From the Stanley Foundation Bipolar Network: New findings on suicide attempts, substance abuse, obesity, and more

Even with psychiatry’s most effective and best studied agents, many patients with bipolar disorder are inadequately treated and respond insufficiently to available psychopharmacologic agents. To address this problem, the Stanley Foundation Bipolar Network (SFBN) was created to explore acute and long-term response to treatment of bipolar disorder.

For the past 6 years, our group (Box) has followed an international cohort of patients with bipolar disorder and offered them opportunities to participate in clinical trials at seven field centers. We have made considerable progress as we focused on the longitudinal course of bipolar illness and evaluated various combinations of psychopharmacologic therapies. The SFBN also has explored factors that increase the risk of suicide, quantified the incidence of anxiety disorder and substance abuse, and looked at other variables that may affect treatment outcome.

This report for the readers of Current Psychiatry provides a brief state-of-the-art overview of what we have learned about the course and management of bipolar disorder. It brings together and summarizes the findings from studies published, in press, or under review. Our goal is to update current findings, which may help you provide optimum care for these at-risk patients.

Box

In part one, we discuss the demographics of our cohort of 676 community-based bipolar patients, including risk factors for suicide attempts, frequency of comorbid psychiatric diagnoses, problems of overweight and obesity, and preliminary findings about thyroiditis.

In part two, we describe our clinical trials assessing mood stabilizers and adjunctive agents such as atypical antipsychotics, second-generation antidepressants, and anticonvulsants. We also will address a soon-to-be analyzed study of omega-3 fatty acids.

Table 1

CHARACTERISTICS OF THE 676 BIPOLAR OUTPATIENTS

Study population

The SFBN recruited outpatients with bipolar disorders I, II, or not otherwise specified (NOS). We did not exclude patients with comorbid illnesses, except those with active substance abuse disorder requiring treatment in another setting.¹ Patients were recruited almost exclusively from the community and rarely from inpatient hospitalization. The average age was 41, and 43% were college graduates. Most were employed but indicated that their illness limited their employment level or ability to function at work (Table 1).

One striking finding was a decadelong lag between the onset of symptoms reaching thresholds for diagnosis and the onset of first treatment.² This long delay could have adverse consequences for illness outcome and represents a major public health target. Age of onset appeared to have both genetic/familial and environmental determinants.³ Subjects with a history of both extreme early life adversities (i.e., physical or sexual abuse) and a positive family history of mood disorder had the earliest onset of bipolar illness. Those who had neither of these factors had late-onset illness.

Suicide attempts

Prior to network entry, 25 to 50% of our study population had made a serious suicide attempt (defined as requiring medical attention and/or hospitalization), pointing to bipolar disorder’s potential lethality.

History of abuse A history of physical or sexual abuse in childhood or adolescence was a prominent risk factor for attempted suicide.⁴ With either type of abuse there was an approximate 15% increase in incidence of suicide attempts over the baseline rate of about 25%. More than 55% of patients with a history of both physical and sexual abuse had made a serious suicide attempt. The frequency of physical and sexual abuse was also positively related to increased incidence of suicide attempts. Taken together, these data suggest a “stressor dose-response” relationship between adverse childhood or adolescent experiences and an increased incidence of suicide attempts.

Table 2

FACTORS THAT APPEAR TO INCREASE SUICIDE RISK IN BIPOLAR DISORDER*

Comorbidities Other factors that appear to be associated with bipolar disorder and increased risk of attempted suicide include anxiety and eating disorders, early onset of symptoms, at least four previous hospitalizations for depression, and medical comorbidity (Table 2). Limited access to psychiatric and medical services and inadequate health insurance also were correlated with having made a serious suicide attempt. Thus, lack of medical care might exacerbate demoralization and increase the risk of suicide.

Family history of suicide or serious suicide attempts and drug abuse were associated with an increase in suicide attempts, but family history of unipolar or bipolar illness were not. These data are consistent with other studies suggesting that vulnerability to suicide may have a separate genetic component from that of mood disorders per se.

Severity of illness Increased severity of bipolar illness also was associated with prior psychosocial stressors³ and serious suicide attempts. We confirmed self-reported history, using daily mood charting, the clinician-rated Inventory of Depressive Symptomatology (IDS-C), and the Young Mania Rating Scale (YMRS) to rate increase in percentage of time ill, percentage of time depressed, and severity of depression.

Clinical implications We are uncertain how directly these data regarding suicide attempts relate to completed suicide. However, patients with bipolar disorder are among those at highest risk for completed suicide, and a prior serious attempt is often a precursor to completed suicide.^5,6

Factors that appear particularly related to increased risk of suicide in patients with bipolar disorder are family history of suicide, history of early psychosocial stressors, comorbid personality disorders, substance abuse, and a relatively severe course of bipolar illness. Patients with these risk factors need support for two types of psychosocial stressors:

• poor access to health care
• stressors related to concurrent events (e.g., occurring with new affective episodes).

It may also be important for clinicians to consider the prophylactic use of lithium because of its demonstrated ability to reduce mortality in bipolar illness.⁷ Additionally, we need data on the efficacy of new drugs in preventing affective episodes and reducing suicidal ideation and acts.

Common comorbidities

We found considerable axis I lifetime comorbidities in the SFBN cohort (Table 3), including a 42% incidence of anxiety disorder and a similarly high rate of substance abuse. In addition to bipolar disorder, patients averaged approximately two lifetime comorbid diagnoses:

• 35% had none
• 65% had one or more
• 42% had two or more
• 24% had three or more.

Table 3

PSYCHIATRIC COMORBIDITY IN BIPOLAR OUTPATIENTS (%)*.

Men with bipolar disorder had a higher absolute prevalence of alcoholism, but the relative risk compared with the general population was much higher in women (odds ratio 7.35) compared with men (odds ratio 2.77). In women, alcohol use and abuse were related to history of social phobia, greater number of depressive episodes prior to network entry, and history of abusing more than one substance. In men, alcohol comorbidity was related to history of alcohol abuse in first-degree relatives and history of early physical abuse.

These data suggest that female patients, in particular, were self-medicating their affective episodes and comorbid anxiety disorders with alcohol. They suggest the importance of asking patients directly about alcohol use to identify the need for primary and secondary prevention. In an adolescent or young adult, affective illness—and bipolar disorder in particular—should be considered a major risk factor for subsequent problems with alcohol and drug abuse. When taking a careful history, the treating physician should include questions regarding any substance abuse.

Overweight and obesity

One-half of the women and two-thirds of the men in the SFBN were overweight at network entry.⁸ Although this rate of overweight sounds alarmingly high, it was not significantly different from rates in the general U.S. population. A greater percentage of women than men in the network had morbid obesity, however.

In our cohort, being overweight or obese was associated with an increased incidence of cardiovascular disease, diabetes, arthritis, hypertension, hypothyroidism, and cancer. The degree of obesity also correlated significantly with past use of the numerous psychotropic drugs that have been associated with weight gain. Also, as might be expected, increased weight was associated with physical inactivity.

Many of the psychotropic drugs routinely used to treat bipolar disorder are associated with weight gain. Among these are the mood stabilizers lithium and valproate and the atypical antipsychotics, with the exception of ziprasidone (and, to follow, aripiprazole). Lithium’s liability to cause weight gain may be counterbalanced by its antisuicide effects and its ability to reverse excess medical mortality associated with affective illness. Thus, lithium should continue to play a major therapeutic role in bipolar disorder.

It may be more effective and easier to prevent weight gain than to attempt to reduce weight that has been gained. Recommending exercise and other weight-reduction measures may be helpful, as may co-administering drugs associated with weight loss, such as topiramate.⁹

Thyroiditis

Antithyroid antibodies were detected in 28% of network patients, compared with rates of 3% in the general population and 18% in psychiatric controls.¹⁰ The increased rate was associated with the need to augment thyroid function in 17% of network patients, but it was not related to age, mood state, rapid cycling status, or lithium treatment.

These data indicate that bipolar patients are prone to autoimmune thyroid changes. Further analysis is required to ascertain whether this finding has therapeutic implications, especially related to adjunctive T3 and T4 treatment.¹¹

Even with psychiatry’s most effective and best studied agents, many patients with bipolar disorder are inadequately treated and respond insufficiently to available psychopharmacologic agents. To address this problem, the Stanley Foundation Bipolar Network (SFBN) was created to explore acute and long-term response to treatment of bipolar disorder.

For the past 6 years, our group (Box) has followed an international cohort of patients with bipolar disorder and offered them opportunities to participate in clinical trials at seven field centers. We have made considerable progress as we focused on the longitudinal course of bipolar illness and evaluated various combinations of psychopharmacologic therapies. The SFBN also has explored factors that increase the risk of suicide, quantified the incidence of anxiety disorder and substance abuse, and looked at other variables that may affect treatment outcome.

This report for the readers of Current Psychiatry provides a brief state-of-the-art overview of what we have learned about the course and management of bipolar disorder. It brings together and summarizes the findings from studies published, in press, or under review. Our goal is to update current findings, which may help you provide optimum care for these at-risk patients.

Box

In part one, we discuss the demographics of our cohort of 676 community-based bipolar patients, including risk factors for suicide attempts, frequency of comorbid psychiatric diagnoses, problems of overweight and obesity, and preliminary findings about thyroiditis.

In part two, we describe our clinical trials assessing mood stabilizers and adjunctive agents such as atypical antipsychotics, second-generation antidepressants, and anticonvulsants. We also will address a soon-to-be analyzed study of omega-3 fatty acids.

Table 1

CHARACTERISTICS OF THE 676 BIPOLAR OUTPATIENTS

Study population

The SFBN recruited outpatients with bipolar disorders I, II, or not otherwise specified (NOS). We did not exclude patients with comorbid illnesses, except those with active substance abuse disorder requiring treatment in another setting.¹ Patients were recruited almost exclusively from the community and rarely from inpatient hospitalization. The average age was 41, and 43% were college graduates. Most were employed but indicated that their illness limited their employment level or ability to function at work (Table 1).

One striking finding was a decadelong lag between the onset of symptoms reaching thresholds for diagnosis and the onset of first treatment.² This long delay could have adverse consequences for illness outcome and represents a major public health target. Age of onset appeared to have both genetic/familial and environmental determinants.³ Subjects with a history of both extreme early life adversities (i.e., physical or sexual abuse) and a positive family history of mood disorder had the earliest onset of bipolar illness. Those who had neither of these factors had late-onset illness.

Suicide attempts

Prior to network entry, 25 to 50% of our study population had made a serious suicide attempt (defined as requiring medical attention and/or hospitalization), pointing to bipolar disorder’s potential lethality.

History of abuse A history of physical or sexual abuse in childhood or adolescence was a prominent risk factor for attempted suicide.⁴ With either type of abuse there was an approximate 15% increase in incidence of suicide attempts over the baseline rate of about 25%. More than 55% of patients with a history of both physical and sexual abuse had made a serious suicide attempt. The frequency of physical and sexual abuse was also positively related to increased incidence of suicide attempts. Taken together, these data suggest a “stressor dose-response” relationship between adverse childhood or adolescent experiences and an increased incidence of suicide attempts.

Table 2

FACTORS THAT APPEAR TO INCREASE SUICIDE RISK IN BIPOLAR DISORDER*

Comorbidities Other factors that appear to be associated with bipolar disorder and increased risk of attempted suicide include anxiety and eating disorders, early onset of symptoms, at least four previous hospitalizations for depression, and medical comorbidity (Table 2). Limited access to psychiatric and medical services and inadequate health insurance also were correlated with having made a serious suicide attempt. Thus, lack of medical care might exacerbate demoralization and increase the risk of suicide.

Family history of suicide or serious suicide attempts and drug abuse were associated with an increase in suicide attempts, but family history of unipolar or bipolar illness were not. These data are consistent with other studies suggesting that vulnerability to suicide may have a separate genetic component from that of mood disorders per se.

Severity of illness Increased severity of bipolar illness also was associated with prior psychosocial stressors³ and serious suicide attempts. We confirmed self-reported history, using daily mood charting, the clinician-rated Inventory of Depressive Symptomatology (IDS-C), and the Young Mania Rating Scale (YMRS) to rate increase in percentage of time ill, percentage of time depressed, and severity of depression.

Clinical implications We are uncertain how directly these data regarding suicide attempts relate to completed suicide. However, patients with bipolar disorder are among those at highest risk for completed suicide, and a prior serious attempt is often a precursor to completed suicide.^5,6

Factors that appear particularly related to increased risk of suicide in patients with bipolar disorder are family history of suicide, history of early psychosocial stressors, comorbid personality disorders, substance abuse, and a relatively severe course of bipolar illness. Patients with these risk factors need support for two types of psychosocial stressors:

• poor access to health care
• stressors related to concurrent events (e.g., occurring with new affective episodes).

It may also be important for clinicians to consider the prophylactic use of lithium because of its demonstrated ability to reduce mortality in bipolar illness.⁷ Additionally, we need data on the efficacy of new drugs in preventing affective episodes and reducing suicidal ideation and acts.

Common comorbidities

We found considerable axis I lifetime comorbidities in the SFBN cohort (Table 3), including a 42% incidence of anxiety disorder and a similarly high rate of substance abuse. In addition to bipolar disorder, patients averaged approximately two lifetime comorbid diagnoses:

• 35% had none
• 65% had one or more
• 42% had two or more
• 24% had three or more.

Table 3

PSYCHIATRIC COMORBIDITY IN BIPOLAR OUTPATIENTS (%)*.

Men with bipolar disorder had a higher absolute prevalence of alcoholism, but the relative risk compared with the general population was much higher in women (odds ratio 7.35) compared with men (odds ratio 2.77). In women, alcohol use and abuse were related to history of social phobia, greater number of depressive episodes prior to network entry, and history of abusing more than one substance. In men, alcohol comorbidity was related to history of alcohol abuse in first-degree relatives and history of early physical abuse.

These data suggest that female patients, in particular, were self-medicating their affective episodes and comorbid anxiety disorders with alcohol. They suggest the importance of asking patients directly about alcohol use to identify the need for primary and secondary prevention. In an adolescent or young adult, affective illness—and bipolar disorder in particular—should be considered a major risk factor for subsequent problems with alcohol and drug abuse. When taking a careful history, the treating physician should include questions regarding any substance abuse.

Overweight and obesity

One-half of the women and two-thirds of the men in the SFBN were overweight at network entry.⁸ Although this rate of overweight sounds alarmingly high, it was not significantly different from rates in the general U.S. population. A greater percentage of women than men in the network had morbid obesity, however.

In our cohort, being overweight or obese was associated with an increased incidence of cardiovascular disease, diabetes, arthritis, hypertension, hypothyroidism, and cancer. The degree of obesity also correlated significantly with past use of the numerous psychotropic drugs that have been associated with weight gain. Also, as might be expected, increased weight was associated with physical inactivity.

Many of the psychotropic drugs routinely used to treat bipolar disorder are associated with weight gain. Among these are the mood stabilizers lithium and valproate and the atypical antipsychotics, with the exception of ziprasidone (and, to follow, aripiprazole). Lithium’s liability to cause weight gain may be counterbalanced by its antisuicide effects and its ability to reverse excess medical mortality associated with affective illness. Thus, lithium should continue to play a major therapeutic role in bipolar disorder.

It may be more effective and easier to prevent weight gain than to attempt to reduce weight that has been gained. Recommending exercise and other weight-reduction measures may be helpful, as may co-administering drugs associated with weight loss, such as topiramate.⁹

Thyroiditis

Antithyroid antibodies were detected in 28% of network patients, compared with rates of 3% in the general population and 18% in psychiatric controls.¹⁰ The increased rate was associated with the need to augment thyroid function in 17% of network patients, but it was not related to age, mood state, rapid cycling status, or lithium treatment.

These data indicate that bipolar patients are prone to autoimmune thyroid changes. Further analysis is required to ascertain whether this finding has therapeutic implications, especially related to adjunctive T3 and T4 treatment.¹¹

Even with psychiatry’s most effective and best studied agents, many patients with bipolar disorder are inadequately treated and respond insufficiently to available psychopharmacologic agents. To address this problem, the Stanley Foundation Bipolar Network (SFBN) was created to explore acute and long-term response to treatment of bipolar disorder.

For the past 6 years, our group (Box) has followed an international cohort of patients with bipolar disorder and offered them opportunities to participate in clinical trials at seven field centers. We have made considerable progress as we focused on the longitudinal course of bipolar illness and evaluated various combinations of psychopharmacologic therapies. The SFBN also has explored factors that increase the risk of suicide, quantified the incidence of anxiety disorder and substance abuse, and looked at other variables that may affect treatment outcome.

This report for the readers of Current Psychiatry provides a brief state-of-the-art overview of what we have learned about the course and management of bipolar disorder. It brings together and summarizes the findings from studies published, in press, or under review. Our goal is to update current findings, which may help you provide optimum care for these at-risk patients.

Box

In part one, we discuss the demographics of our cohort of 676 community-based bipolar patients, including risk factors for suicide attempts, frequency of comorbid psychiatric diagnoses, problems of overweight and obesity, and preliminary findings about thyroiditis.

In part two, we describe our clinical trials assessing mood stabilizers and adjunctive agents such as atypical antipsychotics, second-generation antidepressants, and anticonvulsants. We also will address a soon-to-be analyzed study of omega-3 fatty acids.

Table 1

CHARACTERISTICS OF THE 676 BIPOLAR OUTPATIENTS

Study population

The SFBN recruited outpatients with bipolar disorders I, II, or not otherwise specified (NOS). We did not exclude patients with comorbid illnesses, except those with active substance abuse disorder requiring treatment in another setting.¹ Patients were recruited almost exclusively from the community and rarely from inpatient hospitalization. The average age was 41, and 43% were college graduates. Most were employed but indicated that their illness limited their employment level or ability to function at work (Table 1).

One striking finding was a decadelong lag between the onset of symptoms reaching thresholds for diagnosis and the onset of first treatment.² This long delay could have adverse consequences for illness outcome and represents a major public health target. Age of onset appeared to have both genetic/familial and environmental determinants.³ Subjects with a history of both extreme early life adversities (i.e., physical or sexual abuse) and a positive family history of mood disorder had the earliest onset of bipolar illness. Those who had neither of these factors had late-onset illness.

Suicide attempts

Prior to network entry, 25 to 50% of our study population had made a serious suicide attempt (defined as requiring medical attention and/or hospitalization), pointing to bipolar disorder’s potential lethality.

History of abuse A history of physical or sexual abuse in childhood or adolescence was a prominent risk factor for attempted suicide.⁴ With either type of abuse there was an approximate 15% increase in incidence of suicide attempts over the baseline rate of about 25%. More than 55% of patients with a history of both physical and sexual abuse had made a serious suicide attempt. The frequency of physical and sexual abuse was also positively related to increased incidence of suicide attempts. Taken together, these data suggest a “stressor dose-response” relationship between adverse childhood or adolescent experiences and an increased incidence of suicide attempts.

Table 2

FACTORS THAT APPEAR TO INCREASE SUICIDE RISK IN BIPOLAR DISORDER*

Comorbidities Other factors that appear to be associated with bipolar disorder and increased risk of attempted suicide include anxiety and eating disorders, early onset of symptoms, at least four previous hospitalizations for depression, and medical comorbidity (Table 2). Limited access to psychiatric and medical services and inadequate health insurance also were correlated with having made a serious suicide attempt. Thus, lack of medical care might exacerbate demoralization and increase the risk of suicide.

Family history of suicide or serious suicide attempts and drug abuse were associated with an increase in suicide attempts, but family history of unipolar or bipolar illness were not. These data are consistent with other studies suggesting that vulnerability to suicide may have a separate genetic component from that of mood disorders per se.

Severity of illness Increased severity of bipolar illness also was associated with prior psychosocial stressors³ and serious suicide attempts. We confirmed self-reported history, using daily mood charting, the clinician-rated Inventory of Depressive Symptomatology (IDS-C), and the Young Mania Rating Scale (YMRS) to rate increase in percentage of time ill, percentage of time depressed, and severity of depression.

Clinical implications We are uncertain how directly these data regarding suicide attempts relate to completed suicide. However, patients with bipolar disorder are among those at highest risk for completed suicide, and a prior serious attempt is often a precursor to completed suicide.^5,6

Factors that appear particularly related to increased risk of suicide in patients with bipolar disorder are family history of suicide, history of early psychosocial stressors, comorbid personality disorders, substance abuse, and a relatively severe course of bipolar illness. Patients with these risk factors need support for two types of psychosocial stressors:

• poor access to health care
• stressors related to concurrent events (e.g., occurring with new affective episodes).

It may also be important for clinicians to consider the prophylactic use of lithium because of its demonstrated ability to reduce mortality in bipolar illness.⁷ Additionally, we need data on the efficacy of new drugs in preventing affective episodes and reducing suicidal ideation and acts.

Common comorbidities

We found considerable axis I lifetime comorbidities in the SFBN cohort (Table 3), including a 42% incidence of anxiety disorder and a similarly high rate of substance abuse. In addition to bipolar disorder, patients averaged approximately two lifetime comorbid diagnoses:

• 35% had none
• 65% had one or more
• 42% had two or more
• 24% had three or more.

Table 3

PSYCHIATRIC COMORBIDITY IN BIPOLAR OUTPATIENTS (%)*.

Men with bipolar disorder had a higher absolute prevalence of alcoholism, but the relative risk compared with the general population was much higher in women (odds ratio 7.35) compared with men (odds ratio 2.77). In women, alcohol use and abuse were related to history of social phobia, greater number of depressive episodes prior to network entry, and history of abusing more than one substance. In men, alcohol comorbidity was related to history of alcohol abuse in first-degree relatives and history of early physical abuse.

These data suggest that female patients, in particular, were self-medicating their affective episodes and comorbid anxiety disorders with alcohol. They suggest the importance of asking patients directly about alcohol use to identify the need for primary and secondary prevention. In an adolescent or young adult, affective illness—and bipolar disorder in particular—should be considered a major risk factor for subsequent problems with alcohol and drug abuse. When taking a careful history, the treating physician should include questions regarding any substance abuse.

Overweight and obesity

One-half of the women and two-thirds of the men in the SFBN were overweight at network entry.⁸ Although this rate of overweight sounds alarmingly high, it was not significantly different from rates in the general U.S. population. A greater percentage of women than men in the network had morbid obesity, however.

In our cohort, being overweight or obese was associated with an increased incidence of cardiovascular disease, diabetes, arthritis, hypertension, hypothyroidism, and cancer. The degree of obesity also correlated significantly with past use of the numerous psychotropic drugs that have been associated with weight gain. Also, as might be expected, increased weight was associated with physical inactivity.

Many of the psychotropic drugs routinely used to treat bipolar disorder are associated with weight gain. Among these are the mood stabilizers lithium and valproate and the atypical antipsychotics, with the exception of ziprasidone (and, to follow, aripiprazole). Lithium’s liability to cause weight gain may be counterbalanced by its antisuicide effects and its ability to reverse excess medical mortality associated with affective illness. Thus, lithium should continue to play a major therapeutic role in bipolar disorder.

It may be more effective and easier to prevent weight gain than to attempt to reduce weight that has been gained. Recommending exercise and other weight-reduction measures may be helpful, as may co-administering drugs associated with weight loss, such as topiramate.⁹

Thyroiditis

Antithyroid antibodies were detected in 28% of network patients, compared with rates of 3% in the general population and 18% in psychiatric controls.¹⁰ The increased rate was associated with the need to augment thyroid function in 17% of network patients, but it was not related to age, mood state, rapid cycling status, or lithium treatment.

These data indicate that bipolar patients are prone to autoimmune thyroid changes. Further analysis is required to ascertain whether this finding has therapeutic implications, especially related to adjunctive T3 and T4 treatment.¹¹