Evidence-Based Reviews

Fourteen clinical trials in the past 3 years have examined the potential of omega-3 fatty acids in treating psychiatric disorders. Preliminary findings in at least 700 patients suggest that:

• omega-3 fatty acids used as adjuncts or monotherapy appear well-tolerated and safe in psychiatric disorders
• efficacy data vary by disorder
• the two marine omega-3 fatty acids may differ in efficacy.

Although we cannot offer specific guidance for using omega-3 fatty acids at this time, we can update you on recent trials of these “fish oils” in depression, bipolar disorder, schizophrenia, and other psychiatric disorders.

Treating depression

Prevalence rates of major depression^1,2 and suicidal ideation³ decrease in populations as fish consumption increases. Some studies^4,5 have shown omega-3 fatty acid deficiency in erythrocyte membranes and serum of depressed patients. This putative deficiency has been hypothesized to lead to:

• alterations in membrane fluidity, which affect monoamine (particularly serotonin) neurotransmission^6,7
• an imbalance between omega-6 and omega-3 fatty acids, which affects the inflammatory response system (Box).^5-12
• Nemets et al. ¹³ Twenty patients with recurrent major depression taking maintenance antidepressants were randomly assigned to adjunctive ethyl-EPA, 2 grams/d, or placebo for 4 weeks. Patients given ethyl-EPA showed significantly greater improvement than the placebo group in depressive symptoms, as measured by the Hamilton Rating Scale for Depression (HRSD).¹³
• Peet and Horrobin. ¹⁴ Seventy depressed patients taking antidepressants were randomly assigned to adjunctive ethyl-EPA (1, 2, or 4 grams/d) or placebo for 12 weeks. Only the group taking ethyl-EPA, 1 gram/d, showed significantly greater improvement than the placebo group.
• Su et al. ¹⁵ Twenty-eight patients taking antidepressants for major depression were randomly assigned to adjunctive omega-3 fatty acids (4.4 grams/d of EPA plus 2.2 grams/d of DHA) or placebo. After 8 weeks, depressive symptoms improved significantly more in the adjunctive treatment group.
• Marangell et al. ¹⁶ Thirty-six patients with mild to moderate depression (defined as a score of 17 on the 28-item HRSD) were randomly assigned to monotherapy with DHA, 2 grams/d, or placebo. Response rates after 6 weeks were comparable (27.8% with DHA versus 23.5% with placebo).

Box

Table 1

Controlled trials of omega-3 fatty acids in treating major depression

Analysis. For patients with unipolar depression who were treated with omega-3 fatty acids:

• the most promisingresults have been seen with adjunctive EPA
• safety and tolerability have been good across studies.

No positive monotherapy studies have been published. Studies are needed to confirm EPA’s efficacy in unipolar depression and to determine the most effective dosage.

Treating bipolar disorder

EPA and DHA have been studied in bipolar disorder (Table 2) because their actions in modulating signal transduction pathways resemble those of lithium and valproate.^10,17 Biochemical studies also have shown decreased AA and DHA in erythrocyte membranes of manic patients compared with controls.¹⁸

• Stoll et al. ¹⁹ Thirty patients receiving usual treatment for bipolar disorder were randomly assigned to adjunctive omega-3 fatty acids (6.2 grams/d of EPA plus 3.4 grams/d of DHA) or placebo for 4 months. Results were promising; patients receiving the omega-3 fatty acids remained in remission significantly longer than the placebo group.
• Keck et al. ^20,21 On the other hand, two more-recent studies were disappointing. Both were 4-month, randomized, controlled trials in which patients received adjunctive EPA, 6 grams/d, or placebo. One study enrolled 59 patients with acute bipolar depression;²⁰ the other enrolled 62 patients with rapid-cycling bipolar disorder.²¹ EPA was well-tolerated, but both studies found little difference in effectiveness between EPA and placebo.

Table 2

Controlled trials of adjunctive omega-3 fatty acids in treating bipolar disorder

Analysis. Further studies are needed to determine omega-3 fatty acids’ usefulness in treating bipolar illness.

Treating schizophrenia

Essential fatty acid deficiency and resulting lipid membrane abnormalities have been hypothesized to play a role in schizophrenia onset.²² Moreover, epidemiologic data suggest an association between high fish consumption and positive outcomes in patients with schizophrenia.²³

Open-label trials, adjunctive therapy

• Mellor et al. ²⁴ Twenty patients receiving antipsychotics for schizophrenia were treated for 6 weeks with 10 grams/d of a fish oil formulation containing 1.7 grams of EPA and 1.1 grams of DHA (Table 3). Psychotic symptoms improved significantly and were correlated with increased omega-3 fatty acid levels in erythrocyte membranes. Tardive dyskinesia also improved significantly, as measured by Abnormal Involuntary Movement Scale (AIMS) scores.
• Arvindakshan et al. ²⁵ Thirty-three patients receiving antipsychotics for schizophrenia were given omega-3 fatty acids (360 mg/d of EPA and 240 mg/d of DHA) plus antioxidants (800 IU vitamin E and 1,000 IU vitamin C) for 4 months. Symptom and quality-of-life measures improved significantly, and clinical improvement was retained after 4 months of supplement washout.

Table 3

Clinical trials of omega-3 fatty acids in treating schizophrenia

Controlled trials, adjunctive therapy

• Peet et al. ²⁶ In a 3-month study, 45 patients with schizophrenia were randomly assigned to adjunctive EPA or DHA (2 grams/d) or placebo. Those receiving EPA showed significantly greater improvement as measured by the Positive and Negative Syndrome Scale (PANSS), compared with DHA or placebo.
• Fenton et al. ²⁷ In a 16-week study, 87 patients with schizophrenia or schizoaffective disorder were randomly assigned to adjunctive ethyl-EPA, 3 grams/d, or placebo. Little difference was noted in outcome measures of psychotic symptoms, mood, cognition, or extrapyramidal symptoms.
• Peet et al. ²⁸ In a 12-week study. 115 patients with schizophrenia receiving typical antipsychotics, clozapine, or other atypical antipsychotics were randomly assigned to adjunctive ethyl-EPA (1, 2, or 4 grams/d) or placebo. Those taking clozapine improved significantly more with 2 grams/d of ethyl-EPA compared with patients receiving placebo. Little difference was noted between ethyl-EPA and placebo among patients taking typical or atypical antipsychotics.
• Emsley et al. ²⁹ Forty patients with schizophrenia were randomly assigned to adjunctive ethyl-EPA, 3 grams/d, or placebo across 12 weeks. The ethyl-EPA group showed greater improvement in total PANSS scores and reduced dyskinesia, compared with placebo. Further analysis suggested, however, that the reduced dyskinesia scores at least partially accounted for the PANSS changes.

Controlled trial, monotherapy

• Peet et al. ²⁶ Twenty-six patients with schizophrenia were randomly assigned to EPA, 2 grams/d, or placebo. After 3 months, those receiving EPA had significantly lower PANSS scores, and fewer (8 of 14) required antipsychotics than did those receiving placebo (12 of 12).

Analysis. Adjunctive ethyl-EPA (and perhaps combinations of EPA and DHA) may help patients with schizophrenia who are taking typical or atypical antipsychotics. EPA monotherapy also may be useful. Data are limited, however, and studies are needed before such use could be recommended.

Treating other disorders

Postpartum depression. The developing fetus and neonate require DHA from maternal stores for neurologic development. Maternal DHA depletion³⁰ has been hypothesized to put mothers at risk for postpartum depression.³¹ An ecological study with data from 23 countries found that higher concentrations of DHA in maternal breast milk and greater seafood consumption predicted lower postpartum depression rates.³²

In a randomized, controlled trial, giving DHA, 200 mg/d, to breastfeeding women during the first 4 months postpartum increased maternal plasma phospholipid content by 8%, compared with a 31% decrease in women given placebo.³³

Data from randomized, controlled trials are needed to assess whether omega-3 fatty acid supplementation during pregnancy and the postpartum protects against postpartum depression.

Borderline personality disorder. In an 8-week controlled trial, Zanarini and Frankenburg³⁴ randomly assigned 20 subjects with borderline personality disorder to monotherapy with ethyl-EPA, 1 gram/d, or placebo. Depressive symptoms improved and aggression decreased significantly in the ethyl-EPA group, suggesting the need for further research.

ADHD. Low DHA levels have been found in serum³⁵ and erythrocytes³⁶ of hyperactive children when compared with controls. Limited data in boys ages 6 to 12 also suggest an inverse relationship between plasma omega-3 fatty acids and behavior problems, as measured by the Connors’ Rating Scale.³⁷

More research is needed into omega-3 fatty acids’ potential role in treating attention-deficit/hyperactivity disorder (ADHD), even though results of one controlled trial of adjunctive DHA in ADHD were disappointing.³⁸

Dementia. Some large, prospective, epidemiologic studies^39-41—but not others⁴²—found an inverse relationship between dietary intake of omega-3 fatty acids and risk of cognitive decline or dementia.

Related resources

• USDA Nutrient Data Laboratory. http://www.nalusda.gov/fnic/foodcomp (accessed Dec. 1, 2003)
• Stoll AL. The omega-3 connection: the groundbreaking omega-3 antidepression diet and brain program. New York: Simon and Schuster, 2001.

Drug brand names

• Clozapine • Clozaril

Disclosure

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

Fourteen clinical trials in the past 3 years have examined the potential of omega-3 fatty acids in treating psychiatric disorders. Preliminary findings in at least 700 patients suggest that:

• omega-3 fatty acids used as adjuncts or monotherapy appear well-tolerated and safe in psychiatric disorders
• efficacy data vary by disorder
• the two marine omega-3 fatty acids may differ in efficacy.

Although we cannot offer specific guidance for using omega-3 fatty acids at this time, we can update you on recent trials of these “fish oils” in depression, bipolar disorder, schizophrenia, and other psychiatric disorders.

Treating depression

Prevalence rates of major depression^1,2 and suicidal ideation³ decrease in populations as fish consumption increases. Some studies^4,5 have shown omega-3 fatty acid deficiency in erythrocyte membranes and serum of depressed patients. This putative deficiency has been hypothesized to lead to:

• alterations in membrane fluidity, which affect monoamine (particularly serotonin) neurotransmission^6,7
• an imbalance between omega-6 and omega-3 fatty acids, which affects the inflammatory response system (Box).^5-12
• Nemets et al. ¹³ Twenty patients with recurrent major depression taking maintenance antidepressants were randomly assigned to adjunctive ethyl-EPA, 2 grams/d, or placebo for 4 weeks. Patients given ethyl-EPA showed significantly greater improvement than the placebo group in depressive symptoms, as measured by the Hamilton Rating Scale for Depression (HRSD).¹³
• Peet and Horrobin. ¹⁴ Seventy depressed patients taking antidepressants were randomly assigned to adjunctive ethyl-EPA (1, 2, or 4 grams/d) or placebo for 12 weeks. Only the group taking ethyl-EPA, 1 gram/d, showed significantly greater improvement than the placebo group.
• Su et al. ¹⁵ Twenty-eight patients taking antidepressants for major depression were randomly assigned to adjunctive omega-3 fatty acids (4.4 grams/d of EPA plus 2.2 grams/d of DHA) or placebo. After 8 weeks, depressive symptoms improved significantly more in the adjunctive treatment group.
• Marangell et al. ¹⁶ Thirty-six patients with mild to moderate depression (defined as a score of 17 on the 28-item HRSD) were randomly assigned to monotherapy with DHA, 2 grams/d, or placebo. Response rates after 6 weeks were comparable (27.8% with DHA versus 23.5% with placebo).

Box

Table 1

Controlled trials of omega-3 fatty acids in treating major depression

Analysis. For patients with unipolar depression who were treated with omega-3 fatty acids:

• the most promisingresults have been seen with adjunctive EPA
• safety and tolerability have been good across studies.

No positive monotherapy studies have been published. Studies are needed to confirm EPA’s efficacy in unipolar depression and to determine the most effective dosage.

Treating bipolar disorder

EPA and DHA have been studied in bipolar disorder (Table 2) because their actions in modulating signal transduction pathways resemble those of lithium and valproate.^10,17 Biochemical studies also have shown decreased AA and DHA in erythrocyte membranes of manic patients compared with controls.¹⁸

• Stoll et al. ¹⁹ Thirty patients receiving usual treatment for bipolar disorder were randomly assigned to adjunctive omega-3 fatty acids (6.2 grams/d of EPA plus 3.4 grams/d of DHA) or placebo for 4 months. Results were promising; patients receiving the omega-3 fatty acids remained in remission significantly longer than the placebo group.
• Keck et al. ^20,21 On the other hand, two more-recent studies were disappointing. Both were 4-month, randomized, controlled trials in which patients received adjunctive EPA, 6 grams/d, or placebo. One study enrolled 59 patients with acute bipolar depression;²⁰ the other enrolled 62 patients with rapid-cycling bipolar disorder.²¹ EPA was well-tolerated, but both studies found little difference in effectiveness between EPA and placebo.

Table 2

Controlled trials of adjunctive omega-3 fatty acids in treating bipolar disorder

Analysis. Further studies are needed to determine omega-3 fatty acids’ usefulness in treating bipolar illness.

Treating schizophrenia

Essential fatty acid deficiency and resulting lipid membrane abnormalities have been hypothesized to play a role in schizophrenia onset.²² Moreover, epidemiologic data suggest an association between high fish consumption and positive outcomes in patients with schizophrenia.²³

Open-label trials, adjunctive therapy

• Mellor et al. ²⁴ Twenty patients receiving antipsychotics for schizophrenia were treated for 6 weeks with 10 grams/d of a fish oil formulation containing 1.7 grams of EPA and 1.1 grams of DHA (Table 3). Psychotic symptoms improved significantly and were correlated with increased omega-3 fatty acid levels in erythrocyte membranes. Tardive dyskinesia also improved significantly, as measured by Abnormal Involuntary Movement Scale (AIMS) scores.
• Arvindakshan et al. ²⁵ Thirty-three patients receiving antipsychotics for schizophrenia were given omega-3 fatty acids (360 mg/d of EPA and 240 mg/d of DHA) plus antioxidants (800 IU vitamin E and 1,000 IU vitamin C) for 4 months. Symptom and quality-of-life measures improved significantly, and clinical improvement was retained after 4 months of supplement washout.

Table 3

Clinical trials of omega-3 fatty acids in treating schizophrenia

Controlled trials, adjunctive therapy

• Peet et al. ²⁶ In a 3-month study, 45 patients with schizophrenia were randomly assigned to adjunctive EPA or DHA (2 grams/d) or placebo. Those receiving EPA showed significantly greater improvement as measured by the Positive and Negative Syndrome Scale (PANSS), compared with DHA or placebo.
• Fenton et al. ²⁷ In a 16-week study, 87 patients with schizophrenia or schizoaffective disorder were randomly assigned to adjunctive ethyl-EPA, 3 grams/d, or placebo. Little difference was noted in outcome measures of psychotic symptoms, mood, cognition, or extrapyramidal symptoms.
• Peet et al. ²⁸ In a 12-week study. 115 patients with schizophrenia receiving typical antipsychotics, clozapine, or other atypical antipsychotics were randomly assigned to adjunctive ethyl-EPA (1, 2, or 4 grams/d) or placebo. Those taking clozapine improved significantly more with 2 grams/d of ethyl-EPA compared with patients receiving placebo. Little difference was noted between ethyl-EPA and placebo among patients taking typical or atypical antipsychotics.
• Emsley et al. ²⁹ Forty patients with schizophrenia were randomly assigned to adjunctive ethyl-EPA, 3 grams/d, or placebo across 12 weeks. The ethyl-EPA group showed greater improvement in total PANSS scores and reduced dyskinesia, compared with placebo. Further analysis suggested, however, that the reduced dyskinesia scores at least partially accounted for the PANSS changes.

Controlled trial, monotherapy

• Peet et al. ²⁶ Twenty-six patients with schizophrenia were randomly assigned to EPA, 2 grams/d, or placebo. After 3 months, those receiving EPA had significantly lower PANSS scores, and fewer (8 of 14) required antipsychotics than did those receiving placebo (12 of 12).

Analysis. Adjunctive ethyl-EPA (and perhaps combinations of EPA and DHA) may help patients with schizophrenia who are taking typical or atypical antipsychotics. EPA monotherapy also may be useful. Data are limited, however, and studies are needed before such use could be recommended.

Treating other disorders

Postpartum depression. The developing fetus and neonate require DHA from maternal stores for neurologic development. Maternal DHA depletion³⁰ has been hypothesized to put mothers at risk for postpartum depression.³¹ An ecological study with data from 23 countries found that higher concentrations of DHA in maternal breast milk and greater seafood consumption predicted lower postpartum depression rates.³²

In a randomized, controlled trial, giving DHA, 200 mg/d, to breastfeeding women during the first 4 months postpartum increased maternal plasma phospholipid content by 8%, compared with a 31% decrease in women given placebo.³³

Data from randomized, controlled trials are needed to assess whether omega-3 fatty acid supplementation during pregnancy and the postpartum protects against postpartum depression.

Borderline personality disorder. In an 8-week controlled trial, Zanarini and Frankenburg³⁴ randomly assigned 20 subjects with borderline personality disorder to monotherapy with ethyl-EPA, 1 gram/d, or placebo. Depressive symptoms improved and aggression decreased significantly in the ethyl-EPA group, suggesting the need for further research.

ADHD. Low DHA levels have been found in serum³⁵ and erythrocytes³⁶ of hyperactive children when compared with controls. Limited data in boys ages 6 to 12 also suggest an inverse relationship between plasma omega-3 fatty acids and behavior problems, as measured by the Connors’ Rating Scale.³⁷

More research is needed into omega-3 fatty acids’ potential role in treating attention-deficit/hyperactivity disorder (ADHD), even though results of one controlled trial of adjunctive DHA in ADHD were disappointing.³⁸

Dementia. Some large, prospective, epidemiologic studies^39-41—but not others⁴²—found an inverse relationship between dietary intake of omega-3 fatty acids and risk of cognitive decline or dementia.

Related resources

• USDA Nutrient Data Laboratory. http://www.nalusda.gov/fnic/foodcomp (accessed Dec. 1, 2003)
• Stoll AL. The omega-3 connection: the groundbreaking omega-3 antidepression diet and brain program. New York: Simon and Schuster, 2001.

Drug brand names

• Clozapine • Clozaril

Disclosure

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

Fourteen clinical trials in the past 3 years have examined the potential of omega-3 fatty acids in treating psychiatric disorders. Preliminary findings in at least 700 patients suggest that:

• omega-3 fatty acids used as adjuncts or monotherapy appear well-tolerated and safe in psychiatric disorders
• efficacy data vary by disorder
• the two marine omega-3 fatty acids may differ in efficacy.

Although we cannot offer specific guidance for using omega-3 fatty acids at this time, we can update you on recent trials of these “fish oils” in depression, bipolar disorder, schizophrenia, and other psychiatric disorders.

Treating depression

Prevalence rates of major depression^1,2 and suicidal ideation³ decrease in populations as fish consumption increases. Some studies^4,5 have shown omega-3 fatty acid deficiency in erythrocyte membranes and serum of depressed patients. This putative deficiency has been hypothesized to lead to:

• alterations in membrane fluidity, which affect monoamine (particularly serotonin) neurotransmission^6,7
• an imbalance between omega-6 and omega-3 fatty acids, which affects the inflammatory response system (Box).^5-12
• Nemets et al. ¹³ Twenty patients with recurrent major depression taking maintenance antidepressants were randomly assigned to adjunctive ethyl-EPA, 2 grams/d, or placebo for 4 weeks. Patients given ethyl-EPA showed significantly greater improvement than the placebo group in depressive symptoms, as measured by the Hamilton Rating Scale for Depression (HRSD).¹³
• Peet and Horrobin. ¹⁴ Seventy depressed patients taking antidepressants were randomly assigned to adjunctive ethyl-EPA (1, 2, or 4 grams/d) or placebo for 12 weeks. Only the group taking ethyl-EPA, 1 gram/d, showed significantly greater improvement than the placebo group.
• Su et al. ¹⁵ Twenty-eight patients taking antidepressants for major depression were randomly assigned to adjunctive omega-3 fatty acids (4.4 grams/d of EPA plus 2.2 grams/d of DHA) or placebo. After 8 weeks, depressive symptoms improved significantly more in the adjunctive treatment group.
• Marangell et al. ¹⁶ Thirty-six patients with mild to moderate depression (defined as a score of 17 on the 28-item HRSD) were randomly assigned to monotherapy with DHA, 2 grams/d, or placebo. Response rates after 6 weeks were comparable (27.8% with DHA versus 23.5% with placebo).

Box

Table 1

Controlled trials of omega-3 fatty acids in treating major depression

Analysis. For patients with unipolar depression who were treated with omega-3 fatty acids:

• the most promisingresults have been seen with adjunctive EPA
• safety and tolerability have been good across studies.

No positive monotherapy studies have been published. Studies are needed to confirm EPA’s efficacy in unipolar depression and to determine the most effective dosage.

Treating bipolar disorder

EPA and DHA have been studied in bipolar disorder (Table 2) because their actions in modulating signal transduction pathways resemble those of lithium and valproate.^10,17 Biochemical studies also have shown decreased AA and DHA in erythrocyte membranes of manic patients compared with controls.¹⁸

• Stoll et al. ¹⁹ Thirty patients receiving usual treatment for bipolar disorder were randomly assigned to adjunctive omega-3 fatty acids (6.2 grams/d of EPA plus 3.4 grams/d of DHA) or placebo for 4 months. Results were promising; patients receiving the omega-3 fatty acids remained in remission significantly longer than the placebo group.
• Keck et al. ^20,21 On the other hand, two more-recent studies were disappointing. Both were 4-month, randomized, controlled trials in which patients received adjunctive EPA, 6 grams/d, or placebo. One study enrolled 59 patients with acute bipolar depression;²⁰ the other enrolled 62 patients with rapid-cycling bipolar disorder.²¹ EPA was well-tolerated, but both studies found little difference in effectiveness between EPA and placebo.

Table 2

Controlled trials of adjunctive omega-3 fatty acids in treating bipolar disorder

Analysis. Further studies are needed to determine omega-3 fatty acids’ usefulness in treating bipolar illness.

Treating schizophrenia

Essential fatty acid deficiency and resulting lipid membrane abnormalities have been hypothesized to play a role in schizophrenia onset.²² Moreover, epidemiologic data suggest an association between high fish consumption and positive outcomes in patients with schizophrenia.²³

Open-label trials, adjunctive therapy

• Mellor et al. ²⁴ Twenty patients receiving antipsychotics for schizophrenia were treated for 6 weeks with 10 grams/d of a fish oil formulation containing 1.7 grams of EPA and 1.1 grams of DHA (Table 3). Psychotic symptoms improved significantly and were correlated with increased omega-3 fatty acid levels in erythrocyte membranes. Tardive dyskinesia also improved significantly, as measured by Abnormal Involuntary Movement Scale (AIMS) scores.
• Arvindakshan et al. ²⁵ Thirty-three patients receiving antipsychotics for schizophrenia were given omega-3 fatty acids (360 mg/d of EPA and 240 mg/d of DHA) plus antioxidants (800 IU vitamin E and 1,000 IU vitamin C) for 4 months. Symptom and quality-of-life measures improved significantly, and clinical improvement was retained after 4 months of supplement washout.

Table 3

Clinical trials of omega-3 fatty acids in treating schizophrenia

Controlled trials, adjunctive therapy

• Peet et al. ²⁶ In a 3-month study, 45 patients with schizophrenia were randomly assigned to adjunctive EPA or DHA (2 grams/d) or placebo. Those receiving EPA showed significantly greater improvement as measured by the Positive and Negative Syndrome Scale (PANSS), compared with DHA or placebo.
• Fenton et al. ²⁷ In a 16-week study, 87 patients with schizophrenia or schizoaffective disorder were randomly assigned to adjunctive ethyl-EPA, 3 grams/d, or placebo. Little difference was noted in outcome measures of psychotic symptoms, mood, cognition, or extrapyramidal symptoms.
• Peet et al. ²⁸ In a 12-week study. 115 patients with schizophrenia receiving typical antipsychotics, clozapine, or other atypical antipsychotics were randomly assigned to adjunctive ethyl-EPA (1, 2, or 4 grams/d) or placebo. Those taking clozapine improved significantly more with 2 grams/d of ethyl-EPA compared with patients receiving placebo. Little difference was noted between ethyl-EPA and placebo among patients taking typical or atypical antipsychotics.
• Emsley et al. ²⁹ Forty patients with schizophrenia were randomly assigned to adjunctive ethyl-EPA, 3 grams/d, or placebo across 12 weeks. The ethyl-EPA group showed greater improvement in total PANSS scores and reduced dyskinesia, compared with placebo. Further analysis suggested, however, that the reduced dyskinesia scores at least partially accounted for the PANSS changes.

Controlled trial, monotherapy

• Peet et al. ²⁶ Twenty-six patients with schizophrenia were randomly assigned to EPA, 2 grams/d, or placebo. After 3 months, those receiving EPA had significantly lower PANSS scores, and fewer (8 of 14) required antipsychotics than did those receiving placebo (12 of 12).

Analysis. Adjunctive ethyl-EPA (and perhaps combinations of EPA and DHA) may help patients with schizophrenia who are taking typical or atypical antipsychotics. EPA monotherapy also may be useful. Data are limited, however, and studies are needed before such use could be recommended.

Treating other disorders

Postpartum depression. The developing fetus and neonate require DHA from maternal stores for neurologic development. Maternal DHA depletion³⁰ has been hypothesized to put mothers at risk for postpartum depression.³¹ An ecological study with data from 23 countries found that higher concentrations of DHA in maternal breast milk and greater seafood consumption predicted lower postpartum depression rates.³²

In a randomized, controlled trial, giving DHA, 200 mg/d, to breastfeeding women during the first 4 months postpartum increased maternal plasma phospholipid content by 8%, compared with a 31% decrease in women given placebo.³³

Data from randomized, controlled trials are needed to assess whether omega-3 fatty acid supplementation during pregnancy and the postpartum protects against postpartum depression.

Borderline personality disorder. In an 8-week controlled trial, Zanarini and Frankenburg³⁴ randomly assigned 20 subjects with borderline personality disorder to monotherapy with ethyl-EPA, 1 gram/d, or placebo. Depressive symptoms improved and aggression decreased significantly in the ethyl-EPA group, suggesting the need for further research.

ADHD. Low DHA levels have been found in serum³⁵ and erythrocytes³⁶ of hyperactive children when compared with controls. Limited data in boys ages 6 to 12 also suggest an inverse relationship between plasma omega-3 fatty acids and behavior problems, as measured by the Connors’ Rating Scale.³⁷

More research is needed into omega-3 fatty acids’ potential role in treating attention-deficit/hyperactivity disorder (ADHD), even though results of one controlled trial of adjunctive DHA in ADHD were disappointing.³⁸

Dementia. Some large, prospective, epidemiologic studies^39-41—but not others⁴²—found an inverse relationship between dietary intake of omega-3 fatty acids and risk of cognitive decline or dementia.

Related resources

• USDA Nutrient Data Laboratory. http://www.nalusda.gov/fnic/foodcomp (accessed Dec. 1, 2003)
• Stoll AL. The omega-3 connection: the groundbreaking omega-3 antidepression diet and brain program. New York: Simon and Schuster, 2001.

Drug brand names

• Clozapine • Clozaril

Disclosure

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

Potentially fatal neuroleptic malignant syndrome (NMS)—though less common than in the past—can happen with either conventional or atypical antipsychotics.^1,2 To help you protect patients when prescribing antipsychotics or consulting with other clinicians about these drugs, this article discusses:

• risk factors and clinical features that warn of NMS onset
• differential diagnosis of disease states most often confused with NMS
• management recommendations, including supportive measures and specific interventions such as benzodiazepines, dopamine agonists, dantrolene, and electroconvulsive therapy (ECT).

WHY NMS REMAINS RELEVANT

NMS remains a risk in susceptible patients receiving atypical antipsychotics, according to clinical reports and drug adverse event surveys (Figure).²

Moreover, NMS continues to be reported with conventional antipsychotics, which remain in widespread use. Patients who receive long-acting depot conventional antipsychotics are at risk for prolonged NMS episodes.

Figure 55 NMS cases reported with use of antipsychotics, 1998-2002

Probable or definite neuroleptic malignant syndrome cases associated with antipsychotic monotherapy reported to the Neuroleptic Malignant Syndrome Information Service.NMS in medical settings. Psychiatrists may be consulted when patients develop NMS while receiving conventional antipsychotics or other dopaminereceptor antagonists used in medical settings.^3,4 Haloperidol remains the recommended drug of choice for treating agitation and delirium and continues to be the single most common trigger of NMS. Although often overlooked, antiemetics and sedatives with neuroleptic properties—such as prochlorperazine, metoclopramide, and promethazine—also have triggered NMS.

Other hyperthermic conditions. NMS is often considered in the differential diagnosis of patients who develop fever or encephalopathy while being treated with psychotropics. In these acute, complex, and often grave situations, psychiatrists may be consulted to recommend treatment for behavioral control or to distinguish NMS from other conditions.

NEWER VS. OLDER ANTIPSYCHOTICS

Has NMS incidence declined with the atypical agents? Probably, but providing proof is difficult:

• NMS is uncommon; its incidence in psychiatric patients treated with conventional antipsychotics is approximately 0.2%.⁵ To demonstrate reduced NMS incidence with atypicals, a very large sample of patients would be required to reach statistical significance.
• As doctors have used lower doses of conventional agents—which reduces the risk of NMS—any beneficial impact from atypicals has become more difficult to detect.^5,6
• Reports of NMS frequency with atypicals may be inflated by bias in publishing adverse events with newer versus older agents.
• Patients switched to atypicals may represent a high-risk group that is intolerant or resistant to conventional antipsychotics.

So far, few unequivocal cases of NMS have been attributed to the use of quetiapine, ziprasidone, or aripiprazole, the most recently introduced atypicals. Moreover, case reports of NMS associated with clozapine, risperidone, or olanzapine² are often difficult to interpret because of incomplete clinical details, varying diagnostic criteria, and concomitant use of more than one antipsychotic.

Milder NMS? Do the newer antipsychotics produce an “atypical” or milder form of NMS? Case reports indicate that extreme temperature elevations and extrapyramidal dysfunction are less frequent in NMS associated with atypical compared with conventional antipsychotics.² However, case descriptions of NMS were heterogeneous even with conventional agents, and clinicians’ growing awareness of NMS even before atypicals were introduced allowed for earlier diagnosis of mild and partial NMS cases.⁷

CLINICAL FEATURES OF NMS

Regardless of drug selection, it is important to recognize early and mild signs of NMS. Any case can progress to a fulminant form that is more difficult to treat.

Patients at risk. NMS may be more likely to develop in patients with:^5,6,8

• dehydration
• agitation
• low serum iron
• underlying brain damage
• catatonia.

Some patients may have genetic abnormalities in central dopamine systems that increase their susceptibility to NMS.^6,9

Fifteen to 20% of patients who develop NMS have experienced a previous episode while taking antipsychotics, which is why taking a careful drug history is important.^5,6 Although most often reported with therapeutic antipsychotic doses, NMS has been associated with rapid dose titration, especially when given parenterally.⁸

On the other hand, the practical value of these risk factors is often limited in individual cases and may lead one to overestimate NMS risk. NMS is rare and idiosyncratic. Risk factors may not outweigh antipsychotics’ benefits when these drugs are indicated for a patient with psychosis.

Incipient NMS. Identifying early signs of NMS may be impossible in fulminant cases, but patients with incipient NMS may show:

• unexpected mental status changes
• new-onset catatonia
• refractory extrapyramidal and bulbar signs such as rigidity, dysphagia, or dysarthria.^5,7,10

Other clues to NMS onset include tachycardia, tachypnea, and elevated temperature or serum creatine phosphokinase (CPK). These signs, however, do not precede or progress to NMS in all cases. A high index of suspicion for NMS, tempered by sound clinical judgment, is called for when assessing all patients receiving antipsychotics.

Diagnostic criteria. Clinical signs of NMS as a fullblown hypermetabolic syndrome are distinctive and well described (Table 1).^5,6,11,12 Elevated temperature is accompanied by profuse sweating. Extreme temperatures (>104° F), especially if prolonged or associated with hypoxia or hypotension, pose a high risk for brain damage, rhabdomyolysis, disseminated intravascular coagulation, multisystem organ failure, and death.

Muscle rigidity is a characteristic finding and may be accompanied by tremors, cogwheeling, myoclonus, or rhabdomyolysis. Changes in vital signs—such as tachycardia and tachypnea—are typical.

Mental status examination usually reveals catatonic signs of mutism and stupor, but delirium and coma also have been described. No laboratory findings are specific for NMS, but elevated white blood cell counts, low serum iron, metabolic acidosis, hypoxia, and elevated serum CPK and catecholamines have been reported.

Table 1

Common clinical features of NMS

Resolution. If recognized promptly, NMS resolves within 1 to 2 weeks in two-thirds of patients after antipsychotics are discontinued. The average recovery time of 7 to 10 days may be prolonged in patients who were taking long-acting depot antipsychotics or in those with persistent residual catatonic symptoms.¹³

Risk of death. NMS remains potentially fatal, especially if high temperatures develop or episodes are prolonged. Causes of death include cardiorespiratory arrest, renal failure, pulmonary emboli, pneumonia, sepsis, disseminated intravascular coagulation, and multisystem organ failure.

DIFFERENTIAL DIAGNOSIS

Differential diagnosis of NMS encompasses disorders that present with fever and encephalopathy.^5,6,12 Primary brain disorders that resemble NMS include:^9,14-16

• infections
• acute psychotic disorders that progress to malignant catatonia or delirious mania
• midbrain structural lesions
• seizures.

Also exclude hormonal and autoimmune disorders and environmental heatstroke (Table 2).^17,18 Similar hyperthermic syndromes have been reported with other toxins and drugs, including malignant hyperthermia of anesthesia, serotonin syndrome, and dopamine agonist withdrawal in patients with Parkinson’s disease (Table 3).^5,6,19

Table 2

7 disease states most often confused with NMS

Table 3

Drugs that can cause NMS-like hyperthermic syndromes

MANAGING NMS

The standard approach to managing patients with NMS includes four steps:

• recognize the diagnosis early
• exclude alternate causes of symptoms
• discontinue suspected triggering drugs
• provide supportive care to reduce temperatures, ensure fluid balance, and detect complications.^5,6,20

Beyond supportive care, several specific therapies have been proposed based on theoretical mechanisms of NMS and meta-analyses of offlabel use in anecdotal clinical reports (Table 4). If benzodiazepines, dopamine agonists, or dantrolene are effective, taper slowly after recovery to prevent rebound symptoms.

Benzodiazepines. Given the concept of NMS as a form of catatonia, benzodiazepines have been used effectively in some cases.^20,21 A trial of lorazepam, 1 to 2 mg parenterally, is a reasonable first step. Higher doses may be required, with adequate monitoring of respiratory status. Oral lorazepam can maintain the therapeutic effect.

Dopamine agonists. To reverse the parkinsonism and dopamine antagonist properties of antipsychotics, dopamine agonists such as bromocriptine or amantadine have been tried and have reduced NMS duration and mortality.^20,22,23 Newer drugs such as ropinorole and pramipexole may also be useful. Dopaminergic drugs, however, can worsen psychosis and cause hypotension and emesis.

Dantrolene may reduce hyperthermia related to skeletal muscle hypermetabolism of any cause and has been effective in rapidly reducing extreme temperatures in some NMS cases.^20,22-26 Dantrolene is given IV, 1 to 2.5 mg/kg every 6 hours. An oral form can be substituted if a response is obtained. Dantrolene can impair respiratory and hepatic function and should not be combined with calcium channel blockers.

ECT is increasingly recognized as an effective NMS treatment and should not be overlooked for patients:

• who fail to respond to drug therapy or supportive care
• with residual catatonic symptoms.^13,20,27,28

Standard ECT is given, although nondepolarizing muscle relaxants instead of succinylcholine are used in patients with serious rhabdomyolysis to avoid the risk of hyperkalemia.²⁰

Recommendation. Although these modalities offer a spectrum of therapeutic options, it is premature to recommend any single remedy over others or over supportive care alone because:

• randomized, controlled trials have not been conducted
• NMS episodes are heterogeneous in presentation and outcome
• the syndrome is often self-limited after antipsychotics are discontinued.

I recommend that you choose therapies empirically, based on the character, severity, and duration of symptoms in a given case.^5,6,20

Table 4

How to treat neuroleptic malignant syndrome

REDUCING RISK OF RECURRENCE

Patients vary in susceptibility to recurrence after they recover from NMS, but the risk approaches 30% with future exposure to antipsychotics.^5,6 You may be able to minimize recurrence risk by:

• reducing risk factors, such as dehydration
• considering alternatives to antipsychotics, such as treating bipolar disorder with lithium or ECT
• using atypical instead of conventional antipsychotics, starting with low dosages and titrating slowly.

Before you reintroduce antipsychotics, carefully document informed consent and your rationale for treatment decisions in the patient’s chart.

Related resources

• Neuroleptic Malignant Syndrome Information Service. Hotline for health professionals. (888) 667-8367. www.nmsis.org
• Mann SC, Caroff SN, Keck PE Jr, Lazarus A. Neuroleptic malignant syndrome and related conditions (2nd ed). Washington, DC: American Psychiatric Publishing, 2003.
• Caroff SN, Mann SC, Francis A, Fricchione GL. Catatonia: from psychopathology to neurobiology. Washington, DC: American Psychiatric Publishing (in press).

Drug brand names

• Amantadine • Symmetrel
• Aripiprazole • Abilify
• Bromocriptine • Parlodel
• Clozapine • Clozaril
• Dantrolene • Dantrium
• Haloperidol • Haldol
• Lorazepam • Ativan
• Metoclopramide • Reglan
• Olanzapine • Zyprexa
• Pramipexole • Mirapex
• Prochlorperazine • Compazine
• Promethazine • Phenergan
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Ropinirole • Requip
• Ziprasidone • Geodon

Disclosure

Dr. Caroff receives research support from Janssen Pharmaceutica and Pfizer Inc., and is a consultant to Eli Lilly and Co. and Bristol-Myers Squibb Co.

Potentially fatal neuroleptic malignant syndrome (NMS)—though less common than in the past—can happen with either conventional or atypical antipsychotics.^1,2 To help you protect patients when prescribing antipsychotics or consulting with other clinicians about these drugs, this article discusses:

• risk factors and clinical features that warn of NMS onset
• differential diagnosis of disease states most often confused with NMS
• management recommendations, including supportive measures and specific interventions such as benzodiazepines, dopamine agonists, dantrolene, and electroconvulsive therapy (ECT).

WHY NMS REMAINS RELEVANT

NMS remains a risk in susceptible patients receiving atypical antipsychotics, according to clinical reports and drug adverse event surveys (Figure).²

Moreover, NMS continues to be reported with conventional antipsychotics, which remain in widespread use. Patients who receive long-acting depot conventional antipsychotics are at risk for prolonged NMS episodes.

Figure 55 NMS cases reported with use of antipsychotics, 1998-2002

Probable or definite neuroleptic malignant syndrome cases associated with antipsychotic monotherapy reported to the Neuroleptic Malignant Syndrome Information Service.NMS in medical settings. Psychiatrists may be consulted when patients develop NMS while receiving conventional antipsychotics or other dopaminereceptor antagonists used in medical settings.^3,4 Haloperidol remains the recommended drug of choice for treating agitation and delirium and continues to be the single most common trigger of NMS. Although often overlooked, antiemetics and sedatives with neuroleptic properties—such as prochlorperazine, metoclopramide, and promethazine—also have triggered NMS.

Other hyperthermic conditions. NMS is often considered in the differential diagnosis of patients who develop fever or encephalopathy while being treated with psychotropics. In these acute, complex, and often grave situations, psychiatrists may be consulted to recommend treatment for behavioral control or to distinguish NMS from other conditions.

NEWER VS. OLDER ANTIPSYCHOTICS

Has NMS incidence declined with the atypical agents? Probably, but providing proof is difficult:

• NMS is uncommon; its incidence in psychiatric patients treated with conventional antipsychotics is approximately 0.2%.⁵ To demonstrate reduced NMS incidence with atypicals, a very large sample of patients would be required to reach statistical significance.
• As doctors have used lower doses of conventional agents—which reduces the risk of NMS—any beneficial impact from atypicals has become more difficult to detect.^5,6
• Reports of NMS frequency with atypicals may be inflated by bias in publishing adverse events with newer versus older agents.
• Patients switched to atypicals may represent a high-risk group that is intolerant or resistant to conventional antipsychotics.

So far, few unequivocal cases of NMS have been attributed to the use of quetiapine, ziprasidone, or aripiprazole, the most recently introduced atypicals. Moreover, case reports of NMS associated with clozapine, risperidone, or olanzapine² are often difficult to interpret because of incomplete clinical details, varying diagnostic criteria, and concomitant use of more than one antipsychotic.

Milder NMS? Do the newer antipsychotics produce an “atypical” or milder form of NMS? Case reports indicate that extreme temperature elevations and extrapyramidal dysfunction are less frequent in NMS associated with atypical compared with conventional antipsychotics.² However, case descriptions of NMS were heterogeneous even with conventional agents, and clinicians’ growing awareness of NMS even before atypicals were introduced allowed for earlier diagnosis of mild and partial NMS cases.⁷

CLINICAL FEATURES OF NMS

Regardless of drug selection, it is important to recognize early and mild signs of NMS. Any case can progress to a fulminant form that is more difficult to treat.

Patients at risk. NMS may be more likely to develop in patients with:^5,6,8

• dehydration
• agitation
• low serum iron
• underlying brain damage
• catatonia.

Some patients may have genetic abnormalities in central dopamine systems that increase their susceptibility to NMS.^6,9

Fifteen to 20% of patients who develop NMS have experienced a previous episode while taking antipsychotics, which is why taking a careful drug history is important.^5,6 Although most often reported with therapeutic antipsychotic doses, NMS has been associated with rapid dose titration, especially when given parenterally.⁸

On the other hand, the practical value of these risk factors is often limited in individual cases and may lead one to overestimate NMS risk. NMS is rare and idiosyncratic. Risk factors may not outweigh antipsychotics’ benefits when these drugs are indicated for a patient with psychosis.

Incipient NMS. Identifying early signs of NMS may be impossible in fulminant cases, but patients with incipient NMS may show:

• unexpected mental status changes
• new-onset catatonia
• refractory extrapyramidal and bulbar signs such as rigidity, dysphagia, or dysarthria.^5,7,10

Other clues to NMS onset include tachycardia, tachypnea, and elevated temperature or serum creatine phosphokinase (CPK). These signs, however, do not precede or progress to NMS in all cases. A high index of suspicion for NMS, tempered by sound clinical judgment, is called for when assessing all patients receiving antipsychotics.

Diagnostic criteria. Clinical signs of NMS as a fullblown hypermetabolic syndrome are distinctive and well described (Table 1).^5,6,11,12 Elevated temperature is accompanied by profuse sweating. Extreme temperatures (>104° F), especially if prolonged or associated with hypoxia or hypotension, pose a high risk for brain damage, rhabdomyolysis, disseminated intravascular coagulation, multisystem organ failure, and death.

Muscle rigidity is a characteristic finding and may be accompanied by tremors, cogwheeling, myoclonus, or rhabdomyolysis. Changes in vital signs—such as tachycardia and tachypnea—are typical.

Mental status examination usually reveals catatonic signs of mutism and stupor, but delirium and coma also have been described. No laboratory findings are specific for NMS, but elevated white blood cell counts, low serum iron, metabolic acidosis, hypoxia, and elevated serum CPK and catecholamines have been reported.

Table 1

Common clinical features of NMS

Resolution. If recognized promptly, NMS resolves within 1 to 2 weeks in two-thirds of patients after antipsychotics are discontinued. The average recovery time of 7 to 10 days may be prolonged in patients who were taking long-acting depot antipsychotics or in those with persistent residual catatonic symptoms.¹³

Risk of death. NMS remains potentially fatal, especially if high temperatures develop or episodes are prolonged. Causes of death include cardiorespiratory arrest, renal failure, pulmonary emboli, pneumonia, sepsis, disseminated intravascular coagulation, and multisystem organ failure.

DIFFERENTIAL DIAGNOSIS

Differential diagnosis of NMS encompasses disorders that present with fever and encephalopathy.^5,6,12 Primary brain disorders that resemble NMS include:^9,14-16

• infections
• acute psychotic disorders that progress to malignant catatonia or delirious mania
• midbrain structural lesions
• seizures.

Also exclude hormonal and autoimmune disorders and environmental heatstroke (Table 2).^17,18 Similar hyperthermic syndromes have been reported with other toxins and drugs, including malignant hyperthermia of anesthesia, serotonin syndrome, and dopamine agonist withdrawal in patients with Parkinson’s disease (Table 3).^5,6,19

Table 2

7 disease states most often confused with NMS

Table 3

Drugs that can cause NMS-like hyperthermic syndromes

MANAGING NMS

The standard approach to managing patients with NMS includes four steps:

• recognize the diagnosis early
• exclude alternate causes of symptoms
• discontinue suspected triggering drugs
• provide supportive care to reduce temperatures, ensure fluid balance, and detect complications.^5,6,20

Beyond supportive care, several specific therapies have been proposed based on theoretical mechanisms of NMS and meta-analyses of offlabel use in anecdotal clinical reports (Table 4). If benzodiazepines, dopamine agonists, or dantrolene are effective, taper slowly after recovery to prevent rebound symptoms.

Benzodiazepines. Given the concept of NMS as a form of catatonia, benzodiazepines have been used effectively in some cases.^20,21 A trial of lorazepam, 1 to 2 mg parenterally, is a reasonable first step. Higher doses may be required, with adequate monitoring of respiratory status. Oral lorazepam can maintain the therapeutic effect.

Dopamine agonists. To reverse the parkinsonism and dopamine antagonist properties of antipsychotics, dopamine agonists such as bromocriptine or amantadine have been tried and have reduced NMS duration and mortality.^20,22,23 Newer drugs such as ropinorole and pramipexole may also be useful. Dopaminergic drugs, however, can worsen psychosis and cause hypotension and emesis.

Dantrolene may reduce hyperthermia related to skeletal muscle hypermetabolism of any cause and has been effective in rapidly reducing extreme temperatures in some NMS cases.^20,22-26 Dantrolene is given IV, 1 to 2.5 mg/kg every 6 hours. An oral form can be substituted if a response is obtained. Dantrolene can impair respiratory and hepatic function and should not be combined with calcium channel blockers.

ECT is increasingly recognized as an effective NMS treatment and should not be overlooked for patients:

• who fail to respond to drug therapy or supportive care
• with residual catatonic symptoms.^13,20,27,28

Standard ECT is given, although nondepolarizing muscle relaxants instead of succinylcholine are used in patients with serious rhabdomyolysis to avoid the risk of hyperkalemia.²⁰

Recommendation. Although these modalities offer a spectrum of therapeutic options, it is premature to recommend any single remedy over others or over supportive care alone because:

• randomized, controlled trials have not been conducted
• NMS episodes are heterogeneous in presentation and outcome
• the syndrome is often self-limited after antipsychotics are discontinued.

I recommend that you choose therapies empirically, based on the character, severity, and duration of symptoms in a given case.^5,6,20

Table 4

How to treat neuroleptic malignant syndrome

REDUCING RISK OF RECURRENCE

Patients vary in susceptibility to recurrence after they recover from NMS, but the risk approaches 30% with future exposure to antipsychotics.^5,6 You may be able to minimize recurrence risk by:

• reducing risk factors, such as dehydration
• considering alternatives to antipsychotics, such as treating bipolar disorder with lithium or ECT
• using atypical instead of conventional antipsychotics, starting with low dosages and titrating slowly.

Before you reintroduce antipsychotics, carefully document informed consent and your rationale for treatment decisions in the patient’s chart.

Related resources

• Neuroleptic Malignant Syndrome Information Service. Hotline for health professionals. (888) 667-8367. www.nmsis.org
• Mann SC, Caroff SN, Keck PE Jr, Lazarus A. Neuroleptic malignant syndrome and related conditions (2nd ed). Washington, DC: American Psychiatric Publishing, 2003.
• Caroff SN, Mann SC, Francis A, Fricchione GL. Catatonia: from psychopathology to neurobiology. Washington, DC: American Psychiatric Publishing (in press).

Drug brand names

• Amantadine • Symmetrel
• Aripiprazole • Abilify
• Bromocriptine • Parlodel
• Clozapine • Clozaril
• Dantrolene • Dantrium
• Haloperidol • Haldol
• Lorazepam • Ativan
• Metoclopramide • Reglan
• Olanzapine • Zyprexa
• Pramipexole • Mirapex
• Prochlorperazine • Compazine
• Promethazine • Phenergan
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Ropinirole • Requip
• Ziprasidone • Geodon

Disclosure

Dr. Caroff receives research support from Janssen Pharmaceutica and Pfizer Inc., and is a consultant to Eli Lilly and Co. and Bristol-Myers Squibb Co.

Potentially fatal neuroleptic malignant syndrome (NMS)—though less common than in the past—can happen with either conventional or atypical antipsychotics.^1,2 To help you protect patients when prescribing antipsychotics or consulting with other clinicians about these drugs, this article discusses:

• risk factors and clinical features that warn of NMS onset
• differential diagnosis of disease states most often confused with NMS
• management recommendations, including supportive measures and specific interventions such as benzodiazepines, dopamine agonists, dantrolene, and electroconvulsive therapy (ECT).

WHY NMS REMAINS RELEVANT

NMS remains a risk in susceptible patients receiving atypical antipsychotics, according to clinical reports and drug adverse event surveys (Figure).²

Moreover, NMS continues to be reported with conventional antipsychotics, which remain in widespread use. Patients who receive long-acting depot conventional antipsychotics are at risk for prolonged NMS episodes.

Figure 55 NMS cases reported with use of antipsychotics, 1998-2002

Probable or definite neuroleptic malignant syndrome cases associated with antipsychotic monotherapy reported to the Neuroleptic Malignant Syndrome Information Service.NMS in medical settings. Psychiatrists may be consulted when patients develop NMS while receiving conventional antipsychotics or other dopaminereceptor antagonists used in medical settings.^3,4 Haloperidol remains the recommended drug of choice for treating agitation and delirium and continues to be the single most common trigger of NMS. Although often overlooked, antiemetics and sedatives with neuroleptic properties—such as prochlorperazine, metoclopramide, and promethazine—also have triggered NMS.

Other hyperthermic conditions. NMS is often considered in the differential diagnosis of patients who develop fever or encephalopathy while being treated with psychotropics. In these acute, complex, and often grave situations, psychiatrists may be consulted to recommend treatment for behavioral control or to distinguish NMS from other conditions.

NEWER VS. OLDER ANTIPSYCHOTICS

Has NMS incidence declined with the atypical agents? Probably, but providing proof is difficult:

• NMS is uncommon; its incidence in psychiatric patients treated with conventional antipsychotics is approximately 0.2%.⁵ To demonstrate reduced NMS incidence with atypicals, a very large sample of patients would be required to reach statistical significance.
• As doctors have used lower doses of conventional agents—which reduces the risk of NMS—any beneficial impact from atypicals has become more difficult to detect.^5,6
• Reports of NMS frequency with atypicals may be inflated by bias in publishing adverse events with newer versus older agents.
• Patients switched to atypicals may represent a high-risk group that is intolerant or resistant to conventional antipsychotics.

So far, few unequivocal cases of NMS have been attributed to the use of quetiapine, ziprasidone, or aripiprazole, the most recently introduced atypicals. Moreover, case reports of NMS associated with clozapine, risperidone, or olanzapine² are often difficult to interpret because of incomplete clinical details, varying diagnostic criteria, and concomitant use of more than one antipsychotic.

Milder NMS? Do the newer antipsychotics produce an “atypical” or milder form of NMS? Case reports indicate that extreme temperature elevations and extrapyramidal dysfunction are less frequent in NMS associated with atypical compared with conventional antipsychotics.² However, case descriptions of NMS were heterogeneous even with conventional agents, and clinicians’ growing awareness of NMS even before atypicals were introduced allowed for earlier diagnosis of mild and partial NMS cases.⁷

CLINICAL FEATURES OF NMS

Regardless of drug selection, it is important to recognize early and mild signs of NMS. Any case can progress to a fulminant form that is more difficult to treat.

Patients at risk. NMS may be more likely to develop in patients with:^5,6,8

• dehydration
• agitation
• low serum iron
• underlying brain damage
• catatonia.

Some patients may have genetic abnormalities in central dopamine systems that increase their susceptibility to NMS.^6,9

Fifteen to 20% of patients who develop NMS have experienced a previous episode while taking antipsychotics, which is why taking a careful drug history is important.^5,6 Although most often reported with therapeutic antipsychotic doses, NMS has been associated with rapid dose titration, especially when given parenterally.⁸

On the other hand, the practical value of these risk factors is often limited in individual cases and may lead one to overestimate NMS risk. NMS is rare and idiosyncratic. Risk factors may not outweigh antipsychotics’ benefits when these drugs are indicated for a patient with psychosis.

Incipient NMS. Identifying early signs of NMS may be impossible in fulminant cases, but patients with incipient NMS may show:

• unexpected mental status changes
• new-onset catatonia
• refractory extrapyramidal and bulbar signs such as rigidity, dysphagia, or dysarthria.^5,7,10

Other clues to NMS onset include tachycardia, tachypnea, and elevated temperature or serum creatine phosphokinase (CPK). These signs, however, do not precede or progress to NMS in all cases. A high index of suspicion for NMS, tempered by sound clinical judgment, is called for when assessing all patients receiving antipsychotics.

Diagnostic criteria. Clinical signs of NMS as a fullblown hypermetabolic syndrome are distinctive and well described (Table 1).^5,6,11,12 Elevated temperature is accompanied by profuse sweating. Extreme temperatures (>104° F), especially if prolonged or associated with hypoxia or hypotension, pose a high risk for brain damage, rhabdomyolysis, disseminated intravascular coagulation, multisystem organ failure, and death.

Muscle rigidity is a characteristic finding and may be accompanied by tremors, cogwheeling, myoclonus, or rhabdomyolysis. Changes in vital signs—such as tachycardia and tachypnea—are typical.

Mental status examination usually reveals catatonic signs of mutism and stupor, but delirium and coma also have been described. No laboratory findings are specific for NMS, but elevated white blood cell counts, low serum iron, metabolic acidosis, hypoxia, and elevated serum CPK and catecholamines have been reported.

Table 1

Common clinical features of NMS

Resolution. If recognized promptly, NMS resolves within 1 to 2 weeks in two-thirds of patients after antipsychotics are discontinued. The average recovery time of 7 to 10 days may be prolonged in patients who were taking long-acting depot antipsychotics or in those with persistent residual catatonic symptoms.¹³

Risk of death. NMS remains potentially fatal, especially if high temperatures develop or episodes are prolonged. Causes of death include cardiorespiratory arrest, renal failure, pulmonary emboli, pneumonia, sepsis, disseminated intravascular coagulation, and multisystem organ failure.

DIFFERENTIAL DIAGNOSIS

Differential diagnosis of NMS encompasses disorders that present with fever and encephalopathy.^5,6,12 Primary brain disorders that resemble NMS include:^9,14-16

• infections
• acute psychotic disorders that progress to malignant catatonia or delirious mania
• midbrain structural lesions
• seizures.

Also exclude hormonal and autoimmune disorders and environmental heatstroke (Table 2).^17,18 Similar hyperthermic syndromes have been reported with other toxins and drugs, including malignant hyperthermia of anesthesia, serotonin syndrome, and dopamine agonist withdrawal in patients with Parkinson’s disease (Table 3).^5,6,19

Table 2

7 disease states most often confused with NMS

Table 3

Drugs that can cause NMS-like hyperthermic syndromes

MANAGING NMS

The standard approach to managing patients with NMS includes four steps:

• recognize the diagnosis early
• exclude alternate causes of symptoms
• discontinue suspected triggering drugs
• provide supportive care to reduce temperatures, ensure fluid balance, and detect complications.^5,6,20

Beyond supportive care, several specific therapies have been proposed based on theoretical mechanisms of NMS and meta-analyses of offlabel use in anecdotal clinical reports (Table 4). If benzodiazepines, dopamine agonists, or dantrolene are effective, taper slowly after recovery to prevent rebound symptoms.

Benzodiazepines. Given the concept of NMS as a form of catatonia, benzodiazepines have been used effectively in some cases.^20,21 A trial of lorazepam, 1 to 2 mg parenterally, is a reasonable first step. Higher doses may be required, with adequate monitoring of respiratory status. Oral lorazepam can maintain the therapeutic effect.

Dopamine agonists. To reverse the parkinsonism and dopamine antagonist properties of antipsychotics, dopamine agonists such as bromocriptine or amantadine have been tried and have reduced NMS duration and mortality.^20,22,23 Newer drugs such as ropinorole and pramipexole may also be useful. Dopaminergic drugs, however, can worsen psychosis and cause hypotension and emesis.

Dantrolene may reduce hyperthermia related to skeletal muscle hypermetabolism of any cause and has been effective in rapidly reducing extreme temperatures in some NMS cases.^20,22-26 Dantrolene is given IV, 1 to 2.5 mg/kg every 6 hours. An oral form can be substituted if a response is obtained. Dantrolene can impair respiratory and hepatic function and should not be combined with calcium channel blockers.

ECT is increasingly recognized as an effective NMS treatment and should not be overlooked for patients:

• who fail to respond to drug therapy or supportive care
• with residual catatonic symptoms.^13,20,27,28

Standard ECT is given, although nondepolarizing muscle relaxants instead of succinylcholine are used in patients with serious rhabdomyolysis to avoid the risk of hyperkalemia.²⁰

Recommendation. Although these modalities offer a spectrum of therapeutic options, it is premature to recommend any single remedy over others or over supportive care alone because:

• randomized, controlled trials have not been conducted
• NMS episodes are heterogeneous in presentation and outcome
• the syndrome is often self-limited after antipsychotics are discontinued.

I recommend that you choose therapies empirically, based on the character, severity, and duration of symptoms in a given case.^5,6,20

Table 4

How to treat neuroleptic malignant syndrome

REDUCING RISK OF RECURRENCE

Patients vary in susceptibility to recurrence after they recover from NMS, but the risk approaches 30% with future exposure to antipsychotics.^5,6 You may be able to minimize recurrence risk by:

• reducing risk factors, such as dehydration
• considering alternatives to antipsychotics, such as treating bipolar disorder with lithium or ECT
• using atypical instead of conventional antipsychotics, starting with low dosages and titrating slowly.

Before you reintroduce antipsychotics, carefully document informed consent and your rationale for treatment decisions in the patient’s chart.

Related resources

• Neuroleptic Malignant Syndrome Information Service. Hotline for health professionals. (888) 667-8367. www.nmsis.org
• Mann SC, Caroff SN, Keck PE Jr, Lazarus A. Neuroleptic malignant syndrome and related conditions (2nd ed). Washington, DC: American Psychiatric Publishing, 2003.
• Caroff SN, Mann SC, Francis A, Fricchione GL. Catatonia: from psychopathology to neurobiology. Washington, DC: American Psychiatric Publishing (in press).

Drug brand names

• Amantadine • Symmetrel
• Aripiprazole • Abilify
• Bromocriptine • Parlodel
• Clozapine • Clozaril
• Dantrolene • Dantrium
• Haloperidol • Haldol
• Lorazepam • Ativan
• Metoclopramide • Reglan
• Olanzapine • Zyprexa
• Pramipexole • Mirapex
• Prochlorperazine • Compazine
• Promethazine • Phenergan
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Ropinirole • Requip
• Ziprasidone • Geodon

Disclosure

Dr. Caroff receives research support from Janssen Pharmaceutica and Pfizer Inc., and is a consultant to Eli Lilly and Co. and Bristol-Myers Squibb Co.

Psychiatrists’ risk of malpractice liability¹ is broadening as courts consider the uncertainties of off-label prescribing, telemedicine, and confidentiality. Juries are holding mental health practitioners responsible for harm done both to and by psychiatric patients.

How you keep medical records, communicate with patients and colleagues, and arrange consultations can reduce your malpractice risk (Box 1).^4-9 We offer recommendations based on court decisions and other evidence for managing:

• traditional risks—such as patient violence and suicide, adverse drug reactions, sex with patients, faulty termination of treatment, and supervisory and consultative relationships⁴
• newer risks—such as recovered memory, off-label prescribing, practice guidelines, and e-mail and confidentiality.

Box 1

This article describes general guidelines and is not intended to constitute legal advice. All practitioners have a responsibility to know the laws of the jurisdictions in which they practice.

PREVENTING PATIENT VIOLENCE

The case that opened Pandora’s box. Prosenjit Poddar, a student at the University of California at Berkeley, was infatuated with coed Tanya Tarasoff and told his psychologist he intended to kill her. The psychologist notified his psychiatric supervisor and called campus police.

The psychologist told police Poddar was dangerous to himself and others. He stated that he would sign an emergency hold if they would bring Poddar to the hospital.

The police apprehended Poddar but released him. Poddar dropped out of therapy and 2 months later fatally stabbed Ms. Tarasoff.

Ms. Tarasoff’s parents sued those who treated Poddar and the University of California.² After a complicated legal course, the California Supreme Court ruled that once a therapist determines—or should have determined—that a patient poses a serious danger of violence to others, “he bears a duty to exercise reasonable care to protect the foreseeable victim of that danger.”³

The 1976 Tarasoff ruling has become a national standard of practice, leading to numerous other patient violence lawsuits. In these cases, psychiatrists are most likely to be found liable when recently released inpatients commit violent acts, particularly if the physician had reason to know the patient was dangerous and failed to take adequate precautions or appropriately assess the patient.⁴

Wider interpretations. Cases in several states have extended the Tarasoff ruling. In at least two cases, this standard has been applied when the patient threatened no specific victim before committing violence:

• A New Jersey court (McIntosh v. Milano, 1979) found a psychiatrist liable for malpractice on grounds that a therapist has a duty to protect society, just as a doctor must protect society by reporting carriers of dangerous diseases.
• A Nebraska court (Lipari v. Sears, Roebuck, and Co., 1980) held that physicians have a duty to protect—even if the specific identity of victims is unknown—so long as the physician should know that the patient presents an unreasonable risk of harm to others.²

Auto accidents. Tarasoff liability also has been extended to auto accidents. In Washington state (Petersen v. Washington, 1983), a psychiatrist was held liable for injuries to victims of an accident caused by a psychiatric patient. The court ruled that the psychiatrist had a duty to take reasonable precautions to protect any foreseeable persons from being endangered by the patient.

In a similar case in Wisconsin (Schuster and Schuster v. Altenberg, et al., 1988), the court ruled that damages could be awarded to anyone whose harm could have been prevented had the physician practiced according to professional standards.²

Other extensions include cases such as Naidu v. Laird, 1988, in which patient violence occurred more than 5 months after hospitalization.² Vermont has extended the Tarasoff precedent to property destruction by psychiatric patients.¹⁰

Recommendation. Most states require a psychiatrist to protect against only specific threats to identifiable victims.¹⁰ To defend yourself against a Tarasoff-type suit, you must show that you:

• carefully assessed the patient’s risk for violence
• provided appropriate care
• and took appropriate precautions.

The most protective evidence is a medical record documenting that you thoroughly assessed a patient for risk of violence (Table).^4,11

If you are unsure about how to manage a patient you believe may be dangerous to himself or others, consult with supervisors, peers, and legal advisors. Many states have Tarasoff-like statutes that specify the conditions that require action and the appropriate actions.

In states without specific statutes, options that generally satisfy Tarasoff requirements include hospitalizing the patient, notifying authorities, and/or warning the potential victim.¹⁰ As the Tarasoff case demonstrated, notifying authorities may not substitute for warning or hospitalizing.²

SUICIDE RISK? DOCUMENT CAREFULLY

Patient suicide accounts for one-fifth of claims covered by the American Psychiatric Association (APA) insurance plan.

In court, key points of challenge to a physician’s judgment in a suicide case include the admission evaluation and any status changes. Thorough risk assessment includes carefully reviewing existing records, evaluating risk factors for suicide, and seeking advice from colleagues or supervisors when appropriate.⁴

Recommendation. Document for every inpatient admission, discharge, or status change that the patient’s risk for suicide was assessed. List risk factors, protective factors, and risk for self-harm.

Explicitly address in the patient’s chart any comments about suicidality (such as heard by nursing staff).⁹ Document your rationale for medical decisions and orders, consistently follow unit policies, and explain risks and benefits of hospitalization to patients and their families.

Before discharge, schedule appropriate follow-up and make reasonable efforts to ensure medication adherence.⁴

SEX WITH PATIENTS IS UNPROTECTED

Sexual involvement with patients is indefensible and uncontestable in malpractice cases. Even so, up to 9% of male therapists and 3% of female therapists report in surveys that they have had sexual interaction with their patients.⁴

In 1985 the APA excluded sex with patients from its malpractice insurance coverage. Courts generally consider a treatment to be within the standard of care if a respectable minority of physicians consider it to be appropriate. Sex with patients is considered an absolute deviation from the standard of care, and no respectable minority of practitioners supports this practice. Because patients are substantially harmed, sex with patients is considered prima facie malpractice.¹²

Table

Is this patient dangerous? Risk factors for violence

WHEN MEDICATIONS CAUSE HARM

Adverse drug reactions—particularly tardive dyskinesia (TD)—are a source of significant losses in malpractice cases. Multimillion-dollar awards have been granted, especially when neuroleptic antipsychotics have been given in excessive dosages without proper monitoring.¹³

Informed consent has been a particularly difficult issue with the use of neuroleptic medications. Many doctors worry that patients who fear developing TD will not take prescribed neuroleptics. A study of North Carolina psychiatrists in the 1980s revealed that only 30% mentioned TD when telling their patients about neuroleptics’ possible side effects.¹³

The fact that a patient develops TD while taking an antipsychotic does not establish grounds for malpractice; a valid malpractice suit must also establish negligence. Negligence could include failing to obtain appropriate informed consent or continuing to prescribe an antipsychotic without adequately examining the patient.⁴

Informed consent does not require a patient to fully understand everything about a medication. The patient must understand the information a reasonable patient would want to know. Obvious misunderstandings must be corrected.

Recommendation. Consider informed consent a process, rather than one event—especially when you give neuroleptics for acute psychotic episodes. You can establish, review, and refresh consent in follow-up visits as medications help patients become more coherent and organized.

If you doubt a patient’s capacity to provide informed consent, a court determination may be necessary. In emergencies, however, treatment becomes a priority, even if the patient’s capacity to make rational decisions has not been established.¹³

TERMINATE TREATMENT WITH CAUTION

Terminating treatment can lead to malpractice, particularly if a patient becomes suicidal or violent. Psychiatrists have the right to choose their patients but cannot terminate care if a patient is acutely ill or requires emergency care.

Ensuring appropriate follow-up for patients at risk for decompensation often requires more than providing a referral or phone number. With the patient’s permission, for example, you could contact his subsequent psychiatrist or work with his support network to ensure that he receives follow-up care.¹⁴

Recommendation. With stable patients, send a written notice of termination and specify a reasonable period, usually 30 days. Send the letter by certified mail, and request a return receipt. Offer to help the patient find a new doctor, and say that you will forward the patient’s records to the new doctor when you receive appropriate release-of-information paperwork.¹⁵

LET THE SUPERVISOR BEWARE

Under the legal concept of respondeat superior (“let the master reply”), liability for the actions of subordinates may be transferred upward to the supervisor.⁴ For psychiatrists, supervisory liability obviously applies to teaching residents but may also apply in joint care, as with psychologists or social workers.

Recommendation. As a co-treating psychiatrist, you may be liable for other therapists’ actions unless you formally distinguish your role as a prescriber and not as a supervisor.⁹

When you prescribe medications for patients of nonphysician therapists, be sure you, the therapist, and patient understand the nature of your collaboration. Document the type of relationship and your discussion with the patient in the patient’s chart.

WATCH OUT FOR ‘CURBSIDE’ CONSULTS

Consult-liaison psychiatrists typically face a lower malpractice risk than do those who provide primary treatment. Duty to care for the patient is usually established by a formal consult request, after which the psychiatrist examines the patient and recommends treatment to the primary team.

You can, however, establish duty without meeting a patient. If sufficiently detailed, an informal “curbside” consult may establish a duty and corresponding liability¹⁶ (Box 2).^4,5,9,17.18

Liability is usually shared with the primary team but may be related to how much responsibility you assume in the patient’s care. Any direct treatment—electroconvulsive therapy, psychotherapy, prescribing, writing orders in the chart—can elevate your risk to the primary level. Similarly, if the patient is harmed because the primary treater followed a consulting psychiatrist’s negligent advice, the psychiatrist can be found solely liable.

When you recommend a treatment, you share a portion of liability for informed consent. If neither you nor the provider obtains appropriate informed consent, you may both share liability for adverse outcomes. Both teams also share the duty to report child and elder abuse.¹⁶

Recommendation. Establish an explicit division of responsibilities with the primary team, including who writes orders and manages medications and who provides follow-up and discharge planning.

For curbside consults, inform the primary physician that you are providing general information and not a specific treatment recommendation. If the case is too complicated for general information to be useful, a formal consultation would serve the patient better. In written consultations, specify:

• the reason for the consult
• the issues addressed
• and the parties responsible for follow-up.¹⁶

RECOVERED MEMORY? FORGET PROSECUTION

In 1994, a father successfully sued his daughter’s therapists for implanting false memories of incest. A California court awarded him $500,000 on grounds that the therapists owed a duty of care to the patient’s parents as well as to the patient. Since then, multimillion-dollar cases have been litigated on grounds of false recovered memories, and some insurers exclude coverage for “revival of memory.”¹²

Most therapists who have been found liable have strongly supported the accuracy of their patients’ memories. These memories have usually contained bizarre features, including satanic abuse, baby breeding, human sacrifice, and cannibalism. Therapists in these cases have often recommended that their patients press charges or file lawsuits against their alleged abusers.

Lawsuits against therapists have been won on grounds that they used unorthodox procedures without informed consent, negligently or recklessly implanted memories of abuse, negligently reinforced such memories, and failed to sufficiently investigate the memories’ accuracy.¹⁹

Box 2

Recommendation. Patients in therapy sometimes report newly found memories. To reduce your risk:

• obtain informed consent from patients before you begin any psychotherapy
• carefully document therapy session details when patients divulge new memories—particularly of abuse
• avoid encouraging patients to act on recovered memories.¹⁹

OFF-LABEL DRUG USE: KNOW THE LITERATURE

Off-label prescribing is both common and legal but may increase a physician’s liability risk if adverse events occur. Cases in Minnesota, Texas, and Louisiana have established precedents for using the Physician’s Desk Reference or package inserts to establish a standard of care.

In 1970 the Minnesota Supreme Court held that deviating from the package insert constituted prima facie evidence of negligence. This interpretation shifts the burden of proof from the plaintiff to the physician, who must then prove that he or she was not negligent when prescribing the drug.²⁰

Recommendation. Off-label prescribing is an important component of modern psychiatric care. Research supports most accepted off-label prescribing, at least to the point of establishing a respectable minority for a standard of care (Box 2).

When prescribing, know which indications are FDA-approved and which are off-label. For off-label prescribing, know the literature supporting that use and notify patients of off-label status as you document informed consent.²⁰

PROS AND CONS OF PRACTICE GUIDELINES

Clinical practice guidelines developed by professional organizations to assist physicians have also acquired legal ramifications. Difficult questions about guidelines include:

• Do they set the standard of care, or are they merely suggestions?
• Do they provide a defense against liability?
• How does a practitioner select between conflicting guidelines?

On the other hand, following clinical guidelines can protect you in cases with adverse outcomes. In a study of insurance company claims, approximately one-fourth of plaintiff’s attorneys who were surveyed said they had refused cases because the physician had followed practice guidelines. Conversely, one-fourth of defense attorneys said they had been influenced to settle cases because the physicians they represented had not followed practice guidelines.²¹

Liability cases involving practice guidelines have produced varying decisions. As a rule of thumb, courts tend to find that more-specific guidelines constitute a standard of care, whereas more-general guidelines are flexible suggestions.

Recommendation. If the court finds that existing guidelines establish the standard of care and your care has deviated from the guidelines with adverse consequences, the burden of proof shifts to you to prove that you were not negligent.¹⁸ When guidelines exist, know them and be prepared to defend decisions that deviate from them.

TELEMEDICINE: DANGERS IN CYBERSPACE

Unauthorized use or disclosure of patients’ electronic information can leave physicians liable for invasion of privacy and breach of confidentiality.²²

E-mail communication with a patient may also be sufficient to establish a duty of care, especially if the patient presents diagnostic information and the physician provides medical advice. Once duty to care is established, the physician is responsible for ongoing care or may face charges of abandonment.

Establishing duty to patients through e-mail is particularly troublesome, as patients may be writing from another state where you are not licensed to practice. Several states have explicitly forbidden unlicensed telemedicine; others have offered limited licenses for telemedicine practice.²²

Using e-mail to communicate with established patients introduces other liabilities. E-mail is legally considered part of the medical record and is subject to discovery in legal proceedings. Failure to preserve important patient e-mail may be evidence of negligence, especially in cases involving the medical record.

On the other hand, e-mail can be surprisingly permanent; it is virtually impossible to definitively delete e-mail that contains sensitive or embarrassing information. Deleted e-mail frequently can be recovered, and every e-mail exists in multiple copies, including the sender’s, the receiver’s, and at least one in a centralized server.²³

Recommendation. Reduce liability risks with informed consent if you use e-mail to communicate with existing patients. Minimize e-mail contact with nonestablished patients, and make sure the confidentiality of patients’ communications is secure.²²

Related resources

• Gutheil TG, Appelbaum PS. Clinical handbook of psychiatry and the law (3rd ed). Philadelphia: Lippincott Williams & Wilkins, 2000.
• American Psychiatric Association. Practice guidelines. http://www.psych.org/clin_res/prac_guide.cfm

Psychiatrists’ risk of malpractice liability¹ is broadening as courts consider the uncertainties of off-label prescribing, telemedicine, and confidentiality. Juries are holding mental health practitioners responsible for harm done both to and by psychiatric patients.

How you keep medical records, communicate with patients and colleagues, and arrange consultations can reduce your malpractice risk (Box 1).^4-9 We offer recommendations based on court decisions and other evidence for managing:

• traditional risks—such as patient violence and suicide, adverse drug reactions, sex with patients, faulty termination of treatment, and supervisory and consultative relationships⁴
• newer risks—such as recovered memory, off-label prescribing, practice guidelines, and e-mail and confidentiality.

Box 1

This article describes general guidelines and is not intended to constitute legal advice. All practitioners have a responsibility to know the laws of the jurisdictions in which they practice.

PREVENTING PATIENT VIOLENCE

The case that opened Pandora’s box. Prosenjit Poddar, a student at the University of California at Berkeley, was infatuated with coed Tanya Tarasoff and told his psychologist he intended to kill her. The psychologist notified his psychiatric supervisor and called campus police.

The psychologist told police Poddar was dangerous to himself and others. He stated that he would sign an emergency hold if they would bring Poddar to the hospital.

The police apprehended Poddar but released him. Poddar dropped out of therapy and 2 months later fatally stabbed Ms. Tarasoff.

Ms. Tarasoff’s parents sued those who treated Poddar and the University of California.² After a complicated legal course, the California Supreme Court ruled that once a therapist determines—or should have determined—that a patient poses a serious danger of violence to others, “he bears a duty to exercise reasonable care to protect the foreseeable victim of that danger.”³

The 1976 Tarasoff ruling has become a national standard of practice, leading to numerous other patient violence lawsuits. In these cases, psychiatrists are most likely to be found liable when recently released inpatients commit violent acts, particularly if the physician had reason to know the patient was dangerous and failed to take adequate precautions or appropriately assess the patient.⁴

Wider interpretations. Cases in several states have extended the Tarasoff ruling. In at least two cases, this standard has been applied when the patient threatened no specific victim before committing violence:

• A New Jersey court (McIntosh v. Milano, 1979) found a psychiatrist liable for malpractice on grounds that a therapist has a duty to protect society, just as a doctor must protect society by reporting carriers of dangerous diseases.
• A Nebraska court (Lipari v. Sears, Roebuck, and Co., 1980) held that physicians have a duty to protect—even if the specific identity of victims is unknown—so long as the physician should know that the patient presents an unreasonable risk of harm to others.²

Auto accidents. Tarasoff liability also has been extended to auto accidents. In Washington state (Petersen v. Washington, 1983), a psychiatrist was held liable for injuries to victims of an accident caused by a psychiatric patient. The court ruled that the psychiatrist had a duty to take reasonable precautions to protect any foreseeable persons from being endangered by the patient.

In a similar case in Wisconsin (Schuster and Schuster v. Altenberg, et al., 1988), the court ruled that damages could be awarded to anyone whose harm could have been prevented had the physician practiced according to professional standards.²

Other extensions include cases such as Naidu v. Laird, 1988, in which patient violence occurred more than 5 months after hospitalization.² Vermont has extended the Tarasoff precedent to property destruction by psychiatric patients.¹⁰

Recommendation. Most states require a psychiatrist to protect against only specific threats to identifiable victims.¹⁰ To defend yourself against a Tarasoff-type suit, you must show that you:

• carefully assessed the patient’s risk for violence
• provided appropriate care
• and took appropriate precautions.

The most protective evidence is a medical record documenting that you thoroughly assessed a patient for risk of violence (Table).^4,11

If you are unsure about how to manage a patient you believe may be dangerous to himself or others, consult with supervisors, peers, and legal advisors. Many states have Tarasoff-like statutes that specify the conditions that require action and the appropriate actions.

In states without specific statutes, options that generally satisfy Tarasoff requirements include hospitalizing the patient, notifying authorities, and/or warning the potential victim.¹⁰ As the Tarasoff case demonstrated, notifying authorities may not substitute for warning or hospitalizing.²

SUICIDE RISK? DOCUMENT CAREFULLY

Patient suicide accounts for one-fifth of claims covered by the American Psychiatric Association (APA) insurance plan.

In court, key points of challenge to a physician’s judgment in a suicide case include the admission evaluation and any status changes. Thorough risk assessment includes carefully reviewing existing records, evaluating risk factors for suicide, and seeking advice from colleagues or supervisors when appropriate.⁴

Recommendation. Document for every inpatient admission, discharge, or status change that the patient’s risk for suicide was assessed. List risk factors, protective factors, and risk for self-harm.

Explicitly address in the patient’s chart any comments about suicidality (such as heard by nursing staff).⁹ Document your rationale for medical decisions and orders, consistently follow unit policies, and explain risks and benefits of hospitalization to patients and their families.

Before discharge, schedule appropriate follow-up and make reasonable efforts to ensure medication adherence.⁴

SEX WITH PATIENTS IS UNPROTECTED

Sexual involvement with patients is indefensible and uncontestable in malpractice cases. Even so, up to 9% of male therapists and 3% of female therapists report in surveys that they have had sexual interaction with their patients.⁴

In 1985 the APA excluded sex with patients from its malpractice insurance coverage. Courts generally consider a treatment to be within the standard of care if a respectable minority of physicians consider it to be appropriate. Sex with patients is considered an absolute deviation from the standard of care, and no respectable minority of practitioners supports this practice. Because patients are substantially harmed, sex with patients is considered prima facie malpractice.¹²

Table

Is this patient dangerous? Risk factors for violence

WHEN MEDICATIONS CAUSE HARM

Adverse drug reactions—particularly tardive dyskinesia (TD)—are a source of significant losses in malpractice cases. Multimillion-dollar awards have been granted, especially when neuroleptic antipsychotics have been given in excessive dosages without proper monitoring.¹³

Informed consent has been a particularly difficult issue with the use of neuroleptic medications. Many doctors worry that patients who fear developing TD will not take prescribed neuroleptics. A study of North Carolina psychiatrists in the 1980s revealed that only 30% mentioned TD when telling their patients about neuroleptics’ possible side effects.¹³

The fact that a patient develops TD while taking an antipsychotic does not establish grounds for malpractice; a valid malpractice suit must also establish negligence. Negligence could include failing to obtain appropriate informed consent or continuing to prescribe an antipsychotic without adequately examining the patient.⁴

Informed consent does not require a patient to fully understand everything about a medication. The patient must understand the information a reasonable patient would want to know. Obvious misunderstandings must be corrected.

Recommendation. Consider informed consent a process, rather than one event—especially when you give neuroleptics for acute psychotic episodes. You can establish, review, and refresh consent in follow-up visits as medications help patients become more coherent and organized.

If you doubt a patient’s capacity to provide informed consent, a court determination may be necessary. In emergencies, however, treatment becomes a priority, even if the patient’s capacity to make rational decisions has not been established.¹³

TERMINATE TREATMENT WITH CAUTION

Terminating treatment can lead to malpractice, particularly if a patient becomes suicidal or violent. Psychiatrists have the right to choose their patients but cannot terminate care if a patient is acutely ill or requires emergency care.

Ensuring appropriate follow-up for patients at risk for decompensation often requires more than providing a referral or phone number. With the patient’s permission, for example, you could contact his subsequent psychiatrist or work with his support network to ensure that he receives follow-up care.¹⁴

Recommendation. With stable patients, send a written notice of termination and specify a reasonable period, usually 30 days. Send the letter by certified mail, and request a return receipt. Offer to help the patient find a new doctor, and say that you will forward the patient’s records to the new doctor when you receive appropriate release-of-information paperwork.¹⁵

LET THE SUPERVISOR BEWARE

Under the legal concept of respondeat superior (“let the master reply”), liability for the actions of subordinates may be transferred upward to the supervisor.⁴ For psychiatrists, supervisory liability obviously applies to teaching residents but may also apply in joint care, as with psychologists or social workers.

Recommendation. As a co-treating psychiatrist, you may be liable for other therapists’ actions unless you formally distinguish your role as a prescriber and not as a supervisor.⁹

When you prescribe medications for patients of nonphysician therapists, be sure you, the therapist, and patient understand the nature of your collaboration. Document the type of relationship and your discussion with the patient in the patient’s chart.

WATCH OUT FOR ‘CURBSIDE’ CONSULTS

Consult-liaison psychiatrists typically face a lower malpractice risk than do those who provide primary treatment. Duty to care for the patient is usually established by a formal consult request, after which the psychiatrist examines the patient and recommends treatment to the primary team.

You can, however, establish duty without meeting a patient. If sufficiently detailed, an informal “curbside” consult may establish a duty and corresponding liability¹⁶ (Box 2).^4,5,9,17.18

Liability is usually shared with the primary team but may be related to how much responsibility you assume in the patient’s care. Any direct treatment—electroconvulsive therapy, psychotherapy, prescribing, writing orders in the chart—can elevate your risk to the primary level. Similarly, if the patient is harmed because the primary treater followed a consulting psychiatrist’s negligent advice, the psychiatrist can be found solely liable.

When you recommend a treatment, you share a portion of liability for informed consent. If neither you nor the provider obtains appropriate informed consent, you may both share liability for adverse outcomes. Both teams also share the duty to report child and elder abuse.¹⁶

Recommendation. Establish an explicit division of responsibilities with the primary team, including who writes orders and manages medications and who provides follow-up and discharge planning.

For curbside consults, inform the primary physician that you are providing general information and not a specific treatment recommendation. If the case is too complicated for general information to be useful, a formal consultation would serve the patient better. In written consultations, specify:

• the reason for the consult
• the issues addressed
• and the parties responsible for follow-up.¹⁶

RECOVERED MEMORY? FORGET PROSECUTION

In 1994, a father successfully sued his daughter’s therapists for implanting false memories of incest. A California court awarded him $500,000 on grounds that the therapists owed a duty of care to the patient’s parents as well as to the patient. Since then, multimillion-dollar cases have been litigated on grounds of false recovered memories, and some insurers exclude coverage for “revival of memory.”¹²

Most therapists who have been found liable have strongly supported the accuracy of their patients’ memories. These memories have usually contained bizarre features, including satanic abuse, baby breeding, human sacrifice, and cannibalism. Therapists in these cases have often recommended that their patients press charges or file lawsuits against their alleged abusers.

Lawsuits against therapists have been won on grounds that they used unorthodox procedures without informed consent, negligently or recklessly implanted memories of abuse, negligently reinforced such memories, and failed to sufficiently investigate the memories’ accuracy.¹⁹

Box 2

Recommendation. Patients in therapy sometimes report newly found memories. To reduce your risk:

• obtain informed consent from patients before you begin any psychotherapy
• carefully document therapy session details when patients divulge new memories—particularly of abuse
• avoid encouraging patients to act on recovered memories.¹⁹

OFF-LABEL DRUG USE: KNOW THE LITERATURE

Off-label prescribing is both common and legal but may increase a physician’s liability risk if adverse events occur. Cases in Minnesota, Texas, and Louisiana have established precedents for using the Physician’s Desk Reference or package inserts to establish a standard of care.

In 1970 the Minnesota Supreme Court held that deviating from the package insert constituted prima facie evidence of negligence. This interpretation shifts the burden of proof from the plaintiff to the physician, who must then prove that he or she was not negligent when prescribing the drug.²⁰

Recommendation. Off-label prescribing is an important component of modern psychiatric care. Research supports most accepted off-label prescribing, at least to the point of establishing a respectable minority for a standard of care (Box 2).

When prescribing, know which indications are FDA-approved and which are off-label. For off-label prescribing, know the literature supporting that use and notify patients of off-label status as you document informed consent.²⁰

PROS AND CONS OF PRACTICE GUIDELINES

Clinical practice guidelines developed by professional organizations to assist physicians have also acquired legal ramifications. Difficult questions about guidelines include:

• Do they set the standard of care, or are they merely suggestions?
• Do they provide a defense against liability?
• How does a practitioner select between conflicting guidelines?

On the other hand, following clinical guidelines can protect you in cases with adverse outcomes. In a study of insurance company claims, approximately one-fourth of plaintiff’s attorneys who were surveyed said they had refused cases because the physician had followed practice guidelines. Conversely, one-fourth of defense attorneys said they had been influenced to settle cases because the physicians they represented had not followed practice guidelines.²¹

Liability cases involving practice guidelines have produced varying decisions. As a rule of thumb, courts tend to find that more-specific guidelines constitute a standard of care, whereas more-general guidelines are flexible suggestions.

Recommendation. If the court finds that existing guidelines establish the standard of care and your care has deviated from the guidelines with adverse consequences, the burden of proof shifts to you to prove that you were not negligent.¹⁸ When guidelines exist, know them and be prepared to defend decisions that deviate from them.

TELEMEDICINE: DANGERS IN CYBERSPACE

Unauthorized use or disclosure of patients’ electronic information can leave physicians liable for invasion of privacy and breach of confidentiality.²²

E-mail communication with a patient may also be sufficient to establish a duty of care, especially if the patient presents diagnostic information and the physician provides medical advice. Once duty to care is established, the physician is responsible for ongoing care or may face charges of abandonment.

Establishing duty to patients through e-mail is particularly troublesome, as patients may be writing from another state where you are not licensed to practice. Several states have explicitly forbidden unlicensed telemedicine; others have offered limited licenses for telemedicine practice.²²

Using e-mail to communicate with established patients introduces other liabilities. E-mail is legally considered part of the medical record and is subject to discovery in legal proceedings. Failure to preserve important patient e-mail may be evidence of negligence, especially in cases involving the medical record.

On the other hand, e-mail can be surprisingly permanent; it is virtually impossible to definitively delete e-mail that contains sensitive or embarrassing information. Deleted e-mail frequently can be recovered, and every e-mail exists in multiple copies, including the sender’s, the receiver’s, and at least one in a centralized server.²³

Recommendation. Reduce liability risks with informed consent if you use e-mail to communicate with existing patients. Minimize e-mail contact with nonestablished patients, and make sure the confidentiality of patients’ communications is secure.²²

Related resources

• Gutheil TG, Appelbaum PS. Clinical handbook of psychiatry and the law (3rd ed). Philadelphia: Lippincott Williams & Wilkins, 2000.
• American Psychiatric Association. Practice guidelines. http://www.psych.org/clin_res/prac_guide.cfm

Psychiatrists’ risk of malpractice liability¹ is broadening as courts consider the uncertainties of off-label prescribing, telemedicine, and confidentiality. Juries are holding mental health practitioners responsible for harm done both to and by psychiatric patients.

How you keep medical records, communicate with patients and colleagues, and arrange consultations can reduce your malpractice risk (Box 1).^4-9 We offer recommendations based on court decisions and other evidence for managing: