherapy (IPT) is an evidence-based psychosocial treatment that adheres to this model.⁵ As a time-limited, manual-driven^6,7 approach, IPT focuses on interpersonal distresses as precipitating and perpetuating factors of depression.⁸

Acute IPT’s efficacy is well-established across >200 empirical studies—making it an evidence-based, first-line treatment for adult depression.^4,9,10 Meta-analyses show that acute IPT is superior to placebo and no-treatment con­trols, and largely comparable to antidepressant medication and other active, first-line psychotherapies, such as cogni­tive-behavioral therapy (CBT).^11,12

Although this review, as well as the liter­ature, focuses largely on adult outpatients with depression, evidence of IPT’s general efficacy exists for adolescents,¹³ chronically depressed patients,¹¹ and depressed inpa­tients.¹⁴ This article presents a case study to describe the structure of IPT when used to treat depressed adults. We also present evidence of IPT’s acute and long-term ef­ficacy in preventing depression recurrence and data to guide its use in practice.

CASE REPORT

‘Safe’ but depressed
Timothy, age 18, is a first-year college student who presents for outpatient psychotherapy to address recurrent depression. He reports general unhappiness, loss of interest in things, low energy, sleep problems, poor academic and work functioning, and low self-esteem. He experienced at least 3 similar depressive episodes while in high school.

The therapist’s diagnostic and interper­sonal assessment suggests that Timothy’s depression is interpersonally driven. Timothy longs for relational intimacy but fears he will fail or burden people with his needs. He has difficulty gauging appropriate lev­els of enmeshment with others and either becomes overdependent or stays at a dis­tance. This “safe” approach to relationships contributes to boredom, loneliness, and isolation. His recent transition to college away from home and the failure of a roman­tic relationship have compounded these experiences.

Interpersonal model of IPT
IPT conceptualizes depression as involving predisposing, precipitating, and perpetu­ating biopsychosocial factors, including:
   • underlying biological and social vul­nerability, such as insecure attach­ ment (ie, tenuous and often negative views of self and others)
   • current interpersonal life stressors
   • inadequate social supports.^15,16

For example, poor early attachment to caregivers can give rise to despair, isolation, and low mood. In turn, this can be exacerbated by poor social and commu­nication skills that promote further rejec­tion and withdrawal of social support and thus, intensified despair, isolation, and low mood. As in Timothy’s case, this vicious cycle underscores psychosocial stressors as a causal factor, maintaining factor, and result of depression. Specifically, IPT con­ceptualizes 4 main biopsychosocial problem domains:
   • grief and loss
   • interpersonal disputes
   • role transitions
   • interpersonal/communication deficits (often connected to isolation).

Working within 1 or 2 of the most salient problem domains, IPT centers on strategies for helping patients solve interpersonal problems based on the notion that modi­fied relationships, revised interpersonal expectations, improved communications, and increased social support will lead to symptom reduction.^15-17

Many techniques are utilized in IPT (Table 1) to help patients modify their interpersonal relationships as a mechanism for decreasing their distress. IPT is prob­lem-focused, aiming to improve patients’ relationships by drawing on their assets and helping to build skills around short­comings. Therefore, IPT focuses on observ­able interpersonal patterns, as opposed to latent personality dynamics.

CASE CONTINUED

Setting goals
When the clinical explains in the non-technical terms the data supporting IPT’s efficacy for depression, including with young adults, Timothy agrees to teeatment with acute IPT. The therapist behins with consciousness-raising techniques to help Timothy adopt the “sick role” by viewing depressing as an illness to be cured. Collaboratively, they establish treatment goals that fit the IPT formulation of depression— ie, revising current relationships and expectations of them, increasing social support, improving communication skills, and solving problems within 1 or 2 of the IPT prob­lem domains.

For Timothy, the most pressing psy­chosocial problems seem to be interper­sonal deficits and role transitions. He ap­pears to be insecurely attached to others, which is a risk factor for poor facilitation of, and boundaries around, good relation­ships. A transition to a new and intimidat­ing interpersonal context—living on a college campus—compounded his vulnerabilities and increased his depression.

Acute treatment. The acute phase of IPT is time-limited—often, 12 to 16 sessions with gradual tapering toward the end (akin to a continuation phase). The time limit’s pur­pose is to focus both patient and therapist on the specific goal of removing the acute “illness” of depression. The IPT clinician takes an interpersonal inventory to learn about the patient’s most important rela­tionships and hones in on the IPT domain foci. Working collaboratively, the thera­pist might help the patient mourn a loss, reconstruct a narrative with a deceased loved one, consider ways to increase social contact, develop assertiveness, label feel­ings and needs, resolve an impasse with a significant other, and so forth.

The IPT therapist is an advocate for the patient and adopts an active stance laced with empathy and warmth. However, the therapist is more than unconditionally ac­cepting as depression is viewed as a prob­lem to be actively resolved.

CASE CONTINUED

Creating new patterns
The therapist uses various IPT strategies to work collaboratively with Timothy. She at­tempts to develop a strong working alliance by building interpersonal safety and trust— which take time with an insecurely attached patient. She tries to provide a new model for how close relationships can develop, while also focusing on current relationships. She and Timothy address his romantic desire for a coworker and work on developing realistic ex­pectations and effective methods for convey­ing his interest.

When Timothy approaches his coworker, she does not reject him—as he expected— but wants to pursue friendship before pos­sibly dating. The therapist then works with Timothy’s emotional reaction and explores ways to effectively convey his emotions to this young woman. Drawing on communica­tion analysis and problem-solving strategies, Timothy is able to sustain this friendship—a shift from his typical retreat when relation­ships have not gone as hoped or expected.

Timothy develops confidence to take more risks in initiating social encounters and starts to confide in his roommates when he feels upset. After 3 months of treatment, his expanded social network and improved in­terpersonal skills result in decreased depres­sion. When Timothy suggests termination, he and the therapist agree to end acute IPT but—given his history of depression—to continue maintenance sessions.

Limited data exist on variables that relate to IPT’s acute success or conditions under which it works best. Although process re­search lags behind acute IPT outcome re­search, some findings can help guide the IPT practitioner. For example, variables shown to predict outcomes of acute IPT for depression include a positive therapeutic alliance, therapist warmth, and psycho­ psycho­therapist use of exploratory techniques (Table 2).

Similarly, IPT has been shown to be more effective in some patients than oth­ers, depending on various moderators of depression. For example:
   • For patients with high cognitive dys­function, IPT outperforms CBT.
   • For patients with higher need for medical reassurance, IPT outperforms selective serotonin reuptake inhibitor (SSRI) pharmacotherapy.
   • For patients with severe depression, CBT outperforms IPT.
   • For patients with low psychomotor activation, response is more rapid with an SSRI than with IPT (Table 3).¹⁸

Durability of acute IPT
One way to understand recurrence pre­vention is to examine the durability of a treatment’s acute effect in the absence of a specific maintenance plan. In theory, patients will continue to apply the skills learned in acute IPT to maintain gains and prevent recurrences, even after they stop seeing the psychotherapist.

Initial findings.  Some research speaks to IPT’s acute-phase durability. The inaugural clinical trial of IPT by Weissman et al¹⁹ included 4 months of acute treatment and a 1-year uncontrolled naturalistic follow-up assessment. At follow-up, depression and global clinical symptoms were the same, whether patients had been acutely treated with IPT alone, pharmacotherapy alone (amitriptyline), combined IPT and pharmacotherapy, or nonscheduled treat­ment with a psychiatrist.

Some patients continued to function well, whereas others did not fully main­tain acute treatment gains. Patients who received IPT acutely, either singly or with medication, showed better social function­ing at follow-up compared with patients who did not receive IPT. This long-term durability of social improvements was an obvious target of IPT.

Support from TDCRP. In the National Institute of Mental Health Treatment of Depression Collaborative Research Project (TDCRP),²⁰ patients in the acute phase of depression were assigned to 16 weeks of IPT, CBT, pharmacotherapy (imipramine) and clinical management (CM), or placebo plus CM. Among those who recovered by acute treatment’s end, MDD relapse rates at 18-month naturalistic follow-up were 33% for IPT, 36% for CBT, 50% for imipramine, and 33% for placebo. Between-group differ­ences were not statistically significant.

Because acute responders to different types of treatment might have different inherent relapse tendencies, these data do not support causal attributions about the enduring effects of acute-phase treatment. The relapse rates do suggest, however, that 16 weeks of acute treatment, irrespec­tive of kind, was insufficient for some pa­tients to achieve full recovery and lasting remission. Consistent with the initial IPT trial,¹⁹ IPT (and CBT) outperformed medi cation and placebo in maintaining rela­tionship quality.²¹

Long-term benefits. A more recent trial by Zobel et al²² examined the durabil­ity of benefits from 5 weeks of acute IPT plus pharmacotherapy and pharmaco­therapy plus CM for inpatients with MDD. Although caution is required in interpret­ing naturalistic follow-up studies, patients in both groups showed decreased depres­sion from baseline to 5-year follow-up. Early symptom reduction was more rapid for patients in the IPT plus pharmacother­apy group, but no significant difference ex­isted at 5 years. More IPT patients than CM patients showed sustained remission (28% vs 11%, respectively). These rates demon­strate a need for longer-term potency of acute treatments and more targeted main­tenance treatments.

IPT-M for preventing recurrence
A second way to understand recurrence prevention is to examine the efficacy of a treatment’s maintenance protocol add­ed to an acute treatment phase. IPT has been adapted as a maintenance treatment (IPT-M), with emphasis on keeping pa­tients well. With this revised focus, IPT-M differs somewhat from acute IPT. Although treatment continues to center on interper­sonal functioning, IPT-M favors:
   • vigilance for possible triggers of new depressive episodes
   • longer-term contact with a therapist
   • reinforcing skills learned
   • addressing an expanded number of interpersonal problem areas (given that such problems can be addressed more ef­ficiently relative to acute treatment).

Efficacy of IPT-M. In the initial trial, Frank et al²³ compared the efficacy of IPT-M with that of pharmacotherapy (imipramine) in preventing depressive relapse among pa­tients with recurrent depression who had responded to ≥16 sessions of acute IPT and imipramine and remained well during a 17- week continuation phase. For maintenance, patients were assigned to IPT-M alone, imipramine alone, placebo alone, IPT-M plus imipramine, or IPT-M plus placebo. Maintenance imipramine was continued at the acute dosage (target 200 mg/d; up to 400 mg/d was allowed). Maintenance IPT was monthly sessions. Patients remained in the trial for 3 years or until depression recurred.

On its own, IPT-M showed some efficacy in preventing recurrence, as the mean time to recurrence was 82 weeks for IPT-M alone and 74 weeks for IPT-M plus placebo. The prophylactic effect of imipramine was stron­ger, however. The mean time to recurrence for imipramine with IPT was 131 weeks, and the mean time to recurrence for imipra­mine without IPT was 124 weeks. Therefore, whereas monthly IPT-M can certainly help prolong wellness and delay recurrence, IPT maintenance treatment with acute doses of imipramine might be even more effective— if the patient is willing to take medication. These findings must be considered with caution because of the inherent inequity be­tween imipramine and IPT-M in regard to maintenance dosage strength.

Frequency of treatment. In another trial, Frank et al²⁴ examined whether the fre­quency of maintenance IPT sessions played a role in its prophylactic effect. Adult wom­en who had achieved depression remission with acute IPT (alone or in combination with SSRI pharmacotherapy) were ran­domized to weekly, bi-weekly, or monthly IPT-M alone for 2 years or until recurrence. Depression recurred during IPT-M in:
   • 26% of patients who had received acute IPT alone
   • 50% of those who had received acute IPT plus an SSRI.

Frequency of IPT-M sessions did not af­fect time to recurrence. Thus, for women who can achieve remission with IPT alone, varied frequencies of IPT-M can be good prophylaxis. For women who need an SSRI to augment acute IPT, IPT-M alone at varied dosages is less effective in pre­venting depression recurrence. Therefore, acute treatment response patterns can in­form maintenance plans, with the most prudent maintenance strategy being to maintain the acute treatment strategy over a longer period.

IPT-M for late-life depression. A trial by Reynolds et al25 examined the efficacy of maintenance nortriptyline and IPT-M in preventing depression recurrence in pa­tients age ≥59 who initially recovered after combined acute and continuation IPT plus nortriptyline. The 4 conditions (with their recurrence rates) were:
   • monthly IPT-M with nortriptyline (20%)
   • monthly IPT-M with placebo (64%)
   • nortriptyline plus medication visits (43%)
   • placebo plus medication visits (90%).

Clearly, the combined active treat­ments outperformed placebo and anti­depressant alone in terms of delaying or preventing recurrence, which suggests an optimal maintenance strategy with this population.

IPT-M for later life. Another trial by the same group²⁶ enrolled patients age ≥70 with MDD that responded to acute IPT plus paroxetine. The maintenance treat­ments to which they were randomly as­signed (and recurrence rates within 2 years) were:
   • paroxetine plus IPT-M (35%)
   • placebo plus IPT-M (68%)
   • paroxetine plus clinical management (37%)
   • placebo plus clinical management (58%).

Recurrence rates were the same for pa­tients receiving medication plus IPT-M and medication plus clinical management, and depression was 2.4 times more likely to recur in patients receiving placebo vs active medication. Therefore, for later life depression, the optimal maintenance strat­egy was the SSRI.

Secondary analyses of data from these seminal trials of IPT-M point to other predictors of how and for whom mainte­nance IPT may work (Table 4). For example:
   • Greater variability of depression symptoms during all forms of mainte­nance treatment is related to a greater risk of recurrence.
   • Persistent insomnia is related to greater risk of recurrent depression.
   • High interpersonal focus in IPT-M sessions is related to longer time to recurrence.

Bottom Line
Interpersonal psychotherapy (IPT) is efficacious for acute depression and for preventing recurrences. Patients treated successfully with acute IPT alone benefit from varied doses of maintenance IPT. Combining IPT-M with antidepressant medication can be more potent than IPT-M alone. For late-life depression, medication appears to be most effective for maintenance treatment.

Related Resources

Media
• Video demonstration, role-play transcripts, lesson plans, and quizzes. In: Appendices in and DVD companion to Ravitz P, Watson P, Grigoriadas S. Interpersonal psychother­apy for depression. New York, NY: Norton; 2013.
• Video demonstration of IPT sessions. In: DVD companion to Dewan, M, Steenbarger, B, Greenberg, R, eds. The art and science of brief psychotherapies: An illustrated guide. 2nd ed. Arlington, VA: American Psychiatric Publishing; 2012.

Text
• Stuart S, Robertson M. Interpersonal psychotherapy: a cli­nician’s guide. London, United Kingdom: Taylor & Francis; 2012.
• Weissman MM, Markowitz JC, Klerman GL. Comprehensive guide to interpersonal psychotherapy. New York, NY: Basic Books; 2000.
• Weissman M, Markowitz J, Klerman GL. Clinician’s quick guide to interpersonal psychotherapy. New York, NY: Oxford University Press; 2007.

Websites
• Interpersonal Psychotherapy Institute. http://iptinstitute.com.
• International Society for Interpersonal Psychotherapy. http://interpersonalpsychotherapy.org.

Drug Brand Names
Amitriptyline • Elavil       Nortriptyline • Pamelor
Imipramine • Tofranil     Paroxetine • Paxil

Acknowledgments
The authors are grateful to Samantha L. Bernecker, MS, and Nicholas R. Morrison for their assistance with the research review.

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

Major depressive disorder (MDD) frequently is recur­rent, with new episodes causing substantial social and economic impairment¹ and increasing the like­lihood of future episodes.² For this reason, contemporary psychiatric practitioners think of depression treatment as long-term and plan thoughtfully for maintenance therapy.

Recognizing the importance of engaging depressed indi­viduals beyond the initial response,³ American Psychiatric Association practice guidelines conceptualize depression treatment as 3 phases:
   • acute treatment, with the aim of remission (symptom removal)
   • continuation treatment, with the aim of preventing re­lapse (symptom return)
   • maintenance treatment, with the aim of preventing re­currence (new episodes).⁴
Interpersonal psychotherapy (IPT) is an evidence-based psychosocial treatment that adheres to this model.⁵ As a time-limited, manual-driven^6,7 approach, IPT focuses on interpersonal distresses as precipitating and perpetuating factors of depression.⁸

Acute IPT’s efficacy is well-established across >200 empirical studies—making it an evidence-based, first-line treatment for adult depression.^4,9,10 Meta-analyses show that acute IPT is superior to placebo and no-treatment con­trols, and largely comparable to antidepressant medication and other active, first-line psychotherapies, such as cogni­tive-behavioral therapy (CBT).^11,12

Although this review, as well as the liter­ature, focuses largely on adult outpatients with depression, evidence of IPT’s general efficacy exists for adolescents,¹³ chronically depressed patients,¹¹ and depressed inpa­tients.¹⁴ This article presents a case study to describe the structure of IPT when used to treat depressed adults. We also present evidence of IPT’s acute and long-term ef­ficacy in preventing depression recurrence and data to guide its use in practice.

CASE REPORT

‘Safe’ but depressed
Timothy, age 18, is a first-year college student who presents for outpatient psychotherapy to address recurrent depression. He reports general unhappiness, loss of interest in things, low energy, sleep problems, poor academic and work functioning, and low self-esteem. He experienced at least 3 similar depressive episodes while in high school.

The therapist’s diagnostic and interper­sonal assessment suggests that Timothy’s depression is interpersonally driven. Timothy longs for relational intimacy but fears he will fail or burden people with his needs. He has difficulty gauging appropriate lev­els of enmeshment with others and either becomes overdependent or stays at a dis­tance. This “safe” approach to relationships contributes to boredom, loneliness, and isolation. His recent transition to college away from home and the failure of a roman­tic relationship have compounded these experiences.

Interpersonal model of IPT
IPT conceptualizes depression as involving predisposing, precipitating, and perpetu­ating biopsychosocial factors, including:
   • underlying biological and social vul­nerability, such as insecure attach­ ment (ie, tenuous and often negative views of self and others)
   • current interpersonal life stressors
   • inadequate social supports.^15,16

For example, poor early attachment to caregivers can give rise to despair, isolation, and low mood. In turn, this can be exacerbated by poor social and commu­nication skills that promote further rejec­tion and withdrawal of social support and thus, intensified despair, isolation, and low mood. As in Timothy’s case, this vicious cycle underscores psychosocial stressors as a causal factor, maintaining factor, and result of depression. Specifically, IPT con­ceptualizes 4 main biopsychosocial problem domains:
   • grief and loss
   • interpersonal disputes
   • role transitions
   • interpersonal/communication deficits (often connected to isolation).

Working within 1 or 2 of the most salient problem domains, IPT centers on strategies for helping patients solve interpersonal problems based on the notion that modi­fied relationships, revised interpersonal expectations, improved communications, and increased social support will lead to symptom reduction.^15-17

Many techniques are utilized in IPT (Table 1) to help patients modify their interpersonal relationships as a mechanism for decreasing their distress. IPT is prob­lem-focused, aiming to improve patients’ relationships by drawing on their assets and helping to build skills around short­comings. Therefore, IPT focuses on observ­able interpersonal patterns, as opposed to latent personality dynamics.

CASE CONTINUED

Setting goals
When the clinical explains in the non-technical terms the data supporting IPT’s efficacy for depression, including with young adults, Timothy agrees to teeatment with acute IPT. The therapist behins with consciousness-raising techniques to help Timothy adopt the “sick role” by viewing depressing as an illness to be cured. Collaboratively, they establish treatment goals that fit the IPT formulation of depression— ie, revising current relationships and expectations of them, increasing social support, improving communication skills, and solving problems within 1 or 2 of the IPT prob­lem domains.

For Timothy, the most pressing psy­chosocial problems seem to be interper­sonal deficits and role transitions. He ap­pears to be insecurely attached to others, which is a risk factor for poor facilitation of, and boundaries around, good relation­ships. A transition to a new and intimidat­ing interpersonal context—living on a college campus—compounded his vulnerabilities and increased his depression.

Acute treatment. The acute phase of IPT is time-limited—often, 12 to 16 sessions with gradual tapering toward the end (akin to a continuation phase). The time limit’s pur­pose is to focus both patient and therapist on the specific goal of removing the acute “illness” of depression. The IPT clinician takes an interpersonal inventory to learn about the patient’s most important rela­tionships and hones in on the IPT domain foci. Working collaboratively, the thera­pist might help the patient mourn a loss, reconstruct a narrative with a deceased loved one, consider ways to increase social contact, develop assertiveness, label feel­ings and needs, resolve an impasse with a significant other, and so forth.

The IPT therapist is an advocate for the patient and adopts an active stance laced with empathy and warmth. However, the therapist is more than unconditionally ac­cepting as depression is viewed as a prob­lem to be actively resolved.

CASE CONTINUED

Creating new patterns
The therapist uses various IPT strategies to work collaboratively with Timothy. She at­tempts to develop a strong working alliance by building interpersonal safety and trust— which take time with an insecurely attached patient. She tries to provide a new model for how close relationships can develop, while also focusing on current relationships. She and Timothy address his romantic desire for a coworker and work on developing realistic ex­pectations and effective methods for convey­ing his interest.

When Timothy approaches his coworker, she does not reject him—as he expected— but wants to pursue friendship before pos­sibly dating. The therapist then works with Timothy’s emotional reaction and explores ways to effectively convey his emotions to this young woman. Drawing on communica­tion analysis and problem-solving strategies, Timothy is able to sustain this friendship—a shift from his typical retreat when relation­ships have not gone as hoped or expected.

Timothy develops confidence to take more risks in initiating social encounters and starts to confide in his roommates when he feels upset. After 3 months of treatment, his expanded social network and improved in­terpersonal skills result in decreased depres­sion. When Timothy suggests termination, he and the therapist agree to end acute IPT but—given his history of depression—to continue maintenance sessions.

Limited data exist on variables that relate to IPT’s acute success or conditions under which it works best. Although process re­search lags behind acute IPT outcome re­search, some findings can help guide the IPT practitioner. For example, variables shown to predict outcomes of acute IPT for depression include a positive therapeutic alliance, therapist warmth, and psycho­ psycho­therapist use of exploratory techniques (Table 2).

Similarly, IPT has been shown to be more effective in some patients than oth­ers, depending on various moderators of depression. For example:
   • For patients with high cognitive dys­function, IPT outperforms CBT.
   • For patients with higher need for medical reassurance, IPT outperforms selective serotonin reuptake inhibitor (SSRI) pharmacotherapy.
   • For patients with severe depression, CBT outperforms IPT.
   • For patients with low psychomotor activation, response is more rapid with an SSRI than with IPT (Table 3).¹⁸

Durability of acute IPT
One way to understand recurrence pre­vention is to examine the durability of a treatment’s acute effect in the absence of a specific maintenance plan. In theory, patients will continue to apply the skills learned in acute IPT to maintain gains and prevent recurrences, even after they stop seeing the psychotherapist.

Initial findings.  Some research speaks to IPT’s acute-phase durability. The inaugural clinical trial of IPT by Weissman et al¹⁹ included 4 months of acute treatment and a 1-year uncontrolled naturalistic follow-up assessment. At follow-up, depression and global clinical symptoms were the same, whether patients had been acutely treated with IPT alone, pharmacotherapy alone (amitriptyline), combined IPT and pharmacotherapy, or nonscheduled treat­ment with a psychiatrist.

Some patients continued to function well, whereas others did not fully main­tain acute treatment gains. Patients who received IPT acutely, either singly or with medication, showed better social function­ing at follow-up compared with patients who did not receive IPT. This long-term durability of social improvements was an obvious target of IPT.

Support from TDCRP. In the National Institute of Mental Health Treatment of Depression Collaborative Research Project (TDCRP),²⁰ patients in the acute phase of depression were assigned to 16 weeks of IPT, CBT, pharmacotherapy (imipramine) and clinical management (CM), or placebo plus CM. Among those who recovered by acute treatment’s end, MDD relapse rates at 18-month naturalistic follow-up were 33% for IPT, 36% for CBT, 50% for imipramine, and 33% for placebo. Between-group differ­ences were not statistically significant.

Because acute responders to different types of treatment might have different inherent relapse tendencies, these data do not support causal attributions about the enduring effects of acute-phase treatment. The relapse rates do suggest, however, that 16 weeks of acute treatment, irrespec­tive of kind, was insufficient for some pa­tients to achieve full recovery and lasting remission. Consistent with the initial IPT trial,¹⁹ IPT (and CBT) outperformed medi cation and placebo in maintaining rela­tionship quality.²¹

Long-term benefits. A more recent trial by Zobel et al²² examined the durabil­ity of benefits from 5 weeks of acute IPT plus pharmacotherapy and pharmaco­therapy plus CM for inpatients with MDD. Although caution is required in interpret­ing naturalistic follow-up studies, patients in both groups showed decreased depres­sion from baseline to 5-year follow-up. Early symptom reduction was more rapid for patients in the IPT plus pharmacother­apy group, but no significant difference ex­isted at 5 years. More IPT patients than CM patients showed sustained remission (28% vs 11%, respectively). These rates demon­strate a need for longer-term potency of acute treatments and more targeted main­tenance treatments.

IPT-M for preventing recurrence
A second way to understand recurrence prevention is to examine the efficacy of a treatment’s maintenance protocol add­ed to an acute treatment phase. IPT has been adapted as a maintenance treatment (IPT-M), with emphasis on keeping pa­tients well. With this revised focus, IPT-M differs somewhat from acute IPT. Although treatment continues to center on interper­sonal functioning, IPT-M favors:
   • vigilance for possible triggers of new depressive episodes
   • longer-term contact with a therapist
   • reinforcing skills learned
   • addressing an expanded number of interpersonal problem areas (given that such problems can be addressed more ef­ficiently relative to acute treatment).

Efficacy of IPT-M. In the initial trial, Frank et al²³ compared the efficacy of IPT-M with that of pharmacotherapy (imipramine) in preventing depressive relapse among pa­tients with recurrent depression who had responded to ≥16 sessions of acute IPT and imipramine and remained well during a 17- week continuation phase. For maintenance, patients were assigned to IPT-M alone, imipramine alone, placebo alone, IPT-M plus imipramine, or IPT-M plus placebo. Maintenance imipramine was continued at the acute dosage (target 200 mg/d; up to 400 mg/d was allowed). Maintenance IPT was monthly sessions. Patients remained in the trial for 3 years or until depression recurred.

On its own, IPT-M showed some efficacy in preventing recurrence, as the mean time to recurrence was 82 weeks for IPT-M alone and 74 weeks for IPT-M plus placebo. The prophylactic effect of imipramine was stron­ger, however. The mean time to recurrence for imipramine with IPT was 131 weeks, and the mean time to recurrence for imipra­mine without IPT was 124 weeks. Therefore, whereas monthly IPT-M can certainly help prolong wellness and delay recurrence, IPT maintenance treatment with acute doses of imipramine might be even more effective— if the patient is willing to take medication. These findings must be considered with caution because of the inherent inequity be­tween imipramine and IPT-M in regard to maintenance dosage strength.

Frequency of treatment. In another trial, Frank et al²⁴ examined whether the fre­quency of maintenance IPT sessions played a role in its prophylactic effect. Adult wom­en who had achieved depression remission with acute IPT (alone or in combination with SSRI pharmacotherapy) were ran­domized to weekly, bi-weekly, or monthly IPT-M alone for 2 years or until recurrence. Depression recurred during IPT-M in:
   • 26% of patients who had received acute IPT alone
   • 50% of those who had received acute IPT plus an SSRI.

Frequency of IPT-M sessions did not af­fect time to recurrence. Thus, for women who can achieve remission with IPT alone, varied frequencies of IPT-M can be good prophylaxis. For women who need an SSRI to augment acute IPT, IPT-M alone at varied dosages is less effective in pre­venting depression recurrence. Therefore, acute treatment response patterns can in­form maintenance plans, with the most prudent maintenance strategy being to maintain the acute treatment strategy over a longer period.

IPT-M for late-life depression. A trial by Reynolds et al25 examined the efficacy of maintenance nortriptyline and IPT-M in preventing depression recurrence in pa­tients age ≥59 who initially recovered after combined acute and continuation IPT plus nortriptyline. The 4 conditions (with their recurrence rates) were:
   • monthly IPT-M with nortriptyline (20%)
   • monthly IPT-M with placebo (64%)
   • nortriptyline plus medication visits (43%)
   • placebo plus medication visits (90%).

Clearly, the combined active treat­ments outperformed placebo and anti­depressant alone in terms of delaying or preventing recurrence, which suggests an optimal maintenance strategy with this population.

IPT-M for later life. Another trial by the same group²⁶ enrolled patients age ≥70 with MDD that responded to acute IPT plus paroxetine. The maintenance treat­ments to which they were randomly as­signed (and recurrence rates within 2 years) were:
   • paroxetine plus IPT-M (35%)
   • placebo plus IPT-M (68%)
   • paroxetine plus clinical management (37%)
   • placebo plus clinical management (58%).

Recurrence rates were the same for pa­tients receiving medication plus IPT-M and medication plus clinical management, and depression was 2.4 times more likely to recur in patients receiving placebo vs active medication. Therefore, for later life depression, the optimal maintenance strat­egy was the SSRI.

Secondary analyses of data from these seminal trials of IPT-M point to other predictors of how and for whom mainte­nance IPT may work (Table 4). For example:
   • Greater variability of depression symptoms during all forms of mainte­nance treatment is related to a greater risk of recurrence.
   • Persistent insomnia is related to greater risk of recurrent depression.
   • High interpersonal focus in IPT-M sessions is related to longer time to recurrence.

Bottom Line
Interpersonal psychotherapy (IPT) is efficacious for acute depression and for preventing recurrences. Patients treated successfully with acute IPT alone benefit from varied doses of maintenance IPT. Combining IPT-M with antidepressant medication can be more potent than IPT-M alone. For late-life depression, medication appears to be most effective for maintenance treatment.

Related Resources

Media
• Video demonstration, role-play transcripts, lesson plans, and quizzes. In: Appendices in and DVD companion to Ravitz P, Watson P, Grigoriadas S. Interpersonal psychother­apy for depression. New York, NY: Norton; 2013.
• Video demonstration of IPT sessions. In: DVD companion to Dewan, M, Steenbarger, B, Greenberg, R, eds. The art and science of brief psychotherapies: An illustrated guide. 2nd ed. Arlington, VA: American Psychiatric Publishing; 2012.

Text
• Stuart S, Robertson M. Interpersonal psychotherapy: a cli­nician’s guide. London, United Kingdom: Taylor & Francis; 2012.
• Weissman MM, Markowitz JC, Klerman GL. Comprehensive guide to interpersonal psychotherapy. New York, NY: Basic Books; 2000.
• Weissman M, Markowitz J, Klerman GL. Clinician’s quick guide to interpersonal psychotherapy. New York, NY: Oxford University Press; 2007.

Websites
• Interpersonal Psychotherapy Institute. http://iptinstitute.com.
• International Society for Interpersonal Psychotherapy. http://interpersonalpsychotherapy.org.

Drug Brand Names
Amitriptyline • Elavil       Nortriptyline • Pamelor
Imipramine • Tofranil     Paroxetine • Paxil

Acknowledgments
The authors are grateful to Samantha L. Bernecker, MS, and Nicholas R. Morrison for their assistance with the research review.

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

Many substances that are not typically thought of as “substances of abuse” possess—when adequate­ly dosed—clinically meaningful psychoactive properties. In addition to the more familiar effects of alcohol, psychostimulants, opioids, Cannabis, and hallucinogens, you may encounter psychiatric phenomena resulting from abuse of more obscure substances, including culinary spices.

The clinician treating a patient in an apparent intoxicated state who has a negative drug screen might ask that patient if he (she) abuses spices. This might be particularly relevant when treating patients thought to have limited access to il­licit substances or those with ready access to large amounts of spices, such as prisoners, young patients, and those working in the food service industry.

Abuse of spices can be a problematic diagnosis
Patients may misuse culinary spices to achieve euphoria, or a “natural high.” They may present with medical or psychiat­ric symptoms, including acute altered mental status, but the psychoactive substances are not identified on routine toxicol­ogy studies. In addition, patients may not attribute their use of spices for psychoactive effect to “drugs,” because these materials are legal and readily available. This may lead to misdiagnosis of a systemic medical disorder or a primary psy­chiatric illness to explain the patient’s symptoms and initiat­ing a psychotropic agent and other psychiatric services when a substance abuse program might be a more appropriate clini­cal intervention.

Some spices contain psychoactive compounds that can alter CNS function (Table^1-7), might be abused for recreational purposes, and can be toxic in an excessive amount. Internet resources, including anonymous web-based communications, and anecdotal materials about non-traditional recreational drugs, are available to anyone with Internet access.⁸ However, little research has been conducted into the preva­lence of abuse (Box)⁹ and spices’ psychoactive properties. The lack of toxicology detection of spices in the medical setting presents a di­agnostic challenge.

The psychoactive plants used in “natural high” products mainly are psychoactively inactive in their natural form, but extracts or alkaloids obtained from them might induce 1 or more of 3 classifications of psychoactivity:
   • stimulant
   • sedative
   • hallucinogenic.

Many of these substances are considered to be aphrodisiac, and some may be abused to increase sexual function.

The following is a review of common spic­es that have been reported to possess poten­tial psychoactive properties.

Nutmeg
Nutmeg (Myristica fragrans) is a common and easily accessible means of reaching euphoria in adults.¹⁰ The aromatic oil of nutmeg contains myristicin, a psychoactive substance that is chemically similar to hal­lucinogenic compounds such as mescaline. Its psychoactive effects could be attributed to metabolic formation of amphetamine de­rivatives from its core ingredients, elemicin, myristicin, and safrole.^11,12

Nutmeg and its active component, my­risticin, produce central monoamine oxi­dase (MAO) inhibition as evidenced by the ability to lower the convulsive dose of IV tryptamine in mice and to increase brain 5-hydroxytryptamine concentra­tions.^13,14 Although myristicin’s potency is not comparable to that of the more potent MAO inhibitors such as tranylcypromine and iproniazid (which is not available in the United States), it seems adequate when compared with its low toxicity.¹⁴ Nutmeg extract is associated with a significant anti­depressant effect in mice, which seemed to be mediated by interaction with the adren­ergic, dopaminergic, and serotonergic sys­tems.¹³ Nutmeg is associated with sustained increase in sexual activity in animal studies, with no evidence of adverse effects and toxicity, suggesting that nutmeg possesses clinically significant aphrodisiac activity.¹⁵

Psychoactive effects can be achieved by ingesting 5 to 15 g of nutmeg.¹¹ Acute nut­meg intoxication produces palpitations, dizziness, anxiety, and hallucinations, mostly resolving within 24 hours, while effects of chronic abuse are reported to be similar to Cannabis use, including euphoria, giddiness, anxiety, fear, sense of impending doom, detachment, confabulation, and hal­lucinations.^11,16 Urine drug screens are nega­tive unless other psychoactive substances have been ingested.¹⁷

Suspected nutmeg intoxication or poison­ing should be treated with supportive treat­ment. Use sedatives with caution because of alternating periods of delirium and obtunda­tion during nutmeg intoxication.¹⁷

In case reports, myristicin poisoning induced CNS neuromodulatory signs that mimicked an anticholinergic hyperstimula­tion state.^12,18 Fatal myristicin poisoning is rare; 2 cases have been reported, 1 in com­bination with flunitrazepam (not available in the United States).^19,20 Nutmeg also has sedative properties and can cause GI symp­toms when ingesting excessive amounts.^1,20,21 Grover et al²¹ described no harmful effects on blood pressure and electrocardiogram; how­ever, Shah et al²² reported palpitations and dry mouth.

Vanilla
Vanilla (species of the genus Vanilla) con­tains piperonal, also known as heliotropin.¹ Piperonal has aromatherapeutic qualities that might elevate mood and well-being. In the early 1990s, the Memorial Sloan- Kettering Cancer Center in New York City described heliotropin as a powerful aroma­therapy tool. Patients who were undergo­ing an MRI in an environment scented with heliotropin demonstrated a 63% reduction in anxiety compared with those who were not exposed to fragrance.²³ The Smell and Taste Treatment and Research Foundation in Chicago found that vanilla can promote sexual arousal.²⁴

Short-term effects of vanillin—a major component of vanilla—include a feeling of relaxation and reduced stress; long-term use can produce an antidepressant effect.¹ There are no reports of vanilla abuse to achieve these effects; however, patients might abuse vanilla extract because of its alcohol content (up to 35% ethanol).²⁵

Fennel
The essential oil of fennel (Foeniculum vul­gare) can be neurotoxic and epileptogenic. Skalli and colleagues recently reported a case of seizure induction in a young woman after ingesting cakes containing fennel oil.²⁶ Fennel oil also has been reported to have significant interaction with the fluoroquinolone-type antibiotics. Be aware of adverse effects associ­ated with fennel ingestion; question patients if atypical seizures or reactions to antibiotics occur.²⁷

Spices such as fennel, dill, cinnamon, saf­fron, and anise also contain psychoactive substances that are chemically similar to my­risticin, which can induce sedation, stimula­tion, or hallucinations.⁷

Black pepper
Piperine, which gives black pepper (Piper ni­grum) its spiciness, enhances thermogenesis of lipid metabolism, accelerates energy me­tabolism, and increases serotonin and endor­phin production in the brain.28 Black pepper is reported to potentiate γ-aminobutyric acid A receptor subtypes,²⁹ and could present possible applications for treating insomnia, epilepsy, and anxiety disorders.

Cloves
Non-culinary uses of clove (Syzygium aro­maticum, a tree in the myrtle family) include flavored cigarettes. However, in 2009 clove cigarettes were banned in the United States as part of a public policy to reduce the number of children who start smoking.³⁰ Eugenol, which constitutes as much as 90% of the essential oil extracted from cloves (and is responsible for the aroma), can cause hepatotoxicity³¹ and palpitations³²; it can be toxic in quantities as low as 5 mL.³³ Eugenol is present in other spic­es, such as nutmeg and cinnamon, and has been reported to have sedative properties.¹

Mace
Mace is made from the covering of nutmeg (Myristica fragrans) seeds. It has a strong aro­ma resembling that of nutmeg. Whole mace contains 4% to 14% of a volatile oil similar to that found in nutmeg. Because mace con­tains the same oils that make nutmeg psy­choactive1 in excessive amounts—although nutmeg seeds are more potent—be aware of the psychoactive potential of mace.

CinnamonCassia cinnamon (Cinnamomum aromaticum) is spicier and tarter than Ceylon cinnamon (Cinnamomum zeylanicum), which has a more flowery aroma. The 2 types of cinnamon can be distinguished by their different chemical composition. Ceylon cinnamon contains eu­genol and benzyl benzoate; cassia cinnamon contains coumarin.³ Eugenol is reported to have sedative effects.¹ Coumarin is a precur­sor molecule in the synthesis of a number of synthetic anticoagulant pharmaceuticals, including coumadin. Because of the toxic component of coumarin, European health agencies have warned against consuming high amounts of cassia.³⁴ There are no re­ports of side effects arising from the occa­sional use of cinnamon as a spice. 

In a study by Frydman-Marom et al,³⁵ cinnamon extract (CEppt) was found to act on the CNS by inhibiting development of Alzheimer’s disease in animal models.

Asarone
Asarone is found in the Asarum family of spices that includes Acorus calamus. Asarone is chemically similar to mescaline. Although anecdotal reports indicate that A. calamus is a hallucinogen, research shows no evidence that it contains hallucinogenic substances.³⁶ Han et al³⁷ reported an antidepressant ef­fect with the essential oil and asarones for the rhizomes of Acorus tatarinowii. In ani­mal studies, asarone was found to reduce spontaneous motor activity, and even in low doses, reduced anxiety without decreasing acuity of perception.³⁸

Ginger
Ginger (Zingiber officinale) is regarded as a sedative, general stimulant, and aphrodisi­ac.^1,4,5 Its main constituents are phenolic com­pounds such as gingerols and shogaols, and sesquiterpenes such as zingiberene.⁴ Ginger is an inhibitor of thromboxane synthetase, a property shared by tricyclic antidepressants.³⁹

Research indicates that 9 compounds found in ginger may interact with the serotonin 5-HT1A receptor, suggesting a possible mechanism for reducing anxiety.⁴⁰ A study by Nievergelt et al⁴¹ indicates that by binding to human serotonin receptors, gin­ger might influence GI function. Ginger ex­tract contains a cholinergic and spasmogenic component, which provides a mechanistic insight for the prokinetic action of ginger.⁴⁰

Turmeric
Turmeric (Curcuma longa) has been investigat­ed for possible benefit in Alzheimer’s disease⁴²; research into curcumin, the active substance of turmeric, is increasing. Although the original report was retracted after publication, cur­cumin was reported to selectively bind to hu­man cannabinoid receptors type 1 (CB1) with nanomolar affinities and to function as an an­tagonist/inverse agonist.⁴³ However, Gertsch et al⁴⁴ found that curcumin did not interact functionally with the CB1 receptor, although this compound appears to share ability of the CB1 receptor inverse agonist.

Galangal
Major constituents identified in the galan­gal (or galanga) rhizome and leaf oil were 1,8-cineole, and β-pinene and cam­phor.6 Galangal, a member of the ginger (Zingiberaceae) family, interacts with MAO inhibitors, H2 receptor antagonists, and pro­ton-pump inhibitors.¹ Anxiolytic, hallucino­genic, and stimulant properties have been reported.1 An excessive amount can induce diarrhea, dizziness, nausea, and vomiting.¹

Saffron
Stigma of saffron (a member of the family Iridaceae) was found to be significantly more effective than placebo and equally as effica­cious as fluoxetine and imipramine in treat­ing depression. Saffron petal was found to be significantly more effective than placebo and as effective as fluoxetine and saffron stigma in a recent systematic review.^45-48

Asafetida
Asafetida (Ferula assa-foetida), when combined with valerian root, is used as a sedative to treat hyperactivity.² The active ingredients of asafet­ida are the resin, endogenous gum, essential oil, propenyl-isobutylsulfide, umbelliferone, and vanillin. Several of the volatile constitu­ents produce a sedative effect.² Additive ef­fects can occur between the hypotensive property of asafetida and dopamine receptor agonists such as bromocriptine mesylate. Use caution when combining asafetida in conjunc­tion with a CNS depressant or a stimulant.² 

Recommendations for treating spice-abusers
Patients may present to psychiatry ser­vices with psychological and physiologi­cal evidence of intoxication with culinary spices that may mimic 1) abuse of other substances, 2) primary psychiatric illness, and 3) primary medical illness. When you encounter a patient with a new psychiat­ric symptom, consider inquiring about the abuse of spices.

Patients might abuse more than 1 spice; a comprehensive screening approach might therefore be useful. Caution patients that in­gesting these substance to excess can have harmful effects. Consider appropriate psy­chopharmacotherapy for underlying psy­chiatric symptoms to help patients who use spices maladaptively to self-medicate psy­chiatric symptoms.

Consider abuse of culinary spices in clini­cal presentations of psychiatric symptoms that do not seem adequate for a diagnosis of a primary anxiety, mood, or psychotic disorder, or in cases atypical psychiatric presentations that are—perhaps to your surprise—associat­ed with negative toxicology studies for com­mon, more familiar substances of abuse.

Physicians practicing in an environment where street drugs are difficult to obtain (eg, prisons) should consider monitoring for possible abuse of spices. Based on the available, albeit limited, literature, it ap­pears that most culinary spice–associated intoxication can be managed:
   • with an elevated level of clinical suspicion
   • by ruling out other causes of intoxication
   • using targeted, empirical psychophar­macotherapy to manage symptoms
   • with supportive care that includes close psychiatric follow-up.

Consider comorbid abuse of other, more familiar substances of abuse in patients who misuse spices. As with inhalant abuse, the concept of “substance abuse” in clinical practice may need to be further expanded to include patients who abuse culinary spices. Patients could be screened for psychiatric illnesses known to increase the risk of sub­stance abuse. These might include—but are not limited to:
   • comorbid psychotic disorders
   • mood disorders, particularly bipolar disorders
   • trauma- and stressor-related disor­ders, particularly posttraumatic stress disorder
   • personality disorders, particularly anti­social, borderline, and narcissistic personality disorders.

Pending the availability of population-based studies on abuse of culinary spices, the usual cautions regarding substance abuse seem to be appropriate when caring for these patients. Assessment for and man­agement of comorbid psychiatric conditions is essential in the comprehensive psychiatric care of patients who abuse substances.

Last, general consideration of a 12-step recovery program appears warranted for these patients; the self-reflection and group support of such programs can be useful in helping patients control their use of these substances. 

Bottom Line
Presentation of culinary spice intoxication can parallel that of other medical or psychiatric illnesses, or other drugs of abuse. Consideration and questioning for abuse of spices is necessary to ascertain the psychoactive effects of these substances when used surreptitiously. Management should follow substance abuse treatment protocols: inquiry into patterns of problematic use and readiness to change, assessment and management of psychiatric comorbidity, and referral to a recovery program.
 

Related Resources
• Srinivasan K. Role of spices beyond food flavoring: nu­traceuticals with multiple health effects. Food Reviews International. 2005;21(2):167-188.
• Parthasarathi U, Hategan A, Bourgeois JA. Out of the cup­board and into the clinic: Nutmeg-induced mood disorder. Current Psychiatry. 2013;12(12):E1-E2.

Drug Brand Names
Bromocriptine mesylate • Parlodel         Imipramine • Tofrani
Flunitrazepam • Rohypnol                     Iproniazid • Marsilid
Fluoxetine • Prozac                               Tranylcypromine • Parnate

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

Many substances that are not typically thought of as “substances of abuse” possess—when adequate­ly dosed—clinically meaningful psychoactive properties. In addition to the more familiar effects of alcohol, psychostimulants, opioids, Cannabis, and hallucinogens, you may encounter psychiatric phenomena resulting from abuse of more obscure substances, including culinary spices.

The clinician treating a patient in an apparent intoxicated state who has a negative drug screen might ask that patient if he (she) abuses spices. This might be particularly relevant when treating patients thought to have limited access to il­licit substances or those with ready access to large amounts of spices, such as prisoners, young patients, and those working in the food service industry.

Abuse of spices can be a problematic diagnosis
Patients may misuse culinary spices to achieve euphoria, or a “natural high.” They may present with medical or psychiat­ric symptoms, including acute altered mental status, but the psychoactive substances are not identified on routine toxicol­ogy studies. In addition, patients may not attribute their use of spices for psychoactive effect to “drugs,” because these materials are legal and readily available. This may lead to misdiagnosis of a systemic medical disorder or a primary psy­chiatric illness to explain the patient’s symptoms and initiat­ing a psychotropic agent and other psychiatric services when a substance abuse program might be a more appropriate clini­cal intervention.

Some spices contain psychoactive compounds that can alter CNS function (Table^1-7), might be abused for recreational purposes, and can be toxic in an excessive amount. Internet resources, including anonymous web-based communications, and anecdotal materials about non-traditional recreational drugs, are available to anyone with Internet access.⁸ However, little research has been conducted into the preva­lence of abuse (Box)⁹ and spices’ psychoactive properties. The lack of toxicology detection of spices in the medical setting presents a di­agnostic challenge.

The psychoactive plants used in “natural high” products mainly are psychoactively inactive in their natural form, but extracts or alkaloids obtained from them might induce 1 or more of 3 classifications of psychoactivity:
   • stimulant
   • sedative
   • hallucinogenic.

Many of these substances are considered to be aphrodisiac, and some may be abused to increase sexual function.

The following is a review of common spic­es that have been reported to possess poten­tial psychoactive properties.

Nutmeg
Nutmeg (Myristica fragrans) is a common and easily accessible means of reaching euphoria in adults.¹⁰ The aromatic oil of nutmeg contains myristicin, a psychoactive substance that is chemically similar to hal­lucinogenic compounds such as mescaline. Its psychoactive effects could be attributed to metabolic formation of amphetamine de­rivatives from its core ingredients, elemicin, myristicin, and safrole.^11,12

Nutmeg and its active component, my­risticin, produce central monoamine oxi­dase (MAO) inhibition as evidenced by the ability to lower the convulsive dose of IV tryptamine in mice and to increase brain 5-hydroxytryptamine concentra­tions.^13,14 Although myristicin’s potency is not comparable to that of the more potent MAO inhibitors such as tranylcypromine and iproniazid (which is not available in the United States), it seems adequate when compared with its low toxicity.¹⁴ Nutmeg extract is associated with a significant anti­depressant effect in mice, which seemed to be mediated by interaction with the adren­ergic, dopaminergic, and serotonergic sys­tems.¹³ Nutmeg is associated with sustained increase in sexual activity in animal studies, with no evidence of adverse effects and toxicity, suggesting that nutmeg possesses clinically significant aphrodisiac activity.¹⁵

Psychoactive effects can be achieved by ingesting 5 to 15 g of nutmeg.¹¹ Acute nut­meg intoxication produces palpitations, dizziness, anxiety, and hallucinations, mostly resolving within 24 hours, while effects of chronic abuse are reported to be similar to Cannabis use, including euphoria, giddiness, anxiety, fear, sense of impending doom, detachment, confabulation, and hal­lucinations.^11,16 Urine drug screens are nega­tive unless other psychoactive substances have been ingested.¹⁷

Suspected nutmeg intoxication or poison­ing should be treated with supportive treat­ment. Use sedatives with caution because of alternating periods of delirium and obtunda­tion during nutmeg intoxication.¹⁷

In case reports, myristicin poisoning induced CNS neuromodulatory signs that mimicked an anticholinergic hyperstimula­tion state.^12,18 Fatal myristicin poisoning is rare; 2 cases have been reported, 1 in com­bination with flunitrazepam (not available in the United States).^19,20 Nutmeg also has sedative properties and can cause GI symp­toms when ingesting excessive amounts.^1,20,21 Grover et al²¹ described no harmful effects on blood pressure and electrocardiogram; how­ever, Shah et al²² reported palpitations and dry mouth.

Vanilla
Vanilla (species of the genus Vanilla) con­tains piperonal, also known as heliotropin.¹ Piperonal has aromatherapeutic qualities that might elevate mood and well-being. In the early 1990s, the Memorial Sloan- Kettering Cancer Center in New York City described heliotropin as a powerful aroma­therapy tool. Patients who were undergo­ing an MRI in an environment scented with heliotropin demonstrated a 63% reduction in anxiety compared with those who were not exposed to fragrance.²³ The Smell and Taste Treatment and Research Foundation in Chicago found that vanilla can promote sexual arousal.²⁴

Short-term effects of vanillin—a major component of vanilla—include a feeling of relaxation and reduced stress; long-term use can produce an antidepressant effect.¹ There are no reports of vanilla abuse to achieve these effects; however, patients might abuse vanilla extract because of its alcohol content (up to 35% ethanol).²⁵

Fennel
The essential oil of fennel (Foeniculum vul­gare) can be neurotoxic and epileptogenic. Skalli and colleagues recently reported a case of seizure induction in a young woman after ingesting cakes containing fennel oil.²⁶ Fennel oil also has been reported to have significant interaction with the fluoroquinolone-type antibiotics. Be aware of adverse effects associ­ated with fennel ingestion; question patients if atypical seizures or reactions to antibiotics occur.²⁷

Spices such as fennel, dill, cinnamon, saf­fron, and anise also contain psychoactive substances that are chemically similar to my­risticin, which can induce sedation, stimula­tion, or hallucinations.⁷

Black pepper
Piperine, which gives black pepper (Piper ni­grum) its spiciness, enhances thermogenesis of lipid metabolism, accelerates energy me­tabolism, and increases serotonin and endor­phin production in the brain.28 Black pepper is reported to potentiate γ-aminobutyric acid A receptor subtypes,²⁹ and could present possible applications for treating insomnia, epilepsy, and anxiety disorders.

Cloves
Non-culinary uses of clove (Syzygium aro­maticum, a tree in the myrtle family) include flavored cigarettes. However, in 2009 clove cigarettes were banned in the United States as part of a public policy to reduce the number of children who start smoking.³⁰ Eugenol, which constitutes as much as 90% of the essential oil extracted from cloves (and is responsible for the aroma), can cause hepatotoxicity³¹ and palpitations³²; it can be toxic in quantities as low as 5 mL.³³ Eugenol is present in other spic­es, such as nutmeg and cinnamon, and has been reported to have sedative properties.¹

Mace
Mace is made from the covering of nutmeg (Myristica fragrans) seeds. It has a strong aro­ma resembling that of nutmeg. Whole mace contains 4% to 14% of a volatile oil similar to that found in nutmeg. Because mace con­tains the same oils that make nutmeg psy­choactive1 in excessive amounts—although nutmeg seeds are more potent—be aware of the psychoactive potential of mace.

CinnamonCassia cinnamon (Cinnamomum aromaticum) is spicier and tarter than Ceylon cinnamon (Cinnamomum zeylanicum), which has a more flowery aroma. The 2 types of cinnamon can be distinguished by their different chemical composition. Ceylon cinnamon contains eu­genol and benzyl benzoate; cassia cinnamon contains coumarin.³ Eugenol is reported to have sedative effects.¹ Coumarin is a precur­sor molecule in the synthesis of a number of synthetic anticoagulant pharmaceuticals, including coumadin. Because of the toxic component of coumarin, European health agencies have warned against consuming high amounts of cassia.³⁴ There are no re­ports of side effects arising from the occa­sional use of cinnamon as a spice. 

In a study by Frydman-Marom et al,³⁵ cinnamon extract (CEppt) was found to act on the CNS by inhibiting development of Alzheimer’s disease in animal models.

Asarone
Asarone is found in the Asarum family of spices that includes Acorus calamus. Asarone is chemically similar to mescaline. Although anecdotal reports indicate that A. calamus is a hallucinogen, research shows no evidence that it contains hallucinogenic substances.³⁶ Han et al³⁷ reported an antidepressant ef­fect with the essential oil and asarones for the rhizomes of Acorus tatarinowii. In ani­mal studies, asarone was found to reduce spontaneous motor activity, and even in low doses, reduced anxiety without decreasing acuity of perception.³⁸

Ginger
Ginger (Zingiber officinale) is regarded as a sedative, general stimulant, and aphrodisi­ac.^1,4,5 Its main constituents are phenolic com­pounds such as gingerols and shogaols, and sesquiterpenes such as zingiberene.⁴ Ginger is an inhibitor of thromboxane synthetase, a property shared by tricyclic antidepressants.³⁹

Research indicates that 9 compounds found in ginger may interact with the serotonin 5-HT1A receptor, suggesting a possible mechanism for reducing anxiety.⁴⁰ A study by Nievergelt et al⁴¹ indicates that by binding to human serotonin receptors, gin­ger might influence GI function. Ginger ex­tract contains a cholinergic and spasmogenic component, which provides a mechanistic insight for the prokinetic action of ginger.⁴⁰

Turmeric
Turmeric (Curcuma longa) has been investigat­ed for possible benefit in Alzheimer’s disease⁴²; research into curcumin, the active substance of turmeric, is increasing. Although the original report was retracted after publication, cur­cumin was reported to selectively bind to hu­man cannabinoid receptors type 1 (CB1) with nanomolar affinities and to function as an an­tagonist/inverse agonist.⁴³ However, Gertsch et al⁴⁴ found that curcumin did not interact functionally with the CB1 receptor, although this compound appears to share ability of the CB1 receptor inverse agonist.

Galangal
Major constituents identified in the galan­gal (or galanga) rhizome and leaf oil were 1,8-cineole, and β-pinene and cam­phor.6 Galangal, a member of the ginger (Zingiberaceae) family, interacts with MAO inhibitors, H2 receptor antagonists, and pro­ton-pump inhibitors.¹ Anxiolytic, hallucino­genic, and stimulant properties have been reported.1 An excessive amount can induce diarrhea, dizziness, nausea, and vomiting.¹

Saffron
Stigma of saffron (a member of the family Iridaceae) was found to be significantly more effective than placebo and equally as effica­cious as fluoxetine and imipramine in treat­ing depression. Saffron petal was found to be significantly more effective than placebo and as effective as fluoxetine and saffron stigma in a recent systematic review.^45-48

Asafetida
Asafetida (Ferula assa-foetida), when combined with valerian root, is used as a sedative to treat hyperactivity.² The active ingredients of asafet­ida are the resin, endogenous gum, essential oil, propenyl-isobutylsulfide, umbelliferone, and vanillin. Several of the volatile constitu­ents produce a sedative effect.² Additive ef­fects can occur between the hypotensive property of asafetida and dopamine receptor agonists such as bromocriptine mesylate. Use caution when combining asafetida in conjunc­tion with a CNS depressant or a stimulant.² 

Recommendations for treating spice-abusers
Patients may present to psychiatry ser­vices with psychological and physiologi­cal evidence of intoxication with culinary spices that may mimic 1) abuse of other substances, 2) primary psychiatric illness, and 3) primary medical illness. When you encounter a patient with a new psychiat­ric symptom, consider inquiring about the abuse of spices.

Patients might abuse more than 1 spice; a comprehensive screening approach might therefore be useful. Caution patients that in­gesting these substance to excess can have harmful effects. Consider appropriate psy­chopharmacotherapy for underlying psy­chiatric symptoms to help patients who use spices maladaptively to self-medicate psy­chiatric symptoms.

Consider abuse of culinary spices in clini­cal presentations of psychiatric symptoms that do not seem adequate for a diagnosis of a primary anxiety, mood, or psychotic disorder, or in cases atypical psychiatric presentations that are—perhaps to your surprise—associat­ed with negative toxicology studies for com­mon, more familiar substances of abuse.

Physicians practicing in an environment where street drugs are difficult to obtain (eg, prisons) should consider monitoring for possible abuse of spices. Based on the available, albeit limited, literature, it ap­pears that most culinary spice–associated intoxication can be managed:
   • with an elevated level of clinical suspicion
   • by ruling out other causes of intoxication
   • using targeted, empirical psychophar­macotherapy to manage symptoms
   • with supportive care that includes close psychiatric follow-up.

Consider comorbid abuse of other, more familiar substances of abuse in patients who misuse spices. As with inhalant abuse, the concept of “substance abuse” in clinical practice may need to be further expanded to include patients who abuse culinary spices. Patients could be screened for psychiatric illnesses known to increase the risk of sub­stance abuse. These might include—but are not limited to:
   • comorbid psychotic disorders
   • mood disorders, particularly bipolar disorders
   • trauma- and stressor-related disor­ders, particularly posttraumatic stress disorder
   • personality disorders, particularly anti­social, borderline, and narcissistic personality disorders.

Pending the availability of population-based studies on abuse of culinary spices, the usual cautions regarding substance abuse seem to be appropriate when caring for these patients. Assessment for and man­agement of comorbid psychiatric conditions is essential in the comprehensive psychiatric care of patients who abuse substances.

Last, general consideration of a 12-step recovery program appears warranted for these patients; the self-reflection and group support of such programs can be useful in helping patients control their use of these substances. 

Bottom Line
Presentation of culinary spice intoxication can parallel that of other medical or psychiatric illnesses, or other drugs of abuse. Consideration and questioning for abuse of spices is necessary to ascertain the psychoactive effects of these substances when used surreptitiously. Management should follow substance abuse treatment protocols: inquiry into patterns of problematic use and readiness to change, assessment and management of psychiatric comorbidity, and referral to a recovery program.
 

Related Resources
• Srinivasan K. Role of spices beyond food flavoring: nu­traceuticals with multiple health effects. Food Reviews International. 2005;21(2):167-188.
• Parthasarathi U, Hategan A, Bourgeois JA. Out of the cup­board and into the clinic: Nutmeg-induced mood disorder. Current Psychiatry. 2013;12(12):E1-E2.

Drug Brand Names
Bromocriptine mesylate • Parlodel         Imipramine • Tofrani
Flunitrazepam • Rohypnol                     Iproniazid • Marsilid
Fluoxetine • Prozac                               Tranylcypromine • Parnate

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

Many substances that are not typically thought of as “substances of abuse” possess—when adequate­ly dosed—clinically meaningful psychoactive properties. In addition to the more familiar effects of alcohol, psychostimulants, opioids, Cannabis, and hallucinogens, you may encounter psychiatric phenomena resulting from abuse of more obscure substances, including culinary spices.

The clinician treating a patient in an apparent intoxicated state who has a negative drug screen might ask that patient if he (she) abuses spices. This might be particularly relevant when treating patients thought to have limited access to il­licit substances or those with ready access to large amounts of spices, such as prisoners, young patients, and those working in the food service industry.

Abuse of spices can be a problematic diagnosis
Patients may misuse culinary spices to achieve euphoria, or a “natural high.” They may present with medical or psychiat­ric symptoms, including acute altered mental status, but the psychoactive substances are not identified on routine toxicol­ogy studies. In addition, patients may not attribute their use of spices for psychoactive effect to “drugs,” because these materials are legal and readily available. This may lead to misdiagnosis of a systemic medical disorder or a primary psy­chiatric illness to explain the patient’s symptoms and initiat­ing a psychotropic agent and other psychiatric services when a substance abuse program might be a more appropriate clini­cal intervention.

Some spices contain psychoactive compounds that can alter CNS function (Table^1-7), might be abused for recreational purposes, and can be toxic in an excessive amount. Internet resources, including anonymous web-based communications, and anecdotal materials about non-traditional recreational drugs, are available to anyone with Internet access.⁸ However, little research has been conducted into the preva­lence of abuse (Box)⁹ and spices’ psychoactive properties. The lack of toxicology detection of spices in the medical setting presents a di­agnostic challenge.

The psychoactive plants used in “natural high” products mainly are psychoactively inactive in their natural form, but extracts or alkaloids obtained from them might induce 1 or more of 3 classifications of psychoactivity:
   • stimulant
   • sedative
   • hallucinogenic.

Many of these substances are considered to be aphrodisiac, and some may be abused to increase sexual function.

The following is a review of common spic­es that have been reported to possess poten­tial psychoactive properties.

Nutmeg
Nutmeg (Myristica fragrans) is a common and easily accessible means of reaching euphoria in adults.¹⁰ The aromatic oil of nutmeg contains myristicin, a psychoactive substance that is chemically similar to hal­lucinogenic compounds such as mescaline. Its psychoactive effects could be attributed to metabolic formation of amphetamine de­rivatives from its core ingredients, elemicin, myristicin, and safrole.^11,12

Nutmeg and its active component, my­risticin, produce central monoamine oxi­dase (MAO) inhibition as evidenced by the ability to lower the convulsive dose of IV tryptamine in mice and to increase brain 5-hydroxytryptamine concentra­tions.^13,14 Although myristicin’s potency is not comparable to that of the more potent MAO inhibitors such as tranylcypromine and iproniazid (which is not available in the United States), it seems adequate when compared with its low toxicity.¹⁴ Nutmeg extract is associated with a significant anti­depressant effect in mice, which seemed to be mediated by interaction with the adren­ergic, dopaminergic, and serotonergic sys­tems.¹³ Nutmeg is associated with sustained increase in sexual activity in animal studies, with no evidence of adverse effects and toxicity, suggesting that nutmeg possesses clinically significant aphrodisiac activity.¹⁵

Psychoactive effects can be achieved by ingesting 5 to 15 g of nutmeg.¹¹ Acute nut­meg intoxication produces palpitations, dizziness, anxiety, and hallucinations, mostly resolving within 24 hours, while effects of chronic abuse are reported to be similar to Cannabis use, including euphoria, giddiness, anxiety, fear, sense of impending doom, detachment, confabulation, and hal­lucinations.^11,16 Urine drug screens are nega­tive unless other psychoactive substances have been ingested.¹⁷

Suspected nutmeg intoxication or poison­ing should be treated with supportive treat­ment. Use sedatives with caution because of alternating periods of delirium and obtunda­tion during nutmeg intoxication.¹⁷

In case reports, myristicin poisoning induced CNS neuromodulatory signs that mimicked an anticholinergic hyperstimula­tion state.^12,18 Fatal myristicin poisoning is rare; 2 cases have been reported, 1 in com­bination with flunitrazepam (not available in the United States).^19,20 Nutmeg also has sedative properties and can cause GI symp­toms when ingesting excessive amounts.^1,20,21 Grover et al²¹ described no harmful effects on blood pressure and electrocardiogram; how­ever, Shah et al²² reported palpitations and dry mouth.

Vanilla
Vanilla (species of the genus Vanilla) con­tains piperonal, also known as heliotropin.¹ Piperonal has aromatherapeutic qualities that might elevate mood and well-being. In the early 1990s, the Memorial Sloan- Kettering Cancer Center in New York City described heliotropin as a powerful aroma­therapy tool. Patients who were undergo­ing an MRI in an environment scented with heliotropin demonstrated a 63% reduction in anxiety compared with those who were not exposed to fragrance.²³ The Smell and Taste Treatment and Research Foundation in Chicago found that vanilla can promote sexual arousal.²⁴

Short-term effects of vanillin—a major component of vanilla—include a feeling of relaxation and reduced stress; long-term use can produce an antidepressant effect.¹ There are no reports of vanilla abuse to achieve these effects; however, patients might abuse vanilla extract because of its alcohol content (up to 35% ethanol).²⁵

Fennel
The essential oil of fennel (Foeniculum vul­gare) can be neurotoxic and epileptogenic. Skalli and colleagues recently reported a case of seizure induction in a young woman after ingesting cakes containing fennel oil.²⁶ Fennel oil also has been reported to have significant interaction with the fluoroquinolone-type antibiotics. Be aware of adverse effects associ­ated with fennel ingestion; question patients if atypical seizures or reactions to antibiotics occur.²⁷

Spices such as fennel, dill, cinnamon, saf­fron, and anise also contain psychoactive substances that are chemically similar to my­risticin, which can induce sedation, stimula­tion, or hallucinations.⁷

Black pepper
Piperine, which gives black pepper (Piper ni­grum) its spiciness, enhances thermogenesis of lipid metabolism, accelerates energy me­tabolism, and increases serotonin and endor­phin production in the brain.28 Black pepper is reported to potentiate γ-aminobutyric acid A receptor subtypes,²⁹ and could present possible applications for treating insomnia, epilepsy, and anxiety disorders.

Cloves
Non-culinary uses of clove (Syzygium aro­maticum, a tree in the myrtle family) include flavored cigarettes. However, in 2009 clove cigarettes were banned in the United States as part of a public policy to reduce the number of children who start smoking.³⁰ Eugenol, which constitutes as much as 90% of the essential oil extracted from cloves (and is responsible for the aroma), can cause hepatotoxicity³¹ and palpitations³²; it can be toxic in quantities as low as 5 mL.³³ Eugenol is present in other spic­es, such as nutmeg and cinnamon, and has been reported to have sedative properties.¹

Mace
Mace is made from the covering of nutmeg (Myristica fragrans) seeds. It has a strong aro­ma resembling that of nutmeg. Whole mace contains 4% to 14% of a volatile oil similar to that found in nutmeg. Because mace con­tains the same oils that make nutmeg psy­choactive1 in excessive amounts—although nutmeg seeds are more potent—be aware of the psychoactive potential of mace.

CinnamonCassia cinnamon (Cinnamomum aromaticum) is spicier and tarter than Ceylon cinnamon (Cinnamomum zeylanicum), which has a more flowery aroma. The 2 types of cinnamon can be distinguished by their different chemical composition. Ceylon cinnamon contains eu­genol and benzyl benzoate; cassia cinnamon contains coumarin.³ Eugenol is reported to have sedative effects.¹ Coumarin is a precur­sor molecule in the synthesis of a number of synthetic anticoagulant pharmaceuticals, including coumadin. Because of the toxic component of coumarin, European health agencies have warned against consuming high amounts of cassia.³⁴ There are no re­ports of side effects arising from the occa­sional use of cinnamon as a spice. 

In a study by Frydman-Marom et al,³⁵ cinnamon extract (CEppt) was found to act on the CNS by inhibiting development of Alzheimer’s disease in animal models.

Asarone
Asarone is found in the Asarum family of spices that includes Acorus calamus. Asarone is chemically similar to mescaline. Although anecdotal reports indicate that A. calamus is a hallucinogen, research shows no evidence that it contains hallucinogenic substances.³⁶ Han et al³⁷ reported an antidepressant ef­fect with the essential oil and asarones for the rhizomes of Acorus tatarinowii. In ani­mal studies, asarone was found to reduce spontaneous motor activity, and even in low doses, reduced anxiety without decreasing acuity of perception.³⁸

Ginger
Ginger (Zingiber officinale) is regarded as a sedative, general stimulant, and aphrodisi­ac.^1,4,5 Its main constituents are phenolic com­pounds such as gingerols and shogaols, and sesquiterpenes such as zingiberene.⁴ Ginger is an inhibitor of thromboxane synthetase, a property shared by tricyclic antidepressants.³⁹

Research indicates that 9 compounds found in ginger may interact with the serotonin 5-HT1A receptor, suggesting a possible mechanism for reducing anxiety.⁴⁰ A study by Nievergelt et al⁴¹ indicates that by binding to human serotonin receptors, gin­ger might influence GI function. Ginger ex­tract contains a cholinergic and spasmogenic component, which provides a mechanistic insight for the prokinetic action of ginger.⁴⁰

Turmeric
Turmeric (Curcuma longa) has been investigat­ed for possible benefit in Alzheimer’s disease⁴²; research into curcumin, the active substance of turmeric, is increasing. Although the original report was retracted after publication, cur­cumin was reported to selectively bind to hu­man cannabinoid receptors type 1 (CB1) with nanomolar affinities and to function as an an­tagonist/inverse agonist.⁴³ However, Gertsch et al⁴⁴ found that curcumin did not interact functionally with the CB1 receptor, although this compound appears to share ability of the CB1 receptor inverse agonist.

Galangal
Major constituents identified in the galan­gal (or galanga) rhizome and leaf oil were 1,8-cineole, and β-pinene and cam­phor.6 Galangal, a member of the ginger (Zingiberaceae) family, interacts with MAO inhibitors, H2 receptor antagonists, and pro­ton-pump inhibitors.¹ Anxiolytic, hallucino­genic, and stimulant properties have been reported.1 An excessive amount can induce diarrhea, dizziness, nausea, and vomiting.¹

Saffron
Stigma of saffron (a member of the family Iridaceae) was found to be significantly more effective than placebo and equally as effica­cious as fluoxetine and imipramine in treat­ing depression. Saffron petal was found to be significantly more effective than placebo and as effective as fluoxetine and saffron stigma in a recent systematic review.^45-48

Asafetida
Asafetida (Ferula assa-foetida), when combined with valerian root, is used as a sedative to treat hyperactivity.² The active ingredients of asafet­ida are the resin, endogenous gum, essential oil, propenyl-isobutylsulfide, umbelliferone, and vanillin. Several of the volatile constitu­ents produce a sedative effect.² Additive ef­fects can occur between the hypotensive property of asafetida and dopamine receptor agonists such as bromocriptine mesylate. Use caution when combining asafetida in conjunc­tion with a CNS depressant or a stimulant.² 

Recommendations for treating spice-abusers
Patients may present to psychiatry ser­vices with psychological and physiologi­cal evidence of intoxication with culinary spices that may mimic 1) abuse of other substances, 2) primary psychiatric illness, and 3) primary medical illness. When you encounter a patient with a new psychiat­ric symptom, consider inquiring about the abuse of spices.

Patients might abuse more than 1 spice; a comprehensive screening approach might therefore be useful. Caution patients that in­gesting these substance to excess can have harmful effects. Consider appropriate psy­chopharmacotherapy for underlying psy­chiatric symptoms to help patients who use spices maladaptively to self-medicate psy­chiatric symptoms.

Consider abuse of culinary spices in clini­cal presentations of psychiatric symptoms that do not seem adequate for a diagnosis of a primary anxiety, mood, or psychotic disorder, or in cases atypical psychiatric presentations that are—perhaps to your surprise—associat­ed with negative toxicology studies for com­mon, more familiar substances of abuse.

Physicians practicing in an environment where street drugs are difficult to obtain (eg, prisons) should consider monitoring for possible abuse of spices. Based on the available, albeit limited, literature, it ap­pears that most culinary spice–associated intoxication can be managed:
   • with an elevated level of clinical suspicion
   • by ruling out other causes of intoxication
   • using targeted, empirical psychophar­macotherapy to manage symptoms
   • with supportive care that includes close psychiatric follow-up.

Consider comorbid abuse of other, more familiar substances of abuse in patients who misuse spices. As with inhalant abuse, the concept of “substance abuse” in clinical practice may need to be further expanded to include patients who abuse culinary spices. Patients could be screened for psychiatric illnesses known to increase the risk of sub­stance abuse. These might include—but are not limited to:
   • comorbid psychotic disorders
   • mood disorders, particularly bipolar disorders
   • trauma- and stressor-related disor­ders, particularly posttraumatic stress disorder
   • personality disorders, particularly anti­social, borderline, and narcissistic personality disorders.

Pending the availability of population-based studies on abuse of culinary spices, the usual cautions regarding substance abuse seem to be appropriate when caring for these patients. Assessment for and man­agement of comorbid psychiatric conditions is essential in the comprehensive psychiatric care of patients who abuse substances.

Last, general consideration of a 12-step recovery program appears warranted for these patients; the self-reflection and group support of such programs can be useful in helping patients control their use of these substances. 

Bottom Line
Presentation of culinary spice intoxication can parallel that of other medical or psychiatric illnesses, or other drugs of abuse. Consideration and questioning for abuse of spices is necessary to ascertain the psychoactive effects of these substances when used surreptitiously. Management should follow substance abuse treatment protocols: inquiry into patterns of problematic use and readiness to change, assessment and management of psychiatric comorbidity, and referral to a recovery program.
 

Related Resources
• Srinivasan K. Role of spices beyond food flavoring: nu­traceuticals with multiple health effects. Food Reviews International. 2005;21(2):167-188.
• Parthasarathi U, Hategan A, Bourgeois JA. Out of the cup­board and into the clinic: Nutmeg-induced mood disorder. Current Psychiatry. 2013;12(12):E1-E2.

Drug Brand Names
Bromocriptine mesylate • Parlodel         Imipramine • Tofrani
Flunitrazepam • Rohypnol                     Iproniazid • Marsilid
Fluoxetine • Prozac                               Tranylcypromine • Parnate

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

In studies of schizophrenia, one of the more striking findings is the delay in the initiation of treatment. That delay ranges from 1 to 2 years for patients experiencing psychotic symptoms to several years if the prodromal phase is taken into account.¹ Yet duration of untreated psychosis has been found to be a critical factor in prognosis, including psychosocial functioning, in patients with schizophrenia.^2,3 Identification of individuals in the prodromal phase not only offers an opportunity to intervene at an earlier symptomatic stage, but might be associated with a better response to antipsychotics and a better overall treatment outcome as well.

What’s in a name?

Several terms, including ultra high risk, clinical high risk, at-risk mental state, psychosis risk syndrome, and schizophrenia/psychosis prodrome, have been used to describe the prodromal phase of schizophrenia. The proposal to include attenuated psychosis syndrome (APS) in the DSM-5—originally intended to capture those with subthreshold delusions, hallucinations, or disorganized behavior, occurring at least once a week for the past month and worsening over the past year—generated a debate about the validity of such a diagnostic category^4,5 that culminated in the inclusion of APS as a condition for further study but not as a term for clinical use.⁶ Its presence in the DSM-5 brings to the forefront the importance of early clinical intervention in patients at risk of developing psychotic illness.

Schizophrenia is not inevitable

The prodromal phase can be viewed as a sequence of evolving symptoms⁷ (Box 1^8,9), starting with subtle differences evident only to the person experiencing them and often progressing to brief limited intermittent psychosis (BLIPS) or attenuated psychosis.⁸

In fact, prodrome is a retrospective diagnosis. The predictive power of conversion to psychosis has been found to fluctuate from as low as 9% to as high as 76%,¹⁰ prompting ethical concerns about a high false-positive rate, the assumption of inevitability associated with the term “schizophrenia prodrome,”⁹ and the potential for overdiagnosis and misdiagnosis. Concerns about psychosocial stigma and exposure to antipsychotic medications have been expressed as well.¹¹

A case for early engagement

In retrospect, patients who eventually progress to psychotic illness are commonly found to have been in the prodromal phase for several years. Yet many patients’ first contact with psychiatric services occurs during a florid episode of acute psychosis. Identifying patients in the early prodromal period offers the opportunity to more effectively engage them and form a therapeutic alliance.¹² Any young adult who presents with a decline in academic or occupational function, social withdrawal, perplexity, and apparent distress or agitation (Table 1^13-16) without a clear precipitating factor should therefore be closely monitored, particularly if he (she) has a family history of psychosis.

Screening tools. A variety of interviews and rating scales (Table 28) have been developed to assess and monitor at-risk persons, a number of which have been designed to detect basic symptoms in the early phase of prodrome. In addition to the structured scales, several self-report tools—including the Prodromal Questionnaire-Brief (PQ-B), Youth Psychosis At Risk Questionnaire-Brief (YPARQ-B), Prime Screen-Revised, and PROD-screen (Screen for prodromal symptoms of psychosis)—have been found to be useful in screening a large sample to identify those who might need further evaluation.¹⁷

Increased risk of conversion. Several clinical factors are associated with an increased risk of conversion to psychotic illness.9 In addition to family history, these include:

  • greater severity and longer duration of attenuated positive symptoms
  • presence of bizarre thoughts and behavior
  • paranoia
  • decline in global assessment of functioning score over the previous year
  • use of either Cannabis or amphetamines.

A history of childhood trauma, increased sensitivity to psychosocial stressors, and dysregulation of the hypothalamicpituitary axis also have been associated with progression to psychosis.¹⁸

Recent evidence suggests that the prodromal phase is a predictor not only for psychosis but also for other disabling psychiatric illnesses, such as bipolar disorder and obsessive-compulsive disorder.¹⁹

From a phenomenological standpoint, disturbance of the sense of self—characterized by features such as depersonalization, derealization, decreased reactivity to other people and the environment, and intense reflectivity to oneself or others—has been proposed as a critical marker for progression to psychosis.²⁰ Another predictor is the perception of negativity of others toward oneself. Examples include heightened sensitivity to rejection or shame, which seems to emerge from a pattern of insecure attachment, and the outsider status experienced by immigrants faced with multiple social, cultural, and language barriers.²¹ The presence of obsessivecompulsive symptoms during the prodromal phase has been linked to significant impairment in functioning, an acute switch to psychosis, and an increased risk of suicide.²²

Monitor or treat? An optimal approach

A key dilemma in the management of patients who exhibit signs and symptoms of schizophrenia prodrome is whether to simply monitor closely or to initiate treatment.

International clinical practice guidelines recommend several practical steps in the monitoring of patients in a prepsychotic state (Table 3),²³ but caution against the use of antipsychotic agents unless the patient meets diagnostic criteria for a psychotic disorder.

CBT. Some evidence supports the initiation of cognitive-behavioral therapy (CBT) during the initial prodromal phase and the addition of alow-dose atypical antipsychotic if the patient progresses to a later phase, characterized by BLIPS/APS.24,25 Evidence also suggests that a combination of CBT and antipsychotic medication might delay, but not prevent, the progression to a psychotic episode.9 Any risk of adverse metabolic complications precludes use ofan atypical antipsychotic.One potential alternative is the use of omega-3 polyunsaturated fatty acids (Box 2).^26,27

A clinically useful approach would be to view schizophrenia/psychosis prodrome not as a distinct diagnostic category but as a cluster of signs and symptoms associated with an increased risk of psychosis, with persons in this phase in need of close follow-up and, possibly, early initiation of an antipsychotic agent. It is important to engage the patient and his family at an early stage to educate them about the diagnostic uncertainty; to help them deal with the stigma; to manage risk factors; and, collaboratively, to decide on an intervention strategy.^23,28

Bottom Line

Despite several drawbacks, the concept of schizophrenia/psychosis prodrome may
be viewed as a cluster of signs and symptoms (rather than a distinct diagnostic category) associated with increased risk for psychosis that need close follow up. Follow up may involve psychoeducational and psychotherapeutic interventions and, need be, early initiation of antipsychotics. In addition, such symptoms may be associated with other psychiatric disorders such as bipolar disorder and obsessive- compulsive disorder. Timely attention and early intervention may alter the course
and improve overall prognosis.

Related Resources
• Early intervention in psychosis. WPA Education Committee’s recommended roles of the psychiatrist. www.wpanet.org/uploads/Education/Educational_Resources/earlyintervention-psychosis.pdf.
• Early Psychosis Prevention and Intervention Centre, Melbourne, Australia. http://eppic.org.au/psychosis.
• International Early Psychosis Association Writing Group. International clinical practice guidelines for early psychosis. Br J Psychiatry. 2005;187:s120-124. http://bjp.rcpsych.org/content/187/48/s120.full.

Disclosures
Dr. Madaan is an employee of University of Virginia Health System. As an employee with the University of Virginia, Dr. Madaan has received research support from Eli Lilly and Company, Forest, Merck, Otsuka, Pfizer, Shire, and Sunovion. He also has served as a consultant for the NOW Coalition for Bipolar Disorder, and on the American Psychiatric Association’s Focus Self-Assessment editorial board. Drs. Bestha and Kolli report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

In studies of schizophrenia, one of the more striking findings is the delay in the initiation of treatment. That delay ranges from 1 to 2 years for patients experiencing psychotic symptoms to several years if the prodromal phase is taken into account.¹ Yet duration of untreated psychosis has been found to be a critical factor in prognosis, including psychosocial functioning, in patients with schizophrenia.^2,3 Identification of individuals in the prodromal phase not only offers an opportunity to intervene at an earlier symptomatic stage, but might be associated with a better response to antipsychotics and a better overall treatment outcome as well.

What’s in a name?

Several terms, including ultra high risk, clinical high risk, at-risk mental state, psychosis risk syndrome, and schizophrenia/psychosis prodrome, have been used to describe the prodromal phase of schizophrenia. The proposal to include attenuated psychosis syndrome (APS) in the DSM-5—originally intended to capture those with subthreshold delusions, hallucinations, or disorganized behavior, occurring at least once a week for the past month and worsening over the past year—generated a debate about the validity of such a diagnostic category^4,5 that culminated in the inclusion of APS as a condition for further study but not as a term for clinical use.⁶ Its presence in the DSM-5 brings to the forefront the importance of early clinical intervention in patients at risk of developing psychotic illness.

Schizophrenia is not inevitable

The prodromal phase can be viewed as a sequence of evolving symptoms⁷ (Box 1^8,9), starting with subtle differences evident only to the person experiencing them and often progressing to brief limited intermittent psychosis (BLIPS) or attenuated psychosis.⁸

In fact, prodrome is a retrospective diagnosis. The predictive power of conversion to psychosis has been found to fluctuate from as low as 9% to as high as 76%,¹⁰ prompting ethical concerns about a high false-positive rate, the assumption of inevitability associated with the term “schizophrenia prodrome,”⁹ and the potential for overdiagnosis and misdiagnosis. Concerns about psychosocial stigma and exposure to antipsychotic medications have been expressed as well.¹¹

A case for early engagement

In retrospect, patients who eventually progress to psychotic illness are commonly found to have been in the prodromal phase for several years. Yet many patients’ first contact with psychiatric services occurs during a florid episode of acute psychosis. Identifying patients in the early prodromal period offers the opportunity to more effectively engage them and form a therapeutic alliance.¹² Any young adult who presents with a decline in academic or occupational function, social withdrawal, perplexity, and apparent distress or agitation (Table 1^13-16) without a clear precipitating factor should therefore be closely monitored, particularly if he (she) has a family history of psychosis.

Screening tools. A variety of interviews and rating scales (Table 28) have been developed to assess and monitor at-risk persons, a number of which have been designed to detect basic symptoms in the early phase of prodrome. In addition to the structured scales, several self-report tools—including the Prodromal Questionnaire-Brief (PQ-B), Youth Psychosis At Risk Questionnaire-Brief (YPARQ-B), Prime Screen-Revised, and PROD-screen (Screen for prodromal symptoms of psychosis)—have been found to be useful in screening a large sample to identify those who might need further evaluation.¹⁷

Increased risk of conversion. Several clinical factors are associated with an increased risk of conversion to psychotic illness.9 In addition to family history, these include:

  • greater severity and longer duration of attenuated positive symptoms
  • presence of bizarre thoughts and behavior
  • paranoia
  • decline in global assessment of functioning score over the previous year
  • use of either Cannabis or amphetamines.

A history of childhood trauma, increased sensitivity to psychosocial stressors, and dysregulation of the hypothalamicpituitary axis also have been associated with progression to psychosis.¹⁸

Recent evidence suggests that the prodromal phase is a predictor not only for psychosis but also for other disabling psychiatric illnesses, such as bipolar disorder and obsessive-compulsive disorder.¹⁹

From a phenomenological standpoint, disturbance of the sense of self—characterized by features such as depersonalization, derealization, decreased reactivity to other people and the environment, and intense reflectivity to oneself or others—has been proposed as a critical marker for progression to psychosis.²⁰ Another predictor is the perception of negativity of others toward oneself. Examples include heightened sensitivity to rejection or shame, which seems to emerge from a pattern of insecure attachment, and the outsider status experienced by immigrants faced with multiple social, cultural, and language barriers.²¹ The presence of obsessivecompulsive symptoms during the prodromal phase has been linked to significant impairment in functioning, an acute switch to psychosis, and an increased risk of suicide.²²

Monitor or treat? An optimal approach

A key dilemma in the management of patients who exhibit signs and symptoms of schizophrenia prodrome is whether to simply monitor closely or to initiate treatment.

International clinical practice guidelines recommend several practical steps in the monitoring of patients in a prepsychotic state (Table 3),²³ but caution against the use of antipsychotic agents unless the patient meets diagnostic criteria for a psychotic disorder.

CBT. Some evidence supports the initiation of cognitive-behavioral therapy (CBT) during the initial prodromal phase and the addition of alow-dose atypical antipsychotic if the patient progresses to a later phase, characterized by BLIPS/APS.24,25 Evidence also suggests that a combination of CBT and antipsychotic medication might delay, but not prevent, the progression to a psychotic episode.9 Any risk of adverse metabolic complications precludes use ofan atypical antipsychotic.One potential alternative is the use of omega-3 polyunsaturated fatty acids (Box 2).^26,27

A clinically useful approach would be to view schizophrenia/psychosis prodrome not as a distinct diagnostic category but as a cluster of signs and symptoms associated with an increased risk of psychosis, with persons in this phase in need of close follow-up and, possibly, early initiation of an antipsychotic agent. It is important to engage the patient and his family at an early stage to educate them about the diagnostic uncertainty; to help them deal with the stigma; to manage risk factors; and, collaboratively, to decide on an intervention strategy.^23,28

Bottom Line

Despite several drawbacks, the concept of schizophrenia/psychosis prodrome may
be viewed as a cluster of signs and symptoms (rather than a distinct diagnostic category) associated with increased risk for psychosis that need close follow up. Follow up may involve psychoeducational and psychotherapeutic interventions and, need be, early initiation of antipsychotics. In addition, such symptoms may be associated with other psychiatric disorders such as bipolar disorder and obsessive- compulsive disorder. Timely attention and early intervention may alter the course
and improve overall prognosis.

Related Resources
• Early intervention in psychosis. WPA Education Committee’s recommended roles of the psychiatrist. www.wpanet.org/uploads/Education/Educational_Resources/earlyintervention-psychosis.pdf.
• Early Psychosis Prevention and Intervention Centre, Melbourne, Australia. http://eppic.org.au/psychosis.
• International Early Psychosis Association Writing Group. International clinical practice guidelines for early psychosis. Br J Psychiatry. 2005;187:s120-124. http://bjp.rcpsych.org/content/187/48/s120.full.

Disclosures
Dr. Madaan is an employee of University of Virginia Health System. As an employee with the University of Virginia, Dr. Madaan has received research support from Eli Lilly and Company, Forest, Merck, Otsuka, Pfizer, Shire, and Sunovion. He also has served as a consultant for the NOW Coalition for Bipolar Disorder, and on the American Psychiatric Association’s Focus Self-Assessment editorial board. Drs. Bestha and Kolli report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

In studies of schizophrenia, one of the more striking findings is the delay in the initiation of treatment. That delay ranges from 1 to 2 years for patients experiencing psychotic symptoms to several years if the prodromal phase is taken into account.¹ Yet duration of untreated psychosis has been found to be a critical factor in prognosis, including psychosocial functioning, in patients with schizophrenia.^2,3 Identification of individuals in the prodromal phase not only offers an opportunity to intervene at an earlier symptomatic stage, but might be associated with a better response to antipsychotics and a better overall treatment outcome as well.

What’s in a name?

Several terms, including ultra high risk, clinical high risk, at-risk mental state, psychosis risk syndrome, and schizophrenia/psychosis prodrome, have been used to describe the prodromal phase of schizophrenia. The proposal to include attenuated psychosis syndrome (APS) in the DSM-5—originally intended to capture those with subthreshold delusions, hallucinations, or disorganized behavior, occurring at least once a week for the past month and worsening over the past year—generated a debate about the validity of such a diagnostic category^4,5 that culminated in the inclusion of APS as a condition for further study but not as a term for clinical use.⁶ Its presence in the DSM-5 brings to the forefront the importance of early clinical intervention in patients at risk of developing psychotic illness.

Schizophrenia is not inevitable

The prodromal phase can be viewed as a sequence of evolving symptoms⁷ (Box 1^8,9), starting with subtle differences evident only to the person experiencing them and often progressing to brief limited intermittent psychosis (BLIPS) or attenuated psychosis.⁸

In fact, prodrome is a retrospective diagnosis. The predictive power of conversion to psychosis has been found to fluctuate from as low as 9% to as high as 76%,¹⁰ prompting ethical concerns about a high false-positive rate, the assumption of inevitability associated with the term “schizophrenia prodrome,”⁹ and the potential for overdiagnosis and misdiagnosis. Concerns about psychosocial stigma and exposure to antipsychotic medications have been expressed as well.¹¹

A case for early engagement

In retrospect, patients who eventually progress to psychotic illness are commonly found to have been in the prodromal phase for several years. Yet many patients’ first contact with psychiatric services occurs during a florid episode of acute psychosis. Identifying patients in the early prodromal period offers the opportunity to more effectively engage them and form a therapeutic alliance.¹² Any young adult who presents with a decline in academic or occupational function, social withdrawal, perplexity, and apparent distress or agitation (Table 1^13-16) without a clear precipitating factor should therefore be closely monitored, particularly if he (she) has a family history of psychosis.

Screening tools. A variety of interviews and rating scales (Table 28) have been developed to assess and monitor at-risk persons, a number of which have been designed to detect basic symptoms in the early phase of prodrome. In addition to the structured scales, several self-report tools—including the Prodromal Questionnaire-Brief (PQ-B), Youth Psychosis At Risk Questionnaire-Brief (YPARQ-B), Prime Screen-Revised, and PROD-screen (Screen for prodromal symptoms of psychosis)—have been found to be useful in screening a large sample to identify those who might need further evaluation.¹⁷

Increased risk of conversion. Several clinical factors are associated with an increased risk of conversion to psychotic illness.9 In addition to family history, these include:

  • greater severity and longer duration of attenuated positive symptoms
  • presence of bizarre thoughts and behavior
  • paranoia
  • decline in global assessment of functioning score over the previous year
  • use of either Cannabis or amphetamines.

A history of childhood trauma, increased sensitivity to psychosocial stressors, and dysregulation of the hypothalamicpituitary axis also have been associated with progression to psychosis.¹⁸

Recent evidence suggests that the prodromal phase is a predictor not only for psychosis but also for other disabling psychiatric illnesses, such as bipolar disorder and obsessive-compulsive disorder.¹⁹

From a phenomenological standpoint, disturbance of the sense of self—characterized by features such as depersonalization, derealization, decreased reactivity to other people and the environment, and intense reflectivity to oneself or others—has been proposed as a critical marker for progression to psychosis.²⁰ Another predictor is the perception of negativity of others toward oneself. Examples include heightened sensitivity to rejection or shame, which seems to emerge from a pattern of insecure attachment, and the outsider status experienced by immigrants faced with multiple social, cultural, and language barriers.²¹ The presence of obsessivecompulsive symptoms during the prodromal phase has been linked to significant impairment in functioning, an acute switch to psychosis, and an increased risk of suicide.²²

Monitor or treat? An optimal approach

A key dilemma in the management of patients who exhibit signs and symptoms of schizophrenia prodrome is whether to simply monitor closely or to initiate treatment.

International clinical practice guidelines recommend several practical steps in the monitoring of patients in a prepsychotic state (Table 3),²³ but caution against the use of antipsychotic agents unless the patient meets diagnostic criteria for a psychotic disorder.

CBT. Some evidence supports the initiation of cognitive-behavioral therapy (CBT) during the initial prodromal phase and the addition of alow-dose atypical antipsychotic if the patient progresses to a later phase, characterized by BLIPS/APS.24,25 Evidence also suggests that a combination of CBT and antipsychotic medication might delay, but not prevent, the progression to a psychotic episode.9 Any risk of adverse metabolic complications precludes use ofan atypical antipsychotic.One potential alternative is the use of omega-3 polyunsaturated fatty acids (Box 2).^26,27

A clinically useful approach would be to view schizophrenia/psychosis prodrome not as a distinct diagnostic category but as a cluster of signs and symptoms associated with an increased risk of psychosis, with persons in this phase in need of close follow-up and, possibly, early initiation of an antipsychotic agent. It is important to engage the patient and his family at an early stage to educate them about the diagnostic uncertainty; to help them deal with the stigma; to manage risk factors; and, collaboratively, to decide on an intervention strategy.^23,28

Bottom Line

Despite several drawbacks, the concept of schizophrenia/psychosis prodrome may
be viewed as a cluster of signs and symptoms (rather than a distinct diagnostic category) associated with increased risk for psychosis that need close follow up. Follow up may involve psychoeducational and psychotherapeutic interventions and, need be, early initiation of antipsychotics. In addition, such symptoms may be associated with other psychiatric disorders such as bipolar disorder and obsessive- compulsive disorder. Timely attention and early intervention may alter the course
and improve overall prognosis.

Related Resources
• Early intervention in psychosis. WPA Education Committee’s recommended roles of the psychiatrist. www.wpanet.org/uploads/Education/Educational_Resources/earlyintervention-psychosis.pdf.
• Early Psychosis Prevention and Intervention Centre, Melbourne, Australia. http://eppic.org.au/psychosis.
• International Early Psychosis Association Writing Group. International clinical practice guidelines for early psychosis. Br J Psychiatry. 2005;187:s120-124. http://bjp.rcpsych.org/content/187/48/s120.full.

Disclosures
Dr. Madaan is an employee of University of Virginia Health System. As an employee with the University of Virginia, Dr. Madaan has received research support from Eli Lilly and Company, Forest, Merck, Otsuka, Pfizer, Shire, and Sunovion. He also has served as a consultant for the NOW Coalition for Bipolar Disorder, and on the American Psychiatric Association’s Focus Self-Assessment editorial board. Drs. Bestha and Kolli report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

Estimates are that 50 to 70 million Americans suffer from a chronic disorder of sleep and wakefulness, hindering daily functioning and affecting health.¹ Psychiatric illness is common among people who have a sleep disorder. The relationship between psychiatric illness and sleep disorders is bidirectional: People with mental illness often have sleep complaints, and a primary sleep disorder often results in neuropsychiatric complications.

What is obstructive sleep apnea?

The most common type of sleep-disordered breathing, obstructive sleep apnea (OSA) is characterized by frequent cessations of breathing during sleep because of an obstruction of the upper airway. The obstruction occurs secondary to inadequate motor tone of the tongue or airway dilator muscles, or both.¹ In addition, many people with OSA have central apneic episodes, in which breathing stops temporarily without airway blockage or respiratory effort.²

The prevalence of OSA is growing as obesity in the United States increases. Risk factors for OSA include obesity, a craniofacial abnormality, an upper-airway abnormality, heredity, smoking, and nasal congestion. OSA plays a role in causing and exacerbating medical illness in people with severe and persistent mental illness, contributing to a significantly shortened life span. Attending to the general health of people who suffer from severe mental illness—including effective treatment of illnesses such as OSA—is crucial.³

Clinical features of OSA

OSA is characterized by hypopnea (a decrease in breathing during sleep) or apnea (an actual pause in breathing). Pauses in breathing during sleep of at least 10 seconds, with obstruction of oronasal airflow despite continuous chest and abdominal movements, are referred to as obstructive apneas. These pauses are associated with a decrease in oxygen saturation or arousal from sleep, or both.¹

Primary features of OSA include sleep fragmentation accompanied by nocturnal hypoxemia and hypercapnia, with resulting excessive daytime sleepiness, mood problems, and poor neurocognitive performance (Table 1). OSA often causes potentially serious organ system dysfunction, including adverse cardiovascular and metabolic effects. Studies have suggested that executive dysfunction can be a feature of OSA, which is thought to be related to prefrontal lobe dysfunction caused by intermittent hypoxia. All of these conditions can contribute significantly to decreased quality of life.¹

The prevalence of OSA in the general population is approximately 20% when the condition is defined as an apnea-hypopnea index >5 events an hour. The index is the number of apnea and hypopnea episodes that occur during 1 hour of sleep.⁴

OSA and psychiatric illness

Psychiatric disorders often are comorbid with OSA. These include depression, anxiety, bipolar disorder, schizophrenia, posttraumatic stress disorder (PTSD), panic disorder, and substance use disorder.

Depression. Several studies have documented that OSA and depressive disorder often are comorbid. Many symptoms are common to both, including fatigue, daytime sleepiness, poor concentration, irritability, and weight gain (Figure), although some core symptoms of depression (eg, sadness, anhedonia, guilt, and agitation) are clearly distinguishable from symptoms of OSA. The current recommendation is that a mood disorder should be considered secondary to OSA, and treated accordingly.⁵

Anxiety. OSA also has been linked to anxiety and nocturnal panic attacks. Frequent awakening due to choking from breathing cessation might play a role in the development of anxiety in patients with OSA, although the association is unproven. Studies have shown a correlation between anxiety disorders and excessive daytime sleepiness, one of the core symptoms of OSA.⁶ OSA is highly prevalent among combat veterans who have PTSD and complain of being overly vigilant at night; experiencing nightmares and frequent awakening; and having non-restorative sleep.⁷ Anecdotal reports suggest an association between OSA and bipolar disorder: namely, that continuous positive airway pressure (CPAP) treatment (see “How is OSA treated?,” below) might switch depressed patients to mania.⁸

Schizophrenia. A strong association exists between OSA and schizophrenia. In a study,⁹ an OSA diagnosis was made 6 times more often in patients with schizophrenia than in patients with other psychiatric illnesses. Obesity, male sex, and chronic antipsychotic administration were risk factors for OSA in patients with
schizophrenia.⁹ OSA might be underdiagnosed in patients with schizophrenia because excessive daytime sleepiness, the most common daytime symptom of OSA, can be misattributed as a negative symptom of the disease or a side effect of pharmacotherapy.

OSA and medical illness

OSA can be comorbid with several medical conditions (Table 2). Sleep research in the past 15 years has demonstrated that chronic sleep deprivation has multiple untoward health consequences apart from excessive daytime sleepiness.¹⁰ Recent research suggests that chronic sleep loss (<7 hours a night), including sleep loss secondary to OSA, has wide-ranging effects on the cardiovascular, endocrine, immune, and nervous systems, including:

• obesity (adults and children)

• diabetes mellitus and impaired glucose tolerance

• cardiovascular disease and hypertension.

Obesity is one of the primary and more modifiable risk factors for OSA (Box). Studies suggest that reducing the severity of obesity would likely benefit people with a sleep disorder, and that treating sleep deprivation and sleep disorders might benefit persons with obesity.¹² Chronic sleep loss can have a deleterious influence on appetite regulation through effects on 2 hormones, leptin and ghrelin, that play a major role in appetite regulation. Chronic sleep loss causes and perpetuates obesity through its interplay with these, and other, hormones.¹²

Diabetes. The link between obesity and diabetes is well-established, as is the long-term morbidity and mortality of these 2 diseases.¹³ Evidence shows that OSA is associated with impaired glucose tolerance and an increased risk of diabetes.¹⁴

Cardiovascular disease. OSA has a strong association with cardiovascular disease, including systemic hypertension, possibly myocardial infarction, congestive heart failure, and stroke.¹⁵ Institution of appropriate treatment for OSA including CPAP can minimize or reverse many of these effects.¹⁶

Making an OSA diagnosis

A diagnostic polysomnogram (PSG), or sleep study, is the standard test when OSA is suspected. It is performed most often at an attended sleep laboratory. Typically, a PSG measures several physiologic measures, including, but not limited to:

•  airflow through mouth and nose

•  stages of sleep (by means of electroencephalography channels)

•  thoracic and abdominal movements (to assess effort of breathing)

•  muscle activity of the chin

•  oxyhemoglobin saturation (to monitor variability in oxygen saturation [SaO₂] during OSA events).

Portable diagnostic instruments can provide reliable information when a patient cannot be studied in a laboratory. Assessments available on portable instruments include cardiopulmonary monitoring of respiration only; PSG; and peripheral arterial tonometry, which measures autonomic manifestations of respiratory obstructive events.^17,18

The severity of OSA is established by the apnea/hypopnea index, which measures the number of apneas and hypopneas per hour of sleep.

How is OSA treated?

CPAP is still the gold standard for treating OSA. CPAP provides a pneumatic splint for the upper airway by administering positive pressure through a nasal or oronasal mask. CPAP distinctly improves daytime sleepiness.^19,20

Pressure is determined initially by titration during PSG, although a number of automated CPAP machines are available in which pressure is adjusted based on the machine’s response to airflow obstruction. Advantages of using PSG to titrate CPAP are direct observation to control mask leak and the ability to observe the effects of body position and sleep stage and clearly distinguish periods of sleep from wakefulness.

Regrettably, adherence to a nightly regimen of CPAP is less than ideal for several reasons, including claustrophobia, interface failure, and other motivational variables. Some patients who experience claustrophobia can use desensitization techniques; others are, ultimately, unable to use the mask.

Oral appliances. A patient who has mild or moderate OSA but who cannot use the CPAP mask might be a good candidate for an oral appliance. These appliances, which hold the mandible in an advanced position during the night, can be effective in such cases.

CPAP autotitration changes the treatment pressure based on feedback from such patient measures as airflow and airway resistance. Autotitrating devices might have a role in beginning treatment in patients with OSA by means of a portable sleep study, in which CPAP titration is not performed. In addition, autotitrating offers the possibility of changing pressure over time—such as with changes in position during the night or over the longer term in response to weight loss or gain.

Surgery. In patients who are unable to use CPAP, surgery might be indicated to relieve an anatomical obstruction, such as adenotonsillar hypertrophy or other type of mass lesion.

Sleep positioning. A patient who demonstrates OSA exclusively while sleeping supine might benefit from being trained to sleep on either side only or arranging pillows so that he can only sleep on his side.

In conclusion

OSA is common and easily treatable. It coexists with, and exacerbates, medical and psychiatric illness. Treating OSA concomitantly with comorbid medical and psychiatric illness is essential to achieve full symptom remission and prevent associated long-term consequences of both medical and psychiatric illness.

BOTTOM LINE

Obstructive sleep apnea (OSA) and psychiatric illness, especially depression, often co-exist. Screen depressed patients—especially those with risk factors for OSA, such as obesity, smoking, and an upper-airway abnormality—for a sleep disorder. This is especially important if a patient complains of daytime somnolence, fatigue, cognitive problems, poor concentration, or weight gain. For optimal results, treat comorbid psychiatric illness and OSA concurrently; the same is true for other sleep disorders.

Related Resources

• Babson KA, Del Re AC, Bonn-Miller MO, et al. The comorbidity of sleep apnea and mood, anxiety, and substance use disorders among obese military veterans within the Veterans Health Administration. J Clin Sleep Med. 2013; 9(12):1253-1258.

• Karkoulias K, Lykouras D, Sampsonas F, et al. The impact of obstructive sleep apnea syndrome severity on physical performance and mental health. The use of SF-36 questionnaire in sleep apnea. Eur Rev Med Pharmacol Sci. 2013;17(4):531-536.

Disclosures

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

Acknowledgment

Dr. Muhammad Awais Aftab, psychiatry resident at Hamad Medical Corporation, Doha, Qatar, and Umair Amin, final year MBBS student at King Edward Medical University, Lahore, Pakistan, assisted with development of the manuscript of this article.

Estimates are that 50 to 70 million Americans suffer from a chronic disorder of sleep and wakefulness, hindering daily functioning and affecting health.¹ Psychiatric illness is common among people who have a sleep disorder. The relationship between psychiatric illness and sleep disorders is bidirectional: People with mental illness often have sleep complaints, and a primary sleep disorder often results in neuropsychiatric complications.

What is obstructive sleep apnea?

The most common type of sleep-disordered breathing, obstructive sleep apnea (OSA) is characterized by frequent cessations of breathing during sleep because of an obstruction of the upper airway. The obstruction occurs secondary to inadequate motor tone of the tongue or airway dilator muscles, or both.¹ In addition, many people with OSA have central apneic episodes, in which breathing stops temporarily without airway blockage or respiratory effort.²

The prevalence of OSA is growing as obesity in the United States increases. Risk factors for OSA include obesity, a craniofacial abnormality, an upper-airway abnormality, heredity, smoking, and nasal congestion. OSA plays a role in causing and exacerbating medical illness in people with severe and persistent mental illness, contributing to a significantly shortened life span. Attending to the general health of people who suffer from severe mental illness—including effective treatment of illnesses such as OSA—is crucial.³

Clinical features of OSA

OSA is characterized by hypopnea (a decrease in breathing during sleep) or apnea (an actual pause in breathing). Pauses in breathing during sleep of at least 10 seconds, with obstruction of oronasal airflow despite continuous chest and abdominal movements, are referred to as obstructive apneas. These pauses are associated with a decrease in oxygen saturation or arousal from sleep, or both.¹

Primary features of OSA include sleep fragmentation accompanied by nocturnal hypoxemia and hypercapnia, with resulting excessive daytime sleepiness, mood problems, and poor neurocognitive performance (Table 1). OSA often causes potentially serious organ system dysfunction, including adverse cardiovascular and metabolic effects. Studies have suggested that executive dysfunction can be a feature of OSA, which is thought to be related to prefrontal lobe dysfunction caused by intermittent hypoxia. All of these conditions can contribute significantly to decreased quality of life.¹

The prevalence of OSA in the general population is approximately 20% when the condition is defined as an apnea-hypopnea index >5 events an hour. The index is the number of apnea and hypopnea episodes that occur during 1 hour of sleep.⁴

OSA and psychiatric illness

Psychiatric disorders often are comorbid with OSA. These include depression, anxiety, bipolar disorder, schizophrenia, posttraumatic stress disorder (PTSD), panic disorder, and substance use disorder.

Depression. Several studies have documented that OSA and depressive disorder often are comorbid. Many symptoms are common to both, including fatigue, daytime sleepiness, poor concentration, irritability, and weight gain (Figure), although some core symptoms of depression (eg, sadness, anhedonia, guilt, and agitation) are clearly distinguishable from symptoms of OSA. The current recommendation is that a mood disorder should be considered secondary to OSA, and treated accordingly.⁵

Anxiety. OSA also has been linked to anxiety and nocturnal panic attacks. Frequent awakening due to choking from breathing cessation might play a role in the development of anxiety in patients with OSA, although the association is unproven. Studies have shown a correlation between anxiety disorders and excessive daytime sleepiness, one of the core symptoms of OSA.⁶ OSA is highly prevalent among combat veterans who have PTSD and complain of being overly vigilant at night; experiencing nightmares and frequent awakening; and having non-restorative sleep.⁷ Anecdotal reports suggest an association between OSA and bipolar disorder: namely, that continuous positive airway pressure (CPAP) treatment (see “How is OSA treated?,” below) might switch depressed patients to mania.⁸

Schizophrenia. A strong association exists between OSA and schizophrenia. In a study,⁹ an OSA diagnosis was made 6 times more often in patients with schizophrenia than in patients with other psychiatric illnesses. Obesity, male sex, and chronic antipsychotic administration were risk factors for OSA in patients with
schizophrenia.⁹ OSA might be underdiagnosed in patients with schizophrenia because excessive daytime sleepiness, the most common daytime symptom of OSA, can be misattributed as a negative symptom of the disease or a side effect of pharmacotherapy.

OSA and medical illness

OSA can be comorbid with several medical conditions (Table 2). Sleep research in the past 15 years has demonstrated that chronic sleep deprivation has multiple untoward health consequences apart from excessive daytime sleepiness.¹⁰ Recent research suggests that chronic sleep loss (<7 hours a night), including sleep loss secondary to OSA, has wide-ranging effects on the cardiovascular, endocrine, immune, and nervous systems, including:

• obesity (adults and children)

• diabetes mellitus and impaired glucose tolerance

• cardiovascular disease and hypertension.

Obesity is one of the primary and more modifiable risk factors for OSA (Box). Studies suggest that reducing the severity of obesity would likely benefit people with a sleep disorder, and that treating sleep deprivation and sleep disorders might benefit persons with obesity.¹² Chronic sleep loss can have a deleterious influence on appetite regulation through effects on 2 hormones, leptin and ghrelin, that play a major role in appetite regulation. Chronic sleep loss causes and perpetuates obesity through its interplay with these, and other, hormones.¹²

Diabetes. The link between obesity and diabetes is well-established, as is the long-term morbidity and mortality of these 2 diseases.¹³ Evidence shows that OSA is associated with impaired glucose tolerance and an increased risk of diabetes.¹⁴

Cardiovascular disease. OSA has a strong association with cardiovascular disease, including systemic hypertension, possibly myocardial infarction, congestive heart failure, and stroke.¹⁵ Institution of appropriate treatment for OSA including CPAP can minimize or reverse many of these effects.¹⁶

Making an OSA diagnosis

A diagnostic polysomnogram (PSG), or sleep study, is the standard test when OSA is suspected. It is performed most often at an attended sleep laboratory. Typically, a PSG measures several physiologic measures, including, but not limited to:

•  airflow through mouth and nose

•  stages of sleep (by means of electroencephalography channels)

•  thoracic and abdominal movements (to assess effort of breathing)

•  muscle activity of the chin

•  oxyhemoglobin saturation (to monitor variability in oxygen saturation [SaO₂] during OSA events).

Portable diagnostic instruments can provide reliable information when a patient cannot be studied in a laboratory. Assessments available on portable instruments include cardiopulmonary monitoring of respiration only; PSG; and peripheral arterial tonometry, which measures autonomic manifestations of respiratory obstructive events.^17,18

The severity of OSA is established by the apnea/hypopnea index, which measures the number of apneas and hypopneas per hour of sleep.

How is OSA treated?

CPAP is still the gold standard for treating OSA. CPAP provides a pneumatic splint for the upper airway by administering positive pressure through a nasal or oronasal mask. CPAP distinctly improves daytime sleepiness.^19,20

Pressure is determined initially by titration during PSG, although a number of automated CPAP machines are available in which pressure is adjusted based on the machine’s response to airflow obstruction. Advantages of using PSG to titrate CPAP are direct observation to control mask leak and the ability to observe the effects of body position and sleep stage and clearly distinguish periods of sleep from wakefulness.

Regrettably, adherence to a nightly regimen of CPAP is less than ideal for several reasons, including claustrophobia, interface failure, and other motivational variables. Some patients who experience claustrophobia can use desensitization techniques; others are, ultimately, unable to use the mask.

Oral appliances. A patient who has mild or moderate OSA but who cannot use the CPAP mask might be a good candidate for an oral appliance. These appliances, which hold the mandible in an advanced position during the night, can be effective in such cases.

CPAP autotitration changes the treatment pressure based on feedback from such patient measures as airflow and airway resistance. Autotitrating devices might have a role in beginning treatment in patients with OSA by means of a portable sleep study, in which CPAP titration is not performed. In addition, autotitrating offers the possibility of changing pressure over time—such as with changes in position during the night or over the longer term in response to weight loss or gain.

Surgery. In patients who are unable to use CPAP, surgery might be indicated to relieve an anatomical obstruction, such as adenotonsillar hypertrophy or other type of mass lesion.

Sleep positioning. A patient who demonstrates OSA exclusively while sleeping supine might benefit from being trained to sleep on either side only or arranging pillows so that he can only sleep on his side.

In conclusion

OSA is common and easily treatable. It coexists with, and exacerbates, medical and psychiatric illness. Treating OSA concomitantly with comorbid medical and psychiatric illness is essential to achieve full symptom remission and prevent associated long-term consequences of both medical and psychiatric illness.

BOTTOM LINE

Obstructive sleep apnea (OSA) and psychiatric illness, especially depression, often co-exist. Screen depressed patients—especially those with risk factors for OSA, such as obesity, smoking, and an upper-airway abnormality—for a sleep disorder. This is especially important if a patient complains of daytime somnolence, fatigue, cognitive problems, poor concentration, or weight gain. For optimal results, treat comorbid psychiatric illness and OSA concurrently; the same is true for other sleep disorders.

Related Resources

• Babson KA, Del Re AC, Bonn-Miller MO, et al. The comorbidity of sleep apnea and mood, anxiety, and substance use disorders among obese military veterans within the Veterans Health Administration. J Clin Sleep Med. 2013; 9(12):1253-1258.

• Karkoulias K, Lykouras D, Sampsonas F, et al. The impact of obstructive sleep apnea syndrome severity on physical performance and mental health. The use of SF-36 questionnaire in sleep apnea. Eur Rev Med Pharmacol Sci. 2013;17(4):531-536.

Disclosures

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

Acknowledgment

Dr. Muhammad Awais Aftab, psychiatry resident at Hamad Medical Corporation, Doha, Qatar, and Umair Amin, final year MBBS student at King Edward Medical University, Lahore, Pakistan, assisted with development of the manuscript of this article.

Estimates are that 50 to 70 million Americans suffer from a chronic disorder of sleep and wakefulness, hindering daily functioning and affecting health.¹ Psychiatric illness is common among people who have a sleep disorder. The relationship between psychiatric illness and sleep disorders is bidirectional: People with mental illness often have sleep complaints, and a primary sleep disorder often results in neuropsychiatric complications.

What is obstructive sleep apnea?

The most common type of sleep-disordered breathing, obstructive sleep apnea (OSA) is characterized by frequent cessations of breathing during sleep because of an obstruction of the upper airway. The obstruction occurs secondary to inadequate motor tone of the tongue or airway dilator muscles, or both.¹ In addition, many people with OSA have central apneic episodes, in which breathing stops temporarily without airway blockage or respiratory effort.²

The prevalence of OSA is growing as obesity in the United States increases. Risk factors for OSA include obesity, a craniofacial abnormality, an upper-airway abnormality, heredity, smoking, and nasal congestion. OSA plays a role in causing and exacerbating medical illness in people with severe and persistent mental illness, contributing to a significantly shortened life span. Attending to the general health of people who suffer from severe mental illness—including effective treatment of illnesses such as OSA—is crucial.³

Clinical features of OSA

OSA is characterized by hypopnea (a decrease in breathing during sleep) or apnea (an actual pause in breathing). Pauses in breathing during sleep of at least 10 seconds, with obstruction of oronasal airflow despite continuous chest and abdominal movements, are referred to as obstructive apneas. These pauses are associated with a decrease in oxygen saturation or arousal from sleep, or both.¹

Primary features of OSA include sleep fragmentation accompanied by nocturnal hypoxemia and hypercapnia, with resulting excessive daytime sleepiness, mood problems, and poor neurocognitive performance (Table 1). OSA often causes potentially serious organ system dysfunction, including adverse cardiovascular and metabolic effects. Studies have suggested that executive dysfunction can be a feature of OSA, which is thought to be related to prefrontal lobe dysfunction caused by intermittent hypoxia. All of these conditions can contribute significantly to decreased quality of life.¹

The prevalence of OSA in the general population is approximately 20% when the condition is defined as an apnea-hypopnea index >5 events an hour. The index is the number of apnea and hypopnea episodes that occur during 1 hour of sleep.⁴

OSA and psychiatric illness

Psychiatric disorders often are comorbid with OSA. These include depression, anxiety, bipolar disorder, schizophrenia, posttraumatic stress disorder (PTSD), panic disorder, and substance use disorder.

Depression. Several studies have documented that OSA and depressive disorder often are comorbid. Many symptoms are common to both, including fatigue, daytime sleepiness, poor concentration, irritability, and weight gain (Figure), although some core symptoms of depression (eg, sadness, anhedonia, guilt, and agitation) are clearly distinguishable from symptoms of OSA. The current recommendation is that a mood disorder should be considered secondary to OSA, and treated accordingly.⁵

Anxiety. OSA also has been linked to anxiety and nocturnal panic attacks. Frequent awakening due to choking from breathing cessation might play a role in the development of anxiety in patients with OSA, although the association is unproven. Studies have shown a correlation between anxiety disorders and excessive daytime sleepiness, one of the core symptoms of OSA.⁶ OSA is highly prevalent among combat veterans who have PTSD and complain of being overly vigilant at night; experiencing nightmares and frequent awakening; and having non-restorative sleep.⁷ Anecdotal reports suggest an association between OSA and bipolar disorder: namely, that continuous positive airway pressure (CPAP) treatment (see “How is OSA treated?,” below) might switch depressed patients to mania.⁸

Schizophrenia. A strong association exists between OSA and schizophrenia. In a study,⁹ an OSA diagnosis was made 6 times more often in patients with schizophrenia than in patients with other psychiatric illnesses. Obesity, male sex, and chronic antipsychotic administration were risk factors for OSA in patients with
schizophrenia.⁹ OSA might be underdiagnosed in patients with schizophrenia because excessive daytime sleepiness, the most common daytime symptom of OSA, can be misattributed as a negative symptom of the disease or a side effect of pharmacotherapy.

OSA and medical illness

OSA can be comorbid with several medical conditions (Table 2). Sleep research in the past 15 years has demonstrated that chronic sleep deprivation has multiple untoward health consequences apart from excessive daytime sleepiness.¹⁰ Recent research suggests that chronic sleep loss (<7 hours a night), including sleep loss secondary to OSA, has wide-ranging effects on the cardiovascular, endocrine, immune, and nervous systems, including:

• obesity (adults and children)

• diabetes mellitus and impaired glucose tolerance

• cardiovascular disease and hypertension.

Obesity is one of the primary and more modifiable risk factors for OSA (Box). Studies suggest that reducing the severity of obesity would likely benefit people with a sleep disorder, and that treating sleep deprivation and sleep disorders might benefit persons with obesity.¹² Chronic sleep loss can have a deleterious influence on appetite regulation through effects on 2 hormones, leptin and ghrelin, that play a major role in appetite regulation. Chronic sleep loss causes and perpetuates obesity through its interplay with these, and other, hormones.¹²

Diabetes. The link between obesity and diabetes is well-established, as is the long-term morbidity and mortality of these 2 diseases.¹³ Evidence shows that OSA is associated with impaired glucose tolerance and an increased risk of diabetes.¹⁴

Cardiovascular disease. OSA has a strong association with cardiovascular disease, including systemic hypertension, possibly myocardial infarction, congestive heart failure, and stroke.¹⁵ Institution of appropriate treatment for OSA including CPAP can minimize or reverse many of these effects.¹⁶

Making an OSA diagnosis

A diagnostic polysomnogram (PSG), or sleep study, is the standard test when OSA is suspected. It is performed most often at an attended sleep laboratory. Typically, a PSG measures several physiologic measures, including, but not limited to:

•  airflow through mouth and nose

•  stages of sleep (by means of electroencephalography channels)

•  thoracic and abdominal movements (to assess effort of breathing)

•  muscle activity of the chin

•  oxyhemoglobin saturation (to monitor variability in oxygen saturation [SaO₂] during OSA events).

Portable diagnostic instruments can provide reliable information when a patient cannot be studied in a laboratory. Assessments available on portable instruments include cardiopulmonary monitoring of respiration only; PSG; and peripheral arterial tonometry, which measures autonomic manifestations of respiratory obstructive events.^17,18

The severity of OSA is established by the apnea/hypopnea index, which measures the number of apneas and hypopneas per hour of sleep.

How is OSA treated?

CPAP is still the gold standard for treating OSA. CPAP provides a pneumatic splint for the upper airway by administering positive pressure through a nasal or oronasal mask. CPAP distinctly improves daytime sleepiness.^19,20

Pressure is determined initially by titration during PSG, although a number of automated CPAP machines are available in which pressure is adjusted based on the machine’s response to airflow obstruction. Advantages of using PSG to titrate CPAP are direct observation to control mask leak and the ability to observe the effects of body position and sleep stage and clearly distinguish periods of sleep from wakefulness.

Regrettably, adherence to a nightly regimen of CPAP is less than ideal for several reasons, including claustrophobia, interface failure, and other motivational variables. Some patients who experience claustrophobia can use desensitization techniques; others are, ultimately, unable to use the mask.

Oral appliances. A patient who has mild or moderate OSA but who cannot use the CPAP mask might be a good candidate for an oral appliance. These appliances, which hold the mandible in an advanced position during the night, can be effective in such cases.

CPAP autotitration changes the treatment pressure based on feedback from such patient measures as airflow and airway resistance. Autotitrating devices might have a role in beginning treatment in patients with OSA by means of a portable sleep study, in which CPAP titration is not performed. In addition, autotitrating offers the possibility of changing pressure over time—such as with changes in position during the night or over the longer term in response to weight loss or gain.

Surgery. In patients who are unable to use CPAP, surgery might be indicated to relieve an anatomical obstruction, such as adenotonsillar hypertrophy or other type of mass lesion.

Sleep positioning. A patient who demonstrates OSA exclusively while sleeping supine might benefit from being trained to sleep on either side only or arranging pillows so that he can only sleep on his side.

In conclusion

OSA is common and easily treatable. It coexists with, and exacerbates, medical and psychiatric illness. Treating OSA concomitantly with comorbid medical and psychiatric illness is essential to achieve full symptom remission and prevent associated long-term consequences of both medical and psychiatric illness.

BOTTOM LINE

Obstructive sleep apnea (OSA) and psychiatric illness, especially depression, often co-exist. Screen depressed patients—especially those with risk factors for OSA, such as obesity, smoking, and an upper-airway abnormality—for a sleep disorder. This is especially important if a patient complains of daytime somnolence, fatigue, cognitive problems, poor concentration, or weight gain. For optimal results, treat comorbid psychiatric illness and OSA concurrently; the same is true for other sleep disorders.

Related Resources

• Babson KA, Del Re AC, Bonn-Miller MO, et al. The comorbidity of sleep apnea and mood, anxiety, and substance use disorders among obese military veterans within the Veterans Health Administration. J Clin Sleep Med. 2013; 9(12):1253-1258.

• Karkoulias K, Lykouras D, Sampsonas F, et al. The impact of obstructive sleep apnea syndrome severity on physical performance and mental health. The use of SF-36 questionnaire in sleep apnea. Eur Rev Med Pharmacol Sci. 2013;17(4):531-536.

Disclosures

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

Acknowledgment

Dr. Muhammad Awais Aftab, psychiatry resident at Hamad Medical Corporation, Doha, Qatar, and Umair Amin, final year MBBS student at King Edward Medical University, Lahore, Pakistan, assisted with development of the manuscript of this article.

Mr. W, age 45, is a divorced Army veteran living on the street who has entered alcohol treatment for the sixth time. He has never stayed sober for longer than 1 month after each of his previous treatment episodes.

On a typical day, Mr. W drinks 40 oz of beer, a pint of vodka, and other alcoholic beverages when available. Although he has used drugs, he reports that he did so only to augment the effects of alcohol. Before entering rehab, Mr. W worked for a television network for 16 years and was promoted to associate vice president. He lost that job as a result of drinking.

Mr. W comes from a large Irish Catholic family and has sustained an active religious faith, going to Mass 2 or 3 times a month. Throughout the interview, he appears introspective and describes frequent periods of “going inside” of himself to “rehash” things. He states that he has never been satisfied with his spiritual life and has been unable to “quiet the hunger inside.”

He describes his benders as “mini-retreats” and comments that focusing on the condensation droplets on a glass of beer is nearly a “sacramental experience” for him. He states: “My drinking is a spiritual thing for me. I believe that every time I drink I am on a spiritual search. I believe this with all my heart. I have this emptiness inside of me and alcohol would temporarily fill the enormous hole in my insides. Just for a short period of time, I would feel at peace and connected to others, and maybe even to God.”

Mr. W observes that “Every time I relapse it’s because I’m going through a spiritual withdrawal. Booze filled the void inside of me and now the void is back again. Physically and psychologically I’m fine. I’m just empty inside and when I can’t stand it any longer, I drink again.”

Few patients can so directly articulate the role they feel that spirituality plays in their substance use disorder. It is important for clinicians to be aware of the dynamics of spirituality and religion in the cause, maintenance, and treatment of substance misuse problems.

In this article, we discuss how spirituality can be assessed and suggest ethical and clinical practice concerns that we believe may support treatment of substance use disorder. We do not advocate incorporating spiritual interventions into clinical practice for patients who are uncomfortable with doing so, nor do we feel that consideration of and respect for patients’ spirituality precludes evidence-based pharmaceutical and behavioral treatment strategies. We believe, however, that addressing these issues can enhance treatment adherence in select patients.

Defining spirituality

Although religion and spirituality are related concepts, they differ.

• Religion has been defined as “an organized system of beliefs, practices, rituals, and symbols through which ones’ relationship to God or others is nurtured and exercised.”¹

• Spirituality is more complex and multifaceted. Reflecting his extensive review of articles on spirituality and addiction, Cook² proposed the following definition:

Spirituality is a distinctive, potentially creative, and universal dimension of
human experience arising within inner subjective awareness of individuals and within communities, social groups, and traditions. It may be experienced as relationship with that which is intimately “inner,” immanent, and personal, within the self and others, and/or as relationship with that which is wholly “other,” transcendent and beyond the self. It is experienced as being of fundamental or ultimate importance and is therefore concerned with matters of meaning and purpose in life, truth, and values.

In some religions, any use of alcohol or drugs is forbidden; in most religions, abuse of these substances violates norms. Those who misuse a substance also might be alienated from their religious and social support community. People struggling with addiction might feel they are compromising their spiritual values directly through the action itself and indirectly because of the harm their substance misuse causes to close friends and family. Misuse of substances also might be an attempt to “fill the void,” as Mr. W described it, of a spiritual longing or a consequence of doubts about meaning, purpose in life, and God.

Perhaps it isn’t surprising that, among psychiatric disorders, substance abuse problems seem to be most associated with spiritual intervention—especially Alcoholics Anonymous (AA), Narcotics Anonymous (NA), and Cocaine Anonymous (CA). Many of the 12 steps contain references to God and spirituality. Although much of the evidence supporting the effectiveness of the spiritual components of AA/NA/CA is correlational,^3,4 the resonance that many persons who are recovering from substance abuse find in the 12-step model suggests that spiritual issues are relevant to understanding patients’ viewpoints and for planning treatment.

Religion and spirituality in risk and recovery

Although alcohol and drugs can have positive religious significance (eg, wine in the Christian Eucharist or in the Hindu practice of Ayurvedic medicine; peyote in some indigenous American religious rituals), substance use and abuse are less prevalent among persons who identify themselves as highly religious or spiritual.⁵ Studies indicate that alcohol use and abuse are less prevalent among persons who identify as Jewish, Muslim, or conservative Protestant, compared with those who are Catholic or liberal Protestant.⁶

Research suggests that consideration and accommodation of religious and spiritual practices in the recovery process is effective^7-9—and preferred—by many patients.¹⁰ Psychiatrists do not need to and, in many cases, should not deliver overtly spiritual treatments to patients recovering from substance abuse. Spirituality and religion are complex issues largely outside the expertise of psychiatry; it would be naïve to consider spirituality and religion as universally beneficial elements for all patients recovering from substance abuse. Instead, psychiatrists should be equipped to:

• assess for religion and spirituality in patients
• be aware of, and supportive of, resources for integrating spirituality into treatment (eg, clergy and hospital chaplains, local AA/NA/CA groups, community religious organizations, spirituality groups).

Assessment

Post and colleagues¹¹ note: “When patients feel that their spiritual needs are neglected in standard clinical environments, many of them may be driven away from effective medical treatment.” This is of particular concern when working with persons who have a substance use disorder—among whom, regrettably, only a minority avail themselves of professional care. You should carefully gauge the importance of these dimensions in how patients understand their disorder and the components of treatment they think their recovery process should involve.

Asking about the religious and spiritual aspects of patients’ lives shows respect for their views and facilitates a therapeutic alliance by recognizing their autonomy in treatment. Pargament and Lomax¹² state: “Religion speaks to highly sensitive issues that lie at the core of the individual’s identity, commitments, values and world view. Patients are unlikely to engage in a conversation about the deepest side of themselves unless their psychiatrist demonstrates an openness to, interest in, and appreciation of the patient’s religiousness.” This exploration process can suggest natural environmental support systems available to complement recovery efforts and can indicate whether consultation with a clergy­person knowledgeable about and sensitive to their particular religious tradition is appropriate.

Assessment of spirituality and religious practice usually should occur during the initial clinical interview. Examples of revealing interview questions are listed in Box 1.

The Table^13-20 lists well-researched psychometric measures that can provide clues to aspects of your patient’s spirituality. These scales yield quantitative results, yet it may be more useful to review with the patient his (her) responses to the items and to pursue issues further based on the responses.

In discussing responses to questions about their spirituality and religious practices, some patients might ask about your views and whether you agree with their views. You could respond with a direct, concise answer, but refocusing the discussion on why the topic of spirituality is important to understanding one’s life and choices might be more therapeutic. This also might be a good time to remind patients that the treatment plan should reflect their view of the role of religion and spirituality in their life.

Of course, some patients are disinclined to discuss spirituality or religion, or prefer that it not be considered in treatment. This is clearly a matter of patient choice, but be aware that the patient may change his (her) mind as the recovery process continues and that the topic can be revisited if desired.

Recommendations for practice

Give careful consideration to ethical and clinical practice issues related to spiritual components in the recovery process. Plante²¹ and Meador and Koenig¹ addressed several relevant ethical principles in considering spirituality in, respectively, psychological and psychiatric practice. Delaney and co-workers²² also presented similar principles, specifically within the context of substance use treatment. These can be summarized as a series of recommendations:

• Although psychiatrists as a group typically have a lower rate of conventional spirituality and religious practice than many of their patients,^23-25 it is important not to ignore the patient’s perspective and show respect for the patient’s spiritual needs. However, if the psychiatrist has strong personal religious beliefs, he (she) must carefully guard against proselytizing or exerting undue, unintentional influence.

• Given the variety of religious traditions in the United States, understanding their particular features, as with other issues of cultural diversity, requires competence and sensitivity. Your work requires study and consultation with knowledgeable peers and experts in various faith traditions. Clergy and clinically trained chaplains, in particular, can conduct more comprehensive spiritual assessments that can yield additional treatment-relevant information.

• Maintaining professional boundaries is critical when dealing with religious and spiritual aspects of the patient’s life and thinking. Keep in mind issues of transference and the authoritative influence of the psychiatrist. The patient should understand the difference between services offered by a mental health professional and those given by a spiritual counselor or member of the clergy. Spiritual and religious issues, such as addressing concerns over guilt and sin and a relationship with God, should be referred to an appropriate clergyperson.

• Spiritual interventions introduced into the therapeutic process always should derive from the patient’s perspective and value system; they should not be imposed from an external source.

• Referral to AA often will help alcohol-dependent patients. The heart of AA’s philosophy is that addiction should be seen as a spiritual problem and that genuine recovery requires a profound spiritual awakening (Box 2). AA, as well as interventions inspired by it (eg, NA), are based on peer support, are readily available, and free. Although there is a dearth of controlled research demonstrating the efficacy of AA compared with other interventions, many recovering alcoholics credit these 12-step programs with their having maintained sobriety and adopting a positive lifestyle.

Recent research has identified specific components of AA participation that seem to be helpful.²⁶ These include activities that are spiritual in nature and other generally active components of substance abuse care. Patient preference should be respected when encouraging AA involvement. For patients who are uncomfortable with AA—especially with its emphasis on spirituality—alternative peer support groups are available, such as SMART Recovery.^27,28 If the patient adopts AA’s philosophy, it might be helpful for you to employ the language of AA and its constructs when talking with him (her).

Useful strategies on how therapists can encourage AA participation and integrate mutual help groups into treatment planning are described by Nowinski.²⁵ Some AA members believe that use of medication is antithetical to the recovery process, but this is not the position of AA²⁹; using FDA-approved medications, such as naltrexone and acamprosate, is evidence-based and often should be a part of the treatment regimen for alcohol dependence.

Bottom Line

Awareness of, and sensitivity to, the religious and spiritual characteristics of patients with substance use disorder can enhance clinical rapport, inform development of individualized treatment plans, and suggest strategies, such as professional consultation, that might increase the prospects for successful treatment.

Related Resources

• Galanter M. The concept of spirituality in relation to addiction recovery and general psychiatry. Recent Dev Alcohol. 2008;18:125-140.
• Monod S, Brennan M, Rochat E, et al. Instruments measuring spirituality in clinical research: a systematic review. J Gen Intern Med. 2011;26(11):1345-1357.

Drug Brand Names

Acamprosate • Campral

Naltrexone • ReVia, Vivitrol

Disclosure

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

Featured Audio
John P. Allen, PhD, MPA, discusses whether spirituality plays a different role in treating substance use disorder than it might in treating other psychiatric illnesses. Dr. Allen works at the Department of Veterans Affairs, Mid-Atlantic Mental Illness Research, Education and Clinical Center, Division of Addictions Research and Treatment, Department of Psychiatry and Behavioral Sciences, Duke University School of Medicine, Durham, North Carolina.

Mr. W, age 45, is a divorced Army veteran living on the street who has entered alcohol treatment for the sixth time. He has never stayed sober for longer than 1 month after each of his previous treatment episodes.

On a typical day, Mr. W drinks 40 oz of beer, a pint of vodka, and other alcoholic beverages when available. Although he has used drugs, he reports that he did so only to augment the effects of alcohol. Before entering rehab, Mr. W worked for a television network for 16 years and was promoted to associate vice president. He lost that job as a result of drinking.

Mr. W comes from a large Irish Catholic family and has sustained an active religious faith, going to Mass 2 or 3 times a month. Throughout the interview, he appears introspective and describes frequent periods of “going inside” of himself to “rehash” things. He states that he has never been satisfied with his spiritual life and has been unable to “quiet the hunger inside.”

He describes his benders as “mini-retreats” and comments that focusing on the condensation droplets on a glass of beer is nearly a “sacramental experience” for him. He states: “My drinking is a spiritual thing for me. I believe that every time I drink I am on a spiritual search. I believe this with all my heart. I have this emptiness inside of me and alcohol would temporarily fill the enormous hole in my insides. Just for a short period of time, I would feel at peace and connected to others, and maybe even to God.”

Mr. W observes that “Every time I relapse it’s because I’m going through a spiritual withdrawal. Booze filled the void inside of me and now the void is back again. Physically and psychologically I’m fine. I’m just empty inside and when I can’t stand it any longer, I drink again.”

Few patients can so directly articulate the role they feel that spirituality plays in their substance use disorder. It is important for clinicians to be aware of the dynamics of spirituality and religion in the cause, maintenance, and treatment of substance misuse problems.

In this article, we discuss how spirituality can be assessed and suggest ethical and clinical practice concerns that we believe may support treatment of substance use disorder. We do not advocate incorporating spiritual interventions into clinical practice for patients who are uncomfortable with doing so, nor do we feel that consideration of and respect for patients’ spirituality precludes evidence-based pharmaceutical and behavioral treatment strategies. We believe, however, that addressing these issues can enhance treatment adherence in select patients.

Defining spirituality

Although religion and spirituality are related concepts, they differ.

• Religion has been defined as “an organized system of beliefs, practices, rituals, and symbols through which ones’ relationship to God or others is nurtured and exercised.”¹

• Spirituality is more complex and multifaceted. Reflecting his extensive review of articles on spirituality and addiction, Cook² proposed the following definition:

Spirituality is a distinctive, potentially creative, and universal dimension of
human experience arising within inner subjective awareness of individuals and within communities, social groups, and traditions. It may be experienced as relationship with that which is intimately “inner,” immanent, and personal, within the self and others, and/or as relationship with that which is wholly “other,” transcendent and beyond the self. It is experienced as being of fundamental or ultimate importance and is therefore concerned with matters of meaning and purpose in life, truth, and values.

In some religions, any use of alcohol or drugs is forbidden; in most religions, abuse of these substances violates norms. Those who misuse a substance also might be alienated from their religious and social support community. People struggling with addiction might feel they are compromising their spiritual values directly through the action itself and indirectly because of the harm their substance misuse causes to close friends and family. Misuse of substances also might be an attempt to “fill the void,” as Mr. W described it, of a spiritual longing or a consequence of doubts about meaning, purpose in life, and God.

Perhaps it isn’t surprising that, among psychiatric disorders, substance abuse problems seem to be most associated with spiritual intervention—especially Alcoholics Anonymous (AA), Narcotics Anonymous (NA), and Cocaine Anonymous (CA). Many of the 12 steps contain references to God and spirituality. Although much of the evidence supporting the effectiveness of the spiritual components of AA/NA/CA is correlational,^3,4 the resonance that many persons who are recovering from substance abuse find in the 12-step model suggests that spiritual issues are relevant to understanding patients’ viewpoints and for planning treatment.

Religion and spirituality in risk and recovery

Although alcohol and drugs can have positive religious significance (eg, wine in the Christian Eucharist or in the Hindu practice of Ayurvedic medicine; peyote in some indigenous American religious rituals), substance use and abuse are less prevalent among persons who identify themselves as highly religious or spiritual.⁵ Studies indicate that alcohol use and abuse are less prevalent among persons who identify as Jewish, Muslim, or conservative Protestant, compared with those who are Catholic or liberal Protestant.⁶

Research suggests that consideration and accommodation of religious and spiritual practices in the recovery process is effective^7-9—and preferred—by many patients.¹⁰ Psychiatrists do not need to and, in many cases, should not deliver overtly spiritual treatments to patients recovering from substance abuse. Spirituality and religion are complex issues largely outside the expertise of psychiatry; it would be naïve to consider spirituality and religion as universally beneficial elements for all patients recovering from substance abuse. Instead, psychiatrists should be equipped to:

• assess for religion and spirituality in patients
• be aware of, and supportive of, resources for integrating spirituality into treatment (eg, clergy and hospital chaplains, local AA/NA/CA groups, community religious organizations, spirituality groups).

Assessment

Post and colleagues¹¹ note: “When patients feel that their spiritual needs are neglected in standard clinical environments, many of them may be driven away from effective medical treatment.” This is of particular concern when working with persons who have a substance use disorder—among whom, regrettably, only a minority avail themselves of professional care. You should carefully gauge the importance of these dimensions in how patients understand their disorder and the components of treatment they think their recovery process should involve.

Asking about the religious and spiritual aspects of patients’ lives shows respect for their views and facilitates a therapeutic alliance by recognizing their autonomy in treatment. Pargament and Lomax¹² state: “Religion speaks to highly sensitive issues that lie at the core of the individual’s identity, commitments, values and world view. Patients are unlikely to engage in a conversation about the deepest side of themselves unless their psychiatrist demonstrates an openness to, interest in, and appreciation of the patient’s religiousness.” This exploration process can suggest natural environmental support systems available to complement recovery efforts and can indicate whether consultation with a clergy­person knowledgeable about and sensitive to their particular religious tradition is appropriate.

Assessment of spirituality and religious practice usually should occur during the initial clinical interview. Examples of revealing interview questions are listed in Box 1.

The Table^13-20 lists well-researched psychometric measures that can provide clues to aspects of your patient’s spirituality. These scales yield quantitative results, yet it may be more useful to review with the patient his (her) responses to the items and to pursue issues further based on the responses.

In discussing responses to questions about their spirituality and religious practices, some patients might ask about your views and whether you agree with their views. You could respond with a direct, concise answer, but refocusing the discussion on why the topic of spirituality is important to understanding one’s life and choices might be more therapeutic. This also might be a good time to remind patients that the treatment plan should reflect their view of the role of religion and spirituality in their life.

Of course, some patients are disinclined to discuss spirituality or religion, or prefer that it not be considered in treatment. This is clearly a matter of patient choice, but be aware that the patient may change his (her) mind as the recovery process continues and that the topic can be revisited if desired.

Recommendations for practice

Give careful consideration to ethical and clinical practice issues related to spiritual components in the recovery process. Plante²¹ and Meador and Koenig¹ addressed several relevant ethical principles in considering spirituality in, respectively, psychological and psychiatric practice. Delaney and co-workers²² also presented similar principles, specifically within the context of substance use treatment. These can be summarized as a series of recommendations:

• Although psychiatrists as a group typically have a lower rate of conventional spirituality and religious practice than many of their patients,^23-25 it is important not to ignore the patient’s perspective and show respect for the patient’s spiritual needs. However, if the psychiatrist has strong personal religious beliefs, he (she) must carefully guard against proselytizing or exerting undue, unintentional influence.

• Given the variety of religious traditions in the United States, understanding their particular features, as with other issues of cultural diversity, requires competence and sensitivity. Your work requires study and consultation with knowledgeable peers and experts in various faith traditions. Clergy and clinically trained chaplains, in particular, can conduct more comprehensive spiritual assessments that can yield additional treatment-relevant information.

• Maintaining professional boundaries is critical when dealing with religious and spiritual aspects of the patient’s life and thinking. Keep in mind issues of transference and the authoritative influence of the psychiatrist. The patient should understand the difference between services offered by a mental health professional and those given by a spiritual counselor or member of the clergy. Spiritual and religious issues, such as addressing concerns over guilt and sin and a relationship with God, should be referred to an appropriate clergyperson.

• Spiritual interventions introduced into the therapeutic process always should derive from the patient’s perspective and value system; they should not be imposed from an external source.

• Referral to AA often will help alcohol-dependent patients. The heart of AA’s philosophy is that addiction should be seen as a spiritual problem and that genuine recovery requires a profound spiritual awakening (Box 2). AA, as well as interventions inspired by it (eg, NA), are based on peer support, are readily available, and free. Although there is a dearth of controlled research demonstrating the efficacy of AA compared with other interventions, many recovering alcoholics credit these 12-step programs with their having maintained sobriety and adopting a positive lifestyle.

Recent research has identified specific components of AA participation that seem to be helpful.²⁶ These include activities that are spiritual in nature and other generally active components of substance abuse care. Patient preference should be respected when encouraging AA involvement. For patients who are uncomfortable with AA—especially with its emphasis on spirituality—alternative peer support groups are available, such as SMART Recovery.^27,28 If the patient adopts AA’s philosophy, it might be helpful for you to employ the language of AA and its constructs when talking with him (her).

Useful strategies on how therapists can encourage AA participation and integrate mutual help groups into treatment planning are described by Nowinski.²⁵ Some AA members believe that use of medication is antithetical to the recovery process, but this is not the position of AA²⁹; using FDA-approved medications, such as naltrexone and acamprosate, is evidence-based and often should be a part of the treatment regimen for alcohol dependence.

Bottom Line

Awareness of, and sensitivity to, the religious and spiritual characteristics of patients with substance use disorder can enhance clinical rapport, inform development of individualized treatment plans, and suggest strategies, such as professional consultation, that might increase the prospects for successful treatment.

Related Resources

• Galanter M. The concept of spirituality in relation to addiction recovery and general psychiatry. Recent Dev Alcohol. 2008;18:125-140.
• Monod S, Brennan M, Rochat E, et al. Instruments measuring spirituality in clinical research: a systematic review. J Gen Intern Med. 2011;26(11):1345-1357.

Drug Brand Names

Acamprosate • Campral

Naltrexone • ReVia, Vivitrol

Disclosure

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

Featured Audio
John P. Allen, PhD, MPA, discusses whether spirituality plays a different role in treating substance use disorder than it might in treating other psychiatric illnesses. Dr. Allen works at the Department of Veterans Affairs, Mid-Atlantic Mental Illness Research, Education and Clinical Center, Division of Addictions Research and Treatment, Department of Psychiatry and Behavioral Sciences, Duke University School of Medicine, Durham, North Carolina.

Mr. W, age 45, is a divorced Army veteran living on the street who has entered alcohol treatment for the sixth time. He has never stayed sober for longer than 1 month after each of his previous treatment episodes.

On a typical day, Mr. W drinks 40 oz of beer, a pint of vodka, and other alcoholic beverages when available. Although he has used drugs, he reports that he did so only to augment the effects of alcohol. Before entering rehab, Mr. W worked for a television network for 16 years and was promoted to associate vice president. He lost that job as a result of drinking.

Mr. W comes from a large Irish Catholic family and has sustained an active religious faith, going to Mass 2 or 3 times a month. Throughout the interview, he appears introspective and describes frequent periods of “going inside” of himself to “rehash” things. He states that he has never been satisfied with his spiritual life and has been unable to “quiet the hunger inside.”

He describes his benders as “mini-retreats” and comments that focusing on the condensation droplets on a glass of beer is nearly a “sacramental experience” for him. He states: “My drinking is a spiritual thing for me. I believe that every time I drink I am on a spiritual search. I believe this with all my heart. I have this emptiness inside of me and alcohol would temporarily fill the enormous hole in my insides. Just for a short period of time, I would feel at peace and connected to others, and maybe even to God.”

Mr. W observes that “Every time I relapse it’s because I’m going through a spiritual withdrawal. Booze filled the void inside of me and now the void is back again. Physically and psychologically I’m fine. I’m just empty inside and when I can’t stand it any longer, I drink again.”

Few patients can so directly articulate the role they feel that spirituality plays in their substance use disorder. It is important for clinicians to be aware of the dynamics of spirituality and religion in the cause, maintenance, and treatment of substance misuse problems.

In this article, we discuss how spirituality can be assessed and suggest ethical and clinical practice concerns that we believe may support treatment of substance use disorder. We do not advocate incorporating spiritual interventions into clinical practice for patients who are uncomfortable with doing so, nor do we feel that consideration of and respect for patients’ spirituality precludes evidence-based pharmaceutical and behavioral treatment strategies. We believe, however, that addressing these issues can enhance treatment adherence in select patients.

Defining spirituality

Although religion and spirituality are related concepts, they differ.

• Religion has been defined as “an organized system of beliefs, practices, rituals, and symbols through which ones’ relationship to God or others is nurtured and exercised.”¹

• Spirituality is more complex and multifaceted. Reflecting his extensive review of articles on spirituality and addiction, Cook² proposed the following definition:

Spirituality is a distinctive, potentially creative, and universal dimension of
human experience arising within inner subjective awareness of individuals and within communities, social groups, and traditions. It may be experienced as relationship with that which is intimately “inner,” immanent, and personal, within the self and others, and/or as relationship with that which is wholly “other,” transcendent and beyond the self. It is experienced as being of fundamental or ultimate importance and is therefore concerned with matters of meaning and purpose in life, truth, and values.

In some religions, any use of alcohol or drugs is forbidden; in most religions, abuse of these substances violates norms. Those who misuse a substance also might be alienated from their religious and social support community. People struggling with addiction might feel they are compromising their spiritual values directly through the action itself and indirectly because of the harm their substance misuse causes to close friends and family. Misuse of substances also might be an attempt to “fill the void,” as Mr. W described it, of a spiritual longing or a consequence of doubts about meaning, purpose in life, and God.

Perhaps it isn’t surprising that, among psychiatric disorders, substance abuse problems seem to be most associated with spiritual intervention—especially Alcoholics Anonymous (AA), Narcotics Anonymous (NA), and Cocaine Anonymous (CA). Many of the 12 steps contain references to God and spirituality. Although much of the evidence supporting the effectiveness of the spiritual components of AA/NA/CA is correlational,^3,4 the resonance that many persons who are recovering from substance abuse find in the 12-step model suggests that spiritual issues are relevant to understanding patients’ viewpoints and for planning treatment.

Religion and spirituality in risk and recovery

Although alcohol and drugs can have positive religious significance (eg, wine in the Christian Eucharist or in the Hindu practice of Ayurvedic medicine; peyote in some indigenous American religious rituals), substance use and abuse are less prevalent among persons who identify themselves as highly religious or spiritual.⁵ Studies indicate that alcohol use and abuse are less prevalent among persons who identify as Jewish, Muslim, or conservative Protestant, compared with those who are Catholic or liberal Protestant.⁶

Research suggests that consideration and accommodation of religious and spiritual practices in the recovery process is effective^7-9—and preferred—by many patients.¹⁰ Psychiatrists do not need to and, in many cases, should not deliver overtly spiritual treatments to patients recovering from substance abuse. Spirituality and religion are complex issues largely outside the expertise of psychiatry; it would be naïve to consider spirituality and religion as universally beneficial elements for all patients recovering from substance abuse. Instead, psychiatrists should be equipped to:

• assess for religion and spirituality in patients
• be aware of, and supportive of, resources for integrating spirituality into treatment (eg, clergy and hospital chaplains, local AA/NA/CA groups, community religious organizations, spirituality groups).

Assessment

Post and colleagues¹¹ note: “When patients feel that their spiritual needs are neglected in standard clinical environments, many of them may be driven away from effective medical treatment.” This is of particular concern when working with persons who have a substance use disorder—among whom, regrettably, only a minority avail themselves of professional care. You should carefully gauge the importance of these dimensions in how patients understand their disorder and the components of treatment they think their recovery process should involve.

Asking about the religious and spiritual aspects of patients’ lives shows respect for their views and facilitates a therapeutic alliance by recognizing their autonomy in treatment. Pargament and Lomax¹² state: “Religion speaks to highly sensitive issues that lie at the core of the individual’s identity, commitments, values and world view. Patients are unlikely to engage in a conversation about the deepest side of themselves unless their psychiatrist demonstrates an openness to, interest in, and appreciation of the patient’s religiousness.” This exploration process can suggest natural environmental support systems available to complement recovery efforts and can indicate whether consultation with a clergy­person knowledgeable about and sensitive to their particular religious tradition is appropriate.

Assessment of spirituality and religious practice usually should occur during the initial clinical interview. Examples of revealing interview questions are listed in Box 1.

The Table^13-20 lists well-researched psychometric measures that can provide clues to aspects of your patient’s spirituality. These scales yield quantitative results, yet it may be more useful to review with the patient his (her) responses to the items and to pursue issues further based on the responses.

In discussing responses to questions about their spirituality and religious practices, some patients might ask about your views and whether you agree with their views. You could respond with a direct, concise answer, but refocusing the discussion on why the topic of spirituality is important to understanding one’s life and choices might be more therapeutic. This also might be a good time to remind patients that the treatment plan should reflect their view of the role of religion and spirituality in their life.

Of course, some patients are disinclined to discuss spirituality or religion, or prefer that it not be considered in treatment. This is clearly a matter of patient choice, but be aware that the patient may change his (her) mind as the recovery process continues and that the topic can be revisited if desired.

Recommendations for practice

Give careful consideration to ethical and clinical practice issues related to spiritual components in the recovery process. Plante²¹ and Meador and Koenig¹ addressed several relevant ethical principles in considering spirituality in, respectively, psychological and psychiatric practice. Delaney and co-workers²² also presented similar principles, specifically within the context of substance use treatment. These can be summarized as a series of recommendations:

• Although psychiatrists as a group typically have a lower rate of conventional spirituality and religious practice than many of their patients,^23-25 it is important not to ignore the patient’s perspective and show respect for the patient’s spiritual needs. However, if the psychiatrist has strong personal religious beliefs, he (she) must carefully guard against proselytizing or exerting undue, unintentional influence.

• Given the variety of religious traditions in the United States, understanding their particular features, as with other issues of cultural diversity, requires competence and sensitivity. Your work requires study and consultation with knowledgeable peers and experts in various faith traditions. Clergy and clinically trained chaplains, in particular, can conduct more comprehensive spiritual assessments that can yield additional treatment-relevant information.

• Maintaining professional boundaries is critical when dealing with religious and spiritual aspects of the patient’s life and thinking. Keep in mind issues of transference and the authoritative influence of the psychiatrist. The patient should understand the difference between services offered by a mental health professional and those given by a spiritual counselor or member of the clergy. Spiritual and religious issues, such as addressing concerns over guilt and sin and a relationship with God, should be referred to an appropriate clergyperson.

• Spiritual interventions introduced into the therapeutic process always should derive from the patient’s perspective and value system; they should not be imposed from an external source.

• Referral to AA often will help alcohol-dependent patients. The heart of AA’s philosophy is that addiction should be seen as a spiritual problem and that genuine recovery requires a profound spiritual awakening (Box 2). AA, as well as interventions inspired by it (eg, NA), are based on peer support, are readily available, and free. Although there is a dearth of controlled research demonstrating the efficacy of AA compared with other interventions, many recovering alcoholics credit these 12-step programs with their having maintained sobriety and adopting a positive lifestyle.

Recent research has identified specific components of AA participation that seem to be helpful.²⁶ These include activities that are spiritual in nature and other generally active components of substance abuse care. Patient preference should be respected when encouraging AA involvement. For patients who are uncomfortable with AA—especially with its emphasis on spirituality—alternative peer support groups are available, such as SMART Recovery.^27,28 If the patient adopts AA’s philosophy, it might be helpful for you to employ the language of AA and its constructs when talking with him (her).

Useful strategies on how therapists can encourage AA participation and integrate mutual help groups into treatment planning are described by Nowinski.²⁵ Some AA members believe that use of medication is antithetical to the recovery process, but this is not the position of AA²⁹; using FDA-approved medications, such as naltrexone and acamprosate, is evidence-based and often should be a part of the treatment regimen for alcohol dependence.

Bottom Line

Awareness of, and sensitivity to, the religious and spiritual characteristics of patients with substance use disorder can enhance clinical rapport, inform development of individualized treatment plans, and suggest strategies, such as professional consultation, that might increase the prospects for successful treatment.

Related Resources

• Galanter M. The concept of spirituality in relation to addiction recovery and general psychiatry. Recent Dev Alcohol. 2008;18:125-140.
• Monod S, Brennan M, Rochat E, et al. Instruments measuring spirituality in clinical research: a systematic review. J Gen Intern Med. 2011;26(11):1345-1357.

Drug Brand Names

Acamprosate • Campral

Naltrexone • ReVia, Vivitrol

Disclosure

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

Featured Audio
John P. Allen, PhD, MPA, discusses whether spirituality plays a different role in treating substance use disorder than it might in treating other psychiatric illnesses. Dr. Allen works at the Department of Veterans Affairs, Mid-Atlantic Mental Illness Research, Education and Clinical Center, Division of Addictions Research and Treatment, Department of Psychiatry and Behavioral Sciences, Duke University School of Medicine, Durham, North Carolina.

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.