Evidence-Based Reviews

WEB AUDIO

Comment on this article

At least 25% and possibly up to 50% of patients with recurrent major depressive disorder (MDD) have features of mild hypomania (the “soft end” of the bipolar spectrum¹) and might be better conceptualized as suffering from a broadly defined bipolar (BP) II disorder.² The challenge is to differentiate MDD from BP II so that we make treatment decisions—such as antidepressants vs mood stabilizers—shown to improve the long-term course of patients’ depressive symptoms.

Diagnosis of BP II often is not straightforward and unfortunately may be delayed several years after patients first present for evaluation. To help clinicians make correct diagnostic decisions, this article:

• describes diagnostic criteria outside of DSM-IV-TR that can assist in identifying BP II disorder
  
• identifies subgroups of recurrently depressed patients whose primary disorder is more likely to be bipolar than unipolar
  
• provides a screening tool validated for identifying “soft” bipolarity
  
• offers a pragmatic clinical perspective on the treatment of BP II disorder.
  

How common is BP II disorder?

As with all psychiatric diagnoses, the prevalence of BP II disorder is a function of the diagnostic criteria used to define it.³ BP II—1 or more depressive episodes with at least 1 hypomanic episode—affects 1% to 2% of the population, based on DSM-IV-TR criteria for hypomania (Box 1). However, the DSM definition of BP II might be too restrictive. Regarding the diagnosis of hypomania, in particular:

• the symptom of “overactivity” should be given as much weight as the stem criteria of “euphoria” and “irritability”
  
• the 4-day threshold for a hypomanic episode probably is too long.
  

The fact that DSM-IV-TR does not associate hypomania with marked functional impairment is somewhat counterintuitive. Most clinicians would agree that functional impairment is a useful criterion for clinical diagnosis of any psychiatric syndrome.

These deficiencies in DSM-IV-TR exclude many patients who experience brief but clinically significant periods of hypomania. A more realistic definition of hypomania within BP II disorder would:

• include overactivity as an additional stem criterion
  
• specify a threshold duration for hypomanic symptoms of at least 1 day rather than 4 days
  
• stipulate the experience of negative consequences of the episode as necessary for the diagnosis (Table 1).
  

In long-term follow-up studies of several thousand individuals, Angst et al⁴ demonstrated that this definition of hypomania is clinically valid in terms of bipolar family history, treatment response, illness course, and clinical characteristics. When this broader definition of hypomania is used, population prevalence estimates for BP II rise from 1% to 2% to at least 5%.⁵

Box 1

Table 1

Proposed hypomania criteria in broadly defined BP II

A. Euphoria, irritability, or overactivity
B. At least 3 of the 7 DSM-IV-TR symptoms of hypomania
C. Hypomanic symptoms of at least 1 day’s duration
D. Experience of negative consequences of hypomanic periods
BP II: bipolar II disorder
Source: Reference 4

Depression’s subgroups

Recurrent MDD is an extremely heterogeneous diagnosis. It includes many clinical presentations of depressive illness that may share little in terms of etiology, pathophysiology, and response to treatment. When carefully assessed, 2 subgroups of recurrently depressed patients in particular appear to be more likely to have a primary bipolar disorder:

• young patients with early-onset severe depression
  
• older adults with difficult-to-treat or treatment-resistant depression.
  

A 15-year follow-up of young adults hospitalized with unipolar depression found that 27% subsequently developed hypomania and an additional 19% experienced at least 1 episode of mania.

 

⁶ Other reports have indicated that at least 40% of young adults with recurrent MDD satisfy broad diagnostic criteria for bipolar disorder.⁷

Higher rates of unrecognized bipolar disorder have been identified in patients with treatment-resistant depression. In a prospective study of 61 consecutive MDD patients referred to a mood disorders clinic, 59% satisfied DSM-IV-TR criteria for bipolar disorder.⁸

Consequences. Undiagnosed BP II disorder is an important clinical issue because bipolar features in patients presumed to have recurrent MDD can adversely affect long-term outcomes. Many of these patients will be treated exclusively with antidepressants despite evidence that antidepressant monotherapy for bipolar depression—at least for some patients—can cause more frequent mood episodes, mood destabilization, and possibly an increase in suicidal behaviors.^9,10

This point is highlighted in the United Kingdom’s National Institute of Health and Clinical Excellence (NICE) guidelines for bipolar disorder, which recommended that antidepressants be prescribed for bipolar depression only in combination with mood stabilizer treatment and withdrawn within 2 to 3 months of recovery.¹¹

The American Psychiatric Association’s (APA) practice guideline for treating bipolar disorder, published in 2002, advises against antidepressants as monotherapy for bipolar depression, recommending instead that lithium or lamotrigine be used first-line. A revised APA guideline is scheduled for publication this year.¹²

Why is BP II underdiagnosed?

Notwithstanding the limitations of DSMIV-TR criteria for hypomania, additional factors contribute to under-recognition of BP II in clinical practice.

Patient insight regarding hypomania is generally poor. Not surprisingly, individuals with severe and disabling depressive episodes often fail to recognize the pathological aspects of brief (and comparatively infrequent) periods of elevated mood and overactivity. For this reason, I always obtain a corroborative history from a relative when assessing a patient for possible bipolar disorder. I find this enormously helpful for confirming or excluding a BP II diagnosis.

Dominant depressive symptoms. The clinical course of bipolar disorders is dominated by low-grade depressive symptoms and recurrent depressive episodes rather than mania or hypomania. This is especially true for BP II disorder, where the ratio of time spent with depressive symptoms relative to time with hypomanic symptoms is approximately 30:1.¹³ The fact that BP II patients in general seek help only during depressive periods means that consultations inevitably focus on the diagnosis and treatment of depression, rather than long-term prophylaxis of both depressive and hypomanic episodes.

Indistinguishable symptoms? Bipolar depressions are generally thought to be clinically indistinguishable from unipolar depressions, but this might not be clear-cut. Although differentiating symptoms of unipolar and bipolar depression can be difficult in clinical practice, evidence suggests that certain symptoms may be more common in bipolar than unipolar depression:

• atypical depressive features such as mood reactivity, overeating, oversleeping, and excessive fatigue¹⁴
  
• depressive psychotic symptoms, especially in younger patients¹⁵
  
• “mixed” depressive episodes (depressive episodes with concurrent manic symptoms).¹⁶
  

Other variables are associated with bipolar outcome in apparently unipolar depression (Table 2). These include shorter but more frequent depressive episodes and a strong family history for mood disorders, such as a first-degree relative with bipolar disorder or multiple family members with MDD. BP II also tends to be highly comorbid with anxiety disorders, alcohol and drug abuse, and personality disorders (especially borderline personality disorder).

How to recognize BP II disorder

To detect and diagnose BP II disorder, systematically assess hypomanic features in all patients who present with recurrent MDD, especially those who have an early age of onset or don’t seem to be responding well to antidepressant monotherapy. As noted, a corroborative history from a close relative is essential. Within a full clinical assessment, use the features listed in Table 2 to help differentiate bipolar depression from unipolar depression.

Screening instruments for hypomania are no substitute for a careful psychiatric history but can be very helpful in everyday clinical practice. The most well-known is the Mood Disorder Questionnaire (MDQ);¹⁷ other options include the Hypomania Checklist (HCL-32)¹⁸ and the Bipolar Spectrum Diagnostic Scale (BSDS).¹⁹ In general, the MDQ performs better at detecting BP I in psychiatric practice settings, whereas the HCL-32 and BSDS may be more useful in primary care and general population settings.²⁰

The BSDS has a particular focus on the softer end of the bipolar spectrum,¹⁹ and in my experience patients like its narrative structure. It can help prompt discussions about previous hypomania symptoms and mood instability. In this sense, the BSDS is a useful adjunct to the routine clinical assessment of patients with recurrent depressive disorders. Click here to view the BSDS.

 

Table 2

Possible indicators of bipolarity in apparently unipolar depression

Atypical features
First-degree relative with bipolar disorder
Antidepressant-induced mania or hypomania
Multiple family members with major depression
Early onset of depression (age
Lack of response to ≥3 antidepressant trials
Psychotic features (before age 35)
Mixed depressive episodes
Brief but frequent episodes of depression
Complex comorbidity (anxiety disorders, drug and alcohol misuse, previous diagnosis of borderline personality disorder)
Source: References 2,13,14

Treatment strategies for BP II

As with all psychiatric disorders, treatment needs to multimodal and tailored to the individual. For a detailed assessment of pharmacologic and psychological options, see Goodwin and Jamison’s authoritative text, chapters 17 to 20.²¹

Pharmacologic options. Because few clinical trials have focused exclusively on BP II patients, much psychiatric practice has been extrapolated from trials involving BP I patients. Obviously, trials with BP II samples are needed, but these may be limited by the restrictive DSM-IV-TR definition of hypomania.

Lithium has the most supporting evidence, showing efficacy for all 3 phases of BP II—treatment of hypomania, treatment of bipolar depression, and prophylaxis against hypomanic and depressive relapses.²² Different medications used in bipolar disorder appear to have different efficacy profiles, however. For example, a systematic review of 14 randomized controlled trials with 2,526 patients found that although lithium, lamotrigine, olanzapine, and valproate were more effective than placebo at preventing relapse due to any mood episode:

• only lithium and olanzapine significantly reduced manic relapses
  
• only lamotrigine and valproate significantly reduced depressive relapses.²³
  

Most guidelines warn against antidepressant monotherapy for bipolar depression, but uncertainty and debate surround antidepressants’ effectiveness and risks (in terms of switching to mania or hypomania) when prescribed alongside mood stabilizers for bipolar depressive episodes.^10,24 In a study of nearly 600 patients with recurrent MDD, we found that those with a history of subthreshold manic symptoms were significantly more likely than those without manic features to respond poorly to antidepressants (P 25

The Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) trial did not find any therapeutic benefit or increased risk of switching to mania for anti depressants plus mood stabilizer vs mood stabilizer alone.²⁶ Many trials of bipolar depression have recruited such heterogeneous groups of patients (including BP I, BP II, and BP NOS; schizoaffective disorder, bipolar type; and even recurrent MDD) that it is difficult to make firm recommendations about pharmacologic options for the depressive phase of BP II disorder.

In my experience, approximately one-third of BP II patients have a history of poor response to antidepressants or adverse effects from antidepressants (extreme irritability, activation, and antidepressant-induced hypomania). In the long term, these patients often do much better on mood stabilizer monotherapy or a combination of mood stabilizers such as lithium plus lamotrigine. The key is to be flexible with treatment options within recommended guidelines and to tailor treatment choices to the individual’s pattern of illness and treatment preferences.

Placebo-controlled evidence supports the short-term (8 weeks) treatment of BP II depression with quetiapine monotherapy.²⁷ A recent systematic review and meta-analysis of individual patient data from randomized, controlled trials comparing lamotrigine with placebo found that lamotrigine has a modest beneficial effect on depressive symptoms in the depressed phase of bipolar disorder.²⁸

Psychological interventions. Some evidence supports cognitive-behavioral therapy (CBT) and interpersonal and social rhythm therapy (IPSRT) in long-term treatment of bipolar disorders, although—as with medication trials—we need to be careful about extrapolating these findings to BP II disorder.²⁹ For example, a recent large-scale randomized controlled trial of CBT for bipolar disorder was largely negative.³⁰ Psychoeducation given in families and groups can be effective long-term options when used as adjuncts to medications.³¹

Managing comorbidities. BP II tends to be a complex, highly comorbid disorder that requires a coordinated, multifaceted approach. Unfortunately, we know little about which combinations of pharmacologic and nonpharmacologic interventions are most beneficial for BP II patients with comorbidities such as alcohol abuse. For this reason, optimal long-term management of the BP II patient requires a high degree of skill, flexibility, and coordination within the treating clinical team (Table 3).

Table 3

Recommendations for treating patients with BP II disorder

Most BP II patients require a multimodal team approach
Look for and treat psychiatric comorbidities, such as alcohol abuse
Lithium remains a gold standard treatment for BP II disorder
Quetiapine or lamotrigine may be helpful for acute bipolar II depression
Avoid antidepressant monotherapy for bipolar depression; some patients should avoid antidepressants altogether
CBT and IPSRT are useful psychological interventions
Family-focused and group psychoeducation are helpful in the long term
Always tailor treatments to the individual
BP II: bipolar II disorder; CBT: cognitive-behavioral therapy; IPSRT: interpersonal and social rhythm therapy

 

Related Resources

• Goodwin GM and the Consensus Group of the British Association for Psychopharmacology. Evidence-based guidelines for treating bipolar disorder: revised second edition—recommendations from the British Association for Psychopharmacology. J Psychopharmacol. 2009;23(4):346-388. www.bap.org.uk/pdfs/Bipolar_guidelines.pdf.
  
• Goodwin FK, Jamison KR. Manic-depressive illness: bipolar disorders and recurrent depression. 2nd ed. New York, NY: Oxford University Press; 2007.
  
• Phelps J. Bipolar psychoeducation. www.psycheducation.org.
  
• Mood Disorders Treatment Team, Cardiff University. Interactive online psychoeducational treatment for bipolar disorder. www.BeatingBipolar.org.
  
• Goodwin GM, Geddes JR. What is the heartland of psychiatry? Br J Psychiatry. 2007;191(3):189-191.
  

Drug Brand Names

• Lamotrigine • Lamictal
  
• Lithium • Various
  
• Olanzapine • Zyprexa
  
• Quetiapine • Seroquel
  
• Valproate • Depakon
  

Disclosure

Dr. Smith receives research funding from the National Institute of Health Research UK, the MRC/Welsh Assembly Government, NARSAD, and the American Psychiatric Institute for Research and Education. He is a speaker for Eli Lilly and Company, AstraZeneca, and Bristol-Myers Squibb and is a consultant to Shire Pharmaceuticals.

WEB AUDIO

Comment on this article

At least 25% and possibly up to 50% of patients with recurrent major depressive disorder (MDD) have features of mild hypomania (the “soft end” of the bipolar spectrum¹) and might be better conceptualized as suffering from a broadly defined bipolar (BP) II disorder.² The challenge is to differentiate MDD from BP II so that we make treatment decisions—such as antidepressants vs mood stabilizers—shown to improve the long-term course of patients’ depressive symptoms.

Diagnosis of BP II often is not straightforward and unfortunately may be delayed several years after patients first present for evaluation. To help clinicians make correct diagnostic decisions, this article:

• describes diagnostic criteria outside of DSM-IV-TR that can assist in identifying BP II disorder
  
• identifies subgroups of recurrently depressed patients whose primary disorder is more likely to be bipolar than unipolar
  
• provides a screening tool validated for identifying “soft” bipolarity
  
• offers a pragmatic clinical perspective on the treatment of BP II disorder.
  

How common is BP II disorder?

As with all psychiatric diagnoses, the prevalence of BP II disorder is a function of the diagnostic criteria used to define it.³ BP II—1 or more depressive episodes with at least 1 hypomanic episode—affects 1% to 2% of the population, based on DSM-IV-TR criteria for hypomania (Box 1). However, the DSM definition of BP II might be too restrictive. Regarding the diagnosis of hypomania, in particular:

• the symptom of “overactivity” should be given as much weight as the stem criteria of “euphoria” and “irritability”
  
• the 4-day threshold for a hypomanic episode probably is too long.
  

The fact that DSM-IV-TR does not associate hypomania with marked functional impairment is somewhat counterintuitive. Most clinicians would agree that functional impairment is a useful criterion for clinical diagnosis of any psychiatric syndrome.

These deficiencies in DSM-IV-TR exclude many patients who experience brief but clinically significant periods of hypomania. A more realistic definition of hypomania within BP II disorder would:

• include overactivity as an additional stem criterion
  
• specify a threshold duration for hypomanic symptoms of at least 1 day rather than 4 days
  
• stipulate the experience of negative consequences of the episode as necessary for the diagnosis (Table 1).
  

In long-term follow-up studies of several thousand individuals, Angst et al⁴ demonstrated that this definition of hypomania is clinically valid in terms of bipolar family history, treatment response, illness course, and clinical characteristics. When this broader definition of hypomania is used, population prevalence estimates for BP II rise from 1% to 2% to at least 5%.⁵

Box 1

Table 1

Proposed hypomania criteria in broadly defined BP II

A. Euphoria, irritability, or overactivity
B. At least 3 of the 7 DSM-IV-TR symptoms of hypomania
C. Hypomanic symptoms of at least 1 day’s duration
D. Experience of negative consequences of hypomanic periods
BP II: bipolar II disorder
Source: Reference 4

Depression’s subgroups

Recurrent MDD is an extremely heterogeneous diagnosis. It includes many clinical presentations of depressive illness that may share little in terms of etiology, pathophysiology, and response to treatment. When carefully assessed, 2 subgroups of recurrently depressed patients in particular appear to be more likely to have a primary bipolar disorder:

• young patients with early-onset severe depression
  
• older adults with difficult-to-treat or treatment-resistant depression.
  

A 15-year follow-up of young adults hospitalized with unipolar depression found that 27% subsequently developed hypomania and an additional 19% experienced at least 1 episode of mania.

 

⁶ Other reports have indicated that at least 40% of young adults with recurrent MDD satisfy broad diagnostic criteria for bipolar disorder.⁷

Higher rates of unrecognized bipolar disorder have been identified in patients with treatment-resistant depression. In a prospective study of 61 consecutive MDD patients referred to a mood disorders clinic, 59% satisfied DSM-IV-TR criteria for bipolar disorder.⁸

Consequences. Undiagnosed BP II disorder is an important clinical issue because bipolar features in patients presumed to have recurrent MDD can adversely affect long-term outcomes. Many of these patients will be treated exclusively with antidepressants despite evidence that antidepressant monotherapy for bipolar depression—at least for some patients—can cause more frequent mood episodes, mood destabilization, and possibly an increase in suicidal behaviors.^9,10

This point is highlighted in the United Kingdom’s National Institute of Health and Clinical Excellence (NICE) guidelines for bipolar disorder, which recommended that antidepressants be prescribed for bipolar depression only in combination with mood stabilizer treatment and withdrawn within 2 to 3 months of recovery.¹¹

The American Psychiatric Association’s (APA) practice guideline for treating bipolar disorder, published in 2002, advises against antidepressants as monotherapy for bipolar depression, recommending instead that lithium or lamotrigine be used first-line. A revised APA guideline is scheduled for publication this year.¹²

Why is BP II underdiagnosed?

Notwithstanding the limitations of DSMIV-TR criteria for hypomania, additional factors contribute to under-recognition of BP II in clinical practice.

Patient insight regarding hypomania is generally poor. Not surprisingly, individuals with severe and disabling depressive episodes often fail to recognize the pathological aspects of brief (and comparatively infrequent) periods of elevated mood and overactivity. For this reason, I always obtain a corroborative history from a relative when assessing a patient for possible bipolar disorder. I find this enormously helpful for confirming or excluding a BP II diagnosis.

Dominant depressive symptoms. The clinical course of bipolar disorders is dominated by low-grade depressive symptoms and recurrent depressive episodes rather than mania or hypomania. This is especially true for BP II disorder, where the ratio of time spent with depressive symptoms relative to time with hypomanic symptoms is approximately 30:1.¹³ The fact that BP II patients in general seek help only during depressive periods means that consultations inevitably focus on the diagnosis and treatment of depression, rather than long-term prophylaxis of both depressive and hypomanic episodes.

Indistinguishable symptoms? Bipolar depressions are generally thought to be clinically indistinguishable from unipolar depressions, but this might not be clear-cut. Although differentiating symptoms of unipolar and bipolar depression can be difficult in clinical practice, evidence suggests that certain symptoms may be more common in bipolar than unipolar depression:

• atypical depressive features such as mood reactivity, overeating, oversleeping, and excessive fatigue¹⁴
  
• depressive psychotic symptoms, especially in younger patients¹⁵
  
• “mixed” depressive episodes (depressive episodes with concurrent manic symptoms).¹⁶
  

Other variables are associated with bipolar outcome in apparently unipolar depression (Table 2). These include shorter but more frequent depressive episodes and a strong family history for mood disorders, such as a first-degree relative with bipolar disorder or multiple family members with MDD. BP II also tends to be highly comorbid with anxiety disorders, alcohol and drug abuse, and personality disorders (especially borderline personality disorder).

How to recognize BP II disorder

To detect and diagnose BP II disorder, systematically assess hypomanic features in all patients who present with recurrent MDD, especially those who have an early age of onset or don’t seem to be responding well to antidepressant monotherapy. As noted, a corroborative history from a close relative is essential. Within a full clinical assessment, use the features listed in Table 2 to help differentiate bipolar depression from unipolar depression.

Screening instruments for hypomania are no substitute for a careful psychiatric history but can be very helpful in everyday clinical practice. The most well-known is the Mood Disorder Questionnaire (MDQ);¹⁷ other options include the Hypomania Checklist (HCL-32)¹⁸ and the Bipolar Spectrum Diagnostic Scale (BSDS).¹⁹ In general, the MDQ performs better at detecting BP I in psychiatric practice settings, whereas the HCL-32 and BSDS may be more useful in primary care and general population settings.²⁰

The BSDS has a particular focus on the softer end of the bipolar spectrum,¹⁹ and in my experience patients like its narrative structure. It can help prompt discussions about previous hypomania symptoms and mood instability. In this sense, the BSDS is a useful adjunct to the routine clinical assessment of patients with recurrent depressive disorders. Click here to view the BSDS.

 

Table 2

Possible indicators of bipolarity in apparently unipolar depression

Atypical features
First-degree relative with bipolar disorder
Antidepressant-induced mania or hypomania
Multiple family members with major depression
Early onset of depression (age
Lack of response to ≥3 antidepressant trials
Psychotic features (before age 35)
Mixed depressive episodes
Brief but frequent episodes of depression
Complex comorbidity (anxiety disorders, drug and alcohol misuse, previous diagnosis of borderline personality disorder)
Source: References 2,13,14

Treatment strategies for BP II

As with all psychiatric disorders, treatment needs to multimodal and tailored to the individual. For a detailed assessment of pharmacologic and psychological options, see Goodwin and Jamison’s authoritative text, chapters 17 to 20.²¹

Pharmacologic options. Because few clinical trials have focused exclusively on BP II patients, much psychiatric practice has been extrapolated from trials involving BP I patients. Obviously, trials with BP II samples are needed, but these may be limited by the restrictive DSM-IV-TR definition of hypomania.

Lithium has the most supporting evidence, showing efficacy for all 3 phases of BP II—treatment of hypomania, treatment of bipolar depression, and prophylaxis against hypomanic and depressive relapses.²² Different medications used in bipolar disorder appear to have different efficacy profiles, however. For example, a systematic review of 14 randomized controlled trials with 2,526 patients found that although lithium, lamotrigine, olanzapine, and valproate were more effective than placebo at preventing relapse due to any mood episode:

• only lithium and olanzapine significantly reduced manic relapses
  
• only lamotrigine and valproate significantly reduced depressive relapses.²³
  

Most guidelines warn against antidepressant monotherapy for bipolar depression, but uncertainty and debate surround antidepressants’ effectiveness and risks (in terms of switching to mania or hypomania) when prescribed alongside mood stabilizers for bipolar depressive episodes.^10,24 In a study of nearly 600 patients with recurrent MDD, we found that those with a history of subthreshold manic symptoms were significantly more likely than those without manic features to respond poorly to antidepressants (P 25

The Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) trial did not find any therapeutic benefit or increased risk of switching to mania for anti depressants plus mood stabilizer vs mood stabilizer alone.²⁶ Many trials of bipolar depression have recruited such heterogeneous groups of patients (including BP I, BP II, and BP NOS; schizoaffective disorder, bipolar type; and even recurrent MDD) that it is difficult to make firm recommendations about pharmacologic options for the depressive phase of BP II disorder.

In my experience, approximately one-third of BP II patients have a history of poor response to antidepressants or adverse effects from antidepressants (extreme irritability, activation, and antidepressant-induced hypomania). In the long term, these patients often do much better on mood stabilizer monotherapy or a combination of mood stabilizers such as lithium plus lamotrigine. The key is to be flexible with treatment options within recommended guidelines and to tailor treatment choices to the individual’s pattern of illness and treatment preferences.

Placebo-controlled evidence supports the short-term (8 weeks) treatment of BP II depression with quetiapine monotherapy.²⁷ A recent systematic review and meta-analysis of individual patient data from randomized, controlled trials comparing lamotrigine with placebo found that lamotrigine has a modest beneficial effect on depressive symptoms in the depressed phase of bipolar disorder.²⁸

Psychological interventions. Some evidence supports cognitive-behavioral therapy (CBT) and interpersonal and social rhythm therapy (IPSRT) in long-term treatment of bipolar disorders, although—as with medication trials—we need to be careful about extrapolating these findings to BP II disorder.²⁹ For example, a recent large-scale randomized controlled trial of CBT for bipolar disorder was largely negative.³⁰ Psychoeducation given in families and groups can be effective long-term options when used as adjuncts to medications.³¹

Managing comorbidities. BP II tends to be a complex, highly comorbid disorder that requires a coordinated, multifaceted approach. Unfortunately, we know little about which combinations of pharmacologic and nonpharmacologic interventions are most beneficial for BP II patients with comorbidities such as alcohol abuse. For this reason, optimal long-term management of the BP II patient requires a high degree of skill, flexibility, and coordination within the treating clinical team (Table 3).

Table 3

Recommendations for treating patients with BP II disorder

Most BP II patients require a multimodal team approach
Look for and treat psychiatric comorbidities, such as alcohol abuse
Lithium remains a gold standard treatment for BP II disorder
Quetiapine or lamotrigine may be helpful for acute bipolar II depression
Avoid antidepressant monotherapy for bipolar depression; some patients should avoid antidepressants altogether
CBT and IPSRT are useful psychological interventions
Family-focused and group psychoeducation are helpful in the long term
Always tailor treatments to the individual
BP II: bipolar II disorder; CBT: cognitive-behavioral therapy; IPSRT: interpersonal and social rhythm therapy

 

Related Resources

• Goodwin GM and the Consensus Group of the British Association for Psychopharmacology. Evidence-based guidelines for treating bipolar disorder: revised second edition—recommendations from the British Association for Psychopharmacology. J Psychopharmacol. 2009;23(4):346-388. www.bap.org.uk/pdfs/Bipolar_guidelines.pdf.
  
• Goodwin FK, Jamison KR. Manic-depressive illness: bipolar disorders and recurrent depression. 2nd ed. New York, NY: Oxford University Press; 2007.
  
• Phelps J. Bipolar psychoeducation. www.psycheducation.org.
  
• Mood Disorders Treatment Team, Cardiff University. Interactive online psychoeducational treatment for bipolar disorder. www.BeatingBipolar.org.
  
• Goodwin GM, Geddes JR. What is the heartland of psychiatry? Br J Psychiatry. 2007;191(3):189-191.
  

Drug Brand Names

• Lamotrigine • Lamictal
  
• Lithium • Various
  
• Olanzapine • Zyprexa
  
• Quetiapine • Seroquel
  
• Valproate • Depakon
  

Disclosure

Dr. Smith receives research funding from the National Institute of Health Research UK, the MRC/Welsh Assembly Government, NARSAD, and the American Psychiatric Institute for Research and Education. He is a speaker for Eli Lilly and Company, AstraZeneca, and Bristol-Myers Squibb and is a consultant to Shire Pharmaceuticals.

WEB AUDIO

Comment on this article

At least 25% and possibly up to 50% of patients with recurrent major depressive disorder (MDD) have features of mild hypomania (the “soft end” of the bipolar spectrum¹) and might be better conceptualized as suffering from a broadly defined bipolar (BP) II disorder.² The challenge is to differentiate MDD from BP II so that we make treatment decisions—such as antidepressants vs mood stabilizers—shown to improve the long-term course of patients’ depressive symptoms.

Diagnosis of BP II often is not straightforward and unfortunately may be delayed several years after patients first present for evaluation. To help clinicians make correct diagnostic decisions, this article:

• describes diagnostic criteria outside of DSM-IV-TR that can assist in identifying BP II disorder
  
• identifies subgroups of recurrently depressed patients whose primary disorder is more likely to be bipolar than unipolar
  
• provides a screening tool validated for identifying “soft” bipolarity
  
• offers a pragmatic clinical perspective on the treatment of BP II disorder.
  

How common is BP II disorder?

As with all psychiatric diagnoses, the prevalence of BP II disorder is a function of the diagnostic criteria used to define it.³ BP II—1 or more depressive episodes with at least 1 hypomanic episode—affects 1% to 2% of the population, based on DSM-IV-TR criteria for hypomania (Box 1). However, the DSM definition of BP II might be too restrictive. Regarding the diagnosis of hypomania, in particular:

• the symptom of “overactivity” should be given as much weight as the stem criteria of “euphoria” and “irritability”
  
• the 4-day threshold for a hypomanic episode probably is too long.
  

The fact that DSM-IV-TR does not associate hypomania with marked functional impairment is somewhat counterintuitive. Most clinicians would agree that functional impairment is a useful criterion for clinical diagnosis of any psychiatric syndrome.

These deficiencies in DSM-IV-TR exclude many patients who experience brief but clinically significant periods of hypomania. A more realistic definition of hypomania within BP II disorder would:

• include overactivity as an additional stem criterion
  
• specify a threshold duration for hypomanic symptoms of at least 1 day rather than 4 days
  
• stipulate the experience of negative consequences of the episode as necessary for the diagnosis (Table 1).
  

In long-term follow-up studies of several thousand individuals, Angst et al⁴ demonstrated that this definition of hypomania is clinically valid in terms of bipolar family history, treatment response, illness course, and clinical characteristics. When this broader definition of hypomania is used, population prevalence estimates for BP II rise from 1% to 2% to at least 5%.⁵

Box 1

Table 1

Proposed hypomania criteria in broadly defined BP II

A. Euphoria, irritability, or overactivity
B. At least 3 of the 7 DSM-IV-TR symptoms of hypomania
C. Hypomanic symptoms of at least 1 day’s duration
D. Experience of negative consequences of hypomanic periods
BP II: bipolar II disorder
Source: Reference 4

Depression’s subgroups

Recurrent MDD is an extremely heterogeneous diagnosis. It includes many clinical presentations of depressive illness that may share little in terms of etiology, pathophysiology, and response to treatment. When carefully assessed, 2 subgroups of recurrently depressed patients in particular appear to be more likely to have a primary bipolar disorder:

• young patients with early-onset severe depression
  
• older adults with difficult-to-treat or treatment-resistant depression.
  

A 15-year follow-up of young adults hospitalized with unipolar depression found that 27% subsequently developed hypomania and an additional 19% experienced at least 1 episode of mania.

 

⁶ Other reports have indicated that at least 40% of young adults with recurrent MDD satisfy broad diagnostic criteria for bipolar disorder.⁷

Higher rates of unrecognized bipolar disorder have been identified in patients with treatment-resistant depression. In a prospective study of 61 consecutive MDD patients referred to a mood disorders clinic, 59% satisfied DSM-IV-TR criteria for bipolar disorder.⁸

Consequences. Undiagnosed BP II disorder is an important clinical issue because bipolar features in patients presumed to have recurrent MDD can adversely affect long-term outcomes. Many of these patients will be treated exclusively with antidepressants despite evidence that antidepressant monotherapy for bipolar depression—at least for some patients—can cause more frequent mood episodes, mood destabilization, and possibly an increase in suicidal behaviors.^9,10

This point is highlighted in the United Kingdom’s National Institute of Health and Clinical Excellence (NICE) guidelines for bipolar disorder, which recommended that antidepressants be prescribed for bipolar depression only in combination with mood stabilizer treatment and withdrawn within 2 to 3 months of recovery.¹¹

The American Psychiatric Association’s (APA) practice guideline for treating bipolar disorder, published in 2002, advises against antidepressants as monotherapy for bipolar depression, recommending instead that lithium or lamotrigine be used first-line. A revised APA guideline is scheduled for publication this year.¹²

Why is BP II underdiagnosed?

Notwithstanding the limitations of DSMIV-TR criteria for hypomania, additional factors contribute to under-recognition of BP II in clinical practice.

Patient insight regarding hypomania is generally poor. Not surprisingly, individuals with severe and disabling depressive episodes often fail to recognize the pathological aspects of brief (and comparatively infrequent) periods of elevated mood and overactivity. For this reason, I always obtain a corroborative history from a relative when assessing a patient for possible bipolar disorder. I find this enormously helpful for confirming or excluding a BP II diagnosis.

Dominant depressive symptoms. The clinical course of bipolar disorders is dominated by low-grade depressive symptoms and recurrent depressive episodes rather than mania or hypomania. This is especially true for BP II disorder, where the ratio of time spent with depressive symptoms relative to time with hypomanic symptoms is approximately 30:1.¹³ The fact that BP II patients in general seek help only during depressive periods means that consultations inevitably focus on the diagnosis and treatment of depression, rather than long-term prophylaxis of both depressive and hypomanic episodes.

Indistinguishable symptoms? Bipolar depressions are generally thought to be clinically indistinguishable from unipolar depressions, but this might not be clear-cut. Although differentiating symptoms of unipolar and bipolar depression can be difficult in clinical practice, evidence suggests that certain symptoms may be more common in bipolar than unipolar depression:

• atypical depressive features such as mood reactivity, overeating, oversleeping, and excessive fatigue¹⁴
  
• depressive psychotic symptoms, especially in younger patients¹⁵
  
• “mixed” depressive episodes (depressive episodes with concurrent manic symptoms).¹⁶
  

Other variables are associated with bipolar outcome in apparently unipolar depression (Table 2). These include shorter but more frequent depressive episodes and a strong family history for mood disorders, such as a first-degree relative with bipolar disorder or multiple family members with MDD. BP II also tends to be highly comorbid with anxiety disorders, alcohol and drug abuse, and personality disorders (especially borderline personality disorder).

How to recognize BP II disorder

To detect and diagnose BP II disorder, systematically assess hypomanic features in all patients who present with recurrent MDD, especially those who have an early age of onset or don’t seem to be responding well to antidepressant monotherapy. As noted, a corroborative history from a close relative is essential. Within a full clinical assessment, use the features listed in Table 2 to help differentiate bipolar depression from unipolar depression.

Screening instruments for hypomania are no substitute for a careful psychiatric history but can be very helpful in everyday clinical practice. The most well-known is the Mood Disorder Questionnaire (MDQ);¹⁷ other options include the Hypomania Checklist (HCL-32)¹⁸ and the Bipolar Spectrum Diagnostic Scale (BSDS).¹⁹ In general, the MDQ performs better at detecting BP I in psychiatric practice settings, whereas the HCL-32 and BSDS may be more useful in primary care and general population settings.²⁰

The BSDS has a particular focus on the softer end of the bipolar spectrum,¹⁹ and in my experience patients like its narrative structure. It can help prompt discussions about previous hypomania symptoms and mood instability. In this sense, the BSDS is a useful adjunct to the routine clinical assessment of patients with recurrent depressive disorders. Click here to view the BSDS.

 

Table 2

Possible indicators of bipolarity in apparently unipolar depression

Atypical features
First-degree relative with bipolar disorder
Antidepressant-induced mania or hypomania
Multiple family members with major depression
Early onset of depression (age
Lack of response to ≥3 antidepressant trials
Psychotic features (before age 35)
Mixed depressive episodes
Brief but frequent episodes of depression
Complex comorbidity (anxiety disorders, drug and alcohol misuse, previous diagnosis of borderline personality disorder)
Source: References 2,13,14

Treatment strategies for BP II

As with all psychiatric disorders, treatment needs to multimodal and tailored to the individual. For a detailed assessment of pharmacologic and psychological options, see Goodwin and Jamison’s authoritative text, chapters 17 to 20.²¹

Pharmacologic options. Because few clinical trials have focused exclusively on BP II patients, much psychiatric practice has been extrapolated from trials involving BP I patients. Obviously, trials with BP II samples are needed, but these may be limited by the restrictive DSM-IV-TR definition of hypomania.

Lithium has the most supporting evidence, showing efficacy for all 3 phases of BP II—treatment of hypomania, treatment of bipolar depression, and prophylaxis against hypomanic and depressive relapses.²² Different medications used in bipolar disorder appear to have different efficacy profiles, however. For example, a systematic review of 14 randomized controlled trials with 2,526 patients found that although lithium, lamotrigine, olanzapine, and valproate were more effective than placebo at preventing relapse due to any mood episode:

• only lithium and olanzapine significantly reduced manic relapses
  
• only lamotrigine and valproate significantly reduced depressive relapses.²³
  

Most guidelines warn against antidepressant monotherapy for bipolar depression, but uncertainty and debate surround antidepressants’ effectiveness and risks (in terms of switching to mania or hypomania) when prescribed alongside mood stabilizers for bipolar depressive episodes.^10,24 In a study of nearly 600 patients with recurrent MDD, we found that those with a history of subthreshold manic symptoms were significantly more likely than those without manic features to respond poorly to antidepressants (P 25

The Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) trial did not find any therapeutic benefit or increased risk of switching to mania for anti depressants plus mood stabilizer vs mood stabilizer alone.²⁶ Many trials of bipolar depression have recruited such heterogeneous groups of patients (including BP I, BP II, and BP NOS; schizoaffective disorder, bipolar type; and even recurrent MDD) that it is difficult to make firm recommendations about pharmacologic options for the depressive phase of BP II disorder.

In my experience, approximately one-third of BP II patients have a history of poor response to antidepressants or adverse effects from antidepressants (extreme irritability, activation, and antidepressant-induced hypomania). In the long term, these patients often do much better on mood stabilizer monotherapy or a combination of mood stabilizers such as lithium plus lamotrigine. The key is to be flexible with treatment options within recommended guidelines and to tailor treatment choices to the individual’s pattern of illness and treatment preferences.

Placebo-controlled evidence supports the short-term (8 weeks) treatment of BP II depression with quetiapine monotherapy.²⁷ A recent systematic review and meta-analysis of individual patient data from randomized, controlled trials comparing lamotrigine with placebo found that lamotrigine has a modest beneficial effect on depressive symptoms in the depressed phase of bipolar disorder.²⁸

Psychological interventions. Some evidence supports cognitive-behavioral therapy (CBT) and interpersonal and social rhythm therapy (IPSRT) in long-term treatment of bipolar disorders, although—as with medication trials—we need to be careful about extrapolating these findings to BP II disorder.²⁹ For example, a recent large-scale randomized controlled trial of CBT for bipolar disorder was largely negative.³⁰ Psychoeducation given in families and groups can be effective long-term options when used as adjuncts to medications.³¹

Managing comorbidities. BP II tends to be a complex, highly comorbid disorder that requires a coordinated, multifaceted approach. Unfortunately, we know little about which combinations of pharmacologic and nonpharmacologic interventions are most beneficial for BP II patients with comorbidities such as alcohol abuse. For this reason, optimal long-term management of the BP II patient requires a high degree of skill, flexibility, and coordination within the treating clinical team (Table 3).

Table 3

Recommendations for treating patients with BP II disorder

Most BP II patients require a multimodal team approach
Look for and treat psychiatric comorbidities, such as alcohol abuse
Lithium remains a gold standard treatment for BP II disorder
Quetiapine or lamotrigine may be helpful for acute bipolar II depression
Avoid antidepressant monotherapy for bipolar depression; some patients should avoid antidepressants altogether
CBT and IPSRT are useful psychological interventions
Family-focused and group psychoeducation are helpful in the long term
Always tailor treatments to the individual
BP II: bipolar II disorder; CBT: cognitive-behavioral therapy; IPSRT: interpersonal and social rhythm therapy

 

Related Resources

• Goodwin GM and the Consensus Group of the British Association for Psychopharmacology. Evidence-based guidelines for treating bipolar disorder: revised second edition—recommendations from the British Association for Psychopharmacology. J Psychopharmacol. 2009;23(4):346-388. www.bap.org.uk/pdfs/Bipolar_guidelines.pdf.
  
• Goodwin FK, Jamison KR. Manic-depressive illness: bipolar disorders and recurrent depression. 2nd ed. New York, NY: Oxford University Press; 2007.
  
• Phelps J. Bipolar psychoeducation. www.psycheducation.org.
  
• Mood Disorders Treatment Team, Cardiff University. Interactive online psychoeducational treatment for bipolar disorder. www.BeatingBipolar.org.
  
• Goodwin GM, Geddes JR. What is the heartland of psychiatry? Br J Psychiatry. 2007;191(3):189-191.
  

Drug Brand Names

• Lamotrigine • Lamictal
  
• Lithium • Various
  
• Olanzapine • Zyprexa
  
• Quetiapine • Seroquel
  
• Valproate • Depakon
  

Disclosure

Dr. Smith receives research funding from the National Institute of Health Research UK, the MRC/Welsh Assembly Government, NARSAD, and the American Psychiatric Institute for Research and Education. He is a speaker for Eli Lilly and Company, AstraZeneca, and Bristol-Myers Squibb and is a consultant to Shire Pharmaceuticals.

Comment on this article

Police take Ms. L, age 23, to the emergency room (ER) after her fiancé called them. He told the police that after a “night of drinking” they argued about a girl he had flirted with. Ms. L took out a loaded gun and threatened to shoot herself. She eventually handed the gun over to the police.

In the ER, Ms. L’s blood alcohol level is 0.20%. She tells the admitting emergency room nurse, “I would never hurt myself. I drank too much and was acting stupid. I just want to go home and sleep it off. I promise not to harm myself.” Emergency room staff observe Ms. L smile and giggle while waiting for a psychiatric evaluation.

What would you do? Hospitalize Ms. L for safety, or accept her promise not to hurt herself and send her home? What criteria would you use?

Knowing how to assess patients such as Ms. L is an essential psychiatric skill, whether or not you trained in forensic psychiatry. This article includes case reports that illustrate techniques for evaluating patients who may harbor suicidal or homicidal thoughts.

Evaluating danger to self

Your role is to weigh an individual’s risk factors for suicide against potential protective factors and to make a judgment call. Potential risk factors for suicide include (but are not limited to):

• current suicidal thoughts
  
• prior suicide attempts
  
• presence of a comorbid psychiatric disorder (particularly depression)
  
• intoxication or ongoing substance use
  
• feelings of hopelessness
  
• marked anxiety
  
• recent stressors
  
• family history of suicide
  
• lack of psychosocial support.¹
  

Not all factors will be present or relevant in every individual. See questions in Table 1 to further evaluate suicidality in patients who report suicidal thoughts.

Also review information that is reasonably available. In the ER, records from other facilities or private psychiatric treatment notes may not be accessed easily. However, in addition to conducting a suicide risk assessment and mental status examination, consider reviewing the collateral information outlined in Table 2.

Do not rely solely on an intoxicated patient’s word that he or she will not self-harm because such statements may not represent the person’s sober state of mind. Use caution in basing a release decision on an intoxicated person’s statements.

Furthermore, do not rely on “no-suicide” contracts. They do not guarantee that a person won’t attempt suicide, and they will not provide legal protection if the patient commits suicide after being released from your care.²

What to document. After completing your evaluation, specifically document:

• that a suicide risk assessment was conducted
  
• what risk factors were present
  
• interventions to address those risk factors
  
• the level of risk determined (minimal, moderate, or high)
  
• factors that may protect the patient against suicide.
  

Protective factors include a desire to live for their family or children, strong psychosocial support in the patient’s life, and the removal of an acute stressor associated with suicidal thinking.³

Table 1

Evaluating suicidality: Sample questions to ask

Do you wish you were dead?
Do you have thoughts about harming yourself?
Do you have an actual plan as to how you would harm yourself? If yes: Have you taken any steps to enact that plan? If so, what were they?
Have you ever attempted suicide before? If yes: What stopped you from enacting this plan? What do you think would keep you from acting on this plan in the future?
Has anyone in your family or close to you committed suicide?
How close have you come to killing yourself?

Table 2

Sources of information to assess suicidality in the ER

Police reports on circumstances that led the patient to come to the ER
ER nursing/physician notes
Family members’/friends’ statements regarding reasons for the patient’s visit
Observations by anyone assigned to monitor the patient while awaiting your consult
Laboratory and physical exam findings, particularly related to substance use and/or self-injurious behavior
Psychiatric records at that facility
Concerns expressed by anyone responsible for the patient if he/she is released from the hospital
ER: emergency room

CASE REPORT: Paranoid and armed

Mr. J, age 21, is brought involuntarily to the psychiatric ER by police. His mother reports he was locked in his room with a gun, claiming “the FBI is going to kill me.”

Mr. J’s mother tells the ER psychiatrist that her son has schizophrenia, paranoid type, and stopped taking risperidone, 3 mg/d, 4 weeks ago. She explains that Mr. J sometimes “hears voices” whispering to him that his medications are poison and to not trust his family. She states that Mr. J also abuses alcohol and methamphetamine and has 2 prior arrests for assault with a deadly weapon.

 

She adds that Mr. J now believes his family is working with the FBI to have him placed in a “secret detention camp.” Mr. J’s mother found a loaded pistol in his room and is “scared of what might happen.” During your psychiatric interview, Mr. J appears frightened and paranoid and provides only minimal answers to your questions. He clenches his teeth while staring intently at you.

Evaluating danger to others

There is good reason to be concerned that Mr. J might behave violently, and you likely have sufficient information to hospitalize him. When creating a long-term violence risk prevention plan, divide the concept of dangerousness into 5 components:

• magnitude of potential harm
  
• likelihood that harm will occur
  
• imminence of harm
  
• frequency of dangerous behavior
  
• situational variables that promote or protect against aggressive behavior.
  

Review a patient’s history of violence because this is the single best predictor of future violent behavior.⁴ Criminal and court records are particularly useful in evaluating the person’s history of violence. Table 3 provides sample questions for eliciting information about a person’s history of violence when records are not readily available.

A person who has used weapons against others may pose a serious risk of future violence. Ask patients whether they own or have ever owned a weapon. In our experience, the recent movement of a weapon—such as transferring a gun from a closet to a nightstand—is particularly ominous in a paranoid person. The greater the psychotic fear, the more likely a paranoid person is to kill someone he misperceives as a persecutor.

Drugs and alcohol are strongly associated with violent behavior.⁵ Most persons involved in violent crimes are under the influence of alcohol or drugs at the time of their aggression.⁶ Stimulants such as cocaine, crack, amphetamines, and phencyclidine are of special concern. These drugs often are associated with feelings of disinhibition, a sense of power, and paranoia. The violence linked with cocaine use differs by gender: men are more likely to perpetrate violent crimes, whereas women are more likely to be the victims of violence.⁷

Table 3

10 questions to ask patients about a history of violence

What is the most violent thing you have ever done?
What types of violent behavior have you engaged in?
What is your understanding of why this violence occurred?
Who was involved in prior violent incidents?
Have you ever been arrested for any type of violent act?
Have you ever been intoxicated at the time you were violent?
Were you experiencing mental health symptoms when violent?
What is the greatest degree of injury you inflicted on someone else?
What weapons have you used when violent?
Have you ever been a victim of violence?

Mental illness and violence

Studies examining whether individuals with mental illness are more violent than the non-mentally ill have yielded mixed results.^8,9 In a study of civilly committed psychiatric patients released into the community, most mentally ill individuals were not violent.¹⁰ Although researchers noted a weak relationship between mental illness and violence, violent conduct was greater only when the person was experiencing acute psychiatric symptoms. Subsequent research suggests that individuals with schizophrenia may have increased rates of violence even when not experiencing active signs of their illness.¹¹

Psychosis. In paranoid psychotic patients, violence often is well planned and in line with their false beliefs.¹² These patients usually direct the violence at a specific person they perceive as a persecutor. Paranoid individuals often target relatives or friends. In addition, community-dwelling paranoid persons are more likely to be dangerous because they have greater access to weapons than institutionalized patients.¹²

Carefully inquire about hallucinations—particularly auditory ones—to determine whether their presence increases the person’s risk to commit a violent act. Patients with schizophrenia are more likely to be violent if their auditory hallucinations generate negative emotions (anger, anxiety, or sadness) and if the patients have not developed successful coping strategies.¹³ Although most patients ignore violent command hallucinations to harm others, the presence of command hallucinations may increase the likelihood of behaving violently,¹⁴ particularly if:

• the voice is familiar to the person,¹⁵ and
  
• the person has delusional beliefs associated with the hallucinations.¹⁶
  

Depression. Individuals who are depressed may strike out against others in despair. After committing a violent act, a depressed person may attempt suicide. Depression is the most common psychiatric diagnosis in murder-suicides.¹⁷ Patients with mania often engage in assaultive or threatening behavior, but serious physical violence is rare.¹² Patients with mania most commonly exhibit violent behavior when they are restrained or have limits set on their behavior.

 

¹⁸

Antisocial personality disorder (APD). Violence by those with APD often is motivated by revenge or occurs during a period of heavy drinking. Violent behavior by these persons frequently is cold, calculated, and lacks emotionality.¹⁹

In addition to DSM-IV-TR personality disorders, be familiar with the psychological construct known as psychopathy. Cleckley²⁰ used the term psychopath to describe a person who is superficially charming, lacks close relationships, is impulsive, and is primarily concerned with self-gratification. Hare et al²¹ developed the Psychopathy Checklist-Revised as a validated measure of psychopathy in adults. Psychopathy is a strong predictor of criminal behavior and violence among adults.²²

Affect. Individuals who are angry and lack empathy for others are at increased risk for violent behavior.²³ Also observe the patient for physical signs and symptoms of changes indicating incipient violence. Berg et al²⁴ noted that signs of imminent violence can include:

• chanting
  
• clenched jaw
  
• flared nostrils
  
• flushed face
  
• darting eyes
  
• close proximity to the clinician
  
• clenched or gripping hands.
  

Asking patients if they are experiencing homicidal ideations may not always elicit important information regarding a patient’s potential thoughts about harming others. For example, in persons who report feeling persecuted, ask what they would do if they came face-to-face with the individual they fear. Some patients may report that they would attempt to avoid all contact to minimize their personal risk. Others might feel a need to make a preemptive strike for protective purposes. In neither situation would the patient have reported experiencing homicidal thoughts.

Static vs dynamic factors. When organizing strategies to decrease risk factors for violence, distinguish static from dynamic factors. Static factors include demographic information and history of violence. Dynamic factors, which are subject to change with intervention, include access to weapons, psychotic symptoms, active substance use, and a person’s living situation.

Organizing a chart that outlines known risk factors, interventions to address dynamic risk factors, and the status of each risk factor/intervention may be helpful. Table 4 provides an example of such a chart for Mr. J. This approach can help you develop a violence prevention plan that addresses each patient’s combination of risk factors.

Table 4

Sample violence risk management chart for Mr. J

Risk factor	Intervention	Status
Paranoia	Antipsychotic medication	Admitted to inpatient psychiatric facility; antipsychotic medications ordered with continued assessments of mental status
Antipsychotic medication nonadherence	Depot form of antipsychotic	Mr. J agreed to depot medication
Gun at home	Remove guns	His mother removed all guns from home
Alcohol and methamphetamine abuse	Evaluate for potential alcohol detox; urine drug screen on admission	Mr. J refused group substance treatment in the hospital; substance use treatment in the community to be arranged prior to discharge

Finally, be familiar with jurisdictional requirements that govern duties to warn or protect third parties your patient may have threatened.

Related resource

• Simon RI, Hales RE, eds. The American Psychiatric Publishing textbook of suicide assessment and management. Arlington, VA: American Psychiatric Publishing, Inc; 2006.
  
• Simon RI, Tardiff K, eds. Textbook of violence assessment and management. Arlington, VA: American Psychiatric Publishing, Inc; 2008.
  

Drug brand names

• Risperidone • Risperdal
  

Disclosure

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

Comment on this article

Police take Ms. L, age 23, to the emergency room (ER) after her fiancé called them. He told the police that after a “night of drinking” they argued about a girl he had flirted with. Ms. L took out a loaded gun and threatened to shoot herself. She eventually handed the gun over to the police.

In the ER, Ms. L’s blood alcohol level is 0.20%. She tells the admitting emergency room nurse, “I would never hurt myself. I drank too much and was acting stupid. I just want to go home and sleep it off. I promise not to harm myself.” Emergency room staff observe Ms. L smile and giggle while waiting for a psychiatric evaluation.

What would you do? Hospitalize Ms. L for safety, or accept her promise not to hurt herself and send her home? What criteria would you use?

Knowing how to assess patients such as Ms. L is an essential psychiatric skill, whether or not you trained in forensic psychiatry. This article includes case reports that illustrate techniques for evaluating patients who may harbor suicidal or homicidal thoughts.

Evaluating danger to self

Your role is to weigh an individual’s risk factors for suicide against potential protective factors and to make a judgment call. Potential risk factors for suicide include (but are not limited to):

• current suicidal thoughts
  
• prior suicide attempts
  
• presence of a comorbid psychiatric disorder (particularly depression)
  
• intoxication or ongoing substance use
  
• feelings of hopelessness
  
• marked anxiety
  
• recent stressors
  
• family history of suicide
  
• lack of psychosocial support.¹
  

Not all factors will be present or relevant in every individual. See questions in Table 1 to further evaluate suicidality in patients who report suicidal thoughts.

Also review information that is reasonably available. In the ER, records from other facilities or private psychiatric treatment notes may not be accessed easily. However, in addition to conducting a suicide risk assessment and mental status examination, consider reviewing the collateral information outlined in Table 2.

Do not rely solely on an intoxicated patient’s word that he or she will not self-harm because such statements may not represent the person’s sober state of mind. Use caution in basing a release decision on an intoxicated person’s statements.

Furthermore, do not rely on “no-suicide” contracts. They do not guarantee that a person won’t attempt suicide, and they will not provide legal protection if the patient commits suicide after being released from your care.²

What to document. After completing your evaluation, specifically document:

• that a suicide risk assessment was conducted
  
• what risk factors were present
  
• interventions to address those risk factors
  
• the level of risk determined (minimal, moderate, or high)
  
• factors that may protect the patient against suicide.
  

Protective factors include a desire to live for their family or children, strong psychosocial support in the patient’s life, and the removal of an acute stressor associated with suicidal thinking.³

Table 1

Evaluating suicidality: Sample questions to ask

Do you wish you were dead?
Do you have thoughts about harming yourself?
Do you have an actual plan as to how you would harm yourself? If yes: Have you taken any steps to enact that plan? If so, what were they?
Have you ever attempted suicide before? If yes: What stopped you from enacting this plan? What do you think would keep you from acting on this plan in the future?
Has anyone in your family or close to you committed suicide?
How close have you come to killing yourself?

Table 2

Sources of information to assess suicidality in the ER

Police reports on circumstances that led the patient to come to the ER
ER nursing/physician notes
Family members’/friends’ statements regarding reasons for the patient’s visit
Observations by anyone assigned to monitor the patient while awaiting your consult
Laboratory and physical exam findings, particularly related to substance use and/or self-injurious behavior
Psychiatric records at that facility
Concerns expressed by anyone responsible for the patient if he/she is released from the hospital
ER: emergency room

CASE REPORT: Paranoid and armed

Mr. J, age 21, is brought involuntarily to the psychiatric ER by police. His mother reports he was locked in his room with a gun, claiming “the FBI is going to kill me.”

Mr. J’s mother tells the ER psychiatrist that her son has schizophrenia, paranoid type, and stopped taking risperidone, 3 mg/d, 4 weeks ago. She explains that Mr. J sometimes “hears voices” whispering to him that his medications are poison and to not trust his family. She states that Mr. J also abuses alcohol and methamphetamine and has 2 prior arrests for assault with a deadly weapon.

 

She adds that Mr. J now believes his family is working with the FBI to have him placed in a “secret detention camp.” Mr. J’s mother found a loaded pistol in his room and is “scared of what might happen.” During your psychiatric interview, Mr. J appears frightened and paranoid and provides only minimal answers to your questions. He clenches his teeth while staring intently at you.

Evaluating danger to others

There is good reason to be concerned that Mr. J might behave violently, and you likely have sufficient information to hospitalize him. When creating a long-term violence risk prevention plan, divide the concept of dangerousness into 5 components:

• magnitude of potential harm
  
• likelihood that harm will occur
  
• imminence of harm
  
• frequency of dangerous behavior
  
• situational variables that promote or protect against aggressive behavior.
  

Review a patient’s history of violence because this is the single best predictor of future violent behavior.⁴ Criminal and court records are particularly useful in evaluating the person’s history of violence. Table 3 provides sample questions for eliciting information about a person’s history of violence when records are not readily available.

A person who has used weapons against others may pose a serious risk of future violence. Ask patients whether they own or have ever owned a weapon. In our experience, the recent movement of a weapon—such as transferring a gun from a closet to a nightstand—is particularly ominous in a paranoid person. The greater the psychotic fear, the more likely a paranoid person is to kill someone he misperceives as a persecutor.

Drugs and alcohol are strongly associated with violent behavior.⁵ Most persons involved in violent crimes are under the influence of alcohol or drugs at the time of their aggression.⁶ Stimulants such as cocaine, crack, amphetamines, and phencyclidine are of special concern. These drugs often are associated with feelings of disinhibition, a sense of power, and paranoia. The violence linked with cocaine use differs by gender: men are more likely to perpetrate violent crimes, whereas women are more likely to be the victims of violence.⁷

Table 3

10 questions to ask patients about a history of violence

What is the most violent thing you have ever done?
What types of violent behavior have you engaged in?
What is your understanding of why this violence occurred?
Who was involved in prior violent incidents?
Have you ever been arrested for any type of violent act?
Have you ever been intoxicated at the time you were violent?
Were you experiencing mental health symptoms when violent?
What is the greatest degree of injury you inflicted on someone else?
What weapons have you used when violent?
Have you ever been a victim of violence?

Mental illness and violence

Studies examining whether individuals with mental illness are more violent than the non-mentally ill have yielded mixed results.^8,9 In a study of civilly committed psychiatric patients released into the community, most mentally ill individuals were not violent.¹⁰ Although researchers noted a weak relationship between mental illness and violence, violent conduct was greater only when the person was experiencing acute psychiatric symptoms. Subsequent research suggests that individuals with schizophrenia may have increased rates of violence even when not experiencing active signs of their illness.¹¹

Psychosis. In paranoid psychotic patients, violence often is well planned and in line with their false beliefs.¹² These patients usually direct the violence at a specific person they perceive as a persecutor. Paranoid individuals often target relatives or friends. In addition, community-dwelling paranoid persons are more likely to be dangerous because they have greater access to weapons than institutionalized patients.¹²

Carefully inquire about hallucinations—particularly auditory ones—to determine whether their presence increases the person’s risk to commit a violent act. Patients with schizophrenia are more likely to be violent if their auditory hallucinations generate negative emotions (anger, anxiety, or sadness) and if the patients have not developed successful coping strategies.¹³ Although most patients ignore violent command hallucinations to harm others, the presence of command hallucinations may increase the likelihood of behaving violently,¹⁴ particularly if:

• the voice is familiar to the person,¹⁵ and
  
• the person has delusional beliefs associated with the hallucinations.¹⁶
  

Depression. Individuals who are depressed may strike out against others in despair. After committing a violent act, a depressed person may attempt suicide. Depression is the most common psychiatric diagnosis in murder-suicides.¹⁷ Patients with mania often engage in assaultive or threatening behavior, but serious physical violence is rare.¹² Patients with mania most commonly exhibit violent behavior when they are restrained or have limits set on their behavior.

 

¹⁸

Antisocial personality disorder (APD). Violence by those with APD often is motivated by revenge or occurs during a period of heavy drinking. Violent behavior by these persons frequently is cold, calculated, and lacks emotionality.¹⁹

In addition to DSM-IV-TR personality disorders, be familiar with the psychological construct known as psychopathy. Cleckley²⁰ used the term psychopath to describe a person who is superficially charming, lacks close relationships, is impulsive, and is primarily concerned with self-gratification. Hare et al²¹ developed the Psychopathy Checklist-Revised as a validated measure of psychopathy in adults. Psychopathy is a strong predictor of criminal behavior and violence among adults.²²

Affect. Individuals who are angry and lack empathy for others are at increased risk for violent behavior.²³ Also observe the patient for physical signs and symptoms of changes indicating incipient violence. Berg et al²⁴ noted that signs of imminent violence can include:

• chanting
  
• clenched jaw
  
• flared nostrils
  
• flushed face
  
• darting eyes
  
• close proximity to the clinician
  
• clenched or gripping hands.
  

Asking patients if they are experiencing homicidal ideations may not always elicit important information regarding a patient’s potential thoughts about harming others. For example, in persons who report feeling persecuted, ask what they would do if they came face-to-face with the individual they fear. Some patients may report that they would attempt to avoid all contact to minimize their personal risk. Others might feel a need to make a preemptive strike for protective purposes. In neither situation would the patient have reported experiencing homicidal thoughts.

Static vs dynamic factors. When organizing strategies to decrease risk factors for violence, distinguish static from dynamic factors. Static factors include demographic information and history of violence. Dynamic factors, which are subject to change with intervention, include access to weapons, psychotic symptoms, active substance use, and a person’s living situation.

Organizing a chart that outlines known risk factors, interventions to address dynamic risk factors, and the status of each risk factor/intervention may be helpful. Table 4 provides an example of such a chart for Mr. J. This approach can help you develop a violence prevention plan that addresses each patient’s combination of risk factors.

Table 4

Sample violence risk management chart for Mr. J

Risk factor	Intervention	Status
Paranoia	Antipsychotic medication	Admitted to inpatient psychiatric facility; antipsychotic medications ordered with continued assessments of mental status
Antipsychotic medication nonadherence	Depot form of antipsychotic	Mr. J agreed to depot medication
Gun at home	Remove guns	His mother removed all guns from home
Alcohol and methamphetamine abuse	Evaluate for potential alcohol detox; urine drug screen on admission	Mr. J refused group substance treatment in the hospital; substance use treatment in the community to be arranged prior to discharge

Finally, be familiar with jurisdictional requirements that govern duties to warn or protect third parties your patient may have threatened.

Related resource

• Simon RI, Hales RE, eds. The American Psychiatric Publishing textbook of suicide assessment and management. Arlington, VA: American Psychiatric Publishing, Inc; 2006.
  
• Simon RI, Tardiff K, eds. Textbook of violence assessment and management. Arlington, VA: American Psychiatric Publishing, Inc; 2008.
  

Drug brand names

• Risperidone • Risperdal
  

Disclosure

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

Comment on this article

Police take Ms. L, age 23, to the emergency room (ER) after her fiancé called them. He told the police that after a “night of drinking” they argued about a girl he had flirted with. Ms. L took out a loaded gun and threatened to shoot herself. She eventually handed the gun over to the police.

In the ER, Ms. L’s blood alcohol level is 0.20%. She tells the admitting emergency room nurse, “I would never hurt myself. I drank too much and was acting stupid. I just want to go home and sleep it off. I promise not to harm myself.” Emergency room staff observe Ms. L smile and giggle while waiting for a psychiatric evaluation.

What would you do? Hospitalize Ms. L for safety, or accept her promise not to hurt herself and send her home? What criteria would you use?

Knowing how to assess patients such as Ms. L is an essential psychiatric skill, whether or not you trained in forensic psychiatry. This article includes case reports that illustrate techniques for evaluating patients who may harbor suicidal or homicidal thoughts.

Evaluating danger to self

Your role is to weigh an individual’s risk factors for suicide against potential protective factors and to make a judgment call. Potential risk factors for suicide include (but are not limited to):

• current suicidal thoughts
  
• prior suicide attempts
  
• presence of a comorbid psychiatric disorder (particularly depression)
  
• intoxication or ongoing substance use
  
• feelings of hopelessness
  
• marked anxiety
  
• recent stressors
  
• family history of suicide
  
• lack of psychosocial support.¹
  

Not all factors will be present or relevant in every individual. See questions in Table 1 to further evaluate suicidality in patients who report suicidal thoughts.

Also review information that is reasonably available. In the ER, records from other facilities or private psychiatric treatment notes may not be accessed easily. However, in addition to conducting a suicide risk assessment and mental status examination, consider reviewing the collateral information outlined in Table 2.

Do not rely solely on an intoxicated patient’s word that he or she will not self-harm because such statements may not represent the person’s sober state of mind. Use caution in basing a release decision on an intoxicated person’s statements.

Furthermore, do not rely on “no-suicide” contracts. They do not guarantee that a person won’t attempt suicide, and they will not provide legal protection if the patient commits suicide after being released from your care.²

What to document. After completing your evaluation, specifically document:

• that a suicide risk assessment was conducted
  
• what risk factors were present
  
• interventions to address those risk factors
  
• the level of risk determined (minimal, moderate, or high)
  
• factors that may protect the patient against suicide.
  

Protective factors include a desire to live for their family or children, strong psychosocial support in the patient’s life, and the removal of an acute stressor associated with suicidal thinking.³

Table 1

Evaluating suicidality: Sample questions to ask

Do you wish you were dead?
Do you have thoughts about harming yourself?
Do you have an actual plan as to how you would harm yourself? If yes: Have you taken any steps to enact that plan? If so, what were they?
Have you ever attempted suicide before? If yes: What stopped you from enacting this plan? What do you think would keep you from acting on this plan in the future?
Has anyone in your family or close to you committed suicide?
How close have you come to killing yourself?

Table 2

Sources of information to assess suicidality in the ER

Police reports on circumstances that led the patient to come to the ER
ER nursing/physician notes
Family members’/friends’ statements regarding reasons for the patient’s visit
Observations by anyone assigned to monitor the patient while awaiting your consult
Laboratory and physical exam findings, particularly related to substance use and/or self-injurious behavior
Psychiatric records at that facility
Concerns expressed by anyone responsible for the patient if he/she is released from the hospital
ER: emergency room

CASE REPORT: Paranoid and armed

Mr. J, age 21, is brought involuntarily to the psychiatric ER by police. His mother reports he was locked in his room with a gun, claiming “the FBI is going to kill me.”

Mr. J’s mother tells the ER psychiatrist that her son has schizophrenia, paranoid type, and stopped taking risperidone, 3 mg/d, 4 weeks ago. She explains that Mr. J sometimes “hears voices” whispering to him that his medications are poison and to not trust his family. She states that Mr. J also abuses alcohol and methamphetamine and has 2 prior arrests for assault with a deadly weapon.

 

She adds that Mr. J now believes his family is working with the FBI to have him placed in a “secret detention camp.” Mr. J’s mother found a loaded pistol in his room and is “scared of what might happen.” During your psychiatric interview, Mr. J appears frightened and paranoid and provides only minimal answers to your questions. He clenches his teeth while staring intently at you.

Evaluating danger to others

There is good reason to be concerned that Mr. J might behave violently, and you likely have sufficient information to hospitalize him. When creating a long-term violence risk prevention plan, divide the concept of dangerousness into 5 components:

• magnitude of potential harm
  
• likelihood that harm will occur
  
• imminence of harm
  
• frequency of dangerous behavior
  
• situational variables that promote or protect against aggressive behavior.
  

Review a patient’s history of violence because this is the single best predictor of future violent behavior.⁴ Criminal and court records are particularly useful in evaluating the person’s history of violence. Table 3 provides sample questions for eliciting information about a person’s history of violence when records are not readily available.

A person who has used weapons against others may pose a serious risk of future violence. Ask patients whether they own or have ever owned a weapon. In our experience, the recent movement of a weapon—such as transferring a gun from a closet to a nightstand—is particularly ominous in a paranoid person. The greater the psychotic fear, the more likely a paranoid person is to kill someone he misperceives as a persecutor.

Drugs and alcohol are strongly associated with violent behavior.⁵ Most persons involved in violent crimes are under the influence of alcohol or drugs at the time of their aggression.⁶ Stimulants such as cocaine, crack, amphetamines, and phencyclidine are of special concern. These drugs often are associated with feelings of disinhibition, a sense of power, and paranoia. The violence linked with cocaine use differs by gender: men are more likely to perpetrate violent crimes, whereas women are more likely to be the victims of violence.⁷

Table 3

10 questions to ask patients about a history of violence

What is the most violent thing you have ever done?
What types of violent behavior have you engaged in?
What is your understanding of why this violence occurred?
Who was involved in prior violent incidents?
Have you ever been arrested for any type of violent act?
Have you ever been intoxicated at the time you were violent?
Were you experiencing mental health symptoms when violent?
What is the greatest degree of injury you inflicted on someone else?
What weapons have you used when violent?
Have you ever been a victim of violence?

Mental illness and violence

Studies examining whether individuals with mental illness are more violent than the non-mentally ill have yielded mixed results.^8,9 In a study of civilly committed psychiatric patients released into the community, most mentally ill individuals were not violent.¹⁰ Although researchers noted a weak relationship between mental illness and violence, violent conduct was greater only when the person was experiencing acute psychiatric symptoms. Subsequent research suggests that individuals with schizophrenia may have increased rates of violence even when not experiencing active signs of their illness.¹¹

Psychosis. In paranoid psychotic patients, violence often is well planned and in line with their false beliefs.¹² These patients usually direct the violence at a specific person they perceive as a persecutor. Paranoid individuals often target relatives or friends. In addition, community-dwelling paranoid persons are more likely to be dangerous because they have greater access to weapons than institutionalized patients.¹²

Carefully inquire about hallucinations—particularly auditory ones—to determine whether their presence increases the person’s risk to commit a violent act. Patients with schizophrenia are more likely to be violent if their auditory hallucinations generate negative emotions (anger, anxiety, or sadness) and if the patients have not developed successful coping strategies.¹³ Although most patients ignore violent command hallucinations to harm others, the presence of command hallucinations may increase the likelihood of behaving violently,¹⁴ particularly if:

• the voice is familiar to the person,¹⁵ and
  
• the person has delusional beliefs associated with the hallucinations.¹⁶
  

Depression. Individuals who are depressed may strike out against others in despair. After committing a violent act, a depressed person may attempt suicide. Depression is the most common psychiatric diagnosis in murder-suicides.¹⁷ Patients with mania often engage in assaultive or threatening behavior, but serious physical violence is rare.¹² Patients with mania most commonly exhibit violent behavior when they are restrained or have limits set on their behavior.

 

¹⁸

Antisocial personality disorder (APD). Violence by those with APD often is motivated by revenge or occurs during a period of heavy drinking. Violent behavior by these persons frequently is cold, calculated, and lacks emotionality.¹⁹

In addition to DSM-IV-TR personality disorders, be familiar with the psychological construct known as psychopathy. Cleckley²⁰ used the term psychopath to describe a person who is superficially charming, lacks close relationships, is impulsive, and is primarily concerned with self-gratification. Hare et al²¹ developed the Psychopathy Checklist-Revised as a validated measure of psychopathy in adults. Psychopathy is a strong predictor of criminal behavior and violence among adults.²²

Affect. Individuals who are angry and lack empathy for others are at increased risk for violent behavior.²³ Also observe the patient for physical signs and symptoms of changes indicating incipient violence. Berg et al²⁴ noted that signs of imminent violence can include:

• chanting
  
• clenched jaw
  
• flared nostrils
  
• flushed face
  
• darting eyes
  
• close proximity to the clinician
  
• clenched or gripping hands.
  

Asking patients if they are experiencing homicidal ideations may not always elicit important information regarding a patient’s potential thoughts about harming others. For example, in persons who report feeling persecuted, ask what they would do if they came face-to-face with the individual they fear. Some patients may report that they would attempt to avoid all contact to minimize their personal risk. Others might feel a need to make a preemptive strike for protective purposes. In neither situation would the patient have reported experiencing homicidal thoughts.

Static vs dynamic factors. When organizing strategies to decrease risk factors for violence, distinguish static from dynamic factors. Static factors include demographic information and history of violence. Dynamic factors, which are subject to change with intervention, include access to weapons, psychotic symptoms, active substance use, and a person’s living situation.

Organizing a chart that outlines known risk factors, interventions to address dynamic risk factors, and the status of each risk factor/intervention may be helpful. Table 4 provides an example of such a chart for Mr. J. This approach can help you develop a violence prevention plan that addresses each patient’s combination of risk factors.

Table 4

Sample violence risk management chart for Mr. J

Risk factor	Intervention	Status
Paranoia	Antipsychotic medication	Admitted to inpatient psychiatric facility; antipsychotic medications ordered with continued assessments of mental status
Antipsychotic medication nonadherence	Depot form of antipsychotic	Mr. J agreed to depot medication
Gun at home	Remove guns	His mother removed all guns from home
Alcohol and methamphetamine abuse	Evaluate for potential alcohol detox; urine drug screen on admission	Mr. J refused group substance treatment in the hospital; substance use treatment in the community to be arranged prior to discharge

Finally, be familiar with jurisdictional requirements that govern duties to warn or protect third parties your patient may have threatened.

Related resource

• Simon RI, Hales RE, eds. The American Psychiatric Publishing textbook of suicide assessment and management. Arlington, VA: American Psychiatric Publishing, Inc; 2006.
  
• Simon RI, Tardiff K, eds. Textbook of violence assessment and management. Arlington, VA: American Psychiatric Publishing, Inc; 2008.
  

Drug brand names

• Risperidone • Risperdal
  

Disclosure

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

Comment on this article

Ms. F, a 53-year-old high school English teacher, is referred to you by her family physician after she was suspended from work for suspected intoxication. She was divorced 2 years ago from her husband of 20 years, and she says her drinking has escalated to 2 bottles of wine every night. She wants to reduce her alcohol use but experiences shakiness, nausea, and diaphoresis when she tries to cut back.

Ms. F began drinking at age 16 “to feel more comfortable in social situations” and has experienced binge drinking with intermittent blackouts. She denies illicit drug use and legal consequences from drinking. Her father died from cirrhosis at age 58. Her mother suffers from depression but is in remission with medication.

Ms. F is hesitant to date or establish intimate relationships. She has stopped attending church, a book club, and her 15-year-old daughter’s booster club activities.

For years, little was known about alcohol use and alcohol-related problems in women such as Ms. F.¹ Alcohol dependence studies rarely included women, so findings and treatment outcomes observed in men were assumed to apply to both genders.

Awareness of gender differences in addiction has grown (Box 1).^2-5 Biological and psychosocial differences between alcohol-dependent women and men now are understood to influence etiology, epidemiology, psychiatric and medical comorbidity, course of illness, and treatment outcomes. This article discusses recent insights into planning treatment to address specific needs of alcohol-dependent women.

Box 1

Accelerated consequences

As a group, women may consume less alcohol than men but progress more rapidly to alcohol-related illnesses and negative consequences. Specifically, alcohol-dependent women develop liver disease, hypertension, and gastrointestinal hemorrhage more rapidly than alcohol-dependent men.³ Cognitive deficits and brain atrophy also develop sooner in alcohol-dependent women than men.⁶ Causes of this accelerated progression—”telescoping”—include gender-specific biological differences:

• Women have lower levels of gastric alcohol dehydrogenase—the enzyme that initiates alcohol metabolism—and therefore experience a higher blood alcohol concentration than men drinking the same amount of alcohol.
  
• Women have less total body water and less capacity to dilute alcohol than men.
  

These factors lead to higher alcohol concentration per drink delivered to target organs via systemic circulation in women than men.³

‘At-risk’ drinking. Gender-related physiologic differences have led to different thresholds for defining “at-risk drinking” and binge drinking for men and women (Table 1).⁷ Alcohol use also has negative effects on women’s reproductive system and menstrual cycle. Women with alcohol dependence have higher rates of sexual dysfunction, irregular menstrual cycles, early menopause, and amenorrhea as compared with nonalcohol-dependent women.⁸

Table 1

Different thresholds: Number of drinks* that increases risk for alcohol-related problems

	Drinks/week	Drinks/day
Men	>14	>4
Women	>7	>3
*A standard drink is 12 ounces of beer, 5 ounces of wine, or 1.5 ounces of spirits
Source: Reference 7

Motives for drinking

Research suggests different motives for alcohol use in girls and women vs boys and men. Women appear more likely to use alcohol to “self-medicate” negative affect or emotional pain (Box 2).^9-12 Men are more likely to use alcohol to enhance pleasurable emotional states, “feel high” or because of social pressures to conform.⁵

Box 2

 

In a study of >1,200 adolescents, girls age 13 With age, drinking for social and enhancement motives increases more among male than female adolescents. Drinking to reduce or manage negative affect is associated with an increased risk of heavy drinking (particularly for adolescent girls), more frequent intoxication, and alcohol dependence.¹⁴ These findings suggest:

• Young women with alcohol use problems may benefit from learning strategies to regulate negative emotions and alleviate depression or anxiety symptoms that may be contributing to their drinking.
  
• Young men with alcohol use problems may benefit from learning to manage peer pressure and from finding alternate sources of pleasure enhancement.⁵
  

CASE CONTINUED: Depressed and anxious

Ms. F admits to depressed mood, crying episodes, isolation from others, anhedonia, feelings of guilt, low motivation, difficulty concentrating at work, restless sleep, and weight loss. These symptoms recurred soon after she and her husband separated 4 years ago. She denies suicidal thoughts or suicide attempts.

She suffered similar episodes in the past, including when she was breastfeeding and abstinent from alcohol after the birth of her daughter. Her obstetrician treated her depression with fluoxetine. Problems with anxiety began in high school, especially associated with parties and dating. In college, she often would drink beer before class presentations.

You diagnose alcohol dependence, major depressive disorder, and social phobia. You also ask Ms. F about a history of trauma. She reports that her father was “real harsh” when he was drinking and often hit her and her sister. She also relates being struck by her ex-husband during arguments. Screening with the Clinician-Administered PTSD Scale is negative for posttraumatic stress disorder (PTSD), however.

Comorbid psychiatric disorders

Gender differences in reasons for alcohol use may be related to women’s higher rate of medical and psychiatric comorbidity (Table 2).^6,8,15,16 Vital signs, physical examination, and lab work are helpful for diagnosis and monitoring of medical comorbidities and complications. The gamma-glutamyl transferase (GGT) test for liver disease and carbohydrate deficient transferrin (CDT) test for chronic heavy alcohol consumption are less sensitive and specific in women than in men.¹⁷ Even so, monitoring GGT and CDT results over time may serve as a valuable marker of continued drinking by women.

Mood and anxiety disorders are significantly more common in women than in men among individuals with alcohol use disorders.^15,16 This pattern is not unique to alcohol-dependent persons, however. In the general population:

• women are more likely than men to meet diagnostic criteria for anxiety, depression, bulimia nervosa, and borderline personality disorder
  
• men are more likely than women to meet diagnostic criteria for antisocial personality disorder.¹⁸
  

Table 2

Comorbid disorders in women with alcohol dependence

Psychiatric Posttraumatic stress disorder Other anxiety disorders (such as panic disorder without agoraphobia, simple phobia, or social phobia) Major depressive disorder Cognitive impairment
Medical Hypertension Fatty liver disease Gastrointestinal hemorrhage Brain atrophy Reproductive system irregularities
Source: References 6,8,15,16

Mood and anxiety disorders are more likely to precede the onset of alcohol use disorders in women than in men. In a longitudinal study,¹⁹ women with major depression at baseline were 7 times more likely to have alcohol dependence at 2-year follow-up than women without major depression. Men with major depression at baseline did not show an increased risk for developing alcohol dependence over time. This finding suggests a different etiologic relationship between depression and alcohol use disorders for women than for men.

Suicide risk. A recent study by Connor et al²⁰ examined suicidal ideation, planning, and attempts in 3,729 alcohol dependent subjects (35% female) and found an association between female gender and both planned (odds ratio [OR] = 3.4) and unplanned suicide attempts (OR = 3.8). Further research is needed to clarify the relationship between female gender, alcohol dependence, and suicide risk, behaviors, and attempts.

Anxiety disorders are the most common psychiatric disorders in women,²¹ and social anxiety and social phobia may play a predisposing role in alcohol dependence.²² Individuals with social anxiety may self-medicate with alcohol as a social lubricant. Some research suggests that anxiety disorders are more severe in alcohol-dependent women than in men with similarly severe alcohol dependence.²²

Posttraumatic stress. Childhood physical and sexual abuse and subsequent PTSD are important risk factors for alcohol abuse or dependence in women. Past physical or sexual abuse can complicate treatment and recovery in women because abuse is associated with increased psychiatric symptoms, more complex treatment needs, and poorer treatment outcomes.

 

²³

Therefore, when assessing and treating alcohol-dependent women, screen for trauma history as well as mood and anxiety disorders. To optimize outcomes, treat these disorders simultaneously with the alcohol use disorder.²⁴

Treatment planning

Underuse of treatment programs. Women with alcohol dependence are more likely to seek treatment in primary care or mental health settings, rather than in alcohol treatment settings.^25,26 Women’s underuse of alcohol treatment programs is likely related to:

• greater stigma associated with alcohol use for women as compared with men
  
• socioeconomic factors, including pregnancy, child care, and concerns about child custody issues.²⁵
  

Even so, women who enter treatment for alcohol use disorders appear to benefit as much as men, with similar outcomes, retention, and relapse rates.^25,26

Gender-specific treatment? Women-only treatment programs have been studied because of observed differences in men’s and women’s interaction styles and the hypothesis that men’s traditional societal dominance could negatively affect women in mixed-gender groups.²⁵ Better treatment outcomes have been hypothesized if treatment is tailored to address women’s unique issues: risk factors for alcohol dependence, course of disease progression, medical problems associated with alcohol dependence, and reasons for relapse.

Gender-specific treatment may provide an environment where women—particularly those with a history of trauma from a male perpetrator—feel safe discussing issues related to their alcohol problems. For practical purposes, these programs also may be more likely to address women’s needs for on-site child care, prenatal care, and mental health programming.

Results from investigations of women-specific treatments have been mixed. Some data suggest that women-focused outpatient and residential treatment programs have higher rates of treatment completion compared with traditional programs.²⁷ Residential programs that allow women to bring their children may have higher rates of retention—a good predictor of better treatment outcomes.

A recent study compared a manual-based 12-session women’s recovery group with mixed-gender, manualized group drug counseling (GDC). The women’s recovery group focused on gender-specific topics such as relationships, the caregiver role, trauma, comorbid psychiatric conditions (including eating, mood, and anxiety disorders), and the effects of drug and alcohol use on women’s health. The women’s recovery group was:

• as effective as mixed-gender GDC in reducing substance use during the 12-week treatment
  
• significantly more effective during the 6-month post-treatment phase.²⁸
  

Pharmacologic treatment. Few studies have investigated potential gender differences in response to pharmacologic treatments for alcohol dependence. One trial found long-acting injectable naltrexone less effective in women than men,²⁹ but other studies—primarily with small numbers of women—found no gender difference in naltrexone’s efficacy.³⁰ Family history, medication compliance, and side effect profiles need to be studied in greater detail to determine potential gender effects on treatment outcomes with pharmacologic agents.

CASE CONTINUED: Developing a treatment plan

Ms. F identifies 3 triggers for her alcohol use: a stressful day at school, arguments with her ex-husband, and feeling lonely. Because these are high-risk situations for relapse, you incorporate strategies to deal with them into her treatment plan. Other factors to consider:

• whether she requires detoxification
  
• an FDA-approved medication for alcohol dependence (acamprosate, oral or injectable naltrexone, or disulfiram)
  
• cognitive-behavioral therapy and medication for major depression and social phobia
  
• referral to psychosocial support groups (such as Alcoholics Anonymous).
  

You encourage Ms. F to explore support from her employer, such as an employee assistance program that may help her resume teaching after successful treatment.

Three factors determine the need for detoxification: the course of previous alcohol withdrawals (alcoholic hallucinosis, seizures, or delirium tremens), elevated vital signs or other evidence of autonomic hyperactivity such as diaphoresis or tremors, and the patient’s general medical condition. During early recovery, monitor patients closely to assess mood and anxiety symptoms. Blood alcohol tests or GGT and CDT are useful to monitor self-reported abstinence.

Educate patients about common withdrawal symptoms and the typical course of recovery. Refer them to a primary care physician for assessment of medical comorbidities of alcohol dependence. With patients’ permission, involve their social support network (family or close friends) in treatment.

Related resources

• National Clearing House for Alcohol and Drug Information. Publications and materials on women and substance abuse. Substance Abuse and Mental Health Services Administration. http://ncadistore.samhsa.gov/catalogresults.aspx?h=drugs&topic=11.
  
• National Institute on Drug Abuse (www.nida.nih.gov). Articles that address women’s health and gender differences. www.drugabuse.gov/NIDA_Notes/NN0013.html.
  

Drug brand names

• Acamprosate • Campral
  
• Disulfiram • Antabuse
  
• Fluoxetine • Prozac
  
• Naltrexone • Vivitrol, ReVia
  

Disclosures

Drs. Payne, Back, Wright, and Hartwell report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

 

Dr. Brady receives research support from Abbott Laboratories, GlaxoSmithKline, Forest Pharmaceuticals, and Wyeth. She is a consultant and speaker for Pfizer Inc., Eli Lilly and Company, Abbott Laboratories, GlaxoSmithKline, and Forest Pharmaceuticals.

Comment on this article

Ms. F, a 53-year-old high school English teacher, is referred to you by her family physician after she was suspended from work for suspected intoxication. She was divorced 2 years ago from her husband of 20 years, and she says her drinking has escalated to 2 bottles of wine every night. She wants to reduce her alcohol use but experiences shakiness, nausea, and diaphoresis when she tries to cut back.

Ms. F began drinking at age 16 “to feel more comfortable in social situations” and has experienced binge drinking with intermittent blackouts. She denies illicit drug use and legal consequences from drinking. Her father died from cirrhosis at age 58. Her mother suffers from depression but is in remission with medication.

Ms. F is hesitant to date or establish intimate relationships. She has stopped attending church, a book club, and her 15-year-old daughter’s booster club activities.

For years, little was known about alcohol use and alcohol-related problems in women such as Ms. F.¹ Alcohol dependence studies rarely included women, so findings and treatment outcomes observed in men were assumed to apply to both genders.

Awareness of gender differences in addiction has grown (Box 1).^2-5 Biological and psychosocial differences between alcohol-dependent women and men now are understood to influence etiology, epidemiology, psychiatric and medical comorbidity, course of illness, and treatment outcomes. This article discusses recent insights into planning treatment to address specific needs of alcohol-dependent women.

Box 1

Accelerated consequences

As a group, women may consume less alcohol than men but progress more rapidly to alcohol-related illnesses and negative consequences. Specifically, alcohol-dependent women develop liver disease, hypertension, and gastrointestinal hemorrhage more rapidly than alcohol-dependent men.³ Cognitive deficits and brain atrophy also develop sooner in alcohol-dependent women than men.⁶ Causes of this accelerated progression—”telescoping”—include gender-specific biological differences:

• Women have lower levels of gastric alcohol dehydrogenase—the enzyme that initiates alcohol metabolism—and therefore experience a higher blood alcohol concentration than men drinking the same amount of alcohol.
  
• Women have less total body water and less capacity to dilute alcohol than men.
  

These factors lead to higher alcohol concentration per drink delivered to target organs via systemic circulation in women than men.³

‘At-risk’ drinking. Gender-related physiologic differences have led to different thresholds for defining “at-risk drinking” and binge drinking for men and women (Table 1).⁷ Alcohol use also has negative effects on women’s reproductive system and menstrual cycle. Women with alcohol dependence have higher rates of sexual dysfunction, irregular menstrual cycles, early menopause, and amenorrhea as compared with nonalcohol-dependent women.⁸

Table 1

Different thresholds: Number of drinks* that increases risk for alcohol-related problems

	Drinks/week	Drinks/day
Men	>14	>4
Women	>7	>3
*A standard drink is 12 ounces of beer, 5 ounces of wine, or 1.5 ounces of spirits
Source: Reference 7

Motives for drinking

Research suggests different motives for alcohol use in girls and women vs boys and men. Women appear more likely to use alcohol to “self-medicate” negative affect or emotional pain (Box 2).^9-12 Men are more likely to use alcohol to enhance pleasurable emotional states, “feel high” or because of social pressures to conform.⁵

Box 2

 

In a study of >1,200 adolescents, girls age 13 With age, drinking for social and enhancement motives increases more among male than female adolescents. Drinking to reduce or manage negative affect is associated with an increased risk of heavy drinking (particularly for adolescent girls), more frequent intoxication, and alcohol dependence.¹⁴ These findings suggest:

• Young women with alcohol use problems may benefit from learning strategies to regulate negative emotions and alleviate depression or anxiety symptoms that may be contributing to their drinking.
  
• Young men with alcohol use problems may benefit from learning to manage peer pressure and from finding alternate sources of pleasure enhancement.⁵
  

CASE CONTINUED: Depressed and anxious

Ms. F admits to depressed mood, crying episodes, isolation from others, anhedonia, feelings of guilt, low motivation, difficulty concentrating at work, restless sleep, and weight loss. These symptoms recurred soon after she and her husband separated 4 years ago. She denies suicidal thoughts or suicide attempts.

She suffered similar episodes in the past, including when she was breastfeeding and abstinent from alcohol after the birth of her daughter. Her obstetrician treated her depression with fluoxetine. Problems with anxiety began in high school, especially associated with parties and dating. In college, she often would drink beer before class presentations.

You diagnose alcohol dependence, major depressive disorder, and social phobia. You also ask Ms. F about a history of trauma. She reports that her father was “real harsh” when he was drinking and often hit her and her sister. She also relates being struck by her ex-husband during arguments. Screening with the Clinician-Administered PTSD Scale is negative for posttraumatic stress disorder (PTSD), however.

Comorbid psychiatric disorders

Gender differences in reasons for alcohol use may be related to women’s higher rate of medical and psychiatric comorbidity (Table 2).^6,8,15,16 Vital signs, physical examination, and lab work are helpful for diagnosis and monitoring of medical comorbidities and complications. The gamma-glutamyl transferase (GGT) test for liver disease and carbohydrate deficient transferrin (CDT) test for chronic heavy alcohol consumption are less sensitive and specific in women than in men.¹⁷ Even so, monitoring GGT and CDT results over time may serve as a valuable marker of continued drinking by women.

Mood and anxiety disorders are significantly more common in women than in men among individuals with alcohol use disorders.^15,16 This pattern is not unique to alcohol-dependent persons, however. In the general population:

• women are more likely than men to meet diagnostic criteria for anxiety, depression, bulimia nervosa, and borderline personality disorder
  
• men are more likely than women to meet diagnostic criteria for antisocial personality disorder.¹⁸
  

Table 2

Comorbid disorders in women with alcohol dependence

Psychiatric Posttraumatic stress disorder Other anxiety disorders (such as panic disorder without agoraphobia, simple phobia, or social phobia) Major depressive disorder Cognitive impairment
Medical Hypertension Fatty liver disease Gastrointestinal hemorrhage Brain atrophy Reproductive system irregularities
Source: References 6,8,15,16

Mood and anxiety disorders are more likely to precede the onset of alcohol use disorders in women than in men. In a longitudinal study,¹⁹ women with major depression at baseline were 7 times more likely to have alcohol dependence at 2-year follow-up than women without major depression. Men with major depression at baseline did not show an increased risk for developing alcohol dependence over time. This finding suggests a different etiologic relationship between depression and alcohol use disorders for women than for men.

Suicide risk. A recent study by Connor et al²⁰ examined suicidal ideation, planning, and attempts in 3,729 alcohol dependent subjects (35% female) and found an association between female gender and both planned (odds ratio [OR] = 3.4) and unplanned suicide attempts (OR = 3.8). Further research is needed to clarify the relationship between female gender, alcohol dependence, and suicide risk, behaviors, and attempts.

Anxiety disorders are the most common psychiatric disorders in women,²¹ and social anxiety and social phobia may play a predisposing role in alcohol dependence.²² Individuals with social anxiety may self-medicate with alcohol as a social lubricant. Some research suggests that anxiety disorders are more severe in alcohol-dependent women than in men with similarly severe alcohol dependence.²²

Posttraumatic stress. Childhood physical and sexual abuse and subsequent PTSD are important risk factors for alcohol abuse or dependence in women. Past physical or sexual abuse can complicate treatment and recovery in women because abuse is associated with increased psychiatric symptoms, more complex treatment needs, and poorer treatment outcomes.

 

²³

Therefore, when assessing and treating alcohol-dependent women, screen for trauma history as well as mood and anxiety disorders. To optimize outcomes, treat these disorders simultaneously with the alcohol use disorder.²⁴

Treatment planning

Underuse of treatment programs. Women with alcohol dependence are more likely to seek treatment in primary care or mental health settings, rather than in alcohol treatment settings.^25,26 Women’s underuse of alcohol treatment programs is likely related to:

• greater stigma associated with alcohol use for women as compared with men
  
• socioeconomic factors, including pregnancy, child care, and concerns about child custody issues.²⁵
  

Even so, women who enter treatment for alcohol use disorders appear to benefit as much as men, with similar outcomes, retention, and relapse rates.^25,26

Gender-specific treatment? Women-only treatment programs have been studied because of observed differences in men’s and women’s interaction styles and the hypothesis that men’s traditional societal dominance could negatively affect women in mixed-gender groups.²⁵ Better treatment outcomes have been hypothesized if treatment is tailored to address women’s unique issues: risk factors for alcohol dependence, course of disease progression, medical problems associated with alcohol dependence, and reasons for relapse.

Gender-specific treatment may provide an environment where women—particularly those with a history of trauma from a male perpetrator—feel safe discussing issues related to their alcohol problems. For practical purposes, these programs also may be more likely to address women’s needs for on-site child care, prenatal care, and mental health programming.

Results from investigations of women-specific treatments have been mixed. Some data suggest that women-focused outpatient and residential treatment programs have higher rates of treatment completion compared with traditional programs.²⁷ Residential programs that allow women to bring their children may have higher rates of retention—a good predictor of better treatment outcomes.

A recent study compared a manual-based 12-session women’s recovery group with mixed-gender, manualized group drug counseling (GDC). The women’s recovery group focused on gender-specific topics such as relationships, the caregiver role, trauma, comorbid psychiatric conditions (including eating, mood, and anxiety disorders), and the effects of drug and alcohol use on women’s health. The women’s recovery group was:

• as effective as mixed-gender GDC in reducing substance use during the 12-week treatment
  
• significantly more effective during the 6-month post-treatment phase.²⁸
  

Pharmacologic treatment. Few studies have investigated potential gender differences in response to pharmacologic treatments for alcohol dependence. One trial found long-acting injectable naltrexone less effective in women than men,²⁹ but other studies—primarily with small numbers of women—found no gender difference in naltrexone’s efficacy.³⁰ Family history, medication compliance, and side effect profiles need to be studied in greater detail to determine potential gender effects on treatment outcomes with pharmacologic agents.

CASE CONTINUED: Developing a treatment plan

Ms. F identifies 3 triggers for her alcohol use: a stressful day at school, arguments with her ex-husband, and feeling lonely. Because these are high-risk situations for relapse, you incorporate strategies to deal with them into her treatment plan. Other factors to consider:

• whether she requires detoxification
  
• an FDA-approved medication for alcohol dependence (acamprosate, oral or injectable naltrexone, or disulfiram)
  
• cognitive-behavioral therapy and medication for major depression and social phobia
  
• referral to psychosocial support groups (such as Alcoholics Anonymous).
  

You encourage Ms. F to explore support from her employer, such as an employee assistance program that may help her resume teaching after successful treatment.

Three factors determine the need for detoxification: the course of previous alcohol withdrawals (alcoholic hallucinosis, seizures, or delirium tremens), elevated vital signs or other evidence of autonomic hyperactivity such as diaphoresis or tremors, and the patient’s general medical condition. During early recovery, monitor patients closely to assess mood and anxiety symptoms. Blood alcohol tests or GGT and CDT are useful to monitor self-reported abstinence.

Educate patients about common withdrawal symptoms and the typical course of recovery. Refer them to a primary care physician for assessment of medical comorbidities of alcohol dependence. With patients’ permission, involve their social support network (family or close friends) in treatment.

Related resources

• National Clearing House for Alcohol and Drug Information. Publications and materials on women and substance abuse. Substance Abuse and Mental Health Services Administration. http://ncadistore.samhsa.gov/catalogresults.aspx?h=drugs&topic=11.
  
• National Institute on Drug Abuse (www.nida.nih.gov). Articles that address women’s health and gender differences. www.drugabuse.gov/NIDA_Notes/NN0013.html.
  

Drug brand names

• Acamprosate • Campral
  
• Disulfiram • Antabuse
  
• Fluoxetine • Prozac
  
• Naltrexone • Vivitrol, ReVia
  

Disclosures

Drs. Payne, Back, Wright, and Hartwell report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

 

Dr. Brady receives research support from Abbott Laboratories, GlaxoSmithKline, Forest Pharmaceuticals, and Wyeth. She is a consultant and speaker for Pfizer Inc., Eli Lilly and Company, Abbott Laboratories, GlaxoSmithKline, and Forest Pharmaceuticals.

Comment on this article

Ms. F, a 53-year-old high school English teacher, is referred to you by her family physician after she was suspended from work for suspected intoxication. She was divorced 2 years ago from her husband of 20 years, and she says her drinking has escalated to 2 bottles of wine every night. She wants to reduce her alcohol use but experiences shakiness, nausea, and diaphoresis when she tries to cut back.

Ms. F began drinking at age 16 “to feel more comfortable in social situations” and has experienced binge drinking with intermittent blackouts. She denies illicit drug use and legal consequences from drinking. Her father died from cirrhosis at age 58. Her mother suffers from depression but is in remission with medication.

Ms. F is hesitant to date or establish intimate relationships. She has stopped attending church, a book club, and her 15-year-old daughter’s booster club activities.

For years, little was known about alcohol use and alcohol-related problems in women such as Ms. F.¹ Alcohol dependence studies rarely included women, so findings and treatment outcomes observed in men were assumed to apply to both genders.

Awareness of gender differences in addiction has grown (Box 1).^2-5 Biological and psychosocial differences between alcohol-dependent women and men now are understood to influence etiology, epidemiology, psychiatric and medical comorbidity, course of illness, and treatment outcomes. This article discusses recent insights into planning treatment to address specific needs of alcohol-dependent women.

Box 1

Accelerated consequences

As a group, women may consume less alcohol than men but progress more rapidly to alcohol-related illnesses and negative consequences. Specifically, alcohol-dependent women develop liver disease, hypertension, and gastrointestinal hemorrhage more rapidly than alcohol-dependent men.³ Cognitive deficits and brain atrophy also develop sooner in alcohol-dependent women than men.⁶ Causes of this accelerated progression—”telescoping”—include gender-specific biological differences:

• Women have lower levels of gastric alcohol dehydrogenase—the enzyme that initiates alcohol metabolism—and therefore experience a higher blood alcohol concentration than men drinking the same amount of alcohol.
  
• Women have less total body water and less capacity to dilute alcohol than men.
  

These factors lead to higher alcohol concentration per drink delivered to target organs via systemic circulation in women than men.³

‘At-risk’ drinking. Gender-related physiologic differences have led to different thresholds for defining “at-risk drinking” and binge drinking for men and women (Table 1).⁷ Alcohol use also has negative effects on women’s reproductive system and menstrual cycle. Women with alcohol dependence have higher rates of sexual dysfunction, irregular menstrual cycles, early menopause, and amenorrhea as compared with nonalcohol-dependent women.⁸

Table 1

Different thresholds: Number of drinks* that increases risk for alcohol-related problems

	Drinks/week	Drinks/day
Men	>14	>4
Women	>7	>3
*A standard drink is 12 ounces of beer, 5 ounces of wine, or 1.5 ounces of spirits
Source: Reference 7

Motives for drinking

Research suggests different motives for alcohol use in girls and women vs boys and men. Women appear more likely to use alcohol to “self-medicate” negative affect or emotional pain (Box 2).^9-12 Men are more likely to use alcohol to enhance pleasurable emotional states, “feel high” or because of social pressures to conform.⁵

Box 2

 

In a study of >1,200 adolescents, girls age 13 With age, drinking for social and enhancement motives increases more among male than female adolescents. Drinking to reduce or manage negative affect is associated with an increased risk of heavy drinking (particularly for adolescent girls), more frequent intoxication, and alcohol dependence.¹⁴ These findings suggest:

• Young women with alcohol use problems may benefit from learning strategies to regulate negative emotions and alleviate depression or anxiety symptoms that may be contributing to their drinking.
  
• Young men with alcohol use problems may benefit from learning to manage peer pressure and from finding alternate sources of pleasure enhancement.⁵
  

CASE CONTINUED: Depressed and anxious

Ms. F admits to depressed mood, crying episodes, isolation from others, anhedonia, feelings of guilt, low motivation, difficulty concentrating at work, restless sleep, and weight loss. These symptoms recurred soon after she and her husband separated 4 years ago. She denies suicidal thoughts or suicide attempts.

She suffered similar episodes in the past, including when she was breastfeeding and abstinent from alcohol after the birth of her daughter. Her obstetrician treated her depression with fluoxetine. Problems with anxiety began in high school, especially associated with parties and dating. In college, she often would drink beer before class presentations.

You diagnose alcohol dependence, major depressive disorder, and social phobia. You also ask Ms. F about a history of trauma. She reports that her father was “real harsh” when he was drinking and often hit her and her sister. She also relates being struck by her ex-husband during arguments. Screening with the Clinician-Administered PTSD Scale is negative for posttraumatic stress disorder (PTSD), however.

Comorbid psychiatric disorders

Gender differences in reasons for alcohol use may be related to women’s higher rate of medical and psychiatric comorbidity (Table 2).^6,8,15,16 Vital signs, physical examination, and lab work are helpful for diagnosis and monitoring of medical comorbidities and complications. The gamma-glutamyl transferase (GGT) test for liver disease and carbohydrate deficient transferrin (CDT) test for chronic heavy alcohol consumption are less sensitive and specific in women than in men.¹⁷ Even so, monitoring GGT and CDT results over time may serve as a valuable marker of continued drinking by women.

Mood and anxiety disorders are significantly more common in women than in men among individuals with alcohol use disorders.^15,16 This pattern is not unique to alcohol-dependent persons, however. In the general population:

• women are more likely than men to meet diagnostic criteria for anxiety, depression, bulimia nervosa, and borderline personality disorder
  
• men are more likely than women to meet diagnostic criteria for antisocial personality disorder.¹⁸
  

Table 2

Comorbid disorders in women with alcohol dependence

Psychiatric Posttraumatic stress disorder Other anxiety disorders (such as panic disorder without agoraphobia, simple phobia, or social phobia) Major depressive disorder Cognitive impairment
Medical Hypertension Fatty liver disease Gastrointestinal hemorrhage Brain atrophy Reproductive system irregularities
Source: References 6,8,15,16

Mood and anxiety disorders are more likely to precede the onset of alcohol use disorders in women than in men. In a longitudinal study,¹⁹ women with major depression at baseline were 7 times more likely to have alcohol dependence at 2-year follow-up than women without major depression. Men with major depression at baseline did not show an increased risk for developing alcohol dependence over time. This finding suggests a different etiologic relationship between depression and alcohol use disorders for women than for men.

Suicide risk. A recent study by Connor et al²⁰ examined suicidal ideation, planning, and attempts in 3,729 alcohol dependent subjects (35% female) and found an association between female gender and both planned (odds ratio [OR] = 3.4) and unplanned suicide attempts (OR = 3.8). Further research is needed to clarify the relationship between female gender, alcohol dependence, and suicide risk, behaviors, and attempts.

Anxiety disorders are the most common psychiatric disorders in women,²¹ and social anxiety and social phobia may play a predisposing role in alcohol dependence.²² Individuals with social anxiety may self-medicate with alcohol as a social lubricant. Some research suggests that anxiety disorders are more severe in alcohol-dependent women than in men with similarly severe alcohol dependence.²²

Posttraumatic stress. Childhood physical and sexual abuse and subsequent PTSD are important risk factors for alcohol abuse or dependence in women. Past physical or sexual abuse can complicate treatment and recovery in women because abuse is associated with increased psychiatric symptoms, more complex treatment needs, and poorer treatment outcomes.

 

²³

Therefore, when assessing and treating alcohol-dependent women, screen for trauma history as well as mood and anxiety disorders. To optimize outcomes, treat these disorders simultaneously with the alcohol use disorder.²⁴

Treatment planning

Underuse of treatment programs. Women with alcohol dependence are more likely to seek treatment in primary care or mental health settings, rather than in alcohol treatment settings.^25,26 Women’s underuse of alcohol treatment programs is likely related to:

• greater stigma associated with alcohol use for women as compared with men
  
• socioeconomic factors, including pregnancy, child care, and concerns about child custody issues.²⁵
  

Even so, women who enter treatment for alcohol use disorders appear to benefit as much as men, with similar outcomes, retention, and relapse rates.^25,26

Gender-specific treatment? Women-only treatment programs have been studied because of observed differences in men’s and women’s interaction styles and the hypothesis that men’s traditional societal dominance could negatively affect women in mixed-gender groups.²⁵ Better treatment outcomes have been hypothesized if treatment is tailored to address women’s unique issues: risk factors for alcohol dependence, course of disease progression, medical problems associated with alcohol dependence, and reasons for relapse.

Gender-specific treatment may provide an environment where women—particularly those with a history of trauma from a male perpetrator—feel safe discussing issues related to their alcohol problems. For practical purposes, these programs also may be more likely to address women’s needs for on-site child care, prenatal care, and mental health programming.

Results from investigations of women-specific treatments have been mixed. Some data suggest that women-focused outpatient and residential treatment programs have higher rates of treatment completion compared with traditional programs.²⁷ Residential programs that allow women to bring their children may have higher rates of retention—a good predictor of better treatment outcomes.

A recent study compared a manual-based 12-session women’s recovery group with mixed-gender, manualized group drug counseling (GDC). The women’s recovery group focused on gender-specific topics such as relationships, the caregiver role, trauma, comorbid psychiatric conditions (including eating, mood, and anxiety disorders), and the effects of drug and alcohol use on women’s health. The women’s recovery group was:

• as effective as mixed-gender GDC in reducing substance use during the 12-week treatment
  
• significantly more effective during the 6-month post-treatment phase.²⁸
  

Pharmacologic treatment. Few studies have investigated potential gender differences in response to pharmacologic treatments for alcohol dependence. One trial found long-acting injectable naltrexone less effective in women than men,²⁹ but other studies—primarily with small numbers of women—found no gender difference in naltrexone’s efficacy.³⁰ Family history, medication compliance, and side effect profiles need to be studied in greater detail to determine potential gender effects on treatment outcomes with pharmacologic agents.

CASE CONTINUED: Developing a treatment plan

Ms. F identifies 3 triggers for her alcohol use: a stressful day at school, arguments with her ex-husband, and feeling lonely. Because these are high-risk situations for relapse, you incorporate strategies to deal with them into her treatment plan. Other factors to consider:

• whether she requires detoxification
  
• an FDA-approved medication for alcohol dependence (acamprosate, oral or injectable naltrexone, or disulfiram)
  
• cognitive-behavioral therapy and medication for major depression and social phobia
  
• referral to psychosocial support groups (such as Alcoholics Anonymous).
  

You encourage Ms. F to explore support from her employer, such as an employee assistance program that may help her resume teaching after successful treatment.

Three factors determine the need for detoxification: the course of previous alcohol withdrawals (alcoholic hallucinosis, seizures, or delirium tremens), elevated vital signs or other evidence of autonomic hyperactivity such as diaphoresis or tremors, and the patient’s general medical condition. During early recovery, monitor patients closely to assess mood and anxiety symptoms. Blood alcohol tests or GGT and CDT are useful to monitor self-reported abstinence.

Educate patients about common withdrawal symptoms and the typical course of recovery. Refer them to a primary care physician for assessment of medical comorbidities of alcohol dependence. With patients’ permission, involve their social support network (family or close friends) in treatment.

Related resources

• National Clearing House for Alcohol and Drug Information. Publications and materials on women and substance abuse. Substance Abuse and Mental Health Services Administration. http://ncadistore.samhsa.gov/catalogresults.aspx?h=drugs&topic=11.
  
• National Institute on Drug Abuse (www.nida.nih.gov). Articles that address women’s health and gender differences. www.drugabuse.gov/NIDA_Notes/NN0013.html.
  

Drug brand names

• Acamprosate • Campral
  
• Disulfiram • Antabuse
  
• Fluoxetine • Prozac
  
• Naltrexone • Vivitrol, ReVia
  

Disclosures

Drs. Payne, Back, Wright, and Hartwell report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

 

Dr. Brady receives research support from Abbott Laboratories, GlaxoSmithKline, Forest Pharmaceuticals, and Wyeth. She is a consultant and speaker for Pfizer Inc., Eli Lilly and Company, Abbott Laboratories, GlaxoSmithKline, and Forest Pharmaceuticals.

Comment on this article

Mrs. S, age 44, is on leave from her job as a bank cashier because depressive symptoms interfered with her performance. At a university-based psychiatric clinic she reports feeling depressed, reduced interest in daily activities, problems with sleep onset and maintenance, inconsistent appetite, low energy, hopelessness, and decreased memory and concentration.

The resident psychiatrist diagnoses major depressive disorder (MDD) and starts Mrs. S on sertraline, 50 mg/d. The dosage is gradually titrated to 200 mg/d, and after 8 weeks she reports substantial improvement.

Mrs. S returns to her job but experiences residual low energy, lethargy, and inconsistent sleep. Her work schedule and caring for her 2 children at home prevent her from continuing weekly cognitive-behavioral therapy (CBT), but she soon notices that she feels more energetic. She reports that because of high gasoline prices she has been walking several miles daily to commute by train to work. The resident psychiatrist sees this as an opportunity to reinforce the benefits of exercise for depression.

Antidepressants alone do not adequately treat many patients with depression. In the STAR*D Project—which compared long-term outcomes of various depression treatments—only 28% to 33% of outpatients achieved remission with selective serotonin reuptake inhibitor (SSRI) monotherapy. Rates were somewhat higher with bupropion or serotonin norepinephrine reuptake inhibitor (SNRI) monotherapy, but greater benefit was obtained from augmenting SSRIs.¹

Combining antidepressants with psychotherapy² and lifestyle changes—particularly exercise—makes sense intuitively and is supported by well-designed studies:

• The 60% of adults in the National Comorbidity Survey who said they exercised regularly reported lower rates of depression and anxiety, compared with less active adults.³
• A meta-analysis of 11 randomized, controlled trials supports the use of exercise as an effective intervention for clinical depression.⁴

Box 1

This article examines the evidence supporting exercise for treating and preventing clinical depression. We begin by addressing clinicians’ concerns about motivating depressed patients to exercise.

Overcoming barriers

Physician issues. Busy physicians often omit discussions about exercise during brief office visits. Only 34% of 9,299 patients in a population-based survey⁵ reported that their doctors counseled them about exercise during their most recent visits. Counseling patients does not have to be time-intensive, however. A study of the Physician-based Assessment and Counseling for Exercise (PACE) project showed that 70% of physicians could provide exercise counseling in 3 to 5 minutes, and most patients reported following their physicians’ advice.⁶

Highly depressed individuals are at risk to quit when they encounter barriers to exercise and to respond to difficulties with frustration and self-disappointment. Thus, depressed patients may need support and encouragement to initiate and maintain regular exercise routines.⁷ Set small, realistic goals for them, and discuss how to solve problems and remove barriers to increase their likelihood to exercise.

Interventions are most likely to be effective when you counsel patients about exercise as prescription and discuss exercise at each visit.⁸ Previously sedentary patients have shown short-term moderate increases in physical activity in response to physician counseling. In a study of 212 adults (mean age 39, 84% female), the PACE project significantly increased minutes of weekly walking.⁹ More than one-half (52%) of patients increased their physical activity, compared with 12% of controls whose physicians did not provide the PACE intervention.

Patient issues. Lack of time and no appropriate space to exercise are common complaints, particularly among residents of regions with long, cold winters. Some patients perceive regular exercise as monotonous or boring, and others may lack the necessary initiative because of poor physical health, fear, negative experiences, or lack of knowledge about exercising. These barriers can be pronounced in older depressed persons. In a cross-sectional study of 645 residents of Jyväskylä, Finland, those age >75 with depressive symptoms were more than twice as likely to be physically inactive as nondepressed residents.¹⁰

An intensive exercise program is not the optimal starting point for many patients. Even walking or light jogging can be an effective exercise for depressed individuals with physical limitations. For these patients, a consultation with their primary physician may be necessary if a more intensive program has to be recommended.

Exercise as monotherapy

A dose-response relationship? Various mechanisms have been suggested for the benefits of exercise in depression (Box 1). Exercise alone—without medication—may be an effective treatment for mild and in some cases moderate MDD, and aerobic exercise may reduce depressive symptoms in a dose-response relationship.¹¹

 

A study of exercise in a supervised laboratory setting demonstrated this relationship in 80 adults age 20 to 45 with mild-to-moderate depressive symptoms. Subjects were randomly assigned to an exercise control group (3 days/week of flexibility exercise) or 1 of 4 aerobic exercise groups that varied in total energy expenditure (a “low dose” of 7.0 kcal/kg/week or a “public health dose” of 17.5 kcal/kg/week). The 17-item Hamilton Rating Scale for Depression (HRSD) was the primary outcome measure.

After 12 weeks, HRSD scores declined from baseline by 47% in subjects engaged in the public health dose of aerobic exercise—a significant reduction. Depressive symptoms declined by 30% in the low-dose exercisers, but this was comparable to the 29% reduction in the control group.

Comment. The effective exercise dose in this study is similar to the public health recommendation of 30 minutes of moderate-to-vigorous activity on all or most days per week (see Related Resources). Antidepressant effects have been associated with more modest physical activity, however, which may be easier to initiate and maintain for individuals with depression. The study did not find significant differences in outcomes based on the subjects’ age, gender, or exercise frequency. Nevertheless, the exercise dose may be important to produce an antidepressant effect.

An inverse relationship? Compared with occasional exercise, habitual physical activity usually is associated with greater cardiorespiratory fitness. Whether habitual activity also results in fewer depressive symptoms and greater emotional well-being remains to be seen.

A large, cross-sectional, National Institutes of Health-funded study of 5,451 men and 1,277 women¹² suggests an inverse relationship between physical activity and depressive symptoms. Subjects underwent a treadmill exercise test to evaluate physical fitness. A 20-point self-report scale assessed depressive symptoms, and the General Well-Being Schedule¹³ was used to assess emotional well-being. Depressive symptoms were more severe in “inactive” and “insufficiently active” subjects compared with “sufficiently active” and “highly active” subjects.

On the other hand, although regular exercise may be associated with reduced depressive symptoms in the population at large, no cause-effect relationship was found in a population-based, longitudinal study of 5,952 twins.¹⁴

A prospective, randomized, controlled trial¹⁵ suggests that exercise could be an important treatment tool in patients diagnosed with MDD. The 202 adult subjects (153 women, 49 men) were randomly assigned to 1 of 4 treatments:

• supervised exercise in a group setting
• home-based exercise
• antidepressant medication (sertraline, 50 to 200 mg/d)
• placebo pills.

Patients underwent the structured clinical interview for depression and completed the HRSD. After 16 weeks, 41% of participants achieved remission, defined as no longer meeting MDD criteria and a HRSD score <8. Compared with placebo controls, patients receiving active treatments tended to have higher remission rates:

• 45% with supervised exercise
• 40% with home-based exercise
• 47% with medication
• 31% with placebo.

Comment. The placebo response rate was relatively high in this study, and antidepressant dosages might not have been optimal. These factors could explain why remission rates with supervised exercise and antidepressant medication were comparable. The study might have been more reliable if it had included a medication plus exercise arm. Patients treated in an office setting might not fare as well as these study subjects whose exercise was supervised.

Postpartum depression occurs in an estimated 13% of new mothers.¹⁶ In a controlled trial, 80 women with depression at 4 weeks postpartum were assigned to either:

• an exercise support program (1 hour supervised exercise and 2 sessions at home each week for 3 months)
• standard care.

Box 2

 

No subjects received medication. Women in the exercise support program were less likely to have high scores on the Edinburgh Postnatal Depression Scale, compared with controls. Women who exercised also reported a greater sense of well-being. Differences between the 2 groups were not statistically significant at 4 weeks post partum but achieved significance at 5 months.¹⁷

Depressive symptoms may exacerbate fatigue in postpartum women.¹⁸ A study of 88 women with postpartum depression showed the benefits of a home-based exercise program on physical and mental fatigue.¹⁹ This finding may be important because fatigue often is associated with treatment-resistant depression and may increase the likelihood of relapse in women with postpartum depression.²⁰

Late-life depression. Exercise can benefit the depressed elderly as well. In a 10-week randomized, controlled trial²¹ of volunteers age ≥60 with major or minor depression or dysthymia, progressive resistance training (PRT) significantly reduced depression, as measured by the Beck Depression Inventory (BDI) and HRSD. PRT also improved quality of life, vitality, social functioning, and emotional well-being when compared with a control group (Box 2).

A dose-response relationship of exercise for treating late-life depression was shown in a blinded, controlled trial²² of 60 community-dwelling, depressed subjects age >60. These patients were randomly assigned to high-intensity PRT, low-intensity PRT, or standard care by a general practitioner (GP). A ≥50% reduction in HRSD score was achieved by:

• 61% of the high-intensity PRT group
• 29% of the low-intensity PRT group
• 21% of the GP care group.

Sleep quality improved in all participants, with the greatest relative change in the high-intensity PRT group.

Exercise vs psychotherapy. The benefits of exercise may be comparable or superior to those of cognitive or group psychotherapy.^23,24 This may be good news for patients such as Mrs. S who lack time or financial resources for regular psychotherapy.

Adjunctive exercise

In depressed patients, exercise may increase the perceived quality of life when combined with medication. This was demonstrated in a randomized, 32-week naturalistic study of 30 women, age 40 to 60, with treatment-resistant MDD.²⁵ The 10 women who received various antidepressants plus physical exercise showed significantly greater long-term improvement in depression symptoms, as measured by the HRSD and Global Assessment of Functioning (GAF) scores, compared with 20 women who received pharmacotherapy alone.²⁶ Study limitations included the absence of a placebo arm, small sample size, and inclusion of subjects with comorbid anxiety disorders.

Group aerobic exercise programs can be an effective and feasible treatment for depression, particularly for older adults. In a controlled trial,²⁷ 156 men and women age >50 with MDD were randomly assigned to 3 groups: a program of aerobic exercise; sertraline, ≤200 mg/d; or exercise plus sertraline. HRSD and BDI scores before and after treatment were the primary outcome measures. Secondary measures included aerobic capacity, life satisfaction, self-esteem, anxiety, and dysfunctional cognitions. After 16 weeks of treatment, similar percentages of patients in each group no longer met DSM-IV-TR criteria for MDD:

• 60.4% of patients in the exercise-only group
• 68.8% of patients in the medication-only group
• 65.5% of patients receiving exercise plus medication.

Depression severity appeared to predict the rate of response to the different treatments. Patients who received medication alone seemed to have the most rapid response to treatment. Patients with less severe depression appeared to respond more quickly to exercise plus medication than those with more severe depression.

Long-term benefits

Because depression is a chronic, relapsing illness, any treatment will be widely accepted only if its benefits are long-term. A study of aerobic exercise in 156 adults age ≥50 with MDD²⁸ found that benefits were sustained for >6 months.

Participants were randomly assigned to 4 months of aerobic exercise; sertraline, ≤200 mg/d; or a combination of exercise and sertraline. Aerobic exercise consisted of 30 minutes of brisk walking and jogging on a treadmill, with training ranges equivalent to 70% to 85% of individuals’ maximum heart rate. Appropriate warm-up and cool-down sessions of 5 to 10 minutes were included.

Depressive symptoms improved significantly from baseline in all 3 groups—as assessed by clinical interview, HRSD, and BDI—and after 4 months a comparable number in each group no longer met diagnostic criteria for MDD. When subjects were reassessed 6 months later, the exercisers had significantly lower relapse rates than those receiving medication (P=.01). Those who continued to exercise also were less likely to meet MDD criteria at the end of the 10-month study.

Box 3

 

Even when unsupervised, exercise can have long-term benefits—as was shown in a randomized, blinded, controlled study of 32 elderly subjects.²⁹ An active treatment group underwent 10 weeks of supervised weight lifting, followed by 10 weeks of unsupervised exercise. Controls received no active treatment. Depression scores as measured by BDI were significantly lower at 20 weeks and 26 months in exercisers compared with controls. An antidepressant effect was seen in 73% of exercisers vs 36% of controls at 20 weeks of treatment.

Comment. These studies show that exercise can maintain an anti depressant effect for 10 to 26 months, but additional randomized controlled studies are needed.

Preventing depression? Inactive nondepressed individuals may be at greater risk to develop depression compared with active individuals, according to a 29-year longitudinal study of Californians age 17 to 94. This association was somewhat diminished when findings were adjusted for the Alameda County residents’ physical health, socioeconomic status, social supports, life events, and other health habits.³⁰ The authors recommended that exercise programs be offered in community mental health programs.

Box 4

Simple steps to build physical activity into daily life

The American Heart Association offers helpful tips for increasing daily exercise at home, at work, and at play. For additional suggestions, go to www.americanheart.org.
At home	At the office	At play
Do housework yourself instead of hiring someone else to do it	Brainstorm project ideas with a coworker while taking a walk	Plan family outings and vacations that include physical
Work in the garden or mow the grass (using a riding mower doesn’t count); rake leaves, prune, dig, and pick up trash	Stand while talking on the telephone	activity (hiking, backpacking, swimming, etc.)
Go out for a short walk before breakfast, after dinner or both; start with 5 to 10 minutes and work up to 30 minutes	Walk down the hall to speak with someone rather than using the telephone	See the sights in new cities by walking, jogging, or bicycling
Walk or bike to the corner store instead of driving	Take the stairs instead of the elevator, or get off a few floors early and take the stairs the rest of the way	Make a date with a friend to enjoy your favorite physical activities, and do them regularly
When walking, increase the pace from leisurely to brisk; choose a hilly route	Schedule exercise time on your business calendar, and treat it as any other important appointment	Play your favorite music while exercising, something that motivates you
		Dance with someone or by yourself; take dancing lessons
		Join a recreational club that emphasizes physical activity
		When golfing, walk the course instead of using a cart

CASE CONTINUED: Removing barriers to exercise

The resident psychiatrist treating Mrs. S encourages her to join an aerobic exercise class at the nearby fitness facility. Because cost is a potential barrier, he helps her negotiate a discount for the first 6 months of membership. Her husband agrees in a joint counseling session to help more with the care of their children so that she can attend the classes.

With continued sertraline, 200 mg/d, and aerobic exercise, Mrs. S’s residual depressive symptoms gradually improve. She still has days when she is unable to attend the exercise classes, but she benefits from the program and is functioning better at work and home.

Getting started

We recommend that psychiatrists inquire about physical activity at every visit to gauge patients’ perception and motivation to exercise. Find ways to overcome patients’ fears and negative experiences with exercise. Provide information to help increase physical activity among patients with depressive symptoms¹⁰ (see Related Resources).

Encourage patients to take steps each day to increase their physical activity (Box 3). Depending on the severity of the individual’s depression and inactivity, a realistic starting point may be to take the stairs instead of an elevator, play with children and pets, or take short brisk walks in the yard or neighborhood (Box 4). Consider stationary bikes or swimming as alternatives for physically handicapped individuals and patients who have undergone knee replacements.

Related resources

• 2008 physical activity guidelines for Americans. U.S. Department of Health and Human Services; 2008:vi-viii. www.health.gov/paguidelines.
• American College of Sports Medicine/American Health Association physical activity guidelines and keys to exercise success. www.acsm.org.
• American Heart Association. www.americanheart.org.
• U.S. Department of Health and Human Services. Quick Guide for Healthy Living. Get Active. www.healthfinder.gov/prevention/ViewTopic.aspx?topicID=22.

 

Drug brand names

• Bupropion • Wellbutrin
• Sertraline • Zoloft

Disclosure

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

Comment on this article

Mrs. S, age 44, is on leave from her job as a bank cashier because depressive symptoms interfered with her performance. At a university-based psychiatric clinic she reports feeling depressed, reduced interest in daily activities, problems with sleep onset and maintenance, inconsistent appetite, low energy, hopelessness, and decreased memory and concentration.

The resident psychiatrist diagnoses major depressive disorder (MDD) and starts Mrs. S on sertraline, 50 mg/d. The dosage is gradually titrated to 200 mg/d, and after 8 weeks she reports substantial improvement.

Mrs. S returns to her job but experiences residual low energy, lethargy, and inconsistent sleep. Her work schedule and caring for her 2 children at home prevent her from continuing weekly cognitive-behavioral therapy (CBT), but she soon notices that she feels more energetic. She reports that because of high gasoline prices she has been walking several miles daily to commute by train to work. The resident psychiatrist sees this as an opportunity to reinforce the benefits of exercise for depression.

Antidepressants alone do not adequately treat many patients with depression. In the STAR*D Project—which compared long-term outcomes of various depression treatments—only 28% to 33% of outpatients achieved remission with selective serotonin reuptake inhibitor (SSRI) monotherapy. Rates were somewhat higher with bupropion or serotonin norepinephrine reuptake inhibitor (SNRI) monotherapy, but greater benefit was obtained from augmenting SSRIs.¹

Combining antidepressants with psychotherapy² and lifestyle changes—particularly exercise—makes sense intuitively and is supported by well-designed studies:

• The 60% of adults in the National Comorbidity Survey who said they exercised regularly reported lower rates of depression and anxiety, compared with less active adults.³
• A meta-analysis of 11 randomized, controlled trials supports the use of exercise as an effective intervention for clinical depression.⁴

Box 1

This article examines the evidence supporting exercise for treating and preventing clinical depression. We begin by addressing clinicians’ concerns about motivating depressed patients to exercise.

Overcoming barriers

Physician issues. Busy physicians often omit discussions about exercise during brief office visits. Only 34% of 9,299 patients in a population-based survey⁵ reported that their doctors counseled them about exercise during their most recent visits. Counseling patients does not have to be time-intensive, however. A study of the Physician-based Assessment and Counseling for Exercise (PACE) project showed that 70% of physicians could provide exercise counseling in 3 to 5 minutes, and most patients reported following their physicians’ advice.⁶

Highly depressed individuals are at risk to quit when they encounter barriers to exercise and to respond to difficulties with frustration and self-disappointment. Thus, depressed patients may need support and encouragement to initiate and maintain regular exercise routines.⁷ Set small, realistic goals for them, and discuss how to solve problems and remove barriers to increase their likelihood to exercise.

Interventions are most likely to be effective when you counsel patients about exercise as prescription and discuss exercise at each visit.⁸ Previously sedentary patients have shown short-term moderate increases in physical activity in response to physician counseling. In a study of 212 adults (mean age 39, 84% female), the PACE project significantly increased minutes of weekly walking.⁹ More than one-half (52%) of patients increased their physical activity, compared with 12% of controls whose physicians did not provide the PACE intervention.

Patient issues. Lack of time and no appropriate space to exercise are common complaints, particularly among residents of regions with long, cold winters. Some patients perceive regular exercise as monotonous or boring, and others may lack the necessary initiative because of poor physical health, fear, negative experiences, or lack of knowledge about exercising. These barriers can be pronounced in older depressed persons. In a cross-sectional study of 645 residents of Jyväskylä, Finland, those age >75 with depressive symptoms were more than twice as likely to be physically inactive as nondepressed residents.¹⁰

An intensive exercise program is not the optimal starting point for many patients. Even walking or light jogging can be an effective exercise for depressed individuals with physical limitations. For these patients, a consultation with their primary physician may be necessary if a more intensive program has to be recommended.

Exercise as monotherapy

A dose-response relationship? Various mechanisms have been suggested for the benefits of exercise in depression (Box 1). Exercise alone—without medication—may be an effective treatment for mild and in some cases moderate MDD, and aerobic exercise may reduce depressive symptoms in a dose-response relationship.¹¹

 

A study of exercise in a supervised laboratory setting demonstrated this relationship in 80 adults age 20 to 45 with mild-to-moderate depressive symptoms. Subjects were randomly assigned to an exercise control group (3 days/week of flexibility exercise) or 1 of 4 aerobic exercise groups that varied in total energy expenditure (a “low dose” of 7.0 kcal/kg/week or a “public health dose” of 17.5 kcal/kg/week). The 17-item Hamilton Rating Scale for Depression (HRSD) was the primary outcome measure.

After 12 weeks, HRSD scores declined from baseline by 47% in subjects engaged in the public health dose of aerobic exercise—a significant reduction. Depressive symptoms declined by 30% in the low-dose exercisers, but this was comparable to the 29% reduction in the control group.

Comment. The effective exercise dose in this study is similar to the public health recommendation of 30 minutes of moderate-to-vigorous activity on all or most days per week (see Related Resources). Antidepressant effects have been associated with more modest physical activity, however, which may be easier to initiate and maintain for individuals with depression. The study did not find significant differences in outcomes based on the subjects’ age, gender, or exercise frequency. Nevertheless, the exercise dose may be important to produce an antidepressant effect.

An inverse relationship? Compared with occasional exercise, habitual physical activity usually is associated with greater cardiorespiratory fitness. Whether habitual activity also results in fewer depressive symptoms and greater emotional well-being remains to be seen.

A large, cross-sectional, National Institutes of Health-funded study of 5,451 men and 1,277 women¹² suggests an inverse relationship between physical activity and depressive symptoms. Subjects underwent a treadmill exercise test to evaluate physical fitness. A 20-point self-report scale assessed depressive symptoms, and the General Well-Being Schedule¹³ was used to assess emotional well-being. Depressive symptoms were more severe in “inactive” and “insufficiently active” subjects compared with “sufficiently active” and “highly active” subjects.

On the other hand, although regular exercise may be associated with reduced depressive symptoms in the population at large, no cause-effect relationship was found in a population-based, longitudinal study of 5,952 twins.¹⁴

A prospective, randomized, controlled trial¹⁵ suggests that exercise could be an important treatment tool in patients diagnosed with MDD. The 202 adult subjects (153 women, 49 men) were randomly assigned to 1 of 4 treatments:

• supervised exercise in a group setting
• home-based exercise
• antidepressant medication (sertraline, 50 to 200 mg/d)
• placebo pills.

Patients underwent the structured clinical interview for depression and completed the HRSD. After 16 weeks, 41% of participants achieved remission, defined as no longer meeting MDD criteria and a HRSD score <8. Compared with placebo controls, patients receiving active treatments tended to have higher remission rates:

• 45% with supervised exercise
• 40% with home-based exercise
• 47% with medication
• 31% with placebo.

Comment. The placebo response rate was relatively high in this study, and antidepressant dosages might not have been optimal. These factors could explain why remission rates with supervised exercise and antidepressant medication were comparable. The study might have been more reliable if it had included a medication plus exercise arm. Patients treated in an office setting might not fare as well as these study subjects whose exercise was supervised.

Postpartum depression occurs in an estimated 13% of new mothers.¹⁶ In a controlled trial, 80 women with depression at 4 weeks postpartum were assigned to either:

• an exercise support program (1 hour supervised exercise and 2 sessions at home each week for 3 months)
• standard care.

Box 2

 

No subjects received medication. Women in the exercise support program were less likely to have high scores on the Edinburgh Postnatal Depression Scale, compared with controls. Women who exercised also reported a greater sense of well-being. Differences between the 2 groups were not statistically significant at 4 weeks post partum but achieved significance at 5 months.¹⁷

Depressive symptoms may exacerbate fatigue in postpartum women.¹⁸ A study of 88 women with postpartum depression showed the benefits of a home-based exercise program on physical and mental fatigue.¹⁹ This finding may be important because fatigue often is associated with treatment-resistant depression and may increase the likelihood of relapse in women with postpartum depression.²⁰

Late-life depression. Exercise can benefit the depressed elderly as well. In a 10-week randomized, controlled trial²¹ of volunteers age ≥60 with major or minor depression or dysthymia, progressive resistance training (PRT) significantly reduced depression, as measured by the Beck Depression Inventory (BDI) and HRSD. PRT also improved quality of life, vitality, social functioning, and emotional well-being when compared with a control group (Box 2).

A dose-response relationship of exercise for treating late-life depression was shown in a blinded, controlled trial²² of 60 community-dwelling, depressed subjects age >60. These patients were randomly assigned to high-intensity PRT, low-intensity PRT, or standard care by a general practitioner (GP). A ≥50% reduction in HRSD score was achieved by:

• 61% of the high-intensity PRT group
• 29% of the low-intensity PRT group
• 21% of the GP care group.

Sleep quality improved in all participants, with the greatest relative change in the high-intensity PRT group.

Exercise vs psychotherapy. The benefits of exercise may be comparable or superior to those of cognitive or group psychotherapy.^23,24 This may be good news for patients such as Mrs. S who lack time or financial resources for regular psychotherapy.

Adjunctive exercise

In depressed patients, exercise may increase the perceived quality of life when combined with medication. This was demonstrated in a randomized, 32-week naturalistic study of 30 women, age 40 to 60, with treatment-resistant MDD.²⁵ The 10 women who received various antidepressants plus physical exercise showed significantly greater long-term improvement in depression symptoms, as measured by the HRSD and Global Assessment of Functioning (GAF) scores, compared with 20 women who received pharmacotherapy alone.²⁶ Study limitations included the absence of a placebo arm, small sample size, and inclusion of subjects with comorbid anxiety disorders.

Group aerobic exercise programs can be an effective and feasible treatment for depression, particularly for older adults. In a controlled trial,²⁷ 156 men and women age >50 with MDD were randomly assigned to 3 groups: a program of aerobic exercise; sertraline, ≤200 mg/d; or exercise plus sertraline. HRSD and BDI scores before and after treatment were the primary outcome measures. Secondary measures included aerobic capacity, life satisfaction, self-esteem, anxiety, and dysfunctional cognitions. After 16 weeks of treatment, similar percentages of patients in each group no longer met DSM-IV-TR criteria for MDD:

• 60.4% of patients in the exercise-only group
• 68.8% of patients in the medication-only group
• 65.5% of patients receiving exercise plus medication.

Depression severity appeared to predict the rate of response to the different treatments. Patients who received medication alone seemed to have the most rapid response to treatment. Patients with less severe depression appeared to respond more quickly to exercise plus medication than those with more severe depression.

Long-term benefits

Because depression is a chronic, relapsing illness, any treatment will be widely accepted only if its benefits are long-term. A study of aerobic exercise in 156 adults age ≥50 with MDD²⁸ found that benefits were sustained for >6 months.

Participants were randomly assigned to 4 months of aerobic exercise; sertraline, ≤200 mg/d; or a combination of exercise and sertraline. Aerobic exercise consisted of 30 minutes of brisk walking and jogging on a treadmill, with training ranges equivalent to 70% to 85% of individuals’ maximum heart rate. Appropriate warm-up and cool-down sessions of 5 to 10 minutes were included.

Depressive symptoms improved significantly from baseline in all 3 groups—as assessed by clinical interview, HRSD, and BDI—and after 4 months a comparable number in each group no longer met diagnostic criteria for MDD. When subjects were reassessed 6 months later, the exercisers had significantly lower relapse rates than those receiving medication (P=.01). Those who continued to exercise also were less likely to meet MDD criteria at the end of the 10-month study.

Box 3

 

Even when unsupervised, exercise can have long-term benefits—as was shown in a randomized, blinded, controlled study of 32 elderly subjects.²⁹ An active treatment group underwent 10 weeks of supervised weight lifting, followed by 10 weeks of unsupervised exercise. Controls received no active treatment. Depression scores as measured by BDI were significantly lower at 20 weeks and 26 months in exercisers compared with controls. An antidepressant effect was seen in 73% of exercisers vs 36% of controls at 20 weeks of treatment.

Comment. These studies show that exercise can maintain an anti depressant effect for 10 to 26 months, but additional randomized controlled studies are needed.

Preventing depression? Inactive nondepressed individuals may be at greater risk to develop depression compared with active individuals, according to a 29-year longitudinal study of Californians age 17 to 94. This association was somewhat diminished when findings were adjusted for the Alameda County residents’ physical health, socioeconomic status, social supports, life events, and other health habits.³⁰ The authors recommended that exercise programs be offered in community mental health programs.

Box 4

Simple steps to build physical activity into daily life

The American Heart Association offers helpful tips for increasing daily exercise at home, at work, and at play. For additional suggestions, go to www.americanheart.org.
At home	At the office	At play
Do housework yourself instead of hiring someone else to do it	Brainstorm project ideas with a coworker while taking a walk	Plan family outings and vacations that include physical
Work in the garden or mow the grass (using a riding mower doesn’t count); rake leaves, prune, dig, and pick up trash	Stand while talking on the telephone	activity (hiking, backpacking, swimming, etc.)
Go out for a short walk before breakfast, after dinner or both; start with 5 to 10 minutes and work up to 30 minutes	Walk down the hall to speak with someone rather than using the telephone	See the sights in new cities by walking, jogging, or bicycling
Walk or bike to the corner store instead of driving	Take the stairs instead of the elevator, or get off a few floors early and take the stairs the rest of the way	Make a date with a friend to enjoy your favorite physical activities, and do them regularly
When walking, increase the pace from leisurely to brisk; choose a hilly route	Schedule exercise time on your business calendar, and treat it as any other important appointment	Play your favorite music while exercising, something that motivates you
		Dance with someone or by yourself; take dancing lessons
		Join a recreational club that emphasizes physical activity
		When golfing, walk the course instead of using a cart

CASE CONTINUED: Removing barriers to exercise

The resident psychiatrist treating Mrs. S encourages her to join an aerobic exercise class at the nearby fitness facility. Because cost is a potential barrier, he helps her negotiate a discount for the first 6 months of membership. Her husband agrees in a joint counseling session to help more with the care of their children so that she can attend the classes.

With continued sertraline, 200 mg/d, and aerobic exercise, Mrs. S’s residual depressive symptoms gradually improve. She still has days when she is unable to attend the exercise classes, but she benefits from the program and is functioning better at work and home.

Getting started

We recommend that psychiatrists inquire about physical activity at every visit to gauge patients’ perception and motivation to exercise. Find ways to overcome patients’ fears and negative experiences with exercise. Provide information to help increase physical activity among patients with depressive symptoms¹⁰ (see Related Resources).

Encourage patients to take steps each day to increase their physical activity (Box 3). Depending on the severity of the individual’s depression and inactivity, a realistic starting point may be to take the stairs instead of an elevator, play with children and pets, or take short brisk walks in the yard or neighborhood (Box 4). Consider stationary bikes or swimming as alternatives for physically handicapped individuals and patients who have undergone knee replacements.

Related resources

• 2008 physical activity guidelines for Americans. U.S. Department of Health and Human Services; 2008:vi-viii. www.health.gov/paguidelines.
• American College of Sports Medicine/American Health Association physical activity guidelines and keys to exercise success. www.acsm.org.
• American Heart Association. www.americanheart.org.
• U.S. Department of Health and Human Services. Quick Guide for Healthy Living. Get Active. www.healthfinder.gov/prevention/ViewTopic.aspx?topicID=22.

 

Drug brand names

• Bupropion • Wellbutrin
• Sertraline • Zoloft

Disclosure

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

Comment on this article

Mrs. S, age 44, is on leave from her job as a bank cashier because depressive symptoms interfered with her performance. At a university-based psychiatric clinic she reports feeling depressed, reduced interest in daily activities, problems with sleep onset and maintenance, inconsistent appetite, low energy, hopelessness, and decreased memory and concentration.

The resident psychiatrist diagnoses major depressive disorder (MDD) and starts Mrs. S on sertraline, 50 mg/d. The dosage is gradually titrated to 200 mg/d, and after 8 weeks she reports substantial improvement.

Mrs. S returns to her job but experiences residual low energy, lethargy, and inconsistent sleep. Her work schedule and caring for her 2 children at home prevent her from continuing weekly cognitive-behavioral therapy (CBT), but she soon notices that she feels more energetic. She reports that because of high gasoline prices she has been walking several miles daily to commute by train to work. The resident psychiatrist sees this as an opportunity to reinforce the benefits of exercise for depression.

Antidepressants alone do not adequately treat many patients with depression. In the STAR*D Project—which compared long-term outcomes of various depression treatments—only 28% to 33% of outpatients achieved remission with selective serotonin reuptake inhibitor (SSRI) monotherapy. Rates were somewhat higher with bupropion or serotonin norepinephrine reuptake inhibitor (SNRI) monotherapy, but greater benefit was obtained from augmenting SSRIs.¹

Combining antidepressants with psychotherapy² and lifestyle changes—particularly exercise—makes sense intuitively and is supported by well-designed studies:

• The 60% of adults in the National Comorbidity Survey who said they exercised regularly reported lower rates of depression and anxiety, compared with less active adults.³
• A meta-analysis of 11 randomized, controlled trials supports the use of exercise as an effective intervention for clinical depression.⁴

Box 1

This article examines the evidence supporting exercise for treating and preventing clinical depression. We begin by addressing clinicians’ concerns about motivating depressed patients to exercise.

Overcoming barriers

Physician issues. Busy physicians often omit discussions about exercise during brief office visits. Only 34% of 9,299 patients in a population-based survey⁵ reported that their doctors counseled them about exercise during their most recent visits. Counseling patients does not have to be time-intensive, however. A study of the Physician-based Assessment and Counseling for Exercise (PACE) project showed that 70% of physicians could provide exercise counseling in 3 to 5 minutes, and most patients reported following their physicians’ advice.⁶

Highly depressed individuals are at risk to quit when they encounter barriers to exercise and to respond to difficulties with frustration and self-disappointment. Thus, depressed patients may need support and encouragement to initiate and maintain regular exercise routines.⁷ Set small, realistic goals for them, and discuss how to solve problems and remove barriers to increase their likelihood to exercise.

Interventions are most likely to be effective when you counsel patients about exercise as prescription and discuss exercise at each visit.⁸ Previously sedentary patients have shown short-term moderate increases in physical activity in response to physician counseling. In a study of 212 adults (mean age 39, 84% female), the PACE project significantly increased minutes of weekly walking.⁹ More than one-half (52%) of patients increased their physical activity, compared with 12% of controls whose physicians did not provide the PACE intervention.

Patient issues. Lack of time and no appropriate space to exercise are common complaints, particularly among residents of regions with long, cold winters. Some patients perceive regular exercise as monotonous or boring, and others may lack the necessary initiative because of poor physical health, fear, negative experiences, or lack of knowledge about exercising. These barriers can be pronounced in older depressed persons. In a cross-sectional study of 645 residents of Jyväskylä, Finland, those age >75 with depressive symptoms were more than twice as likely to be physically inactive as nondepressed residents.¹⁰

An intensive exercise program is not the optimal starting point for many patients. Even walking or light jogging can be an effective exercise for depressed individuals with physical limitations. For these patients, a consultation with their primary physician may be necessary if a more intensive program has to be recommended.

Exercise as monotherapy

A dose-response relationship? Various mechanisms have been suggested for the benefits of exercise in depression (Box 1). Exercise alone—without medication—may be an effective treatment for mild and in some cases moderate MDD, and aerobic exercise may reduce depressive symptoms in a dose-response relationship.¹¹

 

A study of exercise in a supervised laboratory setting demonstrated this relationship in 80 adults age 20 to 45 with mild-to-moderate depressive symptoms. Subjects were randomly assigned to an exercise control group (3 days/week of flexibility exercise) or 1 of 4 aerobic exercise groups that varied in total energy expenditure (a “low dose” of 7.0 kcal/kg/week or a “public health dose” of 17.5 kcal/kg/week). The 17-item Hamilton Rating Scale for Depression (HRSD) was the primary outcome measure.

After 12 weeks, HRSD scores declined from baseline by 47% in subjects engaged in the public health dose of aerobic exercise—a significant reduction. Depressive symptoms declined by 30% in the low-dose exercisers, but this was comparable to the 29% reduction in the control group.

Comment. The effective exercise dose in this study is similar to the public health recommendation of 30 minutes of moderate-to-vigorous activity on all or most days per week (see Related Resources). Antidepressant effects have been associated with more modest physical activity, however, which may be easier to initiate and maintain for individuals with depression. The study did not find significant differences in outcomes based on the subjects’ age, gender, or exercise frequency. Nevertheless, the exercise dose may be important to produce an antidepressant effect.

An inverse relationship? Compared with occasional exercise, habitual physical activity usually is associated with greater cardiorespiratory fitness. Whether habitual activity also results in fewer depressive symptoms and greater emotional well-being remains to be seen.

A large, cross-sectional, National Institutes of Health-funded study of 5,451 men and 1,277 women¹² suggests an inverse relationship between physical activity and depressive symptoms. Subjects underwent a treadmill exercise test to evaluate physical fitness. A 20-point self-report scale assessed depressive symptoms, and the General Well-Being Schedule¹³ was used to assess emotional well-being. Depressive symptoms were more severe in “inactive” and “insufficiently active” subjects compared with “sufficiently active” and “highly active” subjects.

On the other hand, although regular exercise may be associated with reduced depressive symptoms in the population at large, no cause-effect relationship was found in a population-based, longitudinal study of 5,952 twins.¹⁴

A prospective, randomized, controlled trial¹⁵ suggests that exercise could be an important treatment tool in patients diagnosed with MDD. The 202 adult subjects (153 women, 49 men) were randomly assigned to 1 of 4 treatments:

• supervised exercise in a group setting
• home-based exercise
• antidepressant medication (sertraline, 50 to 200 mg/d)
• placebo pills.

Patients underwent the structured clinical interview for depression and completed the HRSD. After 16 weeks, 41% of participants achieved remission, defined as no longer meeting MDD criteria and a HRSD score <8. Compared with placebo controls, patients receiving active treatments tended to have higher remission rates:

• 45% with supervised exercise
• 40% with home-based exercise
• 47% with medication
• 31% with placebo.

Comment. The placebo response rate was relatively high in this study, and antidepressant dosages might not have been optimal. These factors could explain why remission rates with supervised exercise and antidepressant medication were comparable. The study might have been more reliable if it had included a medication plus exercise arm. Patients treated in an office setting might not fare as well as these study subjects whose exercise was supervised.

Postpartum depression occurs in an estimated 13% of new mothers.¹⁶ In a controlled trial, 80 women with depression at 4 weeks postpartum were assigned to either:

• an exercise support program (1 hour supervised exercise and 2 sessions at home each week for 3 months)
• standard care.

Box 2

 

No subjects received medication. Women in the exercise support program were less likely to have high scores on the Edinburgh Postnatal Depression Scale, compared with controls. Women who exercised also reported a greater sense of well-being. Differences between the 2 groups were not statistically significant at 4 weeks post partum but achieved significance at 5 months.¹⁷

Depressive symptoms may exacerbate fatigue in postpartum women.¹⁸ A study of 88 women with postpartum depression showed the benefits of a home-based exercise program on physical and mental fatigue.¹⁹ This finding may be important because fatigue often is associated with treatment-resistant depression and may increase the likelihood of relapse in women with postpartum depression.²⁰

Late-life depression. Exercise can benefit the depressed elderly as well. In a 10-week randomized, controlled trial²¹ of volunteers age ≥60 with major or minor depression or dysthymia, progressive resistance training (PRT) significantly reduced depression, as measured by the Beck Depression Inventory (BDI) and HRSD. PRT also improved quality of life, vitality, social functioning, and emotional well-being when compared with a control group (Box 2).

A dose-response relationship of exercise for treating late-life depression was shown in a blinded, controlled trial²² of 60 community-dwelling, depressed subjects age >60. These patients were randomly assigned to high-intensity PRT, low-intensity PRT, or standard care by a general practitioner (GP). A ≥50% reduction in HRSD score was achieved by:

• 61% of the high-intensity PRT group
• 29% of the low-intensity PRT group
• 21% of the GP care group.

Sleep quality improved in all participants, with the greatest relative change in the high-intensity PRT group.

Exercise vs psychotherapy. The benefits of exercise may be comparable or superior to those of cognitive or group psychotherapy.^23,24 This may be good news for patients such as Mrs. S who lack time or financial resources for regular psychotherapy.

Adjunctive exercise

In depressed patients, exercise may increase the perceived quality of life when combined with medication. This was demonstrated in a randomized, 32-week naturalistic study of 30 women, age 40 to 60, with treatment-resistant MDD.²⁵ The 10 women who received various antidepressants plus physical exercise showed significantly greater long-term improvement in depression symptoms, as measured by the HRSD and Global Assessment of Functioning (GAF) scores, compared with 20 women who received pharmacotherapy alone.²⁶ Study limitations included the absence of a placebo arm, small sample size, and inclusion of subjects with comorbid anxiety disorders.

Group aerobic exercise programs can be an effective and feasible treatment for depression, particularly for older adults. In a controlled trial,²⁷ 156 men and women age >50 with MDD were randomly assigned to 3 groups: a program of aerobic exercise; sertraline, ≤200 mg/d; or exercise plus sertraline. HRSD and BDI scores before and after treatment were the primary outcome measures. Secondary measures included aerobic capacity, life satisfaction, self-esteem, anxiety, and dysfunctional cognitions. After 16 weeks of treatment, similar percentages of patients in each group no longer met DSM-IV-TR criteria for MDD:

• 60.4% of patients in the exercise-only group
• 68.8% of patients in the medication-only group
• 65.5% of patients receiving exercise plus medication.

Depression severity appeared to predict the rate of response to the different treatments. Patients who received medication alone seemed to have the most rapid response to treatment. Patients with less severe depression appeared to respond more quickly to exercise plus medication than those with more severe depression.

Long-term benefits

Because depression is a chronic, relapsing illness, any treatment will be widely accepted only if its benefits are long-term. A study of aerobic exercise in 156 adults age ≥50 with MDD²⁸ found that benefits were sustained for >6 months.

Participants were randomly assigned to 4 months of aerobic exercise; sertraline, ≤200 mg/d; or a combination of exercise and sertraline. Aerobic exercise consisted of 30 minutes of brisk walking and jogging on a treadmill, with training ranges equivalent to 70% to 85% of individuals’ maximum heart rate. Appropriate warm-up and cool-down sessions of 5 to 10 minutes were included.

Depressive symptoms improved significantly from baseline in all 3 groups—as assessed by clinical interview, HRSD, and BDI—and after 4 months a comparable number in each group no longer met diagnostic criteria for MDD. When subjects were reassessed 6 months later, the exercisers had significantly lower relapse rates than those receiving medication (P=.01). Those who continued to exercise also were less likely to meet MDD criteria at the end of the 10-month study.

Box 3

 

Even when unsupervised, exercise can have long-term benefits—as was shown in a randomized, blinded, controlled study of 32 elderly subjects.²⁹ An active treatment group underwent 10 weeks of supervised weight lifting, followed by 10 weeks of unsupervised exercise. Controls received no active treatment. Depression scores as measured by BDI were significantly lower at 20 weeks and 26 months in exercisers compared with controls. An antidepressant effect was seen in 73% of exercisers vs 36% of controls at 20 weeks of treatment.

Comment. These studies show that exercise can maintain an anti depressant effect for 10 to 26 months, but additional randomized controlled studies are needed.

Preventing depression? Inactive nondepressed individuals may be at greater risk to develop depression compared with active individuals, according to a 29-year longitudinal study of Californians age 17 to 94. This association was somewhat diminished when findings were adjusted for the Alameda County residents’ physical health, socioeconomic status, social supports, life events, and other health habits.³⁰ The authors recommended that exercise programs be offered in community mental health programs.

Box 4

Simple steps to build physical activity into daily life

The American Heart Association offers helpful tips for increasing daily exercise at home, at work, and at play. For additional suggestions, go to www.americanheart.org.
At home	At the office	At play
Do housework yourself instead of hiring someone else to do it	Brainstorm project ideas with a coworker while taking a walk	Plan family outings and vacations that include physical
Work in the garden or mow the grass (using a riding mower doesn’t count); rake leaves, prune, dig, and pick up trash	Stand while talking on the telephone	activity (hiking, backpacking, swimming, etc.)
Go out for a short walk before breakfast, after dinner or both; start with 5 to 10 minutes and work up to 30 minutes	Walk down the hall to speak with someone rather than using the telephone	See the sights in new cities by walking, jogging, or bicycling
Walk or bike to the corner store instead of driving	Take the stairs instead of the elevator, or get off a few floors early and take the stairs the rest of the way	Make a date with a friend to enjoy your favorite physical activities, and do them regularly
When walking, increase the pace from leisurely to brisk; choose a hilly route	Schedule exercise time on your business calendar, and treat it as any other important appointment	Play your favorite music while exercising, something that motivates you
		Dance with someone or by yourself; take dancing lessons
		Join a recreational club that emphasizes physical activity
		When golfing, walk the course instead of using a cart

CASE CONTINUED: Removing barriers to exercise

The resident psychiatrist treating Mrs. S encourages her to join an aerobic exercise class at the nearby fitness facility. Because cost is a potential barrier, he helps her negotiate a discount for the first 6 months of membership. Her husband agrees in a joint counseling session to help more with the care of their children so that she can attend the classes.

With continued sertraline, 200 mg/d, and aerobic exercise, Mrs. S’s residual depressive symptoms gradually improve. She still has days when she is unable to attend the exercise classes, but she benefits from the program and is functioning better at work and home.

Getting started

We recommend that psychiatrists inquire about physical activity at every visit to gauge patients’ perception and motivation to exercise. Find ways to overcome patients’ fears and negative experiences with exercise. Provide information to help increase physical activity among patients with depressive symptoms¹⁰ (see Related Resources).

Encourage patients to take steps each day to increase their physical activity (Box 3). Depending on the severity of the individual’s depression and inactivity, a realistic starting point may be to take the stairs instead of an elevator, play with children and pets, or take short brisk walks in the yard or neighborhood (Box 4). Consider stationary bikes or swimming as alternatives for physically handicapped individuals and patients who have undergone knee replacements.

Related resources

• 2008 physical activity guidelines for Americans. U.S. Department of Health and Human Services; 2008:vi-viii. www.health.gov/paguidelines.
• American College of Sports Medicine/American Health Association physical activity guidelines and keys to exercise success. www.acsm.org.
• American Heart Association. www.americanheart.org.
• U.S. Department of Health and Human Services. Quick Guide for Healthy Living. Get Active. www.healthfinder.gov/prevention/ViewTopic.aspx?topicID=22.

 

Drug brand names

• Bupropion • Wellbutrin
• Sertraline • Zoloft

Disclosure

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

Comment on this article

Clinical studies indicate that clozapine and olanzapine carry a high risk of treatment-related metabolic dysfunction—including weight gain, hyperlipidemia, and glucose intolerance—but certain patients with high metabolic liabilities who take atypical antipsychotics do not necessarily develop these adverse effects. Though the underlying mechanism for atypical antipsychotic-related weight gain is strongly associated with central histamine H1 antagonism and increased appetite, the pharmacologic basis for other metabolic changes is not fully understood and may involve weight-independent mechanisms.

One potentially relevant research area is peptide hormones’ impact on the regulation of food intake, body weight, and other metabolic parameters. As research has elucidated the properties of 1 of these hormones—leptin—investigators have started to examine possible correlations between changes in serum levels of leptin and weight gain during atypical anti-psychotic treatment.

This article summarizes available clinical data on the interaction of atypical antipsychotics with leptin and indicates directions for future research on interactions between psychotropic medications and metabolic hormones.

Leptin’s function

Since its initial sequencing as the product of the obese (ob) gene in 1994, leptin has garnered substantial attention as a metabolic regulatory hormone.¹ Leptin is produced primarily by fat cells as part of a long-term central feedback mechanism involving central control of appetite and peripheral metabolic activity regulation. Leptin is a 167 amino acid, 16-kilodalton protein that binds to cell surface receptors (the product of the diabetes [db] gene) at both central (ventromedial hypothalamic) and peripheral sites (liver, skeletal muscle, and pancreatic β-cells).²

Evidence for leptin’s activity is seen in ob/ob mice, whose genetic inability to produce leptin is manifested phenotypically in overeating and obesity. Administering recombinant leptin to these mice results in reduced appetite and weight loss.³

On average, women have greater fat mass and higher serum leptin levels than men. Humans rarely have mutations in both copies of the ob gene, but those who do are severely obese and respond to exogenous leptin. Heterozygotes are not quite as heavy.

Leptin circulates in a free form but in humans is predominantly bound to the soluble leptin receptor (sOB-R). Levels of sOB-R increase with weight loss—with concomitant decreases in leptin levels—and these effects can be seen even during 72-hour fasts.⁴ Leptin levels are positively correlated with fat mass, but the fact that obese individuals have chronically elevated leptin levels argues for some level of leptin insensitivity or resistance to the hormone’s appetite-suppressing effects.²

Drug effects

Clozapine and olanzapine. Literature on leptin and antipsychotic-related obesity is relatively well developed. The first papers focused on the association between clozapine and olanzapine and increases in serum leptin levels.^5,6 As patients gained substantial weight on clozapine and olanzapine, serum leptin also rose, but neither weight nor leptin changes were seen in patients exposed to haloperidol or those who did not receive antipsychotics.⁶

Numerous subsequent prospective trials of patients treated with olanzapine^4,7,8 and clozapine^9-11 confirmed previousl established associations among use of these medications, weight gain, and increased serum leptin levels. Olanzapine- and clozapine-exposed subjects experienced marked increases in adiposity, weight, and serum leptin (Box 1). ^5,9,12-16

Other agents. For agents associated with less weight gain liability—such as high-potency typical antipsychotics,^12,17,18 sulpiride,¹⁹ quetiapine,¹⁸ or risperidone^20,21—comparative trials noted modest weight gain and leptin increases. Prospective trials of weight-modifying strategies using adjunctive amantadine⁸ or nizatidine²² found positive effects of the adjunctive medication, with proportional decreases in leptin levels compared with antipsychotics alone.

Because the other 2 atypical antipsychotics—ziprasidone and aripiprazole—were found to be weight-neutral or have the lowest weight-gain burden, few studies have examined the relationship between leptin with weight gain in patients taking these drugs. One study reported no significant body weight or leptin level change in patients after 4-week trial of ziprasidone.²³

Box 1

 

Other metabolic parameters

In humans, elevated serum leptin levels are associated with adverse metabolic markers, particularly those associated with insulin activity (including insulin itself) and serum triglycerides.²⁴ Several antipsychotic studies measured metabolic outcomes along with serum leptin levels but did not specifically calculate correlation coefficients between leptin and other parameters.^{7,8,11,16,17,19}

Nonetheless, in many instances leptin levels increased significantly without significant changes in serum insulin or other glycemic or lipid measures.^11,25 One cross-sectional study in bipolar subjects also found no correlation between any glucose or lipid parameter and leptin levels.²⁶ A few studies reported significant correlations among leptin and serum insulin,^13,27 glucose,¹⁵ and serum triglycerides,¹⁸ although most did not control for body mass index (BMI).

Diagnosis effects

As the association was established between antipsychotic-induced weight gain and changes in serum leptin, investigators sought to understand whether disease influences modified the drug effects.

Schizophrenia. One early cross-sectional analysis of 14 olanzapine-treated schizophrenia patients noted that 57% had elevated serum leptin when compared with normal levels adjusted for BMI and gender,²⁷ but the absence of a weight-matched control group limits interpretation of these findings.

To separate diagnosis and treatment effects, Arranz²⁸ performed a cross-sectional study of 50 drug-naïve schizophrenia patients, 50 drug-free schizophrenia patients, and 50 unmatched healthy controls. Leptin levels across all cohorts were positively correlated with age and BMI, and—as found in several other studies (Box 2)^{9,12,13,20,25,28-30}—women had higher levels than men in all 3 cohorts. The antipsychotic-free patients were older and heavier than the other 2 cohorts and had higher serum leptin levels, but neuroleptic-naïve schizophrenia subjects did not differ from controls. The absence of BMI matching between the drug-free patients and other cohorts limits the ability to make definitive statements about the treatment’s impact on leptin levels.

Other studies removed these limitations by matching schizophrenia patients with controls on the basis of gender, BMI, and—in some cases—age. These studies indicate conclusively that—when matched appropriately with nonpsychiatric subjects—patients with schizophrenia do not exhibit greater-than-expected serum leptin levels, regardless of antipsychotic drug exposure.^{7,11,12,19,26,28-31}

Other diagnoses. The only controlled comparative study of medication-treated bipolar patients vs matched controls also reported no significant difference in leptin levels.²⁶ Interestingly, a 6-month prospective study of risperidone in autistic children noted no increase in serum leptin despite a 5.6-kg mean weight gain.²¹

Lastly, a single 12-week prospective trial compared the effects of antipsychotics on levodopa psychosis in Parkinson’s disease subjects treated with olanzapine (n=10), risperidone (n=10), quetiapine (n=10), or solely with antiparkinsonian medications (n=10); an unmedicated, healthy cohort (n=8) served as controls.³² Only olanzapine was associated with significant weight gain, but BMI changes were positively correlated with changes in leptin levels across all cohorts.

Box 2

Clinical implications

Driven by obesity’s public health impact, researchers have achieved a basic understanding of the regulation of appetite and body weight, including identifying genetic polymorphisms and other obesity risk markers. Evidence exploring the association between peptide metabolic regulatory hormones and antipsychotic-induced weight gain and metabolic dysfunction is accumulating.

Overall, evidence strongly suggests that leptin levels increase during long-term antipsychotic treatment and are highly correlated with weight and BMI changes. Although the increase in serum leptin often parallels substantial weight gain, these changes appear to be more the result of weight gain than a direct effect of the anti-psychotic on the leptin feedback pathway.²⁹ Virtually none of the papers we reviewed examined the association between leptin and glucose-insulin measures independent of the effect of weight changes.

Predicting weight gain? Because increased serum leptin is likely the result of weight gain in patients taking antipsychotics, measuring leptin for clinical prediction or monitoring of weight gain may not be very useful. Measuring weight or BMI will be more feasible in most clinical settings. However, leptin level changes may help us understand the potential mechanism of hormonal feedback and its physiologic effect in weight gain.

 

Medications such as olanzapine and clozapine carry substantial metabolic burdens but are effective treatments for some patients who do not respond to other antipsychotics. Elucidating mechanisms by which antipsychotic medications affect metabolic parameters remains important for:

• quantifying patient risk
• informing the frequency and targets of metabolic monitoring during antipsychotic therapy
• permitting the development of novel agents without these limitations.

Related resource

• Leucht S, Corves C, Arbter D, et al. Second-generation versus first-generation antipsychotic drugs for schizophrenia: a meta-analysis. Lancet. 2009;373(9657):31-41.

Drug brand names

• Amantadine • Symmetrel
• Aripiprazole • Abilify
• Clozapine • Clozaril
• Haloperidol • Haldol
• Nizatidine • Axid
• Olanzapine • Zyprexa
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Ziprasidone • Geodon

Disclosures

Dr. Jin receives grant/research support from the National Institutes of Health, the National Institute of Mental Health, Otsuka Pharmaceuticals, and the Stanley Medical Research Foundation. He is a consultant to the Stanley Medical Research Foundation.

Dr. Meyer receives grant/research support from Bristol-Myers Squibb, the National Institutes of Health, the National Institute of Mental Health, and Pfizer Inc. He is a consultant to Bristol-Myers Squibb, Janssen Pharmaceutica, Organon USA (now Merck), Pfizer Inc., Vanda Pharmaceuticals, and Wyeth Pharmaceuticals (now Pfizer Inc.) and a speaker for AstraZeneca, Bristol-Myers Squibb, Dainippon Sumitomo Pharma, and Pfizer Inc.

Comment on this article

Clinical studies indicate that clozapine and olanzapine carry a high risk of treatment-related metabolic dysfunction—including weight gain, hyperlipidemia, and glucose intolerance—but certain patients with high metabolic liabilities who take atypical antipsychotics do not necessarily develop these adverse effects. Though the underlying mechanism for atypical antipsychotic-related weight gain is strongly associated with central histamine H1 antagonism and increased appetite, the pharmacologic basis for other metabolic changes is not fully understood and may involve weight-independent mechanisms.

One potentially relevant research area is peptide hormones’ impact on the regulation of food intake, body weight, and other metabolic parameters. As research has elucidated the properties of 1 of these hormones—leptin—investigators have started to examine possible correlations between changes in serum levels of leptin and weight gain during atypical anti-psychotic treatment.

This article summarizes available clinical data on the interaction of atypical antipsychotics with leptin and indicates directions for future research on interactions between psychotropic medications and metabolic hormones.

Leptin’s function

Since its initial sequencing as the product of the obese (ob) gene in 1994, leptin has garnered substantial attention as a metabolic regulatory hormone.¹ Leptin is produced primarily by fat cells as part of a long-term central feedback mechanism involving central control of appetite and peripheral metabolic activity regulation. Leptin is a 167 amino acid, 16-kilodalton protein that binds to cell surface receptors (the product of the diabetes [db] gene) at both central (ventromedial hypothalamic) and peripheral sites (liver, skeletal muscle, and pancreatic β-cells).²

Evidence for leptin’s activity is seen in ob/ob mice, whose genetic inability to produce leptin is manifested phenotypically in overeating and obesity. Administering recombinant leptin to these mice results in reduced appetite and weight loss.³

On average, women have greater fat mass and higher serum leptin levels than men. Humans rarely have mutations in both copies of the ob gene, but those who do are severely obese and respond to exogenous leptin. Heterozygotes are not quite as heavy.

Leptin circulates in a free form but in humans is predominantly bound to the soluble leptin receptor (sOB-R). Levels of sOB-R increase with weight loss—with concomitant decreases in leptin levels—and these effects can be seen even during 72-hour fasts.⁴ Leptin levels are positively correlated with fat mass, but the fact that obese individuals have chronically elevated leptin levels argues for some level of leptin insensitivity or resistance to the hormone’s appetite-suppressing effects.²

Drug effects

Clozapine and olanzapine. Literature on leptin and antipsychotic-related obesity is relatively well developed. The first papers focused on the association between clozapine and olanzapine and increases in serum leptin levels.^5,6 As patients gained substantial weight on clozapine and olanzapine, serum leptin also rose, but neither weight nor leptin changes were seen in patients exposed to haloperidol or those who did not receive antipsychotics.⁶

Numerous subsequent prospective trials of patients treated with olanzapine^4,7,8 and clozapine^9-11 confirmed previousl established associations among use of these medications, weight gain, and increased serum leptin levels. Olanzapine- and clozapine-exposed subjects experienced marked increases in adiposity, weight, and serum leptin (Box 1). ^5,9,12-16

Other agents. For agents associated with less weight gain liability—such as high-potency typical antipsychotics,^12,17,18 sulpiride,¹⁹ quetiapine,¹⁸ or risperidone^20,21—comparative trials noted modest weight gain and leptin increases. Prospective trials of weight-modifying strategies using adjunctive amantadine⁸ or nizatidine²² found positive effects of the adjunctive medication, with proportional decreases in leptin levels compared with antipsychotics alone.

Because the other 2 atypical antipsychotics—ziprasidone and aripiprazole—were found to be weight-neutral or have the lowest weight-gain burden, few studies have examined the relationship between leptin with weight gain in patients taking these drugs. One study reported no significant body weight or leptin level change in patients after 4-week trial of ziprasidone.²³

Box 1

 

Other metabolic parameters

In humans, elevated serum leptin levels are associated with adverse metabolic markers, particularly those associated with insulin activity (including insulin itself) and serum triglycerides.²⁴ Several antipsychotic studies measured metabolic outcomes along with serum leptin levels but did not specifically calculate correlation coefficients between leptin and other parameters.^{7,8,11,16,17,19}

Nonetheless, in many instances leptin levels increased significantly without significant changes in serum insulin or other glycemic or lipid measures.^11,25 One cross-sectional study in bipolar subjects also found no correlation between any glucose or lipid parameter and leptin levels.²⁶ A few studies reported significant correlations among leptin and serum insulin,^13,27 glucose,¹⁵ and serum triglycerides,¹⁸ although most did not control for body mass index (BMI).

Diagnosis effects

As the association was established between antipsychotic-induced weight gain and changes in serum leptin, investigators sought to understand whether disease influences modified the drug effects.

Schizophrenia. One early cross-sectional analysis of 14 olanzapine-treated schizophrenia patients noted that 57% had elevated serum leptin when compared with normal levels adjusted for BMI and gender,²⁷ but the absence of a weight-matched control group limits interpretation of these findings.

To separate diagnosis and treatment effects, Arranz²⁸ performed a cross-sectional study of 50 drug-naïve schizophrenia patients, 50 drug-free schizophrenia patients, and 50 unmatched healthy controls. Leptin levels across all cohorts were positively correlated with age and BMI, and—as found in several other studies (Box 2)^{9,12,13,20,25,28-30}—women had higher levels than men in all 3 cohorts. The antipsychotic-free patients were older and heavier than the other 2 cohorts and had higher serum leptin levels, but neuroleptic-naïve schizophrenia subjects did not differ from controls. The absence of BMI matching between the drug-free patients and other cohorts limits the ability to make definitive statements about the treatment’s impact on leptin levels.

Other studies removed these limitations by matching schizophrenia patients with controls on the basis of gender, BMI, and—in some cases—age. These studies indicate conclusively that—when matched appropriately with nonpsychiatric subjects—patients with schizophrenia do not exhibit greater-than-expected serum leptin levels, regardless of antipsychotic drug exposure.^{7,11,12,19,26,28-31}

Other diagnoses. The only controlled comparative study of medication-treated bipolar patients vs matched controls also reported no significant difference in leptin levels.²⁶ Interestingly, a 6-month prospective study of risperidone in autistic children noted no increase in serum leptin despite a 5.6-kg mean weight gain.²¹

Lastly, a single 12-week prospective trial compared the effects of antipsychotics on levodopa psychosis in Parkinson’s disease subjects treated with olanzapine (n=10), risperidone (n=10), quetiapine (n=10), or solely with antiparkinsonian medications (n=10); an unmedicated, healthy cohort (n=8) served as controls.³² Only olanzapine was associated with significant weight gain, but BMI changes were positively correlated with changes in leptin levels across all cohorts.

Box 2

Clinical implications

Driven by obesity’s public health impact, researchers have achieved a basic understanding of the regulation of appetite and body weight, including identifying genetic polymorphisms and other obesity risk markers. Evidence exploring the association between peptide metabolic regulatory hormones and antipsychotic-induced weight gain and metabolic dysfunction is accumulating.

Overall, evidence strongly suggests that leptin levels increase during long-term antipsychotic treatment and are highly correlated with weight and BMI changes. Although the increase in serum leptin often parallels substantial weight gain, these changes appear to be more the result of weight gain than a direct effect of the anti-psychotic on the leptin feedback pathway.²⁹ Virtually none of the papers we reviewed examined the association between leptin and glucose-insulin measures independent of the effect of weight changes.

Predicting weight gain? Because increased serum leptin is likely the result of weight gain in patients taking antipsychotics, measuring leptin for clinical prediction or monitoring of weight gain may not be very useful. Measuring weight or BMI will be more feasible in most clinical settings. However, leptin level changes may help us understand the potential mechanism of hormonal feedback and its physiologic effect in weight gain.

 

Medications such as olanzapine and clozapine carry substantial metabolic burdens but are effective treatments for some patients who do not respond to other antipsychotics. Elucidating mechanisms by which antipsychotic medications affect metabolic parameters remains important for:

• quantifying patient risk
• informing the frequency and targets of metabolic monitoring during antipsychotic therapy
• permitting the development of novel agents without these limitations.

Related resource

• Leucht S, Corves C, Arbter D, et al. Second-generation versus first-generation antipsychotic drugs for schizophrenia: a meta-analysis. Lancet. 2009;373(9657):31-41.

Drug brand names

• Amantadine • Symmetrel
• Aripiprazole • Abilify
• Clozapine • Clozaril
• Haloperidol • Haldol
• Nizatidine • Axid
• Olanzapine • Zyprexa
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Ziprasidone • Geodon

Disclosures

Dr. Jin receives grant/research support from the National Institutes of Health, the National Institute of Mental Health, Otsuka Pharmaceuticals, and the Stanley Medical Research Foundation. He is a consultant to the Stanley Medical Research Foundation.

Dr. Meyer receives grant/research support from Bristol-Myers Squibb, the National Institutes of Health, the National Institute of Mental Health, and Pfizer Inc. He is a consultant to Bristol-Myers Squibb, Janssen Pharmaceutica, Organon USA (now Merck), Pfizer Inc., Vanda Pharmaceuticals, and Wyeth Pharmaceuticals (now Pfizer Inc.) and a speaker for AstraZeneca, Bristol-Myers Squibb, Dainippon Sumitomo Pharma, and Pfizer Inc.

Comment on this article

Clinical studies indicate that clozapine and olanzapine carry a high risk of treatment-related metabolic dysfunction—including weight gain, hyperlipidemia, and glucose intolerance—but certain patients with high metabolic liabilities who take atypical antipsychotics do not necessarily develop these adverse effects. Though the underlying mechanism for atypical antipsychotic-related weight gain is strongly associated with central histamine H1 antagonism and increased appetite, the pharmacologic basis for other metabolic changes is not fully understood and may involve weight-independent mechanisms.

One potentially relevant research area is peptide hormones’ impact on the regulation of food intake, body weight, and other metabolic parameters. As research has elucidated the properties of 1 of these hormones—leptin—investigators have started to examine possible correlations between changes in serum levels of leptin and weight gain during atypical anti-psychotic treatment.

This article summarizes available clinical data on the interaction of atypical antipsychotics with leptin and indicates directions for future research on interactions between psychotropic medications and metabolic hormones.

Leptin’s function

Since its initial sequencing as the product of the obese (ob) gene in 1994, leptin has garnered substantial attention as a metabolic regulatory hormone.¹ Leptin is produced primarily by fat cells as part of a long-term central feedback mechanism involving central control of appetite and peripheral metabolic activity regulation. Leptin is a 167 amino acid, 16-kilodalton protein that binds to cell surface receptors (the product of the diabetes [db] gene) at both central (ventromedial hypothalamic) and peripheral sites (liver, skeletal muscle, and pancreatic β-cells).²

Evidence for leptin’s activity is seen in ob/ob mice, whose genetic inability to produce leptin is manifested phenotypically in overeating and obesity. Administering recombinant leptin to these mice results in reduced appetite and weight loss.³

On average, women have greater fat mass and higher serum leptin levels than men. Humans rarely have mutations in both copies of the ob gene, but those who do are severely obese and respond to exogenous leptin. Heterozygotes are not quite as heavy.

Leptin circulates in a free form but in humans is predominantly bound to the soluble leptin receptor (sOB-R). Levels of sOB-R increase with weight loss—with concomitant decreases in leptin levels—and these effects can be seen even during 72-hour fasts.⁴ Leptin levels are positively correlated with fat mass, but the fact that obese individuals have chronically elevated leptin levels argues for some level of leptin insensitivity or resistance to the hormone’s appetite-suppressing effects.²

Drug effects

Clozapine and olanzapine. Literature on leptin and antipsychotic-related obesity is relatively well developed. The first papers focused on the association between clozapine and olanzapine and increases in serum leptin levels.^5,6 As patients gained substantial weight on clozapine and olanzapine, serum leptin also rose, but neither weight nor leptin changes were seen in patients exposed to haloperidol or those who did not receive antipsychotics.⁶

Numerous subsequent prospective trials of patients treated with olanzapine^4,7,8 and clozapine^9-11 confirmed previousl established associations among use of these medications, weight gain, and increased serum leptin levels. Olanzapine- and clozapine-exposed subjects experienced marked increases in adiposity, weight, and serum leptin (Box 1). ^5,9,12-16

Other agents. For agents associated with less weight gain liability—such as high-potency typical antipsychotics,^12,17,18 sulpiride,¹⁹ quetiapine,¹⁸ or risperidone^20,21—comparative trials noted modest weight gain and leptin increases. Prospective trials of weight-modifying strategies using adjunctive amantadine⁸ or nizatidine²² found positive effects of the adjunctive medication, with proportional decreases in leptin levels compared with antipsychotics alone.

Because the other 2 atypical antipsychotics—ziprasidone and aripiprazole—were found to be weight-neutral or have the lowest weight-gain burden, few studies have examined the relationship between leptin with weight gain in patients taking these drugs. One study reported no significant body weight or leptin level change in patients after 4-week trial of ziprasidone.²³

Box 1

 

Other metabolic parameters

In humans, elevated serum leptin levels are associated with adverse metabolic markers, particularly those associated with insulin activity (including insulin itself) and serum triglycerides.²⁴ Several antipsychotic studies measured metabolic outcomes along with serum leptin levels but did not specifically calculate correlation coefficients between leptin and other parameters.^{7,8,11,16,17,19}

Nonetheless, in many instances leptin levels increased significantly without significant changes in serum insulin or other glycemic or lipid measures.^11,25 One cross-sectional study in bipolar subjects also found no correlation between any glucose or lipid parameter and leptin levels.²⁶ A few studies reported significant correlations among leptin and serum insulin,^13,27 glucose,¹⁵ and serum triglycerides,¹⁸ although most did not control for body mass index (BMI).

Diagnosis effects

As the association was established between antipsychotic-induced weight gain and changes in serum leptin, investigators sought to understand whether disease influences modified the drug effects.

Schizophrenia. One early cross-sectional analysis of 14 olanzapine-treated schizophrenia patients noted that 57% had elevated serum leptin when compared with normal levels adjusted for BMI and gender,²⁷ but the absence of a weight-matched control group limits interpretation of these findings.

To separate diagnosis and treatment effects, Arranz²⁸ performed a cross-sectional study of 50 drug-naïve schizophrenia patients, 50 drug-free schizophrenia patients, and 50 unmatched healthy controls. Leptin levels across all cohorts were positively correlated with age and BMI, and—as found in several other studies (Box 2)^{9,12,13,20,25,28-30}—women had higher levels than men in all 3 cohorts. The antipsychotic-free patients were older and heavier than the other 2 cohorts and had higher serum leptin levels, but neuroleptic-naïve schizophrenia subjects did not differ from controls. The absence of BMI matching between the drug-free patients and other cohorts limits the ability to make definitive statements about the treatment’s impact on leptin levels.

Other studies removed these limitations by matching schizophrenia patients with controls on the basis of gender, BMI, and—in some cases—age. These studies indicate conclusively that—when matched appropriately with nonpsychiatric subjects—patients with schizophrenia do not exhibit greater-than-expected serum leptin levels, regardless of antipsychotic drug exposure.^{7,11,12,19,26,28-31}

Other diagnoses. The only controlled comparative study of medication-treated bipolar patients vs matched controls also reported no significant difference in leptin levels.²⁶ Interestingly, a 6-month prospective study of risperidone in autistic children noted no increase in serum leptin despite a 5.6-kg mean weight gain.²¹

Lastly, a single 12-week prospective trial compared the effects of antipsychotics on levodopa psychosis in Parkinson’s disease subjects treated with olanzapine (n=10), risperidone (n=10), quetiapine (n=10), or solely with antiparkinsonian medications (n=10); an unmedicated, healthy cohort (n=8) served as controls.³² Only olanzapine was associated with significant weight gain, but BMI changes were positively correlated with changes in leptin levels across all cohorts.

Box 2

Clinical implications

Driven by obesity’s public health impact, researchers have achieved a basic understanding of the regulation of appetite and body weight, including identifying genetic polymorphisms and other obesity risk markers. Evidence exploring the association between peptide metabolic regulatory hormones and antipsychotic-induced weight gain and metabolic dysfunction is accumulating.

Overall, evidence strongly suggests that leptin levels increase during long-term antipsychotic treatment and are highly correlated with weight and BMI changes. Although the increase in serum leptin often parallels substantial weight gain, these changes appear to be more the result of weight gain than a direct effect of the anti-psychotic on the leptin feedback pathway.²⁹ Virtually none of the papers we reviewed examined the association between leptin and glucose-insulin measures independent of the effect of weight changes.

Predicting weight gain? Because increased serum leptin is likely the result of weight gain in patients taking antipsychotics, measuring leptin for clinical prediction or monitoring of weight gain may not be very useful. Measuring weight or BMI will be more feasible in most clinical settings. However, leptin level changes may help us understand the potential mechanism of hormonal feedback and its physiologic effect in weight gain.

 

Medications such as olanzapine and clozapine carry substantial metabolic burdens but are effective treatments for some patients who do not respond to other antipsychotics. Elucidating mechanisms by which antipsychotic medications affect metabolic parameters remains important for:

• quantifying patient risk
• informing the frequency and targets of metabolic monitoring during antipsychotic therapy
• permitting the development of novel agents without these limitations.

Related resource

• Leucht S, Corves C, Arbter D, et al. Second-generation versus first-generation antipsychotic drugs for schizophrenia: a meta-analysis. Lancet. 2009;373(9657):31-41.

Drug brand names

• Amantadine • Symmetrel
• Aripiprazole • Abilify
• Clozapine • Clozaril
• Haloperidol • Haldol
• Nizatidine • Axid
• Olanzapine • Zyprexa
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Ziprasidone • Geodon

Disclosures

Dr. Jin receives grant/research support from the National Institutes of Health, the National Institute of Mental Health, Otsuka Pharmaceuticals, and the Stanley Medical Research Foundation. He is a consultant to the Stanley Medical Research Foundation.

Dr. Meyer receives grant/research support from Bristol-Myers Squibb, the National Institutes of Health, the National Institute of Mental Health, and Pfizer Inc. He is a consultant to Bristol-Myers Squibb, Janssen Pharmaceutica, Organon USA (now Merck), Pfizer Inc., Vanda Pharmaceuticals, and Wyeth Pharmaceuticals (now Pfizer Inc.) and a speaker for AstraZeneca, Bristol-Myers Squibb, Dainippon Sumitomo Pharma, and Pfizer Inc.

Comment on this article

Mr. R, age 45, developed severe depression 4 years ago after his mother died. He had suffered previous major depressive episodes and was treated effiectively with fluoxetine for 15 years. This time he took a medical leave from his job as an engineer and received disability. After numerous medication trials and psychotherapy, his symptoms improved.

Mr. R is ready to think about returning to work, but he will need to refresh his skills and consider starting at a lower level than before. Headlines remind him daily about increasing unemployment and decreasing prospects of finding a job.

During his illness, Mr. R and his family depleted their savings and incurred substantial debt. His wife has not worked outside the home while caring for him and their 4 children. She is increasingly anxious and depressed. The couple argue often about money but share a common hope: that Mr. R will find a job in the next few months.

How is the recession affecting psychiatric practice? Christopher Palmer, MD, the psychiatrist who treated Mr. R, says, “We in psychiatry and psychology are well-equipped to help people who are unemployed, underemployed, and financially ruined. We do it all the time. The difference in this economy is that we’re going to be seeing a lot more people.”

Psychiatrists who read Current Psychiatry and were polled in March 2009 agree. Most were seeing an increase in patients experiencing psychological stress because of the recession, which by then had persisted 16 months. “All my patients are reporting increased stress as a result of the economic situation. The more successful my patient is, the more distress they seem to be feeling,” says a psychiatrist from Melbourne, FL.

This article on the psychological effects of the recession discusses the results of an online survey of Current Psychiatry readers, with analysis and recommendations from an interview with Dr. Palmer and colleagues Jeffrey Rediger, MD, MDiv, and Carol Kauffman, PhD, ABPP, PCC, from McLean Hospital, Belmont, MA, and the department of psychiatry, Harvard Medical School.

	Carol Kauffman, PhD, ABPP, PCC, is director of the Institute of Coaching, McLean Hospital, Belmont, MA, and assistant clinical professor, department of psychiatry, Harvard Medical School. A veteran psychologist, she maintains an executive coaching practice in the United States and Europe.
	Christopher Palmer, MD, is medical director of continuing medical education, McLean Hospital. His outpatient practice focuses on substance abuse, sleep disorders, mood and anxiety disorders, psychotic disorders, and individual and family psychotherapy.
	Jeffrey Rediger, MD, MDiv, is medical director, adult psychiatric program, McLean Hospital SouthEast. He also is an instructor, department of psychiatry, Harvard Medical School and has a master of divinity degree. He publishes in the fields of medicine, psychiatry, and spirituality.

Survey results

Methods. Using an e-mail questionnaire (Box), Current Psychiatry contacted 45 Reader Reactors—clinical psychiatrists who provide feedback to our editorial staff about topics being considered for publication. The 15 readers who responded practice psychiatry in the Northeast (New York and New Jersey), the South (Florida and Georgia), the West (California, Washington, and Oregon), and the Midwest (Pennsylvania, Illinois, and Missouri).

Nine of 11 readers who answered all questions in the survey said they have seen an increase in patients describing psychological reactions to the effects of the economic recession. A reader from Red Bank, NJ, reported, “I see a pattern of issues: ‘I was just laid off.’ ‘I am afraid I will be laid off.’ ‘Others have been laid off, and I’m overwhelmed with their work as well as my own.’ ‘I was planning to retire in a couple years, but now I will have to work longer than I was planning.’” Two psychiatrists reported no increase in patients with economic worries—in a prison and a state hospital with geriatric patients with cognitive impairment.

Timeline. For some survey respondents, the increase in patients with economy-related problems emerged in mid-to-late 2008—particularly in October—but others report seeing symptoms sooner. A reader from Harrisburg, PA, said, “I’ve noticed this increase for the past 4 to 5 months (dramatic), but there has been a general increase for 1 to 2 years.”

These observations mirror the rise in unemployment in the 16 months since the recession officially began in December 2007. In March 2009, the U.S. Bureau of Labor Statistics reported a national unemployment rate of 8.5% (13.2 million unemployed), which was a 25-year high. That same month, employers eliminated 663,000 jobs, for a total of 5.1 million layoffs since the recession began. Two-thirds of all layoffs occurred between November 2008 and March 2009.¹

 

Symptoms. Depression, anxiety, or both are the most common symptoms associated with patients’ financial difficulties, survey respondents say. Other symptoms include insomnia, hopelessness, helplessness, loss of trust, anger, bitterness, resentment, suicidal ideation or attempts, numbness, desires for retaliation, increased alcohol/drug use, fear of being unable to afford medications or of losing a job, paranoia, and marital problems. Readers’ comments include:

• Augusta, GA: “Patients with depression and anxiety symptoms have increased in the emergency department.”
• Portland, OR: “I see people giving up and planning to live on unemployment as long as possible.”
• Fresno, CA: “Some married people are wishing they were single and did not have children.”
• Red Bank, NJ: “Some who have adapted are doing well, often with a low-overhead business, meeting a specialty need, or entering into a business that meets an emerging need.”

Who is affected? Overall, readers estimated that 70% to 100% of affected patients had pre-existing psychiatric disorders, whereas 20% to 30% had not sought treatment in the past. “Individuals with preexisting problems are having considerable difficulty,” one psychiatrist said.

Similarly, Dr. Jeffrey Rediger, medical director of the adult psychiatric inpatient service at McLean SouthEast, Brockton, MA, told Current Psychiatry, “For some people who were functioning marginally before the recession, this stress has pushed them over the edge. But we’re also seeing a number of young to middle-aged adults who are seeking treatment and hospitalization for the first time.”

Box

Interview: Emerging patterns

When interviewed March 17, 2009, Dr. Rediger, Dr. Palmer, and Dr. Kauffman discussed their experiences, provided case examples, and suggested treatments they have found useful for recession-stressed psychiatric patients.

DR. PALMER: People went into panic mode in September/October. Losing a job, a retirement plan, or a home is about who we are and our worth as human beings. My sense is that most people are resilient and adaptive and will be fine despite the recession, but a portion of the population is impaired in adaptability.

DR. REDIGER: Would you explain what you mean?

DR. PALMER: A lot of people become so defiant, so angry, that they withdraw instead of adapting to a new way of life that they consider inferior. They’re humiliated; they feel complete and utter failure. For example, the contractor who owns his own business and says there’s no way he’s going to work for somebody else. He may have to go work for somebody else, get his personal finances in order for a year or two, and then start up a business again. But he has to survive in the meantime.

DR. REDIGER: People are walking around with a lot fear and self-blame. They don’t talk about this very easily; they may say things are fine, but they feel terrible. I wonder how much people are blaming themselves, perhaps for overextending their credit.

DR. PALMER: I think most of these people sensed their finances were marginal before the recession hit. They felt out of control, but their options were limited as housing prices rose beyond affordability. Clinically, I’m seeing increased rates of depression, anxiety, hopelessness. Denial is a big one; there’s a mindset that this can’t be happening.

Helplessness and dread

DR. KAUFFMAN: I resonate with the hopelessness. A lot of people tell me they are experiencing a sense of free fall, and I’ve been working with them to recalibrate a sense of empowerment. First I try some reality testing. I’ll say, “Maybe you’re feeling anxious, helpless, a little denial, fear. Is your survival in danger? Yes or no?” If the answer is no, then I’ll say, “So what can you do so you’re not living as if your survival is in danger?”

 

DR. REDIGER: Some people—such as the patient in the case report I submitted (Case Report 1)—are paralyzed by dread and anxiety. Two years ago their house was like an ATM machine, but now they feel trapped and worry that they can’t meet the mortgage payments.

DR. REDIGER: An economic recession is stressful because money represents power, control, and survival. The recession is not just about money. It’s about security, identity, and loss of face.

DR. KAUFFMAN: The evidence is pretty clear that financial losses are a risk factor for suicide, especially among men.^2,3 You can go up and down Maslow’s hierarchy of needs and see what money means to people. I’ve also noticed that economic stress is a trigger for my clients with posttraumatic stress disorder. They feel out of control of a situation they thought they controlled.

DR. PALMER: An economic downturn can trigger learned helplessness. A construction worker has applied to 50 different construction companies, and none are hiring. He concludes, “I have to wait until the economy turns around, and then I’ll get another job in construction because that’s what I do.” He thinks he doesn’t have enough money or isn’t smart enough to get a degree, or whatever.

DR. REDIGER: And that’s another reason why someone with a history of trauma might experience a reactivation. Learned helplessness can be an aspect of chronic, repeated trauma. A person learns not to try any longer.

DR. PALMER: An inflexible perfectionist would probably have the most difficult time. A person who feels “there are rights and wrongs in the world, and the right thing is that I should be working. My family has grown accustomed to a certain lifestyle, and it’s my job to keep that up.”

DR. REDIGER: “If I work hard, this should be given to me.”

DR. PALMER: Right. A person with more flexibility might think in terms of problem-solving. “I worked in construction (or whatever), and now I can’t get a job. Therefore, I’ll go into a different field and take a lesser salary. The family will have to cut the budget, and the kids will go to a public college instead of a fancy private college.”

Case Report 1

Putting losses into perspective

DR. KAUFFMAN: Here’s where a cognitive-behavioral intervention with a goal to increase the flexibility—not just content—of thinking can help. You can ask patients, “What is most important to you? Is it money? Or is it your relationship with your family?” Or you could ask questions such as, “In the challenges you’re facing, what opportunities are there for you to do things that matter to you?”

 

For people who feel hopeless, I often describe this true story. A pilot was flying a jet cross-country when his engines flamed out and the plane began spinning downward. He tried everything, but nothing worked until he lowered the landing gear. This changed the vortex of forces, so that when the pilot went through his emergency procedures again he was able to pull the plane out of the death spiral.

When people become paralyzed by their problems, you can say the equivalent of “what’s your landing gear?” What small thing you could do that might create a different experience for you?

DR. REDIGER: So you’re saying, “If the big picture is too overwhelming, what’s something small you can do today?”

DR. KAUFFMAN: Yes, but not that the small thing is insignificant. As in the case report I submitted (Case Report 2), doing a small thing that makes a difference in a huge problem increases one’s internal locus of control. Feeling more empowered may lead the person to take on another thing.

DR. REDIGER: People have enormous resources that they don’t always know how to tap into. We may be experiencing a material recession but also an opportunity to recover what truly matters to us.

DR. KAUFFMAN: We’re talking about challenging people’s values and encouraging flexibility of thinking. This is a low-cost, powerful strategy that anyone can use to cope with the economic recession.

DR. PALMER: So you begin by challenging assumptions, cognitive-behavioral therapy (CBT), adaptive mechanisms, coming up with a plan, and implementing the plan, then being flexible, assessing if it’s working, and—if it’s not—coming up with another plan or revising it. That process has to be done first, before things I would recommend that are unrelated to the person’s immediate problem. If somebody tells you, “I just got laid off from work,” and you say, “Exercise could help,” he’s going to say, “Did you not hear me? I just got laid off from work.”

DR. KAUFFMAN: Evidence supports the positive psychology that 2 factors are key to sustaining hope:

• a sense of agency that you can achieve a goal
• multiple pathways planned out to reach the goal.⁴

Together, these 2 factors—which Snyder called “the will and the way⁵—are the highest predictors of performance, health, and ability to withstand adversity.

DR. PALMER: Along with CBT, I remind patients to stay connected, to see and talk to people every day. This doesn’t mean getting together to watch television; it means having real conversations. Other people can help you get unstuck. Evidence also indicates that a social network mitigates against depression and anxiety. The happier your friends are, the happier you are.⁶

Case Report 2

 

Addressing depression

DR. KAUFFMAN: Medication also can play a useful role for some patients.

DR. PALMER: Patients who meet criteria for major depression—in particular if they’re having suicidal thoughts—absolutely need psychotropics. Mr. R, my case patient, benefited greatly from CBT and medication. We also worked on financial planning and handling financial conflicts with his wife and children. He is exercising, doing volunteer work, and staying connected with friends and family. He is hoping to find a job in the next few months.

DR. REDIGER: For a person who’s going though a stressful period, I try to keep medication time-limited. We talk about treating symptoms, but it’s important to look at what’s causing the patient’s problems and address it.

DR. PALMER: During this recession, a lot of people are going to be down but not clinically depressed. If the depression is mild to moderate, I sometimes recommend exercise instead of medication (such as when a patient is refusing medication or has had serious side effects from medications). I recommend exercise for all my outpatients—even if they’re taking psychotropics—because exercise has been shown to be as effective as antidepressants for moderate depression.^7,8

DR. REDIGER: We’ve also been encouraging people who’ve lost jobs to volunteer in the community. Having a reason to get out of the house takes the mind off one’s worries.

DR. KAUFFMAN: The “3 good things in life” exercise studied by psychologist Martin E.P. Seligman, PhD, has been shown in a 6-month, randomized, placebo-controlled study to increase happiness and decrease depressive symptoms.⁹ In this exercise, you look back at the end of each day and write down 3 things that went well, their causes, and an explanation for each good thing. Ask yourself, “When was I at my best today? What happened today that I feel grateful for? What did I do to make that good thing happen?”

DR. REDIGER: Remind people to talk to their children about the recession, too. If they have to move to a different home or to a different school, let their children know things are going on and how to think about that. This can help kids understand how to deal with their anxiety.

Related resources

• Getting through tough economic times. A SAMHSA guide. Substance Abuse and Mental Health Services Administration. U.S. Department of Health and Human Services. www.samhsa.gov/economy.
• Seligman MEP. Authentic happiness: using the new positive psychology to realize your potential for lasting fulfillment. New York, NY: Simon & Schuster; 2002.
• Positive Psychology Center. University of Pennsylvania, Philadelphia. www.ppc.sas.upenn.edu.

Drug brand names

• Escitalopram • Lexapro
• Fluoxetine • Prozac
• Lorazepam • Ativan

Disclosure

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

Acknowledgment

This article was researched and written by Current Psychiatry Editor Alice V. Luddington, ELS, and Senior Associate Editor Erica Vonderheid.

Comment on this article

Mr. R, age 45, developed severe depression 4 years ago after his mother died. He had suffered previous major depressive episodes and was treated effiectively with fluoxetine for 15 years. This time he took a medical leave from his job as an engineer and received disability. After numerous medication trials and psychotherapy, his symptoms improved.

Mr. R is ready to think about returning to work, but he will need to refresh his skills and consider starting at a lower level than before. Headlines remind him daily about increasing unemployment and decreasing prospects of finding a job.

During his illness, Mr. R and his family depleted their savings and incurred substantial debt. His wife has not worked outside the home while caring for him and their 4 children. She is increasingly anxious and depressed. The couple argue often about money but share a common hope: that Mr. R will find a job in the next few months.

How is the recession affecting psychiatric practice? Christopher Palmer, MD, the psychiatrist who treated Mr. R, says, “We in psychiatry and psychology are well-equipped to help people who are unemployed, underemployed, and financially ruined. We do it all the time. The difference in this economy is that we’re going to be seeing a lot more people.”

Psychiatrists who read Current Psychiatry and were polled in March 2009 agree. Most were seeing an increase in patients experiencing psychological stress because of the recession, which by then had persisted 16 months. “All my patients are reporting increased stress as a result of the economic situation. The more successful my patient is, the more distress they seem to be feeling,” says a psychiatrist from Melbourne, FL.

This article on the psychological effects of the recession discusses the results of an online survey of Current Psychiatry readers, with analysis and recommendations from an interview with Dr. Palmer and colleagues Jeffrey Rediger, MD, MDiv, and Carol Kauffman, PhD, ABPP, PCC, from McLean Hospital, Belmont, MA, and the department of psychiatry, Harvard Medical School.

	Carol Kauffman, PhD, ABPP, PCC, is director of the Institute of Coaching, McLean Hospital, Belmont, MA, and assistant clinical professor, department of psychiatry, Harvard Medical School. A veteran psychologist, she maintains an executive coaching practice in the United States and Europe.
	Christopher Palmer, MD, is medical director of continuing medical education, McLean Hospital. His outpatient practice focuses on substance abuse, sleep disorders, mood and anxiety disorders, psychotic disorders, and individual and family psychotherapy.
	Jeffrey Rediger, MD, MDiv, is medical director, adult psychiatric program, McLean Hospital SouthEast. He also is an instructor, department of psychiatry, Harvard Medical School and has a master of divinity degree. He publishes in the fields of medicine, psychiatry, and spirituality.

Survey results

Methods. Using an e-mail questionnaire (Box), Current Psychiatry contacted 45 Reader Reactors—clinical psychiatrists who provide feedback to our editorial staff about topics being considered for publication. The 15 readers who responded practice psychiatry in the Northeast (New York and New Jersey), the South (Florida and Georgia), the West (California, Washington, and Oregon), and the Midwest (Pennsylvania, Illinois, and Missouri).

Nine of 11 readers who answered all questions in the survey said they have seen an increase in patients describing psychological reactions to the effects of the economic recession. A reader from Red Bank, NJ, reported, “I see a pattern of issues: ‘I was just laid off.’ ‘I am afraid I will be laid off.’ ‘Others have been laid off, and I’m overwhelmed with their work as well as my own.’ ‘I was planning to retire in a couple years, but now I will have to work longer than I was planning.’” Two psychiatrists reported no increase in patients with economic worries—in a prison and a state hospital with geriatric patients with cognitive impairment.

Timeline. For some survey respondents, the increase in patients with economy-related problems emerged in mid-to-late 2008—particularly in October—but others report seeing symptoms sooner. A reader from Harrisburg, PA, said, “I’ve noticed this increase for the past 4 to 5 months (dramatic), but there has been a general increase for 1 to 2 years.”

These observations mirror the rise in unemployment in the 16 months since the recession officially began in December 2007. In March 2009, the U.S. Bureau of Labor Statistics reported a national unemployment rate of 8.5% (13.2 million unemployed), which was a 25-year high. That same month, employers eliminated 663,000 jobs, for a total of 5.1 million layoffs since the recession began. Two-thirds of all layoffs occurred between November 2008 and March 2009.¹

 

Symptoms. Depression, anxiety, or both are the most common symptoms associated with patients’ financial difficulties, survey respondents say. Other symptoms include insomnia, hopelessness, helplessness, loss of trust, anger, bitterness, resentment, suicidal ideation or attempts, numbness, desires for retaliation, increased alcohol/drug use, fear of being unable to afford medications or of losing a job, paranoia, and marital problems. Readers’ comments include:

• Augusta, GA: “Patients with depression and anxiety symptoms have increased in the emergency department.”
• Portland, OR: “I see people giving up and planning to live on unemployment as long as possible.”
• Fresno, CA: “Some married people are wishing they were single and did not have children.”
• Red Bank, NJ: “Some who have adapted are doing well, often with a low-overhead business, meeting a specialty need, or entering into a business that meets an emerging need.”

Who is affected? Overall, readers estimated that 70% to 100% of affected patients had pre-existing psychiatric disorders, whereas 20% to 30% had not sought treatment in the past. “Individuals with preexisting problems are having considerable difficulty,” one psychiatrist said.

Similarly, Dr. Jeffrey Rediger, medical director of the adult psychiatric inpatient service at McLean SouthEast, Brockton, MA, told Current Psychiatry, “For some people who were functioning marginally before the recession, this stress has pushed them over the edge. But we’re also seeing a number of young to middle-aged adults who are seeking treatment and hospitalization for the first time.”

Box

Interview: Emerging patterns

When interviewed March 17, 2009, Dr. Rediger, Dr. Palmer, and Dr. Kauffman discussed their experiences, provided case examples, and suggested treatments they have found useful for recession-stressed psychiatric patients.

DR. PALMER: People went into panic mode in September/October. Losing a job, a retirement plan, or a home is about who we are and our worth as human beings. My sense is that most people are resilient and adaptive and will be fine despite the recession, but a portion of the population is impaired in adaptability.

DR. REDIGER: Would you explain what you mean?

DR. PALMER: A lot of people become so defiant, so angry, that they withdraw instead of adapting to a new way of life that they consider inferior. They’re humiliated; they feel complete and utter failure. For example, the contractor who owns his own business and says there’s no way he’s going to work for somebody else. He may have to go work for somebody else, get his personal finances in order for a year or two, and then start up a business again. But he has to survive in the meantime.

DR. REDIGER: People are walking around with a lot fear and self-blame. They don’t talk about this very easily; they may say things are fine, but they feel terrible. I wonder how much people are blaming themselves, perhaps for overextending their credit.

DR. PALMER: I think most of these people sensed their finances were marginal before the recession hit. They felt out of control, but their options were limited as housing prices rose beyond affordability. Clinically, I’m seeing increased rates of depression, anxiety, hopelessness. Denial is a big one; there’s a mindset that this can’t be happening.

Helplessness and dread

DR. KAUFFMAN: I resonate with the hopelessness. A lot of people tell me they are experiencing a sense of free fall, and I’ve been working with them to recalibrate a sense of empowerment. First I try some reality testing. I’ll say, “Maybe you’re feeling anxious, helpless, a little denial, fear. Is your survival in danger? Yes or no?” If the answer is no, then I’ll say, “So what can you do so you’re not living as if your survival is in danger?”

 

DR. REDIGER: Some people—such as the patient in the case report I submitted (Case Report 1)—are paralyzed by dread and anxiety. Two years ago their house was like an ATM machine, but now they feel trapped and worry that they can’t meet the mortgage payments.

DR. REDIGER: An economic recession is stressful because money represents power, control, and survival. The recession is not just about money. It’s about security, identity, and loss of face.

DR. KAUFFMAN: The evidence is pretty clear that financial losses are a risk factor for suicide, especially among men.^2,3 You can go up and down Maslow’s hierarchy of needs and see what money means to people. I’ve also noticed that economic stress is a trigger for my clients with posttraumatic stress disorder. They feel out of control of a situation they thought they controlled.

DR. PALMER: An economic downturn can trigger learned helplessness. A construction worker has applied to 50 different construction companies, and none are hiring. He concludes, “I have to wait until the economy turns around, and then I’ll get another job in construction because that’s what I do.” He thinks he doesn’t have enough money or isn’t smart enough to get a degree, or whatever.

DR. REDIGER: And that’s another reason why someone with a history of trauma might experience a reactivation. Learned helplessness can be an aspect of chronic, repeated trauma. A person learns not to try any longer.

DR. PALMER: An inflexible perfectionist would probably have the most difficult time. A person who feels “there are rights and wrongs in the world, and the right thing is that I should be working. My family has grown accustomed to a certain lifestyle, and it’s my job to keep that up.”

DR. REDIGER: “If I work hard, this should be given to me.”

DR. PALMER: Right. A person with more flexibility might think in terms of problem-solving. “I worked in construction (or whatever), and now I can’t get a job. Therefore, I’ll go into a different field and take a lesser salary. The family will have to cut the budget, and the kids will go to a public college instead of a fancy private college.”

Case Report 1

Putting losses into perspective

DR. KAUFFMAN: Here’s where a cognitive-behavioral intervention with a goal to increase the flexibility—not just content—of thinking can help. You can ask patients, “What is most important to you? Is it money? Or is it your relationship with your family?” Or you could ask questions such as, “In the challenges you’re facing, what opportunities are there for you to do things that matter to you?”

 

For people who feel hopeless, I often describe this true story. A pilot was flying a jet cross-country when his engines flamed out and the plane began spinning downward. He tried everything, but nothing worked until he lowered the landing gear. This changed the vortex of forces, so that when the pilot went through his emergency procedures again he was able to pull the plane out of the death spiral.

When people become paralyzed by their problems, you can say the equivalent of “what’s your landing gear?” What small thing you could do that might create a different experience for you?

DR. REDIGER: So you’re saying, “If the big picture is too overwhelming, what’s something small you can do today?”

DR. KAUFFMAN: Yes, but not that the small thing is insignificant. As in the case report I submitted (Case Report 2), doing a small thing that makes a difference in a huge problem increases one’s internal locus of control. Feeling more empowered may lead the person to take on another thing.

DR. REDIGER: People have enormous resources that they don’t always know how to tap into. We may be experiencing a material recession but also an opportunity to recover what truly matters to us.

DR. KAUFFMAN: We’re talking about challenging people’s values and encouraging flexibility of thinking. This is a low-cost, powerful strategy that anyone can use to cope with the economic recession.

DR. PALMER: So you begin by challenging assumptions, cognitive-behavioral therapy (CBT), adaptive mechanisms, coming up with a plan, and implementing the plan, then being flexible, assessing if it’s working, and—if it’s not—coming up with another plan or revising it. That process has to be done first, before things I would recommend that are unrelated to the person’s immediate problem. If somebody tells you, “I just got laid off from work,” and you say, “Exercise could help,” he’s going to say, “Did you not hear me? I just got laid off from work.”

DR. KAUFFMAN: Evidence supports the positive psychology that 2 factors are key to sustaining hope:

• a sense of agency that you can achieve a goal
• multiple pathways planned out to reach the goal.⁴

Together, these 2 factors—which Snyder called “the will and the way⁵—are the highest predictors of performance, health, and ability to withstand adversity.

DR. PALMER: Along with CBT, I remind patients to stay connected, to see and talk to people every day. This doesn’t mean getting together to watch television; it means having real conversations. Other people can help you get unstuck. Evidence also indicates that a social network mitigates against depression and anxiety. The happier your friends are, the happier you are.⁶

Case Report 2

 

Addressing depression

DR. KAUFFMAN: Medication also can play a useful role for some patients.

DR. PALMER: Patients who meet criteria for major depression—in particular if they’re having suicidal thoughts—absolutely need psychotropics. Mr. R, my case patient, benefited greatly from CBT and medication. We also worked on financial planning and handling financial conflicts with his wife and children. He is exercising, doing volunteer work, and staying connected with friends and family. He is hoping to find a job in the next few months.

DR. REDIGER: For a person who’s going though a stressful period, I try to keep medication time-limited. We talk about treating symptoms, but it’s important to look at what’s causing the patient’s problems and address it.

DR. PALMER: During this recession, a lot of people are going to be down but not clinically depressed. If the depression is mild to moderate, I sometimes recommend exercise instead of medication (such as when a patient is refusing medication or has had serious side effects from medications). I recommend exercise for all my outpatients—even if they’re taking psychotropics—because exercise has been shown to be as effective as antidepressants for moderate depression.^7,8

DR. REDIGER: We’ve also been encouraging people who’ve lost jobs to volunteer in the community. Having a reason to get out of the house takes the mind off one’s worries.

DR. KAUFFMAN: The “3 good things in life” exercise studied by psychologist Martin E.P. Seligman, PhD, has been shown in a 6-month, randomized, placebo-controlled study to increase happiness and decrease depressive symptoms.⁹ In this exercise, you look back at the end of each day and write down 3 things that went well, their causes, and an explanation for each good thing. Ask yourself, “When was I at my best today? What happened today that I feel grateful for? What did I do to make that good thing happen?”

DR. REDIGER: Remind people to talk to their children about the recession, too. If they have to move to a different home or to a different school, let their children know things are going on and how to think about that. This can help kids understand how to deal with their anxiety.

Related resources

• Getting through tough economic times. A SAMHSA guide. Substance Abuse and Mental Health Services Administration. U.S. Department of Health and Human Services. www.samhsa.gov/economy.
• Seligman MEP. Authentic happiness: using the new positive psychology to realize your potential for lasting fulfillment. New York, NY: Simon & Schuster; 2002.
• Positive Psychology Center. University of Pennsylvania, Philadelphia. www.ppc.sas.upenn.edu.

Drug brand names

• Escitalopram • Lexapro
• Fluoxetine • Prozac
• Lorazepam • Ativan

Disclosure

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

Acknowledgment

This article was researched and written by Current Psychiatry Editor Alice V. Luddington, ELS, and Senior Associate Editor Erica Vonderheid.