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Evidence-Based Reviews

From the stanley foundation bipolar network: New findings on suicide attempts, substance abuse, obesity, and more

For 6 years, the Stanley Foundation Bipolar Network has studied outpatients with bipolar disorder—patients much like those psychiatrists see every day. The network’s findings—compiled in this two-part report—offer new insights into the management of this potentially lethal mental disorder.

Vol. 1, No. 8 / August 2002

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.



Since Robert Prien’s pioneering studies in the 1970s, the National Institute of Mental Health (NIMH) had funded little work on prophylaxis of bipolar disorders or acute bipolar depression. Following two NIMH conferences on bipolar illness in 1989 and 1994, the Stanley Foundation Bipolar Network (SFBN) was established to help overcome these research deficiencies, with funding provided by the Theodore and Vada Stanley Foundation.

Patients were recruited into the network from the general community and with the use of newspaper and newsletter advertisements. In contrast to many other clinical populations, few who wished to enter the network were excluded. It was clear, however, that filling out demographic, clinical, and rating forms would require considerable effort from each patient. All patients gave written informed consent to participate in the naturalistic part of the study, and were reconsented for any open or blind randomized clinical trial.

Patients provided daily self-ratings on the National Institute of Mental Health Life Chart Method (NIMH-LCM), a unique longitudinal instrument. Clinicians then completed their own separate LCMs, as more severely ill patients often could not complete their self-ratings, and patients often underestimated the severity and functional disability associated with the hypomanic and manic phases of bipolar illness. With the use of the NIMH-LCM, network investigators were able, for the first time, to assess the details of mood fluctuations associated with bipolar illness and to more precisely delineate the qualitative and quantitative aspects of response to psychopharmacologic interventions.

The SFBN includes seven research field centers in the United States, the Netherlands, and Germany. The leaders of those centers collaborated with Robert M. Post, MD, to prepare this report of the network findings. The collaborators are:

Gabriele S. Leverich, MSW, and Kirk D. Denicoff, MD
 Biological Psychiatry Branch
 National Institute of Mental Health
 Bethesda, MD

Paul E. Keck, Jr., MD, and Susan L. McElroy, MD
 Biological Psychiatry Program
 University of Cincinnati College of Medicine
 Cincinnati, OH

Lori L. Altshuler, MD, and Mark A. Frye, MD
 UCLA Mood Disorders Research Program
 VA Medical Center
 Los Angeles, CA

Willem A. Nolen, MD, and Ralph Kupka, MD
 Altrecht Institute for Mental Health Care
 University Medical Center
 Utrecht, The Netherlands

John Rush, MD, and Trisha Suppes, MD
 Department of Psychiatry
 Southwest Medical Center
 University of Texas, Dallas

Joerg Walden, MD
 Department of Psychiatry
 University of Freiburg
 Freiburg, Germany

Keith Kramlinger, MD
 Mayo Clinic, Rochester, MN
 (Administrative center)

Heinz Grunze, MD
 Psychiatrische Klinik der LMU
 Munich, Germany

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


Mean age



% Female



Diagnosis (%)

 Bipolar I



 Bipolar II



 Bipolar NOS



Marital status (%)







Income (%)













Education (completed, %)

 High school



 Jr. college/technical



 College, 4-year



 Graduate degree



Positive family history (1st-degree relatives, %)

 Bipolar disorder



 Unipolar disorder






 Drug dependence



 Other psychiatric disorder



 Alcohol abuse/dependence



 Suicide (complete or serious attempt)



Environmental adversity (%):



 Physical abuse



 Sexual abuse



Illness course and treatment (age in yrs)

 Age of onset (symptoms)



 Early onset (age <14)



 Age at first treatment



 Age at first hospitalization



Cycling pattern (n = 643, %)

 Rapid (or faster cycling)



 Ultrarapid (or faster cycling)



  Rapid-cycling only



 Ultrarapid cycling only



 Ultradian cycling



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


Course-of-illness characteristics

 Early onset

 More time ill

 More time depressed

 More-severe depression

Social and medical support

 Loss of significant other

 Lack of a confidant

 Single motherhood

 Decreased access to health care

 Lack of medical insurance


 Less education

 Lower income

 Being single


 Axis I

  Eating disorders

  Anxiety disorders

 Axis II

  Cluster A, B, C


Traumatic life events

 Sexual abuse

 Physical abuse


 Family history of suicide and drug abuse

* Identified in the SFBN cohort

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


Any substance abuse disorder














Any anxiety disorder


 Panic disorder


 Social phobia


 Simple phobia










Any eating disorder


 Bulimia nervosa


 Anorexia nervosa


* Lifetime comorbid axis I disorders based on Structured Clinical Interview for DSM-IV (SCID) interviews with 288 SFBN patients.

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

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