Joseph F. Goldberg

The International Society for Bipolar Disorders (ISBD) Task Force Report on Antidepressant Use in Bipolar Disorders

OBJECTIVE The risk-benefit profile of antidepressant medications in bipolar disorder is controversial. When conclusive evidence is lacking, expert consensus can guide treatment decisions. The International Society for Bipolar Disorders (ISBD) convened a task force to seek consensus recommendations on the use of antidepressants in bipolar disorders. METHOD An expert task force iteratively developed consensus through serial consensus-based revisions using the Delphi method. Initial survey items were based on systematic review of the literature. Subsequent surveys included new or reworded items and items that needed to be rerated. This process resulted in the final ISBD Task Force clinical recommendations on antidepressant use in bipolar disorder. RESULTS There is striking incongruity between the wide use of and the weak evidence base for the efficacy and safety of antidepressant drugs in bipolar disorder. Few well-designed, long-term trials of prophylactic benefits have been conducted, and there is insufficient evidence for treatment benefits with antidepressants combined with mood stabilizers. A major concern is the risk for mood switch to hypomania, mania, and mixed states. Integrating the evidence and the experience of the task force members, a consensus was reached on 12 statements on the use of antidepressants in bipolar disorder. CONCLUSIONS Because of limited data, the task force could not make broad statements endorsing antidepressant use but acknowledged that individual bipolar patients may benefit from antidepressants. Regarding safety, serotonin reuptake inhibitors and bupropion may have lower rates of manic switch than tricyclic and tetracyclic antidepressants and norepinephrine-serotonin reuptake inhibitors. The frequency and severity of antidepressant-associated mood elevations appear to be greater in bipolar I than bipolar II disorder. Hence, in bipolar I patients antidepressants should be prescribed only as an adjunct to mood-stabilizing medications.

Manic symptoms during depressive episodes in 1,380 patients with bipolar disorder: findings from the STEP-BD.

OBJECTIVE Little is known about how often bipolar depressive episodes are accompanied by subsyndromal manic symptoms in bipolar I and II disorders. The authors sought to determine the frequency and clinical correlates of manic symptoms during episodes of bipolar depression. METHOD From among 4,107 enrollees in the National Institute of Mental Healths Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD), 1,380 individuals met criteria for bipolar I or II depressive syndromes at the time of enrollment and were assessed for concomitant manic symptoms. Illness characteristics were compared in patients with pure bipolar depressed episodes and those with mixed depressive presentations. RESULTS Two-thirds of the subjects with bipolar depressed episodes had concomitant manic symptoms, most often distractibility, flight of ideas or racing thoughts, and psychomotor agitation. Patients with any mixed features were significantly more likely than those with pure bipolar depressed episodes to have early age at illness onset, rapid cycling in the past year, bipolar I subtype, history of suicide attempts, and more days in the preceding year with irritability or mood elevation. CONCLUSIONS Manic symptoms often accompany bipolar depressive episodes but may easily be overlooked when they appear less prominent than depressive features. Subsyndromal manic symptoms during bipolar I or II depression demarcate a more common, severe, and psychopathologically complex clinical state than pure bipolar depression and merit recognition as a distinct nosologic entity.

The International Society for Bipolar Disorders–Battery for Assessment of Neurocognition (ISBD-BANC)

OBJECTIVES Although cognitive impairment is recognized as an important clinical feature of bipolar disorder, there is no standard cognitive battery that has been developed for use in bipolar disorder research. The aims of this paper were to identify the cognitive measures from the literature that show the greatest magnitude of impairment in bipolar disorder, to use this information to determine whether the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB), developed for use in schizophrenia, might be suitable for bipolar disorder research, and to propose a preliminary battery of cognitive tests for use in bipolar disorder research. METHODS The project was conducted under the auspices of the International Society for Bipolar Disorders and involved a committee that comprised researchers with international expertise in the cognitive aspects of bipolar disorder. In order to identify cognitive tasks that show the largest magnitude of impairment in bipolar disorder, we reviewed the literature on studies assessing cognitive functioning (including social cognition) in bipolar disorder. We further provided a brief review of the cognitive overlap between schizophrenia and bipolar disorder and evaluated the degree to which tasks included in the MCCB (or other identified tasks) might be suitable for use in bipolar disorder. RESULTS Based on evidence that cognitive deficits in bipolar disorder are similar in pattern but less severe than in schizophrenia, it was judged that most subtests comprising the MCCB appear appropriate for use in bipolar disorder. In addition to MCCB tests, other specific measures of more complex verbal learning (e.g., the California Verbal Learning Test) or executive function (Stroop Test, Trail Making Test-part B, Wisconsin Card Sorting Test) also show substantial impairment in bipolar disorder. CONCLUSIONS Our analysis reveals that the MCCB represents a good starting point for assessing cognitive deficits in research studies of bipolar disorder, but that other tasks including more complex verbal learning measures and tests of executive function should also be considered in assessing cognitive compromise in bipolar disorder. Several promising cognitive tasks that require further study in bipolar disorder are also presented.

Identifying and treating cognitive impairment in bipolar disorder

OBJECTIVES The presence of cognitive deficits has become increasingly appreciated across all phases of bipolar disorder. The present review sought to identify domains of cognitive dysfunction, methods of assessment, discrimination of iatrogenic from illness-specific etiologies, and pharmacologic strategies to manage cognitive problems in patients with bipolar disorder. METHODS A selective literature review was performed focusing on studies of descriptive phenomenology and pharmacologic intervention (favoring randomized comparisons when existent but open trials or case reports when not) involving cognition in bipolar disorder populations, healthy volunteers, or other clinical populations. Identification was made of (i) practical strategies for clinical assessment and management of cognitive complaints, (ii) limitations of existing intervention studies, and (iii) recommendations for the design and direction of future research. RESULTS Cognitive deficits involving attention, executive function, and verbal memory are evident across all phases of bipolar disorder. Most existing treatment studies involve nonbipolar populations, prompting caution when extrapolating outcomes to individuals with bipolar disorder. Differentiating medication- from illness-induced cognitive dysfunction requires comprehensive assessment with an appreciation for the cognitive domains most affected by specific medications. No current pharmacotherapies substantially improve cognition in bipolar disorder, although preliminary findings suggest some potential value for adjunctive stimulants such as modafinil and novel experimental agents. CONCLUSIONS Circumscribed cognitive deficits may be both iatrogenic and intrinsic to bipolar disorder. Optimal management hinges on a knowledge of illness-specific cognitive domains as well as of the beneficial or adverse cognitive profiles of common psychotropic medications.

Consistency of remission and outcome in bipolar and unipolar mood disorders: a 10-year prospective follow-up

BACKGROUND Previous studies of the natural course of bipolar disorder have suggested that relapse and psychosocial impairment are more common than many would expect during treatment under routine conditions. The present research sought to identify patterns of consistency in longitudinal recovery after an index manic or depressive episode in patients formerly hospitalized for major affective disorders. The data extend prior findings from the Chicago Follow-up Study involving four successive assessments of course and outcome for bipolar and unipolar patients over a 10-year follow-up interval. METHODS Thirty-four RDC bipolar I manic, 17 psychotic unipolar depressed, and 72 nonpsychotic unipolar depressed patients were assessed at index hospitalization and prospectively followed-up at 2, 4.5, 7.5 and 10 years. Psychosocial functioning, rehospitalization, and overall outcome were rated by standardized instruments. Patterns of consistent remission or impairment in functioning were compared across follow-up periods. RESULTS Consistently good functioning was observed more often among patients with unipolar nonpsychotic depression than bipolar disorder or unipolar psychotic depression. Psychosis at index hospitalization was not associated with poorer outcomes for either the bipolar or unipolar groups, although it significantly predicted psychosis at follow-up more robustly for unipolar than bipolar patients. Less than half of the bipolar cohort had good work performance at each follow-up, while unipolar nonpsychotic depressed patients had consistently better work functioning. Rehospitalization was more common for the bipolar than unipolar patients at the 4.5- and 7.5-year assessments. Sustained remission across follow-ups was associated with remission at subsequent follow-ups regardless of diagnostic polarity at index hospitalization. LIMITATIONS The observational design, small sample size, and naturalistic treatment of subjects in this protocol prompts caution when interpreting treatment outcome findings. The availability of a bipolar cohort with relatively low attrition over a 10-year period may limit the generalizability of the current findings to patients who remain engaged in sustained contact with a long-term research program. CONCLUSIONS Over a 10-year follow-up period, about half of bipolar patients show sustained remissions or patterns of improvement, while 30-40% experience some functional decline. The degree of consistency in remission patterns over time may hold greater prognostic significance than the polarity of an index affective episode in anticipating subsequent levels of psychosocial adjustment in severe mood disorders.

Neurocognitive dysfunction and psychosocial outcome in patients with bipolar I disorder at 15-year follow-up

Burdick KE, Goldberg JF, Harrow M. Neurocognitive dysfunction and psychosocial outcome in patients with bipolar I disorder at 15‐year follow‐up.

Prevalence of bipolar symptoms in epilepsy vs other chronic health disorders

Objective: To estimate the comparative prevalence of bipolar symptoms in respondents with epilepsy vs other chronic medical conditions. Methods: The Mood Disorder Questionnaire (MDQ), a validated screening instrument for bipolar I and II symptoms, in conjunction with questions about current health problems, was sent to a sample of 127,800 people selected to represent the US adult population on selected demographic variables. A total of 85,358 subjects (66.8%) aged 18 or older returned the survey and had usable data. Subjects who identified themselves as having epilepsy were compared to those with migraine, asthma, diabetes mellitus, or a healthy comparison group with regard to relative lifetime prevalence rates of bipolar symptoms and past clinical diagnoses of an affective disorder. Results: Bipolar symptoms, evident in 12.2% of epilepsy patients, were 1.6 to 2.2 times more common in subjects with epilepsy than with migraine, asthma, or diabetes mellitus, and 6.6 times more likely to occur than in the healthy comparison group. A total of 49.7% of patients with epilepsy who screened positive for bipolar symptoms were diagnosed with bipolar disorder by a physician, nearly twice the rate seen in other disorders. However, 26.3% of MDQ positive epilepsy subjects carried a diagnosis of unipolar depression, and 25.8% had neither a uni- nor bipolar depression diagnosis. Conclusion: Bipolar symptoms occurred in 12% of community-based epilepsy patients, and at a rate higher than in other medical disorders. One quarter were unrecognized.

Association Between Bipolar Spectrum Features and Treatment Outcomes in Outpatients With Major Depressive Disorder

CONTEXT It has been suggested that patients with major depressive disorder (MDD) who display pretreatment features suggestive of bipolar disorder or bipolar spectrum features might have poorer treatment outcomes. OBJECTIVE To assess the association between bipolar spectrum features and antidepressant treatment outcome in MDD. DESIGN Open treatment followed by sequential randomized controlled trials. SETTING Primary and specialty psychiatric outpatient centers in the United States. PARTICIPANTS Male and female outpatients aged 18 to 75 years with a DSM-IV diagnosis of nonpsychotic MDD who participated in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study. INTERVENTIONS Open treatment with citalopram followed by up to 3 sequential next-step treatments. MAIN OUTCOME MEASURES Number of treatment levels required to reach protocol-defined remission, as well as failure to return for the postbaseline visit, loss to follow-up, and psychiatric adverse events. For this secondary analysis, putative bipolar spectrum features, including items on the mania and psychosis subscales of the Psychiatric Diagnosis Screening Questionnaire, were examined for association with treatment outcomes. RESULTS Of the 4041 subjects who entered the study, 1198 (30.0%) endorsed at least 1 item on the psychosis scale and 1524 (38.1%) described at least 1 recent maniclike/hypomaniclike symptom. Irritability and psychoticlike symptoms at entry were significantly associated with poorer outcomes across up to 4 treatment levels, as were shorter episodes and some neurovegetative symptoms of depression. However, other indicators of bipolar diathesis including recent maniclike symptoms and family history of bipolar disorder as well as summary measures of bipolar spectrum features were not associated with treatment resistance. CONCLUSION Self-reported psychoticlike symptoms were common in a community sample of outpatients with MDD and strongly associated with poorer outcomes. Overall, the data do not support the hypothesis that unrecognized bipolar spectrum illness contributes substantially to antidepressant treatment resistance.

Neurocognition as a stable endophenotype in bipolar disorder and schizophrenia.

Linkage and association studies have paid increasing attention to neurocognition as a putative endophenotype. However, there exists little documentation of its trait stability in schizophrenia or bipolar disorder. Our aim was to determine the longitudinal stability of neurocognitive performance in bipolar versus schizophrenia probands. We administered a neurocognitive battery at two time points, approximately 5 years apart, in 16 schizophrenia and 16 bipolar disorder age-matched subjects. There were no significant changes over time on variables including education, estimated IQ, depression, psychosis, global functioning, or medication status. Schizophrenia subjects showed significant deterioration in one measure of executive functioning but no significant changes in seven of eight other domains. Bipolar patients showed stability over time in attentional measures but greater variability in other domains. These preliminary findings suggest that neurocognitive domains appear longitudinally stable across broad domains in schizophrenia. In contrast, stable functioning may be more limited to attentional domains in bipolar disorder.

Correlates of suicidal ideation in dysphoric mania

BACKGROUND Previous investigations have reported that suicidal ideation and behavior are more prevalent during mixed than pure mania. Uncertainties exist about whether suicidality in mania arises from multiple concurrent depressive symptoms, or rather, as a categorical phenomenon, reflecting dysphoria without necessarily a full major depression. To elucidate the relationship between suicidal ideation and dysphoric mania, we analyzed clinical and demographic features associated with suicidal versus nonsuicidal dysphoric manic inpatients. METHODS Records were reviewed for 100 DSM-III-R bipolar I manic inpatients at the Payne Whitney Clinic of New York Hospital from 1991-1995. All had > or = 2 concomitant depressive symptoms (other than suicidality). Affective and psychotic symptoms, past suicide attempts, prior illness, and related clinical/demographic variables were assessed by a standardized protocol. RESULTS Suicidal ideation was significantly more common among dysphoric manics who were caucasian, took antidepressant medications in the week prior to admission, had histories of alcohol abuse/dependence, and made past suicide attempts. Suicidal ideation was evident for nearly half of dysphoric manic patients with < or = 3 depressive symptoms who did not meet DSM criteria for a mixed state. No individual manic or depressive symptoms other than dysphoric mood were more common among suicidal than nonsuicidal patients. LIMITATIONS Findings from this retrospective study require confirmation using a prospective assessment. Treatments were naturalistic and may have differentially influenced hospital course and illness characteristics. Factors related to suicide attempts (rare in this cohort) or completions (not a focus of this study) may differ from those related only to suicidal ideation. CONCLUSIONS Caucasian dysphoric manic patients with past suicide attempts and substance abuse may have a significantly elevated risk for suicidality, even when full major depression does not accompany mania. Suicidality is a clinically important consideration in a majority of dysphoric manic patients.