Evidence-Based Reviews

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Epidemiologic data suggest that people who consume diets rich in omega-3 fatty acids (FAs)—long-chain polyunsaturated FAs such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)—have a decreased risk of major depressive disorder (MDD), postpartum depression, and bipolar disorder (BD).^1-5 Omega-3 FA concentration may impact serotonin and dopamine transmission via effects on cell membrane fluidity.⁶ Therefore, decreased intake may increase the risk of several psychiatric disorders. As the average Western diet has changed over the last 2 centuries, omega-3 FA consumption has decreased.⁷ Omega-3 FAs cannot be synthesized by the body and must come from exogenous sources, such as fish and nuts. For a discussion of different types of dietary fats, see Box 1.⁸

Should we advise our patients to increase their omega-3 FA consumption? The American Psychiatric Association (APA) and the American Heart Association (AHA) recommend omega-3 FA consumption for the general population and in some cases, supplementation for specific disorders (Box 2).^9-12 New data has been published since Current Psychiatry last reviewed the evidence for using omega-3 FAs for psychiatric conditions in 2004.⁸ This article looks at the latest evidence on the use of omega-3 FAs to treat mood disorders, schizophrenia, dementia, and other psychiatric conditions.

Box 1

Box 2

Limitations of the data

Reviewing the literature on omega-3 FAs to treat psychiatric disorders is hampered by several difficulties:¹³

• studies may evaluate the use of EPA alone, EPA combined with DHA, or DHA alone
• the doses of EPA and DHA and ratio of EPA to DHA of the supplements used in clinical trials varies greatly
• patients’ dietary consumption of omega-3 FAs is difficult to control
• DSM diagnostic criteria, as well as severity of illness, differ within studies.

In addition, studies may use omega-3 FAs as monotherapy or as adjuncts. All of these factors lead to difficulty interpreting the literature, as well as trouble in extracting data for meta-analysis.

Omega-3 FAs for mood disorders

MDD and other depressive diagnoses. Several meta-analyses examining the use of omega-3 FAs for treating depressive disorders have had equivocal findings. Variability in results might be partially explained by differences in the severity of baseline depression among diverse study populations, diagnostic variation, differing omega-3 supplementation protocols, or other issues.¹³ In addition, publication bias also may affect results.

In a 2011 literature review and meta-analysis of omega-3 FAs as monotherapy or an adjunct to antidepressants to treat MDD, Bloch and Hannestad⁶ concluded that omega-3 FAs offer a small but nonsignificant benefit in treating MDD. This review suggested that omega-3 FAs may be more effective in patients with more severe depression. The effects of varying levels of EPA vs DHA were not examined.

In a systematic review and meta-analysis, Appleton et al¹⁴ concluded that omega-3 FA supplements have little beneficial effect on depressed mood in individuals who do not have a depressive illness diagnosis (eg, MDD). However, this study did not consider the differential effects of EPA vs DHA on treatment response. Patients diagnosed with a depressive illness received greater benefits from omega-3 FA supplementation, although the patients in this study were heterogeneous. Similar to Bloch and Hannestad, Appleton et al¹⁴ found that omega-3 FA supplementation may be most beneficial for depressed patients with more severe symptoms, but is unlikely to help those with mild-to-moderate symptoms or individuals without symptoms who aim to prevent depression.

A meta-analysis by Martins¹⁵ looked at EPA vs DHA to treat depressive illness and found that only supplements that were mostly or completely EPA effectively treated depressive symptoms. Martins also found that severity of illness is key for positive treatment outcomes; there was a significant relationship between higher baseline depression levels and efficacy.¹⁵ Martins noted that omega-3 FA therapy was more effective as a treatment than a preventive strategy, and that adding omega-3 FAs to antidepressants was more efficacious than omega-3 FAs alone.¹⁵

A meta-analysis of clinical trials of omega-3 FAs for depressive illness suggested EPA should be ≥60% of total EPA + DHA.¹⁶

BD. A recent meta-analysis of 6 randomized controlled trials (RCTs) found that adding omega-3 supplements to mood stabilizers in patients with BD was associated with a statistically significant reduction of depressive symptoms, but was not effective for treating mania.¹⁷ The authors suggested patients with BD—especially those with comorbid cardiovascular or metabolic conditions— increase their dietary consumption of foods containing omega-3 FAs (Table)¹⁸ and, if necessary, take a supplement of 1 to 1.5 g/d of mixed EPA and DHA, with a higher ratio of EPA.¹⁹ See Box 3 for a box on how to read omega-3 supplement labels.

In a small RCT of 51 children and adolescents (age 6 to 17) with symptomatic bipolar I or bipolar II disorder, supplementation with flax oil (alpha-linolenic acid, a polyunsaturated omega-3 FA that is a precursor to EPA and DHA) did not affect symptoms as measured by several rating scales.²⁰

Perinatal and postpartum depression. Omega-3 FAs are considered a safe treatment for depressive disorders during pregnancy because they provide neurodevelopmental benefits for neonates and have few contraindications during pregnancy.²¹ RCTs of omega-3 FA monotherapy for perinatal depression have been small (≤51 patients) and produced mixed findings.²¹ A pilot study (N = 16) of patients with postpartum depression found a significant decrease in depressive symptoms with EPA treatment.²² More research is needed before omega-3 FA supplementation can be recommended during pregnancy.

Table

Foods with healthy fats: From best to worst

Box 3

Selecting an omega-3 supplement: What to tell patients

Because nutritional supplements vary, advise patients to look at the supplement facts on the back of a bottle of omega-3 fatty acids. The American Psychiatric Association recommends patients take a total eicosapentaenoic acid (EPA) + docosahexaenoic acid (DHA) of 1 g/d; EPA should be ≥60% of total EPA + DHA.

This image is an example of a label that would meet the appropriate criteria. Total EPA + DHA = 1,490 mg and EPA is 60% of this combined total.

Source: Sublette ME, Ellis SP, Geant AL, et al. Meta-analysis of the effects of eicosapentaenoic acid (EPA) in clinical trials in depression. J Clin Psychiatry. 2011;72(12):1577-1584

Schizophrenia

In a Cochrane review of 8 studies of patients with schizophrenia, adjunctive treatment with omega-3 FAs led to >25% reduction in the Positive and Negative Syndrome Scale, but this improvement was not statistically significant.²³ Omega-3 FAs did not decrease tardive dyskinesia symptoms as measured by the Abnormal Involuntary Movement Scale. The authors stated that results were inconclusive, and use of omega-3 FAs in patients with schizophrenia remains experimental. In a separate meta-analysis that included 335 patients with schizophrenia, EPA augmentation had no beneficial effect on psychotic symptoms.²⁴

In a double-blind RCT of 81 adolescents and young adults (age 13 to 25) at ultra-high risk of psychotic illness, 5% of patients who received 1.2 g/d of omega-3 FAs developed a psychotic disorder compared with 28% of patients receiving placebo.²⁵ The authors concluded that supplementation with omega-3 FAs may be a safe and effective strategy for young patients with subthreshold psychotic symptoms.

Dementia

Studies evaluating the relationship between omega-3 FAs and dementia risk have revealed mixed findings.^26,27 In a pilot study of 10 geriatric patients with moderately severe dementia related to thrombotic cerebrovascular disorder, DHA supplementation led to improved Hamilton Depression Rating Scale and Mini-Mental State Examination (MMSE) scores compared with controls.²⁸ In another study, administering EPA to 64 patients with Alzheimer’s disease significantly improved MMSE scores, with maximum improvement at 3 months, but this benefit dissipated after 6 months of treatment.²⁹ In a study of 22 patients with various types of dementia, Suzuki et al³⁰ found that DHA supplementation improved scores on a Japanese dementia scale. These studies show promise, but more evidence is necessary before recommendations can be made.

Other psychiatric disorders

Omega-3 FAs as monotherapy or an adjunct to psychostimulants does not seem to improve symptoms in children who meet DSM-IV-TR criteria for attention-deficit/hyperactivity disorder (ADHD).^31-33 Studies of omega-3 FAs as treatment for anxiety and personality disorders are limited. To date, omega-3 FAs as adjunctive treatment in obsessive-compulsive disorder (OCD) and monotherapy in borderline personality disorder have not shown efficacy.^34,35

Using omega-3 FAs in practice

Based on new data and several recent meta-analyses, clinical recommendations have emerged. Sarris et al¹⁷ suggested patients with BD increase dietary intake of omega-3 FAs or take a supplement with 1 to 1.5 g/d of mixed EPA and DHA (with a higher ratio of EPA). In MDD, the type of omega-3 FA supplementation seems to be important; EPA seems to be the primary component for efficacy.^15,19 Additionally, the more severe the depression, the more likely symptoms will respond to omega-3 FAs.^6,14,15 Omega-3 FAs are not effective at preventing depression^14,15 and evidence is equivocal for treating perinatal depression.²¹ Omega-3 FA supplementation has not shown efficacy for patients with schizophrenia,^23,24 although it may prevent transition to psychosis in adolescents and young adults at ultra-high risk for a psychotic disorder.²⁵ Data examining omega-3 FA supplementation in postpartum depression²² and dementia^28,29 are limited but show promise. Omega-3 FAs appear to lack efficacy in ADHD,^31-33 OCD,³⁴ and borderline personality disorder.³⁵

Related Resources

• National Center for Complementary and Alternative Medicine. Omega-3 fatty acids. http://nccam.nih.gov/health/omega3.
• National Institutes of Health. Office of Dietary Supplements. Working group report: Omega-3 fatty acids and cardiovascular disease. http://ods.od.nih.gov/Health_Information/omega_3_fatty_acids.aspx.

Disclosure

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

Discuss this article at www.facebook.com/CurrentPsychiatry

Epidemiologic data suggest that people who consume diets rich in omega-3 fatty acids (FAs)—long-chain polyunsaturated FAs such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)—have a decreased risk of major depressive disorder (MDD), postpartum depression, and bipolar disorder (BD).^1-5 Omega-3 FA concentration may impact serotonin and dopamine transmission via effects on cell membrane fluidity.⁶ Therefore, decreased intake may increase the risk of several psychiatric disorders. As the average Western diet has changed over the last 2 centuries, omega-3 FA consumption has decreased.⁷ Omega-3 FAs cannot be synthesized by the body and must come from exogenous sources, such as fish and nuts. For a discussion of different types of dietary fats, see Box 1.⁸

Should we advise our patients to increase their omega-3 FA consumption? The American Psychiatric Association (APA) and the American Heart Association (AHA) recommend omega-3 FA consumption for the general population and in some cases, supplementation for specific disorders (Box 2).^9-12 New data has been published since Current Psychiatry last reviewed the evidence for using omega-3 FAs for psychiatric conditions in 2004.⁸ This article looks at the latest evidence on the use of omega-3 FAs to treat mood disorders, schizophrenia, dementia, and other psychiatric conditions.

Box 1

Box 2

Limitations of the data

Reviewing the literature on omega-3 FAs to treat psychiatric disorders is hampered by several difficulties:¹³

• studies may evaluate the use of EPA alone, EPA combined with DHA, or DHA alone
• the doses of EPA and DHA and ratio of EPA to DHA of the supplements used in clinical trials varies greatly
• patients’ dietary consumption of omega-3 FAs is difficult to control
• DSM diagnostic criteria, as well as severity of illness, differ within studies.

In addition, studies may use omega-3 FAs as monotherapy or as adjuncts. All of these factors lead to difficulty interpreting the literature, as well as trouble in extracting data for meta-analysis.

Omega-3 FAs for mood disorders

MDD and other depressive diagnoses. Several meta-analyses examining the use of omega-3 FAs for treating depressive disorders have had equivocal findings. Variability in results might be partially explained by differences in the severity of baseline depression among diverse study populations, diagnostic variation, differing omega-3 supplementation protocols, or other issues.¹³ In addition, publication bias also may affect results.

In a 2011 literature review and meta-analysis of omega-3 FAs as monotherapy or an adjunct to antidepressants to treat MDD, Bloch and Hannestad⁶ concluded that omega-3 FAs offer a small but nonsignificant benefit in treating MDD. This review suggested that omega-3 FAs may be more effective in patients with more severe depression. The effects of varying levels of EPA vs DHA were not examined.

In a systematic review and meta-analysis, Appleton et al¹⁴ concluded that omega-3 FA supplements have little beneficial effect on depressed mood in individuals who do not have a depressive illness diagnosis (eg, MDD). However, this study did not consider the differential effects of EPA vs DHA on treatment response. Patients diagnosed with a depressive illness received greater benefits from omega-3 FA supplementation, although the patients in this study were heterogeneous. Similar to Bloch and Hannestad, Appleton et al¹⁴ found that omega-3 FA supplementation may be most beneficial for depressed patients with more severe symptoms, but is unlikely to help those with mild-to-moderate symptoms or individuals without symptoms who aim to prevent depression.

A meta-analysis by Martins¹⁵ looked at EPA vs DHA to treat depressive illness and found that only supplements that were mostly or completely EPA effectively treated depressive symptoms. Martins also found that severity of illness is key for positive treatment outcomes; there was a significant relationship between higher baseline depression levels and efficacy.¹⁵ Martins noted that omega-3 FA therapy was more effective as a treatment than a preventive strategy, and that adding omega-3 FAs to antidepressants was more efficacious than omega-3 FAs alone.¹⁵

A meta-analysis of clinical trials of omega-3 FAs for depressive illness suggested EPA should be ≥60% of total EPA + DHA.¹⁶

BD. A recent meta-analysis of 6 randomized controlled trials (RCTs) found that adding omega-3 supplements to mood stabilizers in patients with BD was associated with a statistically significant reduction of depressive symptoms, but was not effective for treating mania.¹⁷ The authors suggested patients with BD—especially those with comorbid cardiovascular or metabolic conditions— increase their dietary consumption of foods containing omega-3 FAs (Table)¹⁸ and, if necessary, take a supplement of 1 to 1.5 g/d of mixed EPA and DHA, with a higher ratio of EPA.¹⁹ See Box 3 for a box on how to read omega-3 supplement labels.

In a small RCT of 51 children and adolescents (age 6 to 17) with symptomatic bipolar I or bipolar II disorder, supplementation with flax oil (alpha-linolenic acid, a polyunsaturated omega-3 FA that is a precursor to EPA and DHA) did not affect symptoms as measured by several rating scales.²⁰

Perinatal and postpartum depression. Omega-3 FAs are considered a safe treatment for depressive disorders during pregnancy because they provide neurodevelopmental benefits for neonates and have few contraindications during pregnancy.²¹ RCTs of omega-3 FA monotherapy for perinatal depression have been small (≤51 patients) and produced mixed findings.²¹ A pilot study (N = 16) of patients with postpartum depression found a significant decrease in depressive symptoms with EPA treatment.²² More research is needed before omega-3 FA supplementation can be recommended during pregnancy.

Table

Foods with healthy fats: From best to worst

Box 3

Selecting an omega-3 supplement: What to tell patients

Because nutritional supplements vary, advise patients to look at the supplement facts on the back of a bottle of omega-3 fatty acids. The American Psychiatric Association recommends patients take a total eicosapentaenoic acid (EPA) + docosahexaenoic acid (DHA) of 1 g/d; EPA should be ≥60% of total EPA + DHA.

This image is an example of a label that would meet the appropriate criteria. Total EPA + DHA = 1,490 mg and EPA is 60% of this combined total.

Source: Sublette ME, Ellis SP, Geant AL, et al. Meta-analysis of the effects of eicosapentaenoic acid (EPA) in clinical trials in depression. J Clin Psychiatry. 2011;72(12):1577-1584

Schizophrenia

In a Cochrane review of 8 studies of patients with schizophrenia, adjunctive treatment with omega-3 FAs led to >25% reduction in the Positive and Negative Syndrome Scale, but this improvement was not statistically significant.²³ Omega-3 FAs did not decrease tardive dyskinesia symptoms as measured by the Abnormal Involuntary Movement Scale. The authors stated that results were inconclusive, and use of omega-3 FAs in patients with schizophrenia remains experimental. In a separate meta-analysis that included 335 patients with schizophrenia, EPA augmentation had no beneficial effect on psychotic symptoms.²⁴

In a double-blind RCT of 81 adolescents and young adults (age 13 to 25) at ultra-high risk of psychotic illness, 5% of patients who received 1.2 g/d of omega-3 FAs developed a psychotic disorder compared with 28% of patients receiving placebo.²⁵ The authors concluded that supplementation with omega-3 FAs may be a safe and effective strategy for young patients with subthreshold psychotic symptoms.

Dementia

Studies evaluating the relationship between omega-3 FAs and dementia risk have revealed mixed findings.^26,27 In a pilot study of 10 geriatric patients with moderately severe dementia related to thrombotic cerebrovascular disorder, DHA supplementation led to improved Hamilton Depression Rating Scale and Mini-Mental State Examination (MMSE) scores compared with controls.²⁸ In another study, administering EPA to 64 patients with Alzheimer’s disease significantly improved MMSE scores, with maximum improvement at 3 months, but this benefit dissipated after 6 months of treatment.²⁹ In a study of 22 patients with various types of dementia, Suzuki et al³⁰ found that DHA supplementation improved scores on a Japanese dementia scale. These studies show promise, but more evidence is necessary before recommendations can be made.

Other psychiatric disorders

Omega-3 FAs as monotherapy or an adjunct to psychostimulants does not seem to improve symptoms in children who meet DSM-IV-TR criteria for attention-deficit/hyperactivity disorder (ADHD).^31-33 Studies of omega-3 FAs as treatment for anxiety and personality disorders are limited. To date, omega-3 FAs as adjunctive treatment in obsessive-compulsive disorder (OCD) and monotherapy in borderline personality disorder have not shown efficacy.^34,35

Using omega-3 FAs in practice

Based on new data and several recent meta-analyses, clinical recommendations have emerged. Sarris et al¹⁷ suggested patients with BD increase dietary intake of omega-3 FAs or take a supplement with 1 to 1.5 g/d of mixed EPA and DHA (with a higher ratio of EPA). In MDD, the type of omega-3 FA supplementation seems to be important; EPA seems to be the primary component for efficacy.^15,19 Additionally, the more severe the depression, the more likely symptoms will respond to omega-3 FAs.^6,14,15 Omega-3 FAs are not effective at preventing depression^14,15 and evidence is equivocal for treating perinatal depression.²¹ Omega-3 FA supplementation has not shown efficacy for patients with schizophrenia,^23,24 although it may prevent transition to psychosis in adolescents and young adults at ultra-high risk for a psychotic disorder.²⁵ Data examining omega-3 FA supplementation in postpartum depression²² and dementia^28,29 are limited but show promise. Omega-3 FAs appear to lack efficacy in ADHD,^31-33 OCD,³⁴ and borderline personality disorder.³⁵

Related Resources

• National Center for Complementary and Alternative Medicine. Omega-3 fatty acids. http://nccam.nih.gov/health/omega3.
• National Institutes of Health. Office of Dietary Supplements. Working group report: Omega-3 fatty acids and cardiovascular disease. http://ods.od.nih.gov/Health_Information/omega_3_fatty_acids.aspx.

Disclosure

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

Discuss this article at www.facebook.com/CurrentPsychiatry

Epidemiologic data suggest that people who consume diets rich in omega-3 fatty acids (FAs)—long-chain polyunsaturated FAs such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)—have a decreased risk of major depressive disorder (MDD), postpartum depression, and bipolar disorder (BD).^1-5 Omega-3 FA concentration may impact serotonin and dopamine transmission via effects on cell membrane fluidity.⁶ Therefore, decreased intake may increase the risk of several psychiatric disorders. As the average Western diet has changed over the last 2 centuries, omega-3 FA consumption has decreased.⁷ Omega-3 FAs cannot be synthesized by the body and must come from exogenous sources, such as fish and nuts. For a discussion of different types of dietary fats, see Box 1.⁸

Should we advise our patients to increase their omega-3 FA consumption? The American Psychiatric Association (APA) and the American Heart Association (AHA) recommend omega-3 FA consumption for the general population and in some cases, supplementation for specific disorders (Box 2).^9-12 New data has been published since Current Psychiatry last reviewed the evidence for using omega-3 FAs for psychiatric conditions in 2004.⁸ This article looks at the latest evidence on the use of omega-3 FAs to treat mood disorders, schizophrenia, dementia, and other psychiatric conditions.

Box 1

Box 2

Limitations of the data

Reviewing the literature on omega-3 FAs to treat psychiatric disorders is hampered by several difficulties:¹³

• studies may evaluate the use of EPA alone, EPA combined with DHA, or DHA alone
• the doses of EPA and DHA and ratio of EPA to DHA of the supplements used in clinical trials varies greatly
• patients’ dietary consumption of omega-3 FAs is difficult to control
• DSM diagnostic criteria, as well as severity of illness, differ within studies.

In addition, studies may use omega-3 FAs as monotherapy or as adjuncts. All of these factors lead to difficulty interpreting the literature, as well as trouble in extracting data for meta-analysis.

Omega-3 FAs for mood disorders

MDD and other depressive diagnoses. Several meta-analyses examining the use of omega-3 FAs for treating depressive disorders have had equivocal findings. Variability in results might be partially explained by differences in the severity of baseline depression among diverse study populations, diagnostic variation, differing omega-3 supplementation protocols, or other issues.¹³ In addition, publication bias also may affect results.

In a 2011 literature review and meta-analysis of omega-3 FAs as monotherapy or an adjunct to antidepressants to treat MDD, Bloch and Hannestad⁶ concluded that omega-3 FAs offer a small but nonsignificant benefit in treating MDD. This review suggested that omega-3 FAs may be more effective in patients with more severe depression. The effects of varying levels of EPA vs DHA were not examined.

In a systematic review and meta-analysis, Appleton et al¹⁴ concluded that omega-3 FA supplements have little beneficial effect on depressed mood in individuals who do not have a depressive illness diagnosis (eg, MDD). However, this study did not consider the differential effects of EPA vs DHA on treatment response. Patients diagnosed with a depressive illness received greater benefits from omega-3 FA supplementation, although the patients in this study were heterogeneous. Similar to Bloch and Hannestad, Appleton et al¹⁴ found that omega-3 FA supplementation may be most beneficial for depressed patients with more severe symptoms, but is unlikely to help those with mild-to-moderate symptoms or individuals without symptoms who aim to prevent depression.

A meta-analysis by Martins¹⁵ looked at EPA vs DHA to treat depressive illness and found that only supplements that were mostly or completely EPA effectively treated depressive symptoms. Martins also found that severity of illness is key for positive treatment outcomes; there was a significant relationship between higher baseline depression levels and efficacy.¹⁵ Martins noted that omega-3 FA therapy was more effective as a treatment than a preventive strategy, and that adding omega-3 FAs to antidepressants was more efficacious than omega-3 FAs alone.¹⁵

A meta-analysis of clinical trials of omega-3 FAs for depressive illness suggested EPA should be ≥60% of total EPA + DHA.¹⁶

BD. A recent meta-analysis of 6 randomized controlled trials (RCTs) found that adding omega-3 supplements to mood stabilizers in patients with BD was associated with a statistically significant reduction of depressive symptoms, but was not effective for treating mania.¹⁷ The authors suggested patients with BD—especially those with comorbid cardiovascular or metabolic conditions— increase their dietary consumption of foods containing omega-3 FAs (Table)¹⁸ and, if necessary, take a supplement of 1 to 1.5 g/d of mixed EPA and DHA, with a higher ratio of EPA.¹⁹ See Box 3 for a box on how to read omega-3 supplement labels.

In a small RCT of 51 children and adolescents (age 6 to 17) with symptomatic bipolar I or bipolar II disorder, supplementation with flax oil (alpha-linolenic acid, a polyunsaturated omega-3 FA that is a precursor to EPA and DHA) did not affect symptoms as measured by several rating scales.²⁰

Perinatal and postpartum depression. Omega-3 FAs are considered a safe treatment for depressive disorders during pregnancy because they provide neurodevelopmental benefits for neonates and have few contraindications during pregnancy.²¹ RCTs of omega-3 FA monotherapy for perinatal depression have been small (≤51 patients) and produced mixed findings.²¹ A pilot study (N = 16) of patients with postpartum depression found a significant decrease in depressive symptoms with EPA treatment.²² More research is needed before omega-3 FA supplementation can be recommended during pregnancy.

Table

Foods with healthy fats: From best to worst

Box 3

Selecting an omega-3 supplement: What to tell patients

Because nutritional supplements vary, advise patients to look at the supplement facts on the back of a bottle of omega-3 fatty acids. The American Psychiatric Association recommends patients take a total eicosapentaenoic acid (EPA) + docosahexaenoic acid (DHA) of 1 g/d; EPA should be ≥60% of total EPA + DHA.

This image is an example of a label that would meet the appropriate criteria. Total EPA + DHA = 1,490 mg and EPA is 60% of this combined total.

Source: Sublette ME, Ellis SP, Geant AL, et al. Meta-analysis of the effects of eicosapentaenoic acid (EPA) in clinical trials in depression. J Clin Psychiatry. 2011;72(12):1577-1584

Schizophrenia

In a Cochrane review of 8 studies of patients with schizophrenia, adjunctive treatment with omega-3 FAs led to >25% reduction in the Positive and Negative Syndrome Scale, but this improvement was not statistically significant.²³ Omega-3 FAs did not decrease tardive dyskinesia symptoms as measured by the Abnormal Involuntary Movement Scale. The authors stated that results were inconclusive, and use of omega-3 FAs in patients with schizophrenia remains experimental. In a separate meta-analysis that included 335 patients with schizophrenia, EPA augmentation had no beneficial effect on psychotic symptoms.²⁴

In a double-blind RCT of 81 adolescents and young adults (age 13 to 25) at ultra-high risk of psychotic illness, 5% of patients who received 1.2 g/d of omega-3 FAs developed a psychotic disorder compared with 28% of patients receiving placebo.²⁵ The authors concluded that supplementation with omega-3 FAs may be a safe and effective strategy for young patients with subthreshold psychotic symptoms.

Dementia

Studies evaluating the relationship between omega-3 FAs and dementia risk have revealed mixed findings.^26,27 In a pilot study of 10 geriatric patients with moderately severe dementia related to thrombotic cerebrovascular disorder, DHA supplementation led to improved Hamilton Depression Rating Scale and Mini-Mental State Examination (MMSE) scores compared with controls.²⁸ In another study, administering EPA to 64 patients with Alzheimer’s disease significantly improved MMSE scores, with maximum improvement at 3 months, but this benefit dissipated after 6 months of treatment.²⁹ In a study of 22 patients with various types of dementia, Suzuki et al³⁰ found that DHA supplementation improved scores on a Japanese dementia scale. These studies show promise, but more evidence is necessary before recommendations can be made.

Other psychiatric disorders

Omega-3 FAs as monotherapy or an adjunct to psychostimulants does not seem to improve symptoms in children who meet DSM-IV-TR criteria for attention-deficit/hyperactivity disorder (ADHD).^31-33 Studies of omega-3 FAs as treatment for anxiety and personality disorders are limited. To date, omega-3 FAs as adjunctive treatment in obsessive-compulsive disorder (OCD) and monotherapy in borderline personality disorder have not shown efficacy.^34,35

Using omega-3 FAs in practice

Based on new data and several recent meta-analyses, clinical recommendations have emerged. Sarris et al¹⁷ suggested patients with BD increase dietary intake of omega-3 FAs or take a supplement with 1 to 1.5 g/d of mixed EPA and DHA (with a higher ratio of EPA). In MDD, the type of omega-3 FA supplementation seems to be important; EPA seems to be the primary component for efficacy.^15,19 Additionally, the more severe the depression, the more likely symptoms will respond to omega-3 FAs.^6,14,15 Omega-3 FAs are not effective at preventing depression^14,15 and evidence is equivocal for treating perinatal depression.²¹ Omega-3 FA supplementation has not shown efficacy for patients with schizophrenia,^23,24 although it may prevent transition to psychosis in adolescents and young adults at ultra-high risk for a psychotic disorder.²⁵ Data examining omega-3 FA supplementation in postpartum depression²² and dementia^28,29 are limited but show promise. Omega-3 FAs appear to lack efficacy in ADHD,^31-33 OCD,³⁴ and borderline personality disorder.³⁵

Related Resources

• National Center for Complementary and Alternative Medicine. Omega-3 fatty acids. http://nccam.nih.gov/health/omega3.
• National Institutes of Health. Office of Dietary Supplements. Working group report: Omega-3 fatty acids and cardiovascular disease. http://ods.od.nih.gov/Health_Information/omega_3_fatty_acids.aspx.

Disclosure

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

Nearly 2.5 million persons die each year in the United States.¹ For the bereaved, these deaths may be among the most painful and disruptive events they will experience. In this article, we evaluate the growing body of research on complicated grief (CG)—which also has been called prolonged grief, chronic grief, traumatic grief, and pathological grief—with an emphasis on how to identify CG and distinguish it from other adaptive and maladaptive reactions to the loss of a loved one. In addition, we review empirical evidence on treating CG, including psychotherapy, pharmacotherapy, and combined treatment approaches.

The bereavement-specific syndrome we refer to as CG currently is being reviewed for possible inclusion in DSM-5 as an official diagnosis. At press time, proposals for DSM-5 included a bereavement-related adjustment disorder within the new Trauma- and Stressor-Related Disorders category, as well as a provisional diagnosis of CG entitled Persistent Complex Bereavement-Related Disorder, which, upon acceptance, would be listed in Section III.²

What is ‘normal’ grief?

Grief is highly variable across individuals and time and may range from an absence of distress to severe and persistent pain and anguish. There’s no simple definition of “normal grief.” However, as clinicians, it’s necessary to understand the range of usual reactions. We recommend 2 considerations when evaluating grief reactions.

First, be aware that grief encompasses a range of cognitions, emotions, and behaviors. It may range from a relative lack of painful thoughts and emotions to intense and disruptive sadness, loneliness, anger, guilt, intrusive thoughts, difficulty concentrating, preoccupation with loss, social withdrawal, and a sense of being overwhelmed by the loss and its consequences. In the months after a loss, bereaved individuals may look for the deceased in a crowd, speak to them, or even experience auditory or visual hallucinations of the deceased. Nonetheless, positive feelings such as relief, peace, and happiness also are common following a loss.³ Moreover, laughter and smiling when discussing a lost loved one predicts reductions in grief symptoms over time.⁴ Overall, grief research suggests that, far from proceeding along standard and uniform stages,⁵ grief is complex and comprises a broad spectrum of thoughts, feelings, and behaviors that vary within and among individuals.

Second, note that in the absence of complications, grief progresses. For those who experience elevated levels of distress, the pain and disruption of loss initially may feel overwhelming but will subside in intensity over time for most individuals.⁵ This is not to say that an individual will never again feel sadness or longing for the deceased; elements of grief are likely to remain. Although the trajectory of grief symptoms varies among individuals and may progress in fits and starts, over time grief becomes more intermittent, less interfering, and is balanced with a sense of interest and purpose in life.

What is CG?

As research on grief experiences has grown, there’s increasing recognition that a minority of bereaved individuals experience more extreme grief symptoms that cause substantial, persistent distress and impairment despite the passage of many months or years. Shear et al⁶ proposed a set of CG diagnostic criteria (Table) in which a cluster of symptoms of intense and persistent separation distress are defined as core symptoms. Similar to other psychiatric diagnoses, the symptoms must be associated with significant distress or impairment.

Table

Proposed diagnostic criteria for complicated grief

Assessing CG symptoms

Among those with persistent elevated distress, a CG diagnosis must be considered in the context of the individual’s social and cultural environment, time since the loss, and duration of symptoms. The hallmark symptom of CG is separation distress with a focus of cognitive, behavioral, and emotional symptoms on the loss and its consequences. CG is associated with substantial distress, functional impairment, and an increased risk for suicide. See the Box for a case study.

Many individuals with CG remain undiagnosed and untreated for years despite high levels of distress and impairment and high risk for negative consequences such as suicide.⁷ Accordingly, there’s a need for greater CG screening. Clinically useful tools for assessing CG include a brief, 5-item dimensional screening assessment⁶ and the patient-rated Inventory of Complicated Grief.⁸

Distinguishing complicated and uncomplicated grief. Exhibiting CG symptoms in the first several months after a loss does not mean an individual has or will develop CG. Most bereaved adults report painful thoughts and emotions in the weeks and months following the loss, including distressed yearning, waves of intense grief, persistent and intrusive thoughts, images related to the death, somatic distress, and a feeling of being disconnected from others. For most individuals, the intensity of this response diminishes within 6 to 18 months after the loved one’s death.⁵ Although the optimal length of time to wait before establishing a diagnosis remains debatable, the earliest CG should be diagnosed is 6 months after a loss.

It’s common for grief to occasionally rise in intensity for days or weeks. This surge may occur many months or years after the loss, even in people who exhibited relatively little distress or impairment. In particular, anniversaries, holidays, or periods of stress may trigger increased grief intensity. However, these surges typically subside naturally within a short time. Accordingly, CG should be diagnosed only when symptoms persist for >1 month.

CG vs other post-loss disorders. CG, major depressive disorder (MDD), and posttraumatic stress disorder (PTSD) often are comorbid in bereaved adults. Simon et al⁹ found 72% of CG patients in a treatment- seeking sample reported a lifetime history of MDD and 53% reported a lifetime history of PTSD. However, CG can be distinguished from these disorders. In the same study, 25% of CG patients had no other axis I diagnosis.⁹ After accounting for comorbid disorders, researchers associated CG severity with work and social impairment. These findings provide clear evidence for the incremental validity of CG—ie, a CG diagnosis gives clinicians additional information that predicts impairment above and beyond other disorders. However, future research needs to further examine CG and its overlap and differentiation from MDD and PTSD.

Distinguishing CG and MDD. Intense yearning or preoccupation with the deceased is a common symptom of CG but not MDD. In addition, CG symptoms possess intentionality. For example, emotional distress such as sadness and anger are prominent features of both CG and MDD. However, in CG, these symptoms are specific to the loss or circumstances of the loss, whereas in MDD they generally are more nebulous and generalized. Similarly, CG entails proximity seeking related to the deceased, and avoidance of reminders of the deceased, whereas MDD includes a more general social withdrawal and anhedonia.

Distinguishing CG and PTSD. CG and loss-related PTSD are distinguished by the predominant emotions and focus of concern associated with each disorder. The predominant emotion in PTSD is fear, whereas in CG it is sadness and longing. In PTSD, intrusive thoughts and memories associated with the trauma generally are associated with the event itself and produce an ongoing sense of threat.¹⁰ Avoidance in PTSD is intended to reduce this threat feeling. By contrast, in CG, intrusive memories focus on the deceased or the circumstances of the death, and avoidance is aimed at preventing painful reminders of the loss or its permanence. Importantly, both syndromes may be present.

Box

Treating CG

When is treatment indicated? For years, bereavement theorists emphasized the need to work through emotions and memories related to the deceased with particular focus on negative material. However, evidence suggests that universal application of treatment to all bereaved individuals is unhelpful. In a recent meta-analysis, Neimeyer et al¹¹ found that the outcomes of grief therapy applied indiscriminately to all bereaved adults or all members of high-risk populations—such as parents whose child experienced a violent death—were no better than would be expected by the passage of time. In contrast, grief therapy applied only to those who develop elevated and persistent distress (eg, CG) led to greater and more enduring improvement in post-loss distress than was observed in control conditions.

These results suggest that most grieving individuals who do not meet criteria for CG (or other psychiatric disorders) will not require intervention. Those who do seek treatment for grief-related distress in the acute grief period should be assessed for bereavement-related depression, anxiety, and suicidality, and treated or referred to professional or community-based resources for support or counseling as clinically indicated.

Evidence for psychotherapy. For those who meet CG criteria, psychotherapy targeting the specific symptoms of CG is helpful. The evidence is strongest for CG treatment (CGT), a 16-session, manualized psychotherapy developed by M. Katherine Shear, MD.¹² CGT is based on an attachment model and cognitive-behavioral therapy (CBT) principles, and is informed by the dual-process theory proposed by Stroebe et al.¹³ According to this theory, natural healing following loss comprises 2 processes:

• a loss-oriented process in which the patient comes to terms with the loss, and
• a restoration-oriented process in which the patient reinvigorates a sense of purpose and meaning in life without the deceased.

CGT focuses on both processes. To address the former, it includes clinician-guided exercises in which the patient revisits the time of the death and planned activities in which the patient reengages with people, places, or thoughts that remind him or her of the deceased. CGT aims to allow the patient to gain an increased tolerance of the distressing thoughts and emotions associated with the loss so that these thoughts can be processed and the finality of the death and its circumstances can be accepted.

The restoration process is addressed by having patients generate and discuss personal goals and aspirations for the near and distant future, as well as scheduling pleasurable and rewarding events. This is accomplished by having patients imagine what they would want for themselves if their grief was less intense and planning concrete steps to take toward these goals. The restoration-oriented process is addressed concurrent with the loss-oriented process to encourage the oscillation between processes thought to be characteristic of a natural healing process following the loss of a loved one.

Other psychotherapy approaches (eg, support groups) may have a role for some individuals, and future research may suggest alternative approaches to CGT. To date, CGT is the most targeted evidence-based psychotherapy with randomized controlled data supporting its use in CG.

Pharmacotherapy for CG. Early research suggested that antidepressants—in particular tricyclics—may effectively reduce depressive symptoms in bereavement-related depression; their effect on CG symptoms, however, may not be as strong.¹⁴ Research on pharmacologic treatment that targets CG symptoms is developing. Because of the overlap between CG, PTSD, and MDD, researchers have hypothesized that antidepressants may be effective. Two open-label studies reported that the selective serotonin reuptake inhibitor (SSRI) escitalopram may be effective for CG.^15,16 Although a post-hoc comparison of paroxetine and nortriptyline¹⁷ showed significant reduction in CG and depressive symptoms with both agents, effects could not be separated from concomitant psychotherapy. Furthermore, an examination of naturalistic data on combining antidepressants with CGT suggested that antidepressants may improve outcomes for individuals receiving CGT.¹⁸ A multicenter, randomized controlled trial funded by the National Institute of Mental Health is examining the potential efficacy of citalopram, an SSRI, alone or in combination with CGT.¹⁹

The efficacy of benzodiazepines, which commonly are prescribed for bereaved individuals, has not been assessed in CG. However, recent research suggests they may not be useful for medically managing recent grief²⁰ and that their use in the aftermath of a loss may lead to long-term dependence in geriatric patients.²¹

Related Resources

• Center for Anxiety and Traumatic Stress Disorders. Massachusetts General Hospital. www.bostongrief.com.
• Zisook S, Shear K. Grief and bereavement: what psychiatrists need to know. World Psychiatry. 2009;8(2):67-74.
• Bonanno G. The other side of sadness: what the new science of bereavement tells us about loss. New York, NY: Basic Books; 2009.

Drug Brand Names

• Citalopram • Celexa
• Nortriptyline • Aventyl, Pamelor
• Escitalopram • Lexapro
• Paroxetine • Paxil

Disclosures

Dr. Simon receives grant or research support from the American Cancer Society, the American Foundation for Suicide Prevention, the Department of Defense, Forest Laboratories, and the National Institute of Mental Health.

Nearly 2.5 million persons die each year in the United States.¹ For the bereaved, these deaths may be among the most painful and disruptive events they will experience. In this article, we evaluate the growing body of research on complicated grief (CG)—which also has been called prolonged grief, chronic grief, traumatic grief, and pathological grief—with an emphasis on how to identify CG and distinguish it from other adaptive and maladaptive reactions to the loss of a loved one. In addition, we review empirical evidence on treating CG, including psychotherapy, pharmacotherapy, and combined treatment approaches.

The bereavement-specific syndrome we refer to as CG currently is being reviewed for possible inclusion in DSM-5 as an official diagnosis. At press time, proposals for DSM-5 included a bereavement-related adjustment disorder within the new Trauma- and Stressor-Related Disorders category, as well as a provisional diagnosis of CG entitled Persistent Complex Bereavement-Related Disorder, which, upon acceptance, would be listed in Section III.²

What is ‘normal’ grief?

Grief is highly variable across individuals and time and may range from an absence of distress to severe and persistent pain and anguish. There’s no simple definition of “normal grief.” However, as clinicians, it’s necessary to understand the range of usual reactions. We recommend 2 considerations when evaluating grief reactions.

First, be aware that grief encompasses a range of cognitions, emotions, and behaviors. It may range from a relative lack of painful thoughts and emotions to intense and disruptive sadness, loneliness, anger, guilt, intrusive thoughts, difficulty concentrating, preoccupation with loss, social withdrawal, and a sense of being overwhelmed by the loss and its consequences. In the months after a loss, bereaved individuals may look for the deceased in a crowd, speak to them, or even experience auditory or visual hallucinations of the deceased. Nonetheless, positive feelings such as relief, peace, and happiness also are common following a loss.³ Moreover, laughter and smiling when discussing a lost loved one predicts reductions in grief symptoms over time.⁴ Overall, grief research suggests that, far from proceeding along standard and uniform stages,⁵ grief is complex and comprises a broad spectrum of thoughts, feelings, and behaviors that vary within and among individuals.

Second, note that in the absence of complications, grief progresses. For those who experience elevated levels of distress, the pain and disruption of loss initially may feel overwhelming but will subside in intensity over time for most individuals.⁵ This is not to say that an individual will never again feel sadness or longing for the deceased; elements of grief are likely to remain. Although the trajectory of grief symptoms varies among individuals and may progress in fits and starts, over time grief becomes more intermittent, less interfering, and is balanced with a sense of interest and purpose in life.

What is CG?

As research on grief experiences has grown, there’s increasing recognition that a minority of bereaved individuals experience more extreme grief symptoms that cause substantial, persistent distress and impairment despite the passage of many months or years. Shear et al⁶ proposed a set of CG diagnostic criteria (Table) in which a cluster of symptoms of intense and persistent separation distress are defined as core symptoms. Similar to other psychiatric diagnoses, the symptoms must be associated with significant distress or impairment.

Table

Proposed diagnostic criteria for complicated grief

Assessing CG symptoms

Among those with persistent elevated distress, a CG diagnosis must be considered in the context of the individual’s social and cultural environment, time since the loss, and duration of symptoms. The hallmark symptom of CG is separation distress with a focus of cognitive, behavioral, and emotional symptoms on the loss and its consequences. CG is associated with substantial distress, functional impairment, and an increased risk for suicide. See the Box for a case study.

Many individuals with CG remain undiagnosed and untreated for years despite high levels of distress and impairment and high risk for negative consequences such as suicide.⁷ Accordingly, there’s a need for greater CG screening. Clinically useful tools for assessing CG include a brief, 5-item dimensional screening assessment⁶ and the patient-rated Inventory of Complicated Grief.⁸

Distinguishing complicated and uncomplicated grief. Exhibiting CG symptoms in the first several months after a loss does not mean an individual has or will develop CG. Most bereaved adults report painful thoughts and emotions in the weeks and months following the loss, including distressed yearning, waves of intense grief, persistent and intrusive thoughts, images related to the death, somatic distress, and a feeling of being disconnected from others. For most individuals, the intensity of this response diminishes within 6 to 18 months after the loved one’s death.⁵ Although the optimal length of time to wait before establishing a diagnosis remains debatable, the earliest CG should be diagnosed is 6 months after a loss.

It’s common for grief to occasionally rise in intensity for days or weeks. This surge may occur many months or years after the loss, even in people who exhibited relatively little distress or impairment. In particular, anniversaries, holidays, or periods of stress may trigger increased grief intensity. However, these surges typically subside naturally within a short time. Accordingly, CG should be diagnosed only when symptoms persist for >1 month.

CG vs other post-loss disorders. CG, major depressive disorder (MDD), and posttraumatic stress disorder (PTSD) often are comorbid in bereaved adults. Simon et al⁹ found 72% of CG patients in a treatment- seeking sample reported a lifetime history of MDD and 53% reported a lifetime history of PTSD. However, CG can be distinguished from these disorders. In the same study, 25% of CG patients had no other axis I diagnosis.⁹ After accounting for comorbid disorders, researchers associated CG severity with work and social impairment. These findings provide clear evidence for the incremental validity of CG—ie, a CG diagnosis gives clinicians additional information that predicts impairment above and beyond other disorders. However, future research needs to further examine CG and its overlap and differentiation from MDD and PTSD.

Distinguishing CG and MDD. Intense yearning or preoccupation with the deceased is a common symptom of CG but not MDD. In addition, CG symptoms possess intentionality. For example, emotional distress such as sadness and anger are prominent features of both CG and MDD. However, in CG, these symptoms are specific to the loss or circumstances of the loss, whereas in MDD they generally are more nebulous and generalized. Similarly, CG entails proximity seeking related to the deceased, and avoidance of reminders of the deceased, whereas MDD includes a more general social withdrawal and anhedonia.

Distinguishing CG and PTSD. CG and loss-related PTSD are distinguished by the predominant emotions and focus of concern associated with each disorder. The predominant emotion in PTSD is fear, whereas in CG it is sadness and longing. In PTSD, intrusive thoughts and memories associated with the trauma generally are associated with the event itself and produce an ongoing sense of threat.¹⁰ Avoidance in PTSD is intended to reduce this threat feeling. By contrast, in CG, intrusive memories focus on the deceased or the circumstances of the death, and avoidance is aimed at preventing painful reminders of the loss or its permanence. Importantly, both syndromes may be present.

Box

Treating CG

When is treatment indicated? For years, bereavement theorists emphasized the need to work through emotions and memories related to the deceased with particular focus on negative material. However, evidence suggests that universal application of treatment to all bereaved individuals is unhelpful. In a recent meta-analysis, Neimeyer et al¹¹ found that the outcomes of grief therapy applied indiscriminately to all bereaved adults or all members of high-risk populations—such as parents whose child experienced a violent death—were no better than would be expected by the passage of time. In contrast, grief therapy applied only to those who develop elevated and persistent distress (eg, CG) led to greater and more enduring improvement in post-loss distress than was observed in control conditions.

These results suggest that most grieving individuals who do not meet criteria for CG (or other psychiatric disorders) will not require intervention. Those who do seek treatment for grief-related distress in the acute grief period should be assessed for bereavement-related depression, anxiety, and suicidality, and treated or referred to professional or community-based resources for support or counseling as clinically indicated.

Evidence for psychotherapy. For those who meet CG criteria, psychotherapy targeting the specific symptoms of CG is helpful. The evidence is strongest for CG treatment (CGT), a 16-session, manualized psychotherapy developed by M. Katherine Shear, MD.¹² CGT is based on an attachment model and cognitive-behavioral therapy (CBT) principles, and is informed by the dual-process theory proposed by Stroebe et al.¹³ According to this theory, natural healing following loss comprises 2 processes:

• a loss-oriented process in which the patient comes to terms with the loss, and
• a restoration-oriented process in which the patient reinvigorates a sense of purpose and meaning in life without the deceased.

CGT focuses on both processes. To address the former, it includes clinician-guided exercises in which the patient revisits the time of the death and planned activities in which the patient reengages with people, places, or thoughts that remind him or her of the deceased. CGT aims to allow the patient to gain an increased tolerance of the distressing thoughts and emotions associated with the loss so that these thoughts can be processed and the finality of the death and its circumstances can be accepted.

The restoration process is addressed by having patients generate and discuss personal goals and aspirations for the near and distant future, as well as scheduling pleasurable and rewarding events. This is accomplished by having patients imagine what they would want for themselves if their grief was less intense and planning concrete steps to take toward these goals. The restoration-oriented process is addressed concurrent with the loss-oriented process to encourage the oscillation between processes thought to be characteristic of a natural healing process following the loss of a loved one.

Other psychotherapy approaches (eg, support groups) may have a role for some individuals, and future research may suggest alternative approaches to CGT. To date, CGT is the most targeted evidence-based psychotherapy with randomized controlled data supporting its use in CG.

Pharmacotherapy for CG. Early research suggested that antidepressants—in particular tricyclics—may effectively reduce depressive symptoms in bereavement-related depression; their effect on CG symptoms, however, may not be as strong.¹⁴ Research on pharmacologic treatment that targets CG symptoms is developing. Because of the overlap between CG, PTSD, and MDD, researchers have hypothesized that antidepressants may be effective. Two open-label studies reported that the selective serotonin reuptake inhibitor (SSRI) escitalopram may be effective for CG.^15,16 Although a post-hoc comparison of paroxetine and nortriptyline¹⁷ showed significant reduction in CG and depressive symptoms with both agents, effects could not be separated from concomitant psychotherapy. Furthermore, an examination of naturalistic data on combining antidepressants with CGT suggested that antidepressants may improve outcomes for individuals receiving CGT.¹⁸ A multicenter, randomized controlled trial funded by the National Institute of Mental Health is examining the potential efficacy of citalopram, an SSRI, alone or in combination with CGT.¹⁹

The efficacy of benzodiazepines, which commonly are prescribed for bereaved individuals, has not been assessed in CG. However, recent research suggests they may not be useful for medically managing recent grief²⁰ and that their use in the aftermath of a loss may lead to long-term dependence in geriatric patients.²¹

Related Resources

• Center for Anxiety and Traumatic Stress Disorders. Massachusetts General Hospital. www.bostongrief.com.
• Zisook S, Shear K. Grief and bereavement: what psychiatrists need to know. World Psychiatry. 2009;8(2):67-74.
• Bonanno G. The other side of sadness: what the new science of bereavement tells us about loss. New York, NY: Basic Books; 2009.

Drug Brand Names

• Citalopram • Celexa
• Nortriptyline • Aventyl, Pamelor
• Escitalopram • Lexapro
• Paroxetine • Paxil

Disclosures

Dr. Simon receives grant or research support from the American Cancer Society, the American Foundation for Suicide Prevention, the Department of Defense, Forest Laboratories, and the National Institute of Mental Health.

Nearly 2.5 million persons die each year in the United States.¹ For the bereaved, these deaths may be among the most painful and disruptive events they will experience. In this article, we evaluate the growing body of research on complicated grief (CG)—which also has been called prolonged grief, chronic grief, traumatic grief, and pathological grief—with an emphasis on how to identify CG and distinguish it from other adaptive and maladaptive reactions to the loss of a loved one. In addition, we review empirical evidence on treating CG, including psychotherapy, pharmacotherapy, and combined treatment approaches.

The bereavement-specific syndrome we refer to as CG currently is being reviewed for possible inclusion in DSM-5 as an official diagnosis. At press time, proposals for DSM-5 included a bereavement-related adjustment disorder within the new Trauma- and Stressor-Related Disorders category, as well as a provisional diagnosis of CG entitled Persistent Complex Bereavement-Related Disorder, which, upon acceptance, would be listed in Section III.²

What is ‘normal’ grief?

Grief is highly variable across individuals and time and may range from an absence of distress to severe and persistent pain and anguish. There’s no simple definition of “normal grief.” However, as clinicians, it’s necessary to understand the range of usual reactions. We recommend 2 considerations when evaluating grief reactions.

First, be aware that grief encompasses a range of cognitions, emotions, and behaviors. It may range from a relative lack of painful thoughts and emotions to intense and disruptive sadness, loneliness, anger, guilt, intrusive thoughts, difficulty concentrating, preoccupation with loss, social withdrawal, and a sense of being overwhelmed by the loss and its consequences. In the months after a loss, bereaved individuals may look for the deceased in a crowd, speak to them, or even experience auditory or visual hallucinations of the deceased. Nonetheless, positive feelings such as relief, peace, and happiness also are common following a loss.³ Moreover, laughter and smiling when discussing a lost loved one predicts reductions in grief symptoms over time.⁴ Overall, grief research suggests that, far from proceeding along standard and uniform stages,⁵ grief is complex and comprises a broad spectrum of thoughts, feelings, and behaviors that vary within and among individuals.

Second, note that in the absence of complications, grief progresses. For those who experience elevated levels of distress, the pain and disruption of loss initially may feel overwhelming but will subside in intensity over time for most individuals.⁵ This is not to say that an individual will never again feel sadness or longing for the deceased; elements of grief are likely to remain. Although the trajectory of grief symptoms varies among individuals and may progress in fits and starts, over time grief becomes more intermittent, less interfering, and is balanced with a sense of interest and purpose in life.

What is CG?

As research on grief experiences has grown, there’s increasing recognition that a minority of bereaved individuals experience more extreme grief symptoms that cause substantial, persistent distress and impairment despite the passage of many months or years. Shear et al⁶ proposed a set of CG diagnostic criteria (Table) in which a cluster of symptoms of intense and persistent separation distress are defined as core symptoms. Similar to other psychiatric diagnoses, the symptoms must be associated with significant distress or impairment.

Table

Proposed diagnostic criteria for complicated grief

Assessing CG symptoms

Among those with persistent elevated distress, a CG diagnosis must be considered in the context of the individual’s social and cultural environment, time since the loss, and duration of symptoms. The hallmark symptom of CG is separation distress with a focus of cognitive, behavioral, and emotional symptoms on the loss and its consequences. CG is associated with substantial distress, functional impairment, and an increased risk for suicide. See the Box for a case study.

Many individuals with CG remain undiagnosed and untreated for years despite high levels of distress and impairment and high risk for negative consequences such as suicide.⁷ Accordingly, there’s a need for greater CG screening. Clinically useful tools for assessing CG include a brief, 5-item dimensional screening assessment⁶ and the patient-rated Inventory of Complicated Grief.⁸

Distinguishing complicated and uncomplicated grief. Exhibiting CG symptoms in the first several months after a loss does not mean an individual has or will develop CG. Most bereaved adults report painful thoughts and emotions in the weeks and months following the loss, including distressed yearning, waves of intense grief, persistent and intrusive thoughts, images related to the death, somatic distress, and a feeling of being disconnected from others. For most individuals, the intensity of this response diminishes within 6 to 18 months after the loved one’s death.⁵ Although the optimal length of time to wait before establishing a diagnosis remains debatable, the earliest CG should be diagnosed is 6 months after a loss.

It’s common for grief to occasionally rise in intensity for days or weeks. This surge may occur many months or years after the loss, even in people who exhibited relatively little distress or impairment. In particular, anniversaries, holidays, or periods of stress may trigger increased grief intensity. However, these surges typically subside naturally within a short time. Accordingly, CG should be diagnosed only when symptoms persist for >1 month.

CG vs other post-loss disorders. CG, major depressive disorder (MDD), and posttraumatic stress disorder (PTSD) often are comorbid in bereaved adults. Simon et al⁹ found 72% of CG patients in a treatment- seeking sample reported a lifetime history of MDD and 53% reported a lifetime history of PTSD. However, CG can be distinguished from these disorders. In the same study, 25% of CG patients had no other axis I diagnosis.⁹ After accounting for comorbid disorders, researchers associated CG severity with work and social impairment. These findings provide clear evidence for the incremental validity of CG—ie, a CG diagnosis gives clinicians additional information that predicts impairment above and beyond other disorders. However, future research needs to further examine CG and its overlap and differentiation from MDD and PTSD.

Distinguishing CG and MDD. Intense yearning or preoccupation with the deceased is a common symptom of CG but not MDD. In addition, CG symptoms possess intentionality. For example, emotional distress such as sadness and anger are prominent features of both CG and MDD. However, in CG, these symptoms are specific to the loss or circumstances of the loss, whereas in MDD they generally are more nebulous and generalized. Similarly, CG entails proximity seeking related to the deceased, and avoidance of reminders of the deceased, whereas MDD includes a more general social withdrawal and anhedonia.

Distinguishing CG and PTSD. CG and loss-related PTSD are distinguished by the predominant emotions and focus of concern associated with each disorder. The predominant emotion in PTSD is fear, whereas in CG it is sadness and longing. In PTSD, intrusive thoughts and memories associated with the trauma generally are associated with the event itself and produce an ongoing sense of threat.¹⁰ Avoidance in PTSD is intended to reduce this threat feeling. By contrast, in CG, intrusive memories focus on the deceased or the circumstances of the death, and avoidance is aimed at preventing painful reminders of the loss or its permanence. Importantly, both syndromes may be present.

Box

Treating CG

When is treatment indicated? For years, bereavement theorists emphasized the need to work through emotions and memories related to the deceased with particular focus on negative material. However, evidence suggests that universal application of treatment to all bereaved individuals is unhelpful. In a recent meta-analysis, Neimeyer et al¹¹ found that the outcomes of grief therapy applied indiscriminately to all bereaved adults or all members of high-risk populations—such as parents whose child experienced a violent death—were no better than would be expected by the passage of time. In contrast, grief therapy applied only to those who develop elevated and persistent distress (eg, CG) led to greater and more enduring improvement in post-loss distress than was observed in control conditions.

These results suggest that most grieving individuals who do not meet criteria for CG (or other psychiatric disorders) will not require intervention. Those who do seek treatment for grief-related distress in the acute grief period should be assessed for bereavement-related depression, anxiety, and suicidality, and treated or referred to professional or community-based resources for support or counseling as clinically indicated.

Evidence for psychotherapy. For those who meet CG criteria, psychotherapy targeting the specific symptoms of CG is helpful. The evidence is strongest for CG treatment (CGT), a 16-session, manualized psychotherapy developed by M. Katherine Shear, MD.¹² CGT is based on an attachment model and cognitive-behavioral therapy (CBT) principles, and is informed by the dual-process theory proposed by Stroebe et al.¹³ According to this theory, natural healing following loss comprises 2 processes:

• a loss-oriented process in which the patient comes to terms with the loss, and
• a restoration-oriented process in which the patient reinvigorates a sense of purpose and meaning in life without the deceased.

CGT focuses on both processes. To address the former, it includes clinician-guided exercises in which the patient revisits the time of the death and planned activities in which the patient reengages with people, places, or thoughts that remind him or her of the deceased. CGT aims to allow the patient to gain an increased tolerance of the distressing thoughts and emotions associated with the loss so that these thoughts can be processed and the finality of the death and its circumstances can be accepted.

The restoration process is addressed by having patients generate and discuss personal goals and aspirations for the near and distant future, as well as scheduling pleasurable and rewarding events. This is accomplished by having patients imagine what they would want for themselves if their grief was less intense and planning concrete steps to take toward these goals. The restoration-oriented process is addressed concurrent with the loss-oriented process to encourage the oscillation between processes thought to be characteristic of a natural healing process following the loss of a loved one.

Other psychotherapy approaches (eg, support groups) may have a role for some individuals, and future research may suggest alternative approaches to CGT. To date, CGT is the most targeted evidence-based psychotherapy with randomized controlled data supporting its use in CG.

Pharmacotherapy for CG. Early research suggested that antidepressants—in particular tricyclics—may effectively reduce depressive symptoms in bereavement-related depression; their effect on CG symptoms, however, may not be as strong.¹⁴ Research on pharmacologic treatment that targets CG symptoms is developing. Because of the overlap between CG, PTSD, and MDD, researchers have hypothesized that antidepressants may be effective. Two open-label studies reported that the selective serotonin reuptake inhibitor (SSRI) escitalopram may be effective for CG.^15,16 Although a post-hoc comparison of paroxetine and nortriptyline¹⁷ showed significant reduction in CG and depressive symptoms with both agents, effects could not be separated from concomitant psychotherapy. Furthermore, an examination of naturalistic data on combining antidepressants with CGT suggested that antidepressants may improve outcomes for individuals receiving CGT.¹⁸ A multicenter, randomized controlled trial funded by the National Institute of Mental Health is examining the potential efficacy of citalopram, an SSRI, alone or in combination with CGT.¹⁹

The efficacy of benzodiazepines, which commonly are prescribed for bereaved individuals, has not been assessed in CG. However, recent research suggests they may not be useful for medically managing recent grief²⁰ and that their use in the aftermath of a loss may lead to long-term dependence in geriatric patients.²¹

Related Resources

• Center for Anxiety and Traumatic Stress Disorders. Massachusetts General Hospital. www.bostongrief.com.
• Zisook S, Shear K. Grief and bereavement: what psychiatrists need to know. World Psychiatry. 2009;8(2):67-74.
• Bonanno G. The other side of sadness: what the new science of bereavement tells us about loss. New York, NY: Basic Books; 2009.

Drug Brand Names

• Citalopram • Celexa
• Nortriptyline • Aventyl, Pamelor
• Escitalopram • Lexapro
• Paroxetine • Paxil

Disclosures

Dr. Simon receives grant or research support from the American Cancer Society, the American Foundation for Suicide Prevention, the Department of Defense, Forest Laboratories, and the National Institute of Mental Health.

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You’ve been treating Mr. H, a 54-year-old factory worker and tobacco user, for depression that developed after a work-related back injury and subsequent disability. His depression has had a fair response to an antidepressant. He also has been maintained on chronic opioids (morphine and oxycodone/acetaminophen) for 18 months by his primary care physician (PCP). At the end of your appointment, he asks you for a refill of the opioids because he “ran out” early because of increased night pain and resultant insomnia and “stress.” He clarifies he has asked for early refills before from his PCP, but lately he has been denied. Because you “seem to listen to me more,” he asks for your help. How should you manage Mr. H?

Opioids are among the most commonly misused prescription drugs in the United States.¹ In 2008, poisoning was the leading cause of death from injury in the United States; roughly 90% of poisonings resulted from drug exposure, and >40% of these drug poisonings were from prescription opioids.² The Centers for Disease Control and Prevention estimates that the number of emergency department (ED) visits for nonmedical use of opioids increased 111% between 2004 and 2008, from 144,600 to 305,900 visits.³ The highest number of visits were for use of oxycodone, hydrocodone, and methadone.³

Increased prescribing of opioids and overdose deaths attributable to prescribed opioids have raised concern among physicians about how to effectively treat pain as well as prevent, recognize, and manage aberrant medication-taking behaviors (AMTBs). Psychiatrists are well-positioned to screen and manage their own patients for prescription opioid use disorder (POUD) or collaborate with opioid prescribers to accomplish the same.

Clarifying terminology

Terminology used to describe POUD and related conditions often is poorly defined or loosely applied. Because emotions often enter discussions between patients and physicians about problems related to opioid therapy, nonstigmatizing and more objective terminology is needed, and clinicians are working toward standardizing this. Relevant terms are defined in Table 1.⁴

The DSM-5 Substance Use Disorders Work Group has proposed using the term opioid use disorder (OUD) to replace the term opioid dependence.⁵ The hope is that removing the word “dependence” from the diagnostic term will reduce confusion between “dependence” due to expected physical dependence (tolerance, withdrawal) on medically prescribed opioids vs true addiction (currently defined as “opioid dependence” in DSM-IV-TR). This Work Group also has proposed combining opioid abuse and opioid dependence criteria into a single diagnosis of OUD, and adding “craving” to the criteria. For the complete proposed criteria, see www.dsm5.org/ProposedRevisions/Pages/proposedrevision.aspx?rid=460.These changes are still under review. In this article, we use the term POUD.

Table 1

Terminology related to prescription opioid use disorder

POUD and chronic pain

The incidence of POUD during opioid therapy for pain is unknown.⁶ Some researchers have suggested it may be as low as 0.2%,⁷ while others estimate that rates of POUD in patients with chronic pain may be similar to those in the general population: 3% to 16%.⁸ When applying the proposed DSM-5 criteria to patients receiving long-term opioid therapy for noncancer pain, the lifetime prevalence of POUD may be as high as 35%.⁹

Prescribers may be contributing to POUD. Roughly 76% of opioids used for nonmedical purposes were prescribed to someone else, 20% were prescribed to the user, and 4% came from other sources.¹ Strategies to reduce POUD risk may be underused. In a retrospective cohort study of 1,612 patient electronic medical records from 8 primary care clinics that managed patients with long-term opioids for chronic noncancer pain (average prescribing duration of 2 years duration, ≥3 monthly prescriptions in 6 months), researchers evaluated how often prescribers used 3 risk reduction practices:

• urine drug tests
• regular office visits (≥1 every 6 months and within 30 days of changing opioid treatment)
• restricted early refills (≤1 opioid refill more than a week early).¹⁰

Risk factors for opioid misuse included age 1 early refill. Researchers found that even for high-risk patients, these strategies were used infrequently. Less than one-quarter of patients with ≥3 risk factors ever had a drug test, and those at increased risk were more likely to receive >1 early refill but no more likely to have more frequent visits. Issues such as patient entitlement, lack of physician education, and time constraints may explain why these strategies are not used more often.¹¹

No one procedure or set of variables is sufficient to identify chronic pain patients who may be at risk for POUD. However, a history of drug or alcohol use disorders may be a significant risk factor.^12,13

Few tools have been developed to help identify those at risk of AMTBs or POUD, and all have limitations.^4,14 Recommended self-report measures include the Current Opioid Misuse Measure and the Opioid Risk Tool.¹⁵ A review of studies in which these kinds of tools were developed revealed limited evidence for their use; most studies had methodological shortcomings, did not use standardized AMTB criteria, and provided little assessment of whether these tools changed clinician behaviors or improved patient outcomes.¹⁶

Evaluating AMTBs

Although diagnosing POUD in pain patients receiving chronic opioids can be challenging, assessing for AMTBs typically is helpful. Once AMTBs are identified, they can be examined to determine what drives their expression (Table 1⁴ and Table 2¹⁷). However, often it is easier to identify AMTBs than to interpret their origins; as much as 30% to 50% of patients who complain of chronic pain may have primary substance dependence to sedatives, opioids, or both.¹¹

Table 2

Aberrant medication-taking behaviors and POUD risk

Although AMTBs are common among chronic nonmalignant pain patients,^18,19 how often AMTBs reflect underlying POUD is uncertain.⁷ It is critical to interpret AMTBs with a balance of caution and care: “react therapeutically, not punitively.”²⁰ Categorizing a patient’s AMTB as more or less likely to support a POUD diagnosis can be helpful, but is not conclusive (Table 2).¹⁷ Clinical correlation often is required. No single AMTB alone is indicative of POUD. When evaluating AMTBs, the treating provider should use a nonjudgmental stance, and consider obtaining collateral data from people who can provide differing perspectives of the patient’s behaviors, such as other clinicians, significant others, family, etc. (a release of information from the patient may be required). Another source of collateral data is prescription monitoring databases. These databases typically are state-based and provide electronic access to prescription information, allowing you to search for patterns—ie, use of multiple prescribers or pharmacies, undisclosed prescriptions, etc. Interest in establishing a single, federal database has been increasing, but striking a balance between carefully monitoring for AMTBs and protecting privacy remains unresolved.

DSM-IV-TR diagnostic criteria for opioid dependence²¹ can be challenging to interpret in patients who are prescribed opioids for pain (Table 3

Assessment is primarily clinical and requires an awareness of appropriate terminology, an index of clinical suspicion, and expertise teasing apart pain, addiction, and pseudoaddiction. In our experience, it is helpful to ask a chronic pain patient whom you suspect might have POUD, “Have you ever used your prescribed opioids for reasons other than improving function or reducing pain, such as for getting a ‘high,’ managing stress, escaping from problems, etc.?” An affirmative response suggests an underlying problem with use of prescribed opioids, indicating a need for more careful questioning to determine if AMTBs or POUD coexist with chronic pain.

Drug testing can help determine if a patient is taking opioids that are not prescribed—as well as illicit drugs or alcohol—and confirm the presence of those that are prescribed. Toxicology screening should include opioids typically screened for (eg, morphine, codeine, heroin) and those for which additional tests may be required (eg, semi-synthetics such as oxycodone and hydrocodone and synthetics such as fentanyl).

Table 3

Identifying addiction in pain patients: Limitations of DSM-IV-TR

Table 4

Possible indicators of addiction in pain patients

Helping POUD patients

Goals of treatment include establishing a therapeutic alliance, educating patients about POUD, reducing relapse risk, and optimizing overall health (including pain and physical function). The ASAM Patient Placement Criteria²² provide guidance regarding level-of-care decisions. Treatment ideally includes a combination of education about POUD and its relationship to chronic pain, pharmacotherapy, psychotherapy—such as motivational enhancement therapy, 12-step facilitation therapy, cognitive-behavioral therapy, and relapse prevention—and referral to self-help groups such as Narcotics Anonymous or Pills Anonymous. Importantly, if pain is genuine, it requires treatment.

Pharmacotherapy. Methadone is recommended as the standard of care for OUD by the National Institutes of Health. Methadone is a full opioid agonist that decreases illicit opioid use, mortality, and related problems and requires highly structured treatment approaches under federal and state regulation. POUD patients may have higher rates of methadone maintenance treatment retention than heroin-dependent patients.²³ Published trials of buprenorphine for OUD have shown good treatment retention and reduction in illicit drug use and adverse events.²⁴ Buprenorphine also decreases mortality among OUD patients.

The first large-scale, randomized clinical trial of buprenorphine specifically for POUD included 653 treatment-seeking outpatients.²⁵ This study was designed to approximate clinical practice and included buprenorphine/naloxone, recommended abstinence, and self-help; one-half of participants received intensive addiction counseling. POUD patients were most likely to reduce prescription opioid misuse during buprenorphine/naloxone treatment. If tapered off buprenorphine/naloxone, even after 12 weeks of treatment, the likelihood of an unsuccessful outcome was high. Moreover, opioid dependence counseling did not seem to afford any difference in outcomes. However, despite clinical effectiveness, over the last decade only 19% of patients admitted primarily for OUD treatment (other than heroin) were planned to be offered buprenorphine or methadone.²⁶

A Cochrane review of oral naltrexone for OUD found that the drug was no better than placebo but concluded that available evidence does not allow an adequate evaluation.²⁷ Opioid antagonists may be of value to patients who do not want to take agonists or partial agonists. Extended-release naltrexone also is available to treat OUD.

See the Box below that details steps the FDA and others have taken to prevent POUD and Table 5 for precautions to incorporate when prescribing opioids long-term.

Box

Table 5

Universal precautions with chronic opioid management

CASE CONTINUED: A closer evaluation

After expressing your appreciation for Mr. H’s kind words and empathy for his chronic pain, you redirect him to his PCP. You ask him to sign a release of information so you and his other clinicians can coordinate his care. When discussing Mr. H with his PCP, you learn the patient has made limited requests for early refills and dose escalation primarily in relation to inadequate pain control and function, has genuine pain pathology, and is greatly distressed over his inability to work. No other AMTBs are present, and a check of the state prescribing database reveals that Mr. H did receive a small quantity of opioids from an ED on 1 occasion.

You and Mr. H’s PCP agree this is “pseudo-addiction” but want to watch Mr. H more closely and look for ways to coordinate his care. The PCP agrees to implement a prescribing agreement, start drug testing (including for the prescribed opioids), and reassess maximizing Mr. H’s function and pain management while you address his combined pain, depression, insomnia, and tobacco use.

Related Resources

• Ries RK, Fiellin D, Miller SC, et al, eds. Principles of addiction medicine. 4th ed. Hagerstown, MD: Lippincott Williams & Wilkins; 2009.
• Department of Veterans Affairs. Department of Defense. VA/DoD clinical practice guideline for management of opioid therapy for chronic pain. Appendix C: sample opioid pain care agreement. http://www.healthquality.va.gov/COT_312_Full-er.pdf. Published May 2010. Accessed June 21, 2012.
• Weaver M, Schnoll S. Addiction issues in prescribing opioids for chronic non-malignant pain. J Addiction Med. 2007;1(1):2-10.
• Weaver M, Heit HA, Savage S, et al. Clinical case discussion: chronic pain management. J Addiction Med. 2007;1(1):11-14.

Drug Brand Names

• Buprenorphine • Subutex
• Buprenorphine/naloxone • Suboxone
• Codeine • Tylenol with codeine, others
• Fentanyl • Duragesic, Actiq
• Hydrocodone • Lortab, Vicodin, others
• Methadone • Dolophine, Methadose
• Morphine • Roxanol
• Naltrexone extended-release • Vivitrol
• Oxycodone • OxyContin, Roxicodone

Disclosures

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

Dr. Frankowski’s time toward this project was provided by the American Board of Addiction Medicine-accredited Cincinnati VA Addiction Medicine Research Fellowship, affiliated with the CeTREAD, Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati, Cincinnati, OH.

The statements in this publication do not necessarily reflect the views or opinions of the Department of Veterans Affairs.

Acknowledgement

The authors thank Catherine Constance and Sandra Mason at the Cincinnati VA Medical Center for their administrative assistance.

Discuss this article at www.facebook.com/CurrentPsychiatry

You’ve been treating Mr. H, a 54-year-old factory worker and tobacco user, for depression that developed after a work-related back injury and subsequent disability. His depression has had a fair response to an antidepressant. He also has been maintained on chronic opioids (morphine and oxycodone/acetaminophen) for 18 months by his primary care physician (PCP). At the end of your appointment, he asks you for a refill of the opioids because he “ran out” early because of increased night pain and resultant insomnia and “stress.” He clarifies he has asked for early refills before from his PCP, but lately he has been denied. Because you “seem to listen to me more,” he asks for your help. How should you manage Mr. H?

Opioids are among the most commonly misused prescription drugs in the United States.¹ In 2008, poisoning was the leading cause of death from injury in the United States; roughly 90% of poisonings resulted from drug exposure, and >40% of these drug poisonings were from prescription opioids.² The Centers for Disease Control and Prevention estimates that the number of emergency department (ED) visits for nonmedical use of opioids increased 111% between 2004 and 2008, from 144,600 to 305,900 visits.³ The highest number of visits were for use of oxycodone, hydrocodone, and methadone.³

Increased prescribing of opioids and overdose deaths attributable to prescribed opioids have raised concern among physicians about how to effectively treat pain as well as prevent, recognize, and manage aberrant medication-taking behaviors (AMTBs). Psychiatrists are well-positioned to screen and manage their own patients for prescription opioid use disorder (POUD) or collaborate with opioid prescribers to accomplish the same.

Clarifying terminology

Terminology used to describe POUD and related conditions often is poorly defined or loosely applied. Because emotions often enter discussions between patients and physicians about problems related to opioid therapy, nonstigmatizing and more objective terminology is needed, and clinicians are working toward standardizing this. Relevant terms are defined in Table 1.⁴

The DSM-5 Substance Use Disorders Work Group has proposed using the term opioid use disorder (OUD) to replace the term opioid dependence.⁵ The hope is that removing the word “dependence” from the diagnostic term will reduce confusion between “dependence” due to expected physical dependence (tolerance, withdrawal) on medically prescribed opioids vs true addiction (currently defined as “opioid dependence” in DSM-IV-TR). This Work Group also has proposed combining opioid abuse and opioid dependence criteria into a single diagnosis of OUD, and adding “craving” to the criteria. For the complete proposed criteria, see www.dsm5.org/ProposedRevisions/Pages/proposedrevision.aspx?rid=460.These changes are still under review. In this article, we use the term POUD.

Table 1

Terminology related to prescription opioid use disorder

POUD and chronic pain

The incidence of POUD during opioid therapy for pain is unknown.⁶ Some researchers have suggested it may be as low as 0.2%,⁷ while others estimate that rates of POUD in patients with chronic pain may be similar to those in the general population: 3% to 16%.⁸ When applying the proposed DSM-5 criteria to patients receiving long-term opioid therapy for noncancer pain, the lifetime prevalence of POUD may be as high as 35%.⁹

Prescribers may be contributing to POUD. Roughly 76% of opioids used for nonmedical purposes were prescribed to someone else, 20% were prescribed to the user, and 4% came from other sources.¹ Strategies to reduce POUD risk may be underused. In a retrospective cohort study of 1,612 patient electronic medical records from 8 primary care clinics that managed patients with long-term opioids for chronic noncancer pain (average prescribing duration of 2 years duration, ≥3 monthly prescriptions in 6 months), researchers evaluated how often prescribers used 3 risk reduction practices:

• urine drug tests
• regular office visits (≥1 every 6 months and within 30 days of changing opioid treatment)
• restricted early refills (≤1 opioid refill more than a week early).¹⁰

Risk factors for opioid misuse included age 1 early refill. Researchers found that even for high-risk patients, these strategies were used infrequently. Less than one-quarter of patients with ≥3 risk factors ever had a drug test, and those at increased risk were more likely to receive >1 early refill but no more likely to have more frequent visits. Issues such as patient entitlement, lack of physician education, and time constraints may explain why these strategies are not used more often.¹¹

No one procedure or set of variables is sufficient to identify chronic pain patients who may be at risk for POUD. However, a history of drug or alcohol use disorders may be a significant risk factor.^12,13

Few tools have been developed to help identify those at risk of AMTBs or POUD, and all have limitations.^4,14 Recommended self-report measures include the Current Opioid Misuse Measure and the Opioid Risk Tool.¹⁵ A review of studies in which these kinds of tools were developed revealed limited evidence for their use; most studies had methodological shortcomings, did not use standardized AMTB criteria, and provided little assessment of whether these tools changed clinician behaviors or improved patient outcomes.¹⁶

Evaluating AMTBs

Although diagnosing POUD in pain patients receiving chronic opioids can be challenging, assessing for AMTBs typically is helpful. Once AMTBs are identified, they can be examined to determine what drives their expression (Table 1⁴ and Table 2¹⁷). However, often it is easier to identify AMTBs than to interpret their origins; as much as 30% to 50% of patients who complain of chronic pain may have primary substance dependence to sedatives, opioids, or both.¹¹

Table 2

Aberrant medication-taking behaviors and POUD risk

Although AMTBs are common among chronic nonmalignant pain patients,^18,19 how often AMTBs reflect underlying POUD is uncertain.⁷ It is critical to interpret AMTBs with a balance of caution and care: “react therapeutically, not punitively.”²⁰ Categorizing a patient’s AMTB as more or less likely to support a POUD diagnosis can be helpful, but is not conclusive (Table 2).¹⁷ Clinical correlation often is required. No single AMTB alone is indicative of POUD. When evaluating AMTBs, the treating provider should use a nonjudgmental stance, and consider obtaining collateral data from people who can provide differing perspectives of the patient’s behaviors, such as other clinicians, significant others, family, etc. (a release of information from the patient may be required). Another source of collateral data is prescription monitoring databases. These databases typically are state-based and provide electronic access to prescription information, allowing you to search for patterns—ie, use of multiple prescribers or pharmacies, undisclosed prescriptions, etc. Interest in establishing a single, federal database has been increasing, but striking a balance between carefully monitoring for AMTBs and protecting privacy remains unresolved.

DSM-IV-TR diagnostic criteria for opioid dependence²¹ can be challenging to interpret in patients who are prescribed opioids for pain (Table 3

Assessment is primarily clinical and requires an awareness of appropriate terminology, an index of clinical suspicion, and expertise teasing apart pain, addiction, and pseudoaddiction. In our experience, it is helpful to ask a chronic pain patient whom you suspect might have POUD, “Have you ever used your prescribed opioids for reasons other than improving function or reducing pain, such as for getting a ‘high,’ managing stress, escaping from problems, etc.?” An affirmative response suggests an underlying problem with use of prescribed opioids, indicating a need for more careful questioning to determine if AMTBs or POUD coexist with chronic pain.

Drug testing can help determine if a patient is taking opioids that are not prescribed—as well as illicit drugs or alcohol—and confirm the presence of those that are prescribed. Toxicology screening should include opioids typically screened for (eg, morphine, codeine, heroin) and those for which additional tests may be required (eg, semi-synthetics such as oxycodone and hydrocodone and synthetics such as fentanyl).

Table 3

Identifying addiction in pain patients: Limitations of DSM-IV-TR

Table 4

Possible indicators of addiction in pain patients

Helping POUD patients

Goals of treatment include establishing a therapeutic alliance, educating patients about POUD, reducing relapse risk, and optimizing overall health (including pain and physical function). The ASAM Patient Placement Criteria²² provide guidance regarding level-of-care decisions. Treatment ideally includes a combination of education about POUD and its relationship to chronic pain, pharmacotherapy, psychotherapy—such as motivational enhancement therapy, 12-step facilitation therapy, cognitive-behavioral therapy, and relapse prevention—and referral to self-help groups such as Narcotics Anonymous or Pills Anonymous. Importantly, if pain is genuine, it requires treatment.

Pharmacotherapy. Methadone is recommended as the standard of care for OUD by the National Institutes of Health. Methadone is a full opioid agonist that decreases illicit opioid use, mortality, and related problems and requires highly structured treatment approaches under federal and state regulation. POUD patients may have higher rates of methadone maintenance treatment retention than heroin-dependent patients.²³ Published trials of buprenorphine for OUD have shown good treatment retention and reduction in illicit drug use and adverse events.²⁴ Buprenorphine also decreases mortality among OUD patients.

The first large-scale, randomized clinical trial of buprenorphine specifically for POUD included 653 treatment-seeking outpatients.²⁵ This study was designed to approximate clinical practice and included buprenorphine/naloxone, recommended abstinence, and self-help; one-half of participants received intensive addiction counseling. POUD patients were most likely to reduce prescription opioid misuse during buprenorphine/naloxone treatment. If tapered off buprenorphine/naloxone, even after 12 weeks of treatment, the likelihood of an unsuccessful outcome was high. Moreover, opioid dependence counseling did not seem to afford any difference in outcomes. However, despite clinical effectiveness, over the last decade only 19% of patients admitted primarily for OUD treatment (other than heroin) were planned to be offered buprenorphine or methadone.²⁶

A Cochrane review of oral naltrexone for OUD found that the drug was no better than placebo but concluded that available evidence does not allow an adequate evaluation.²⁷ Opioid antagonists may be of value to patients who do not want to take agonists or partial agonists. Extended-release naltrexone also is available to treat OUD.

See the Box below that details steps the FDA and others have taken to prevent POUD and Table 5 for precautions to incorporate when prescribing opioids long-term.

Box

Table 5

Universal precautions with chronic opioid management

CASE CONTINUED: A closer evaluation

After expressing your appreciation for Mr. H’s kind words and empathy for his chronic pain, you redirect him to his PCP. You ask him to sign a release of information so you and his other clinicians can coordinate his care. When discussing Mr. H with his PCP, you learn the patient has made limited requests for early refills and dose escalation primarily in relation to inadequate pain control and function, has genuine pain pathology, and is greatly distressed over his inability to work. No other AMTBs are present, and a check of the state prescribing database reveals that Mr. H did receive a small quantity of opioids from an ED on 1 occasion.

You and Mr. H’s PCP agree this is “pseudo-addiction” but want to watch Mr. H more closely and look for ways to coordinate his care. The PCP agrees to implement a prescribing agreement, start drug testing (including for the prescribed opioids), and reassess maximizing Mr. H’s function and pain management while you address his combined pain, depression, insomnia, and tobacco use.

Related Resources

• Ries RK, Fiellin D, Miller SC, et al, eds. Principles of addiction medicine. 4th ed. Hagerstown, MD: Lippincott Williams & Wilkins; 2009.
• Department of Veterans Affairs. Department of Defense. VA/DoD clinical practice guideline for management of opioid therapy for chronic pain. Appendix C: sample opioid pain care agreement. http://www.healthquality.va.gov/COT_312_Full-er.pdf. Published May 2010. Accessed June 21, 2012.
• Weaver M, Schnoll S. Addiction issues in prescribing opioids for chronic non-malignant pain. J Addiction Med. 2007;1(1):2-10.
• Weaver M, Heit HA, Savage S, et al. Clinical case discussion: chronic pain management. J Addiction Med. 2007;1(1):11-14.

Drug Brand Names

• Buprenorphine • Subutex
• Buprenorphine/naloxone • Suboxone
• Codeine • Tylenol with codeine, others
• Fentanyl • Duragesic, Actiq
• Hydrocodone • Lortab, Vicodin, others
• Methadone • Dolophine, Methadose
• Morphine • Roxanol
• Naltrexone extended-release • Vivitrol
• Oxycodone • OxyContin, Roxicodone

Disclosures

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

Dr. Frankowski’s time toward this project was provided by the American Board of Addiction Medicine-accredited Cincinnati VA Addiction Medicine Research Fellowship, affiliated with the CeTREAD, Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati, Cincinnati, OH.

The statements in this publication do not necessarily reflect the views or opinions of the Department of Veterans Affairs.

Acknowledgement

The authors thank Catherine Constance and Sandra Mason at the Cincinnati VA Medical Center for their administrative assistance.

Discuss this article at www.facebook.com/CurrentPsychiatry

You’ve been treating Mr. H, a 54-year-old factory worker and tobacco user, for depression that developed after a work-related back injury and subsequent disability. His depression has had a fair response to an antidepressant. He also has been maintained on chronic opioids (morphine and oxycodone/acetaminophen) for 18 months by his primary care physician (PCP). At the end of your appointment, he asks you for a refill of the opioids because he “ran out” early because of increased night pain and resultant insomnia and “stress.” He clarifies he has asked for early refills before from his PCP, but lately he has been denied. Because you “seem to listen to me more,” he asks for your help. How should you manage Mr. H?

Opioids are among the most commonly misused prescription drugs in the United States.¹ In 2008, poisoning was the leading cause of death from injury in the United States; roughly 90% of poisonings resulted from drug exposure, and >40% of these drug poisonings were from prescription opioids.² The Centers for Disease Control and Prevention estimates that the number of emergency department (ED) visits for nonmedical use of opioids increased 111% between 2004 and 2008, from 144,600 to 305,900 visits.³ The highest number of visits were for use of oxycodone, hydrocodone, and methadone.³

Increased prescribing of opioids and overdose deaths attributable to prescribed opioids have raised concern among physicians about how to effectively treat pain as well as prevent, recognize, and manage aberrant medication-taking behaviors (AMTBs). Psychiatrists are well-positioned to screen and manage their own patients for prescription opioid use disorder (POUD) or collaborate with opioid prescribers to accomplish the same.

Clarifying terminology

Terminology used to describe POUD and related conditions often is poorly defined or loosely applied. Because emotions often enter discussions between patients and physicians about problems related to opioid therapy, nonstigmatizing and more objective terminology is needed, and clinicians are working toward standardizing this. Relevant terms are defined in Table 1.⁴

The DSM-5 Substance Use Disorders Work Group has proposed using the term opioid use disorder (OUD) to replace the term opioid dependence.⁵ The hope is that removing the word “dependence” from the diagnostic term will reduce confusion between “dependence” due to expected physical dependence (tolerance, withdrawal) on medically prescribed opioids vs true addiction (currently defined as “opioid dependence” in DSM-IV-TR). This Work Group also has proposed combining opioid abuse and opioid dependence criteria into a single diagnosis of OUD, and adding “craving” to the criteria. For the complete proposed criteria, see www.dsm5.org/ProposedRevisions/Pages/proposedrevision.aspx?rid=460.These changes are still under review. In this article, we use the term POUD.

Table 1

Terminology related to prescription opioid use disorder

POUD and chronic pain

The incidence of POUD during opioid therapy for pain is unknown.⁶ Some researchers have suggested it may be as low as 0.2%,⁷ while others estimate that rates of POUD in patients with chronic pain may be similar to those in the general population: 3% to 16%.⁸ When applying the proposed DSM-5 criteria to patients receiving long-term opioid therapy for noncancer pain, the lifetime prevalence of POUD may be as high as 35%.⁹

Prescribers may be contributing to POUD. Roughly 76% of opioids used for nonmedical purposes were prescribed to someone else, 20% were prescribed to the user, and 4% came from other sources.¹ Strategies to reduce POUD risk may be underused. In a retrospective cohort study of 1,612 patient electronic medical records from 8 primary care clinics that managed patients with long-term opioids for chronic noncancer pain (average prescribing duration of 2 years duration, ≥3 monthly prescriptions in 6 months), researchers evaluated how often prescribers used 3 risk reduction practices:

• urine drug tests
• regular office visits (≥1 every 6 months and within 30 days of changing opioid treatment)
• restricted early refills (≤1 opioid refill more than a week early).¹⁰

Risk factors for opioid misuse included age 1 early refill. Researchers found that even for high-risk patients, these strategies were used infrequently. Less than one-quarter of patients with ≥3 risk factors ever had a drug test, and those at increased risk were more likely to receive >1 early refill but no more likely to have more frequent visits. Issues such as patient entitlement, lack of physician education, and time constraints may explain why these strategies are not used more often.¹¹

No one procedure or set of variables is sufficient to identify chronic pain patients who may be at risk for POUD. However, a history of drug or alcohol use disorders may be a significant risk factor.^12,13

Few tools have been developed to help identify those at risk of AMTBs or POUD, and all have limitations.^4,14 Recommended self-report measures include the Current Opioid Misuse Measure and the Opioid Risk Tool.¹⁵ A review of studies in which these kinds of tools were developed revealed limited evidence for their use; most studies had methodological shortcomings, did not use standardized AMTB criteria, and provided little assessment of whether these tools changed clinician behaviors or improved patient outcomes.¹⁶

Evaluating AMTBs

Although diagnosing POUD in pain patients receiving chronic opioids can be challenging, assessing for AMTBs typically is helpful. Once AMTBs are identified, they can be examined to determine what drives their expression (Table 1⁴ and Table 2¹⁷). However, often it is easier to identify AMTBs than to interpret their origins; as much as 30% to 50% of patients who complain of chronic pain may have primary substance dependence to sedatives, opioids, or both.¹¹

Table 2

Aberrant medication-taking behaviors and POUD risk

Although AMTBs are common among chronic nonmalignant pain patients,^18,19 how often AMTBs reflect underlying POUD is uncertain.⁷ It is critical to interpret AMTBs with a balance of caution and care: “react therapeutically, not punitively.”²⁰ Categorizing a patient’s AMTB as more or less likely to support a POUD diagnosis can be helpful, but is not conclusive (Table 2).¹⁷ Clinical correlation often is required. No single AMTB alone is indicative of POUD. When evaluating AMTBs, the treating provider should use a nonjudgmental stance, and consider obtaining collateral data from people who can provide differing perspectives of the patient’s behaviors, such as other clinicians, significant others, family, etc. (a release of information from the patient may be required). Another source of collateral data is prescription monitoring databases. These databases typically are state-based and provide electronic access to prescription information, allowing you to search for patterns—ie, use of multiple prescribers or pharmacies, undisclosed prescriptions, etc. Interest in establishing a single, federal database has been increasing, but striking a balance between carefully monitoring for AMTBs and protecting privacy remains unresolved.

DSM-IV-TR diagnostic criteria for opioid dependence²¹ can be challenging to interpret in patients who are prescribed opioids for pain (Table 3

Assessment is primarily clinical and requires an awareness of appropriate terminology, an index of clinical suspicion, and expertise teasing apart pain, addiction, and pseudoaddiction. In our experience, it is helpful to ask a chronic pain patient whom you suspect might have POUD, “Have you ever used your prescribed opioids for reasons other than improving function or reducing pain, such as for getting a ‘high,’ managing stress, escaping from problems, etc.?” An affirmative response suggests an underlying problem with use of prescribed opioids, indicating a need for more careful questioning to determine if AMTBs or POUD coexist with chronic pain.

Drug testing can help determine if a patient is taking opioids that are not prescribed—as well as illicit drugs or alcohol—and confirm the presence of those that are prescribed. Toxicology screening should include opioids typically screened for (eg, morphine, codeine, heroin) and those for which additional tests may be required (eg, semi-synthetics such as oxycodone and hydrocodone and synthetics such as fentanyl).

Table 3

Identifying addiction in pain patients: Limitations of DSM-IV-TR

Table 4

Possible indicators of addiction in pain patients

Helping POUD patients

Goals of treatment include establishing a therapeutic alliance, educating patients about POUD, reducing relapse risk, and optimizing overall health (including pain and physical function). The ASAM Patient Placement Criteria²² provide guidance regarding level-of-care decisions. Treatment ideally includes a combination of education about POUD and its relationship to chronic pain, pharmacotherapy, psychotherapy—such as motivational enhancement therapy, 12-step facilitation therapy, cognitive-behavioral therapy, and relapse prevention—and referral to self-help groups such as Narcotics Anonymous or Pills Anonymous. Importantly, if pain is genuine, it requires treatment.

Pharmacotherapy. Methadone is recommended as the standard of care for OUD by the National Institutes of Health. Methadone is a full opioid agonist that decreases illicit opioid use, mortality, and related problems and requires highly structured treatment approaches under federal and state regulation. POUD patients may have higher rates of methadone maintenance treatment retention than heroin-dependent patients.²³ Published trials of buprenorphine for OUD have shown good treatment retention and reduction in illicit drug use and adverse events.²⁴ Buprenorphine also decreases mortality among OUD patients.

The first large-scale, randomized clinical trial of buprenorphine specifically for POUD included 653 treatment-seeking outpatients.²⁵ This study was designed to approximate clinical practice and included buprenorphine/naloxone, recommended abstinence, and self-help; one-half of participants received intensive addiction counseling. POUD patients were most likely to reduce prescription opioid misuse during buprenorphine/naloxone treatment. If tapered off buprenorphine/naloxone, even after 12 weeks of treatment, the likelihood of an unsuccessful outcome was high. Moreover, opioid dependence counseling did not seem to afford any difference in outcomes. However, despite clinical effectiveness, over the last decade only 19% of patients admitted primarily for OUD treatment (other than heroin) were planned to be offered buprenorphine or methadone.²⁶

A Cochrane review of oral naltrexone for OUD found that the drug was no better than placebo but concluded that available evidence does not allow an adequate evaluation.²⁷ Opioid antagonists may be of value to patients who do not want to take agonists or partial agonists. Extended-release naltrexone also is available to treat OUD.

See the Box below that details steps the FDA and others have taken to prevent POUD and Table 5 for precautions to incorporate when prescribing opioids long-term.

Box

Table 5

Universal precautions with chronic opioid management

CASE CONTINUED: A closer evaluation

After expressing your appreciation for Mr. H’s kind words and empathy for his chronic pain, you redirect him to his PCP. You ask him to sign a release of information so you and his other clinicians can coordinate his care. When discussing Mr. H with his PCP, you learn the patient has made limited requests for early refills and dose escalation primarily in relation to inadequate pain control and function, has genuine pain pathology, and is greatly distressed over his inability to work. No other AMTBs are present, and a check of the state prescribing database reveals that Mr. H did receive a small quantity of opioids from an ED on 1 occasion.

You and Mr. H’s PCP agree this is “pseudo-addiction” but want to watch Mr. H more closely and look for ways to coordinate his care. The PCP agrees to implement a prescribing agreement, start drug testing (including for the prescribed opioids), and reassess maximizing Mr. H’s function and pain management while you address his combined pain, depression, insomnia, and tobacco use.

Related Resources

• Ries RK, Fiellin D, Miller SC, et al, eds. Principles of addiction medicine. 4th ed. Hagerstown, MD: Lippincott Williams & Wilkins; 2009.
• Department of Veterans Affairs. Department of Defense. VA/DoD clinical practice guideline for management of opioid therapy for chronic pain. Appendix C: sample opioid pain care agreement. http://www.healthquality.va.gov/COT_312_Full-er.pdf. Published May 2010. Accessed June 21, 2012.
• Weaver M, Schnoll S. Addiction issues in prescribing opioids for chronic non-malignant pain. J Addiction Med. 2007;1(1):2-10.
• Weaver M, Heit HA, Savage S, et al. Clinical case discussion: chronic pain management. J Addiction Med. 2007;1(1):11-14.

Drug Brand Names

• Buprenorphine • Subutex
• Buprenorphine/naloxone • Suboxone
• Codeine • Tylenol with codeine, others
• Fentanyl • Duragesic, Actiq
• Hydrocodone • Lortab, Vicodin, others
• Methadone • Dolophine, Methadose
• Morphine • Roxanol
• Naltrexone extended-release • Vivitrol
• Oxycodone • OxyContin, Roxicodone

Disclosures

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

Dr. Frankowski’s time toward this project was provided by the American Board of Addiction Medicine-accredited Cincinnati VA Addiction Medicine Research Fellowship, affiliated with the CeTREAD, Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati, Cincinnati, OH.

The statements in this publication do not necessarily reflect the views or opinions of the Department of Veterans Affairs.

Acknowledgement

The authors thank Catherine Constance and Sandra Mason at the Cincinnati VA Medical Center for their administrative assistance.

Discuss this article at www.facebook.com/CurrentPsychiatry

The rate of off-label prescribing of second-generation antipsychotics (SGAs) is estimated to have doubled in the past decade.^1,2 In 2010, quetiapine was the most commonly used SGA in the United States with >10 million prescriptions dispensed.² Clinical experience and reports from patients indicate quetiapine may be useful for treating anxiety. When making medication choices, it can be useful to combine anecdotal evidence with the facts (or lack thereof). Does evidence support or contradict the use of quetiapine for anxiety?

What the research shows

Quetiapine is FDA-approved for treating:

• adults and adolescents with schizophrenia
• adults, children, and adolescents with acute manic episodes associated with bipolar I disorder (BDI) as monotherapy or as an adjunct to lithium or divalproex
• adults with an acute depressive episode associated with bipolar disorder
• adjunctive treatment of major depressive disorder (MDD) in adults
• maintenance treatment of BDI as an adjunct to lithium or divalproex in adults.³

In addition, quetiapine extended-release (XR) is approved as an adjunctive treatment for MDD in adults.⁴

Neither the immediate-release or XR formulation is indicated for treating anxiety, but quetiapine has been studied as a treatment for several anxiety disorders, including posttraumatic stress disorder, social phobia, obsessive-compulsive disorder, and anxiety secondary to mood disorders. It has been most extensively studied as treatment for generalized anxiety disorder (GAD).

Three trials that involved >2,100 patients found quetiapine XR monotherapy is effective for GAD in doses of 50 to 300 mg/d.^5-7 In 2 of the studies, quetiapine XR was as effective as paroxetine and escitalopram for GAD.^5,6 Reviews of off-label SGA use have found that compared with placebo, quetiapine XR monotherapy is effective for GAD (number needed to treat=8).^8,9 Side effects reported in clinical trials of quetiapine included headache, somnolence, sedation, fatigue, dizziness, dry mouth, weight gain, hyperlipidemia, and elevated glucose levels.

What did the FDA say?

In April 2009, the FDA’s Psychopharmacologic Drugs Advisory Committee reviewed whether evidence supported quetiapine XR for treating MDD and GAD.¹⁰ Although the committee found that quetiapine XR monotherapy effectively treated GAD, it concluded it was not acceptably safe.¹¹ The committee expressed concerns over exposing a greatly expanded population to a drug with substantial metabolic side effects, including weight gain (incidence 3% to 23%), increased cholesterol (incidence 7% to 18%), and hyperglycemia.^12-14 Weight gain and metabolic effects have been reported even when quetiapine is prescribed at low doses (≤100 mg/d).^15,16 The FDA did not approve expanding the indication of quetiapine XR to include treatment of GAD.

Our opinion

Quetiapine XR is effective for treating GAD. However, even at low doses, it is associated with substantial side effects and should be reserved for patients with poor response or contraindications (eg, mania) to traditional GAD treatments such as selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors. Published studies assessed quetiapine XR only when used on a scheduled basis, and did not address use of quetiapine immediate release or XR on an as-needed basis for GAD.

Related Resources

• AstraZeneca. Seroquel prescribing information. www1.astrazeneca-us.com/pi/seroquel.pdf.
• AstraZeneca. Seroquel XR prescribing information. www1.astrazeneca-us.com/pi/seroquelxr.pdf.

Drug Brand Names

• Divalproex • Depakote
• Paroxetine • Paxil
• Escitalopram • Lexapro
• Quetiapine • Seroquel
• Lithium • Eskalith, Lithobid

Disclosure

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

Discuss this article at www.facebook.com/CurrentPsychiatry

The rate of off-label prescribing of second-generation antipsychotics (SGAs) is estimated to have doubled in the past decade.^1,2 In 2010, quetiapine was the most commonly used SGA in the United States with >10 million prescriptions dispensed.² Clinical experience and reports from patients indicate quetiapine may be useful for treating anxiety. When making medication choices, it can be useful to combine anecdotal evidence with the facts (or lack thereof). Does evidence support or contradict the use of quetiapine for anxiety?

What the research shows

Quetiapine is FDA-approved for treating:

• adults and adolescents with schizophrenia
• adults, children, and adolescents with acute manic episodes associated with bipolar I disorder (BDI) as monotherapy or as an adjunct to lithium or divalproex
• adults with an acute depressive episode associated with bipolar disorder
• adjunctive treatment of major depressive disorder (MDD) in adults
• maintenance treatment of BDI as an adjunct to lithium or divalproex in adults.³

In addition, quetiapine extended-release (XR) is approved as an adjunctive treatment for MDD in adults.⁴

Neither the immediate-release or XR formulation is indicated for treating anxiety, but quetiapine has been studied as a treatment for several anxiety disorders, including posttraumatic stress disorder, social phobia, obsessive-compulsive disorder, and anxiety secondary to mood disorders. It has been most extensively studied as treatment for generalized anxiety disorder (GAD).

Three trials that involved >2,100 patients found quetiapine XR monotherapy is effective for GAD in doses of 50 to 300 mg/d.^5-7 In 2 of the studies, quetiapine XR was as effective as paroxetine and escitalopram for GAD.^5,6 Reviews of off-label SGA use have found that compared with placebo, quetiapine XR monotherapy is effective for GAD (number needed to treat=8).^8,9 Side effects reported in clinical trials of quetiapine included headache, somnolence, sedation, fatigue, dizziness, dry mouth, weight gain, hyperlipidemia, and elevated glucose levels.

What did the FDA say?

In April 2009, the FDA’s Psychopharmacologic Drugs Advisory Committee reviewed whether evidence supported quetiapine XR for treating MDD and GAD.¹⁰ Although the committee found that quetiapine XR monotherapy effectively treated GAD, it concluded it was not acceptably safe.¹¹ The committee expressed concerns over exposing a greatly expanded population to a drug with substantial metabolic side effects, including weight gain (incidence 3% to 23%), increased cholesterol (incidence 7% to 18%), and hyperglycemia.^12-14 Weight gain and metabolic effects have been reported even when quetiapine is prescribed at low doses (≤100 mg/d).^15,16 The FDA did not approve expanding the indication of quetiapine XR to include treatment of GAD.

Our opinion

Quetiapine XR is effective for treating GAD. However, even at low doses, it is associated with substantial side effects and should be reserved for patients with poor response or contraindications (eg, mania) to traditional GAD treatments such as selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors. Published studies assessed quetiapine XR only when used on a scheduled basis, and did not address use of quetiapine immediate release or XR on an as-needed basis for GAD.

Related Resources

• AstraZeneca. Seroquel prescribing information. www1.astrazeneca-us.com/pi/seroquel.pdf.
• AstraZeneca. Seroquel XR prescribing information. www1.astrazeneca-us.com/pi/seroquelxr.pdf.

Drug Brand Names

• Divalproex • Depakote
• Paroxetine • Paxil
• Escitalopram • Lexapro
• Quetiapine • Seroquel
• Lithium • Eskalith, Lithobid

Disclosure

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

Discuss this article at www.facebook.com/CurrentPsychiatry

The rate of off-label prescribing of second-generation antipsychotics (SGAs) is estimated to have doubled in the past decade.^1,2 In 2010, quetiapine was the most commonly used SGA in the United States with >10 million prescriptions dispensed.² Clinical experience and reports from patients indicate quetiapine may be useful for treating anxiety. When making medication choices, it can be useful to combine anecdotal evidence with the facts (or lack thereof). Does evidence support or contradict the use of quetiapine for anxiety?

What the research shows

Quetiapine is FDA-approved for treating:

• adults and adolescents with schizophrenia
• adults, children, and adolescents with acute manic episodes associated with bipolar I disorder (BDI) as monotherapy or as an adjunct to lithium or divalproex
• adults with an acute depressive episode associated with bipolar disorder
• adjunctive treatment of major depressive disorder (MDD) in adults
• maintenance treatment of BDI as an adjunct to lithium or divalproex in adults.³

In addition, quetiapine extended-release (XR) is approved as an adjunctive treatment for MDD in adults.⁴

Neither the immediate-release or XR formulation is indicated for treating anxiety, but quetiapine has been studied as a treatment for several anxiety disorders, including posttraumatic stress disorder, social phobia, obsessive-compulsive disorder, and anxiety secondary to mood disorders. It has been most extensively studied as treatment for generalized anxiety disorder (GAD).

Three trials that involved >2,100 patients found quetiapine XR monotherapy is effective for GAD in doses of 50 to 300 mg/d.^5-7 In 2 of the studies, quetiapine XR was as effective as paroxetine and escitalopram for GAD.^5,6 Reviews of off-label SGA use have found that compared with placebo, quetiapine XR monotherapy is effective for GAD (number needed to treat=8).^8,9 Side effects reported in clinical trials of quetiapine included headache, somnolence, sedation, fatigue, dizziness, dry mouth, weight gain, hyperlipidemia, and elevated glucose levels.

What did the FDA say?

In April 2009, the FDA’s Psychopharmacologic Drugs Advisory Committee reviewed whether evidence supported quetiapine XR for treating MDD and GAD.¹⁰ Although the committee found that quetiapine XR monotherapy effectively treated GAD, it concluded it was not acceptably safe.¹¹ The committee expressed concerns over exposing a greatly expanded population to a drug with substantial metabolic side effects, including weight gain (incidence 3% to 23%), increased cholesterol (incidence 7% to 18%), and hyperglycemia.^12-14 Weight gain and metabolic effects have been reported even when quetiapine is prescribed at low doses (≤100 mg/d).^15,16 The FDA did not approve expanding the indication of quetiapine XR to include treatment of GAD.

Our opinion

Quetiapine XR is effective for treating GAD. However, even at low doses, it is associated with substantial side effects and should be reserved for patients with poor response or contraindications (eg, mania) to traditional GAD treatments such as selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors. Published studies assessed quetiapine XR only when used on a scheduled basis, and did not address use of quetiapine immediate release or XR on an as-needed basis for GAD.

Related Resources

• AstraZeneca. Seroquel prescribing information. www1.astrazeneca-us.com/pi/seroquel.pdf.
• AstraZeneca. Seroquel XR prescribing information. www1.astrazeneca-us.com/pi/seroquelxr.pdf.

Drug Brand Names

• Divalproex • Depakote
• Paroxetine • Paxil
• Escitalopram • Lexapro
• Quetiapine • Seroquel
• Lithium • Eskalith, Lithobid

Disclosure

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

A suicide rehearsal is a behavioral enactment of a suicide method, usually as part of a suicide plan. A mental suicide rehearsal is a process that evolves over time into a plan. Patients who are intent on attempting suicide usually do not reveal their plans. However, behavioral rehearsals display specific clinical characteristics that speak louder than the guarded patient’s denials, revealing the patient’s suicide plan (Table).

Suicide rehearsals may precede suicide attempts or suicide completions. The percentage of patients who stage suicide rehearsals before attempting or completing suicide is unknown; however, in my experience, suicide rehearsals are relatively common. This article describes suicide rehearsals, and offers 4 cases that illustrate what clinicians can learn from rehearsals to improve their patients’ safety.

Table

Clinical characteristics of suicide rehearsals

The psychology behind suicide rehearsals

Rehearsing suicidal behavior can lower the barrier to a suicide plan, thereby increasing a patient’s resolve and risk. Joiner¹ notes that engaging in behavioral or mental suicide rehearsals increases the risk of suicide. Moreover, rehearsals diminish the prohibition against suicidal behavior and the fear of pain and dying. Examples of rehearsal psychology include:

• overcoming ambivalence about dying
• desensitizing anxiety about performing the suicide act
• testing or “perfecting” the method of a planned suicide
• firming one’s resolve to complete suicide.

Other non-lethal motivations include “a cry for help” and self-injurious behaviors motivated by external gains. Patients who do not intend to attempt suicide may openly rehearse low-risk methods, such as superficial cutting.

Rehearsal characteristics

Suicide rehearsals can be confused with aborted, interrupted, or failed suicide attempts. Suicide rehearsals usually are associated with severe psychiatric illness and high-risk lethal methods of attempting suicide. My experience is that suicide attempts or suicide completions often follow a rehearsal within a few hours or days. However, no short-term suicide risk factors—within hours, days, or weeks—can predict when or if a rehearsed suicide will proceed to a suicide attempt.²

A suicide rehearsal is presumptive evidence that the patient is at acute, high risk for suicide and immediate clinical intervention is necessary. A rehearsal allows the clinician to explore the various methods of suicide that the patient has considered, including prior rehearsals. Knowledge of prior rehearsals can inform the clinician’s management of the current suicide rehearsal.

Suicide rehearsals often are conducted covertly. On inpatient psychiatric units, the rehearsal usually is discovered by staff members or reported by other patients. In outpatient settings, the patient or a significant other may report a rehearsal.

The suicide method displayed in a rehearsal may change. A patient who is rehearsing a hanging may attempt suicide by overdose or a firearm. In a systematic review of prior suicide attempts (N = 1,397), Isometsä et al³ found that 82% of patients used 2 or more different methods in suicide attempts, including the completed suicide. However, in a cohort study of 48,649 individuals admitted to a hospital after an attempted suicide, Runeson et al⁴ found that patients who attempt suicide often used the same method in completed suicide (ie, >90% by hanging for both men and women). Therefore, when taking measures to restrict the patient’s access to lethal means, safety efforts should not be limited to the method used in the suicide rehearsal. Patients can always substitute methods.

Making overall preparations for suicide—for example, making a will, giving away valuable possessions, or putting financial affairs in order—could be confused with a suicide rehearsal, which displays the lethal method to be used in a suicide attempt, often after preparations are made. Suicide rehearsals tend to occur much closer in time to the suicide attempt than preparations for suicide. Similarly, a patient’s plan to hoard drugs for a suicide attempt is not the same as ingesting a sub-lethal dose of a drug to test his or her resolve to die.

By definition, impulsive suicide attempts are not rehearsed. However, an individual’s suicide rehearsal can impulsively segue into a suicide attempt. In a case control study (N = 153) Simon et al⁵ found that 24% of patients spent 6 found that 26% of individuals with lifetime suicide ideation transitioned from suicide ideation to an unplanned suicide attempt. In my experience, a suicide rehearsal before a suicide completion is presumptive evidence against an impulsive suicide.

Patients contemplating suicide may visit Web sites with instructions on “how to suicide,” providing “virtual” opportunities to rehearse suicide.⁷ Patients who are at risk for suicide should be asked if they have searched the Internet for suicide methodology.

What we can learn from rehearsals

Although the following case examples are fictional, they illustrate suicide rehearsals encountered in my clinical and forensic practice.

CASE 1: Looking for a location

Ms. B, a 28-year-old divorced mother of 2, is observed tarrying at the high point of a bridge on successive days. When police arrive and question her, she becomes agitated and distraught. Ms. B admits to “scoping out” the bridge and is taken to a hospital emergency room (ER). In the ER, Ms. B discloses, “I was looking for a good spot to jump.” She tells the triage nurse that she is very depressed but, “I couldn’t do it to my children.” Ms. B is placed in an unlocked room while she waits to be assessed by a psychiatrist. She leaves the ER, runs to a nearby parking garage, and jumps from the top level to her death.

Comment: A patient’s denial of suicide intent following a suicide rehearsal cannot be relied upon. Ms. B’s rehearsal revealed a plan with high-risk suicide intent and a lethal suicide method. Systematic suicide assessment that informs immediate clinical intervention is required.

CASE 2: Changing lethal means

Mr. N, a 43-year-old chief executive officer of a large company, is observed by an assistant loading and unloading a revolver at his desk. Alarmed, the assistant calls the company physician. Mr. N refuses psychiatric treatment, saying, “I’ll be all right; this is just a passing thing.” His wife tells the physician that her husband has a history of bipolar disorder but no prior suicide attempts. Guns and ammunition are removed from the home. One week later, Mr. N is found hanging in his garage. A loaded pistol is discovered in the glove compartment of his car.

Comment: There is no certainty that a subsequent suicide attempt will replicate the rehearsed method. A psychological autopsy was conducted, but no explanation was found for why Mr. N chose hanging after having rehearsed suicide with a loaded handgun. His wife thought that her husband, a very tidy person, did not want to leave a mess.

CASE 3: Grieving and depressed

Mr. O, age 67, is depressed after recently losing his wife. He considers a number of suicide methods. Mr. O decides to use a plastic bag to suffocate himself because he believes that this method will allow him to change his mind. Mr. O practices tying the bag tight around his neck. During this rehearsal, he realizes that he does not want to die. Instead, he pursues grief counseling.

Comment: For some patients, the act of rehearsing suicide can help them resolve ambivalent feelings about wanting to die in favor of wanting to live.

CASE 4: Suicide method and the Internet

Ms. S, a 22-year-old college student, is undergoing outpatient treatment for depression. She is accumulating prescription drugs to take as an overdose. Ms. S also searches the Internet for information about other suicide methods. Because she wants a “sure” method of suicide, she persuades an acquaintance to purchase a handgun. In private, Ms. S places the unloaded gun to her head and plays “Russian roulette,” pulling the trigger several times. Her mother discovers the gun and confronts her daughter. Ms. S is hospitalized on a closed psychiatric unit and tells a staff member, “I was practicing suicide with the gun.” Before Ms. S is discharged from the hospital, her parents are advised to watch for suicidal behaviors, especially the recurrence of rehearsals that indicate an acute, high suicide risk. Ms. S’s Internet use is restricted and monitored.

Comment: Suicide rehearsal with a gun reinforces the belief that a firearm death is quick and easy.⁸ Reaching for a loaded gun takes less time than most other methods of suicide. Patients who rehearse suicide with a gun should be prevented from having access to any firearms, weapons, or other highly lethal means of suicide.

Recognition and intervention

A guarded psychiatric inpatient who is intent on attempting suicide is unmasked when the discovery of a suicidal rehearsal reveals a suicide plan. This creates an opportunity for clinicians to intervene. The patient may attempt to cover up suicidal intent by stating, “I was just playing around” or “I just wanted to get attention.” Recognizing the emergency posed by a suicide rehearsal informs treatment. Safety measures—including 1-to-1 supervision—may be necessary during a period of acute, high suicide risk. The patient’s diagnosis, severity of illness, and treatment require reevaluation.

An outpatient who performs a suicide rehearsal should be considered at acute, high risk for suicide, and immediate psychiatric hospitalization may be necessary. Whether as an inpatient or outpatient, the patient’s suicide intent and plan require careful exploration. The information gained will guide treatment and management decisions. Continuing systematic suicide risk assessment is essential.

Related Resources

• American Association of Suicidology. www.suicidology.org.
• Joiner T. Why people die by suicide. Cambridge, MA: Harvard University Press; 2007.
• American Psychiatric Association. Practice guideline for the assessment and treatment of patients with suicidal behaviors. Washington, DC: American Psychiatric Publishing, Inc. 2003.
• Simon RI. Preventing patient suicide: clinical assessment and management. Arlington, VA: American Psychiatric Publishing, Inc.; 2011.

Disclosure

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

A suicide rehearsal is a behavioral enactment of a suicide method, usually as part of a suicide plan. A mental suicide rehearsal is a process that evolves over time into a plan. Patients who are intent on attempting suicide usually do not reveal their plans. However, behavioral rehearsals display specific clinical characteristics that speak louder than the guarded patient’s denials, revealing the patient’s suicide plan (Table).

Suicide rehearsals may precede suicide attempts or suicide completions. The percentage of patients who stage suicide rehearsals before attempting or completing suicide is unknown; however, in my experience, suicide rehearsals are relatively common. This article describes suicide rehearsals, and offers 4 cases that illustrate what clinicians can learn from rehearsals to improve their patients’ safety.

Table

Clinical characteristics of suicide rehearsals

The psychology behind suicide rehearsals

Rehearsing suicidal behavior can lower the barrier to a suicide plan, thereby increasing a patient’s resolve and risk. Joiner¹ notes that engaging in behavioral or mental suicide rehearsals increases the risk of suicide. Moreover, rehearsals diminish the prohibition against suicidal behavior and the fear of pain and dying. Examples of rehearsal psychology include:

• overcoming ambivalence about dying
• desensitizing anxiety about performing the suicide act
• testing or “perfecting” the method of a planned suicide
• firming one’s resolve to complete suicide.

Other non-lethal motivations include “a cry for help” and self-injurious behaviors motivated by external gains. Patients who do not intend to attempt suicide may openly rehearse low-risk methods, such as superficial cutting.

Rehearsal characteristics

Suicide rehearsals can be confused with aborted, interrupted, or failed suicide attempts. Suicide rehearsals usually are associated with severe psychiatric illness and high-risk lethal methods of attempting suicide. My experience is that suicide attempts or suicide completions often follow a rehearsal within a few hours or days. However, no short-term suicide risk factors—within hours, days, or weeks—can predict when or if a rehearsed suicide will proceed to a suicide attempt.²

A suicide rehearsal is presumptive evidence that the patient is at acute, high risk for suicide and immediate clinical intervention is necessary. A rehearsal allows the clinician to explore the various methods of suicide that the patient has considered, including prior rehearsals. Knowledge of prior rehearsals can inform the clinician’s management of the current suicide rehearsal.

Suicide rehearsals often are conducted covertly. On inpatient psychiatric units, the rehearsal usually is discovered by staff members or reported by other patients. In outpatient settings, the patient or a significant other may report a rehearsal.

The suicide method displayed in a rehearsal may change. A patient who is rehearsing a hanging may attempt suicide by overdose or a firearm. In a systematic review of prior suicide attempts (N = 1,397), Isometsä et al³ found that 82% of patients used 2 or more different methods in suicide attempts, including the completed suicide. However, in a cohort study of 48,649 individuals admitted to a hospital after an attempted suicide, Runeson et al⁴ found that patients who attempt suicide often used the same method in completed suicide (ie, >90% by hanging for both men and women). Therefore, when taking measures to restrict the patient’s access to lethal means, safety efforts should not be limited to the method used in the suicide rehearsal. Patients can always substitute methods.

Making overall preparations for suicide—for example, making a will, giving away valuable possessions, or putting financial affairs in order—could be confused with a suicide rehearsal, which displays the lethal method to be used in a suicide attempt, often after preparations are made. Suicide rehearsals tend to occur much closer in time to the suicide attempt than preparations for suicide. Similarly, a patient’s plan to hoard drugs for a suicide attempt is not the same as ingesting a sub-lethal dose of a drug to test his or her resolve to die.

By definition, impulsive suicide attempts are not rehearsed. However, an individual’s suicide rehearsal can impulsively segue into a suicide attempt. In a case control study (N = 153) Simon et al⁵ found that 24% of patients spent 6 found that 26% of individuals with lifetime suicide ideation transitioned from suicide ideation to an unplanned suicide attempt. In my experience, a suicide rehearsal before a suicide completion is presumptive evidence against an impulsive suicide.

Patients contemplating suicide may visit Web sites with instructions on “how to suicide,” providing “virtual” opportunities to rehearse suicide.⁷ Patients who are at risk for suicide should be asked if they have searched the Internet for suicide methodology.

What we can learn from rehearsals

Although the following case examples are fictional, they illustrate suicide rehearsals encountered in my clinical and forensic practice.

CASE 1: Looking for a location

Ms. B, a 28-year-old divorced mother of 2, is observed tarrying at the high point of a bridge on successive days. When police arrive and question her, she becomes agitated and distraught. Ms. B admits to “scoping out” the bridge and is taken to a hospital emergency room (ER). In the ER, Ms. B discloses, “I was looking for a good spot to jump.” She tells the triage nurse that she is very depressed but, “I couldn’t do it to my children.” Ms. B is placed in an unlocked room while she waits to be assessed by a psychiatrist. She leaves the ER, runs to a nearby parking garage, and jumps from the top level to her death.

Comment: A patient’s denial of suicide intent following a suicide rehearsal cannot be relied upon. Ms. B’s rehearsal revealed a plan with high-risk suicide intent and a lethal suicide method. Systematic suicide assessment that informs immediate clinical intervention is required.

CASE 2: Changing lethal means

Mr. N, a 43-year-old chief executive officer of a large company, is observed by an assistant loading and unloading a revolver at his desk. Alarmed, the assistant calls the company physician. Mr. N refuses psychiatric treatment, saying, “I’ll be all right; this is just a passing thing.” His wife tells the physician that her husband has a history of bipolar disorder but no prior suicide attempts. Guns and ammunition are removed from the home. One week later, Mr. N is found hanging in his garage. A loaded pistol is discovered in the glove compartment of his car.

Comment: There is no certainty that a subsequent suicide attempt will replicate the rehearsed method. A psychological autopsy was conducted, but no explanation was found for why Mr. N chose hanging after having rehearsed suicide with a loaded handgun. His wife thought that her husband, a very tidy person, did not want to leave a mess.

CASE 3: Grieving and depressed

Mr. O, age 67, is depressed after recently losing his wife. He considers a number of suicide methods. Mr. O decides to use a plastic bag to suffocate himself because he believes that this method will allow him to change his mind. Mr. O practices tying the bag tight around his neck. During this rehearsal, he realizes that he does not want to die. Instead, he pursues grief counseling.

Comment: For some patients, the act of rehearsing suicide can help them resolve ambivalent feelings about wanting to die in favor of wanting to live.