The evolution of the concept of bipolar disorder

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Long-term naturalistic treatment of depressive symptoms in bipolar illness with divalproex vs. lithium in the setting of minimal antidepressant use.

OBJECTIVE: Risks have been associated with the long-term use of antidepressant in the treatment of bipolar disorder. We review our naturalistic experience with divalproex versus lithium in treating depressive symptoms of bipolar illness. METHOD: All patients with bipolar disorder treated with lithium or divalproex were identified in a university outpatient psychiatry clinic sample over one year (n=38 patients, 41 treatment trials). Treatment response was based on standard prospective symptom rating scales. Mean duration of follow-up was 90 weeks. RESULTS: Lithium and divalproex were equally effective and tolerated in the total sample. Antidepressant effects were noted despite sparing use of standard antidepressant agents (19% received them). Lithium non-responders responded well to divalproex (50%), and vice versa (44%). Divalproex monotherapy (24%) was more common than lithium monotherapy (7%, P=0.07) and was notably effective in treating depressive symptoms, with a 7/10 response on the CGI-BP and improvement on the HDRS (14.8+/-9.2 to 7.6+/-7.8, P=0.003, duration of prospective follow up 26.7 weeks). CONCLUSIONS: Lithium and divalproex were equally effective and tolerated in this naturalistic sample, but responders may represent distinct subgroups. Both agents, but particularly divalproex, demonstrated long-term antidepressant effects, with limited adjunctive standard antidepressant use.

Gabapentin treatment of the non-refractory bipolar spectrum: an open case series.

OBJECTIVE: To determine if gabapentin is effective in monotherapy or add-on treatment of non-refractory bipolar disorder in open prospective treatment. METHODS: Charts of 21 outpatients meeting DSM-IV criteria for bipolar spectrum disorder (type I, type II, NOS, and cyclothymia) and who were treated with gabapentin were reviewed and clinical response was assessed based on prospective application of the Hamilton Depression Rating Scale (HDRS), the Young Mania Rating Scale (YMRS), the Clinical Global Impression scale (CGI), and the Global Assessment of Functioning scale (GAF). Also, response was rated retrospectively using the Clinical Global Impression scale for Bipolar Disorder (CGI-BP). RESULTS: Eight patients received gabapentin monotherapy and 13 received adjunctive therapy. Similar improvement in depression was noted in the monotherapy group, without induction of mania. Gabapentin was associated with a 43.8% improvement in manic symptoms and a 27.6% improvement in depressive symptoms in the overall sample. In the depressed subsample (n=10), there was a 57.5% improvement in depressive symptoms (P=0.10). Using the CGI-BP, gabapentin was moderately to markedly effective in 43% of patients for overall bipolar illness, 38% for depressive symptoms, and 25% for manic symptoms. Of those in the study, 62% reported side effects, mainly sedation and nausea, with 14% of the total sample discontinuing treatment due to adverse events. CONCLUSIONS: Gabapentin, either alone or as an adjunct, appeared moderately effective in treating depression in this small, uncontrolled, heterogeneous sample of non-refractory bipolar spectrum illness. Coupled with the earlier clinical literature, these data suggest the need for prospective double-blind studies of depressive illness in the bipolar spectrum.

Topiramate treatment of bipolar spectrum disorders: a retrospective chart review.

The objective of this paper was to determine if topiramate is effective as treatment for bipolar spectrum disorders in a naturalistic setting. All charts of outpatients treated with topiramate (n = 76) were reviewed, and clinical response was assessed retrospectively using the Clinical Global Impressions Scale for Improvement. Mild improvement was seen in 47% (n = 36) and moderate-to-marked improvement in 13% (n = 10). Responders received a higher mean dose (180 mg/day) than did nonresponders (83.2 mg/day, p = 0.002). Topiramate dose was also higher in those who lost weight (138.3 mg/day) than in those who did not (70 mg/day, p = 0.007). Weight loss was experienced by 50% of the sample, with a mean loss of 14.2 lbs. Side effects were reported by 82% (n = 62) of the population, including cognitive effects, sedation, parasthesias, nausea, insomnia, headache, and dizziness. Adverse effects led 36% (n = 27) of the total sample to discontinue treatment with topiramate. Topiramate led to significant weight loss in about half of this bipolar population, while also improving mood symptoms at least mildly in most patients. Topiramate response and weight loss were both dose-related, with efficacy, in particular, associated with higher doses (mean = 180 mg/day) than frequently used in current clinical practice.

The bipolar spectrum and the antidepressant view of the world.

Whereas much progress has been made in the diagnosis and treatment of schizophrenia and depression in recent years, bipolar disorder continues to be frequently misunderstood, leading to its inconsistent diagnosis and treatment. In this article, we seek to identify the causes of this problem and suggest possible solutions, based on a critical review of studies concerning the nosology of bipolar disorder and the effects of antidepressant agents. Bipolar disorder appears to be underdiagnosed as well as frequently misdiagnosed as unipolar major depressive disorder. Underdiagnosis can stem from patients' impaired insight into mania and failure to involve family members in the diagnostic process and also from clinicians' inadequate understanding of manic symptoms. Underdiagnosis may also reflect disagreement about the breadth of the bipolar spectrum. We therefore propose a heuristic definition of "bipolar spectrum disorder," a diagnosis that gives greater weight to family history and antidepressant-induced manic symptoms. This diagnosis would include all forms of bipolar illness that are not type I or II . The evidence also suggests that antidepressants are probably overused and mood stabilizers underused. We consequently recommend aggressive use of mood stabilizers and less emphasis on antidepressants. In summary, the state of diagnosis and treatment in bipolar disorder is suboptimal. More diagnostic attention to the criteria for mania is necessary. In addition, the current pattern of antidepressant use in bipolar disorder does not appear to be evidence-based.

Diagnosing bipolar disorder and the effect of antidepressants: a naturalistic study.

OBJECTIVES: To determine if bipolar disorder is accurately diagnosed in clinical practice and to assess the effects of antidepressants on the course of bipolar illness. METHOD: Charts of outpatients with affective disorder diagnoses seen in an outpatient clinic during 1 year (N = 85 with bipolar or unipolar disorders) were reviewed. Past diagnostic and treatment information was obtained by patient report and systematic psychiatric history. Bipolar diagnosis was based on DSM-IV criteria using a SCID-based interview. RESULTS: Bipolar disorder was found to be misdiagnosed as unipolar depression in 37% of patients who first see a mental health professional after their first manic/hypomanic episode. Antidepressants were used earlier and more frequently than mood stabilizers, and 23% of this unselected sample experienced a new or worsening rapid-cycling course attributable to antidepressant use. CONCLUSION: These results suggest that bipolar disorder tends be misdiagnosed as unipolar major depressive disorder and that antidepressants seem to be associated with a worsened course of bipolar illness. However, this naturalistic trial was uncontrolled, and more controlled research is required to confirm or refute these findings.

Insight and outcome in bipolar, unipolar, and anxiety disorders.

We performed a study to assess the relationship between impairment of insight and the long-term outcome in affective and anxiety disorders. Standardized insight assessments were made using the Scale to Assess Unawareness of Mental Disorder (SUMD) in 101 outpatients with psychiatric disorders, mostly affective and anxiety disorders, treated over 1 year in a university-based clinic. Outcome was prospectively assessed with the Clinical Global Impression (CGI) and Global Assessment of Functioning (GAF) rating scales. The mean follow-up period was 3.9 months. Initial impairment of insight did not correlate with poor outcome. However, improvement in insight correlated with good outcome, particularly in bipolar disorder type I (r = .56 to .67, P = .0005). Insight was similarly impaired in bipolar and unipolar major depressive disorders, and more so than in anxiety disorders (P = .002). An association between a lack of improvement in insight and a poor outcome, most significantly in bipolar disorder type I, was observed in this sample. We found a greater relative impairment of insight in mood versus anxiety disorders.

Cholesterol levels in mood disorders: high or low?

OBJECTIVES: To assess cholesterol levels in patients with mood disorders. METHODS: All consecutively admitted patients meeting inclusion criteria (n = 50) who were hospitalized in an affective disorders unit received assessments of cholesterol levels. Correlations were made with diagnosis using DSM-IV criteria, current mood states, and other clinical and demographic features of illness. Exclusion criteria included current alcohol abuse, medical illnesses that could influence cholesterol levels, eating disorders, and age greater than 70 years. RESULTS: Cholesterol levels did not differ based on diagnostic status of unipolar depression or bipolar disorder. In the total sample, cholesterol levels were lower in patients with current manic (170.2 +/- 38.9, p = 0.05) and depressive (182.0 +/- 42.0) than in mixed (226.4 +/- 43.3) episodes (p = 0.05). In subgroups of patients with bipolar disorder, manic episodes (169.9 +/- 38.8, n = 9) were associated with lower cholesterol levels than depressive (201.0 +/- 49.4) or mixed (226.4 +/- 44.4) episodes (p = 0.02 for comparison of manic and mixed episodes). Body mass index (BMI), age, alcohol use, and gender did not account for these findings. CONCLUSIONS: Cholesterol levels were lower in manic and depressive than in mixed episodes. No differences were found between diagnoses of unipolar or bipolar mood disorders. Cholesterol may be a state rather than a trait function, and may be influenced by the acute mood state.

Does olanzapine have antidepressant properties? A retrospective preliminary study.

OBJECTIVE: Mood-stabilizing agents are ideally conceptualized as possessing antimanic and antidepressant properties. While research on olanzapine's antimanic effects is growing, data on its possible antidepressant properties are limited. We sought to determine if olanzapine is effective in the add-on treatment of major affective disorders, particularly depressive symptoms, in a naturalistic setting. METHODS: All charts of patients meeting DSM-IV criteria for bipolar disorder or unipolar major depressive disorder treated with olanzapine in a private psychiatric practice were reviewed and clinical response was assessed retrospectively using the Clinical Global Impression Scale for Improvement (CGI-I). RESULTS: Olanzapine was moderately effective in 6/10 (60%) patients. Side-effects were present in 8/10 (80%), most commonly weight gain. CONCLUSIONS: Olanzapine appears to be moderately effective in open add-on treatment in patients with mainly depressive symptoms. Accumulating evidence suggests that olanzapine, and atypical antipsychotics in general, possess mild to moderate adjunctive antidepressant properties.

What is to be done? Controversies in the diagnosis and treatment of manic-depressive illness.

BACKGROUND: In recent years, much progress has been made in the diagnosis and treatment of schizophrenia and depression. Bipolar disorder, however, remains frequently misunderstood, leading to inconsistent diagnosis and treatment. Why is the case? What is to be done about it? METHODS: We critically review studies in the nosology of bipolar disorder and the effects of antidepressant agents. RESULTS: Bipolar disorder is underdiagnosed and frequently misdiagnosed as unipolar major depressive disorder. Antidepressants are probably overused and mood stabilisers underused. Reasons for underdiagnosis include patients' impaired insight into mania, failure to involve family members in the diagnostic process, and inadequate understanding by clinicians of manic symptoms. We propose using a mnemonic to aid in diagnosis, obtaining family report, and utilising careful clinical interviewing techniques given the limitations of patients' self-report. We recommend aggressive use of mood stabilisers, and less emphasis on antidepressants. CONCLUSIONS: The state of diagnosis and treatment in bipolar disorder is suboptimal. More diagnostic attention to manic criteria is necessary and the current pattern of use of antidepressant use in bipolar disorder needs to change.

Use of atypical antipsychotic agents in bipolar and schizoaffective disorders: review of the empirical literature.

Atypical antipsychotic agents seem to be effective treatments for bipolar disorder, especially as adjunctive treatments. They may be a safer and more effective alternative to the common practice of maintenance adjunctive treatment with traditional antipsychotic agents in patients with bipolar disorder. However, currently available research studies are limited methodologically mainly to open-label, uncontrolled designs. Further research is required before the definitive efficacy of these agents in bipolar disorder is established. If randomized or double-blind data support the open-label data reviewed here, atypical antipsychotic agents may possess an important role in the adjunctive treatment of bipolar disorder.

Cognitive-behavioral group therapy with medication for depressed gay men with AIDS or symptomatic HIV infection.

OBJECTIVE: The feasibility and effectiveness of a combination of group cognitive-behavioral therapy and medication for the treatment of depression among gay men with AIDS or symptomatic HIV infection were evaluated. METHODS: Fifteen patients diagnosed with DSM-IV major depressive disorder or dysthymia were treated in one of two weekly therapy groups in which cognitive-behavioral therapy had been specially modified for the target population. The majority of these patients, including two who had been on medication before joining the groups, also received antidepressant medication. Thirteen of the 15 patients completed therapy, attending an average of 15 of the 20 therapy sessions. RESULTS: The group cognitive-behavioral therapy used in this project appeared to be attractive to most patients; retention, attendance, and therapy compliance were good. Depression scores showed substantial decreases from pre- to posttherapy, with further decreases at one-year follow-up. Patients' self-reports indicated that some aspects of the intervention, particularly the focus on cognitive restructuring, were especially valuable in alleviating their depression. CONCLUSIONS: The modified group cognitive-behavioral therapy described in this study report offers a reasonable option for treatment of this clinically challenging group of patients.

Anticonvulsant therapy and suicide risk in affective disorders.

Patients with major affective disorders are more likely to complete suicide than patients in any other medical group. Established risk factors for completed suicide in affective disorders include acute depression (with turmoil, hopelessness, global insomnia, anhedonia, anxiety and/or panic), mixed episodes, rapid cycling, substance abuse, aggression and/or impulsivity, low serotonergic activity, and hypothalamic-pituitary-adrenal axis activation. Although anticonvulsants have mood-stabilizing and antidepressant properties, few data are available on the antisuicide effects of anticonvulsant treatment in manic-depressive patients. On the other hand, as reviewed elsewhere in this issue, massive data have been accumulated on the antisuicide effect of lithium. This article discusses lithium versus anticonvulsants in the prevention of suicide associated with affective disorders and future treatment strategies to reduce this most serious complication of manic-depressive illness.

Kindling and second messengers: an approach to the neurobiology of recurrence in bipolar disorder.

Since bipolar disorder is inherently a longitudinal illness characterized by recurrence and cycling of mood episodes, neurobiological theories involving kindlinglike phenomena appear to possess a certain explanatory power. An approach to understanding kindlinglike phenomena at the molecular level has been made possible by advances in research on second-messenger systems in the brain. The time frame of interest has shifted from the microseconds of presynaptic events to hours, days, months, and even years in the longer duration of events beyond the synapse--through second messengers, gene regulation, and synthesis of long-acting trophic factors. These complex interlocking systems may explain how environmental stress could interact over time with genetic vulnerability to produce illness. In its two sections, this paper will review an approach to understanding two major aspects of the neurobiology of bipolar disorder: kindling phenomena and second-messenger mechanisms. We will suggest that these two fields of research together help explain the biology of recurrence.

The impact of the discovery of lithium on psychiatric thought and practice in the USA and Europe.

The discovery of lithium has had a major impact on modern psychiatry. By launching the psychopharmacology revolution, lithium forced psychiatrists to become more adept at diagnosis. Lithium research has also provided a window into secular changes in bipolar illness which adversely impact response, produced pharmacoeconomic data on the social costs of psychiatric illness, and played a role in the birth of patient-run advocacy movements. In addition, the development of lithium has demonstrated the closely intertwined purposes of clinical and basic research, and the continued importance of research in the clinical setting.

Bipolar disorder.

Bipolar disorder's unique combination of three characteristics - clear genetic diathesis, distinctive clinical features, early availability of an effective treatment (lithium) - explains its special place in the history of psychiatry and its contribution to the current explosive growth of neuroscience. This article looks at the state of the art in bipolar disorder from the vantage point of: (i) genetics (possible linkages on chromosomes 18 and 21q, polygenic hypothesis, research into genetic markers); (ii) diagnosis (new focus on the subjective aspects of bipolar disorder to offset the current trend of underdiagnosis due to overreliance on standardized interviews and rating scales); (iii) outcome (increase in treatment-resistant forms signaling a change in the natural history of bipolar disorder); (iv) pathophysiology (research into circadian biological rhythms and the kindling hypothesis to explain recurrence); (v) treatment (emergence of the anticonvulsants, suggested role of chronic antidepressant treatment in the development of treatment resistance); (vi) neurobiology (evaluation of regulatory function in relation to affective disturbances, role of postsynaptic second-messenger mechanisms, advances in functional neuroimaging); and (vii) psychosocial research (shedding overly dualistic theories of the past to understand the mind and brain as an entity, thus emphasizing the importance of balancing the psychopharmacological and psychotherapeutic approaches). Future progress in the understanding and treatment of bipolar disorder will rely on successful integration of the biological and psychosocial lines of investigation.

Gabapentin treatment of mood disorders: a preliminary study.

OBJECTIVE: To determine if gabapentin is effective either as adjunctive treatment or as monotherapy for major affective disorders in a naturalistic setting. METHOD: All charts of patients meeting DSM-IV criteria for bipolar disorder or unipolar major depressive disorder treated with gabapentin in a private psychiatric practice were reviewed and clinical response was assessed retrospectively using the Clinical Global Impressions scale for Improvement (CGI-I). RESULTS: Gabapentin was moderately to markedly effective in 30% (15/50) of patients, with statistically nonsignificant differences between patients with bipolar disorder type I, bipolar disorder type II and NOS, and unipolar major depressive disorder. 70% reported side effects, mainly sedation, with 16% of the total sample discontinuing treatment due to adverse events. CONCLUSION: Gabapentin appears to be somewhat effective as add-on treatment in a subgroup of patients with mood disorders in a naturalistic setting. Prospective, controlled studies are required to clarify these pilot data.