Michael E. Thase

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Our primary aim was to describe unique correlates of functioning in bipolar disorder (BD). The study included the first 500 patients enrolled in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD). Patients were 41.9 +/- 12.7 years old, and diagnosed with bipolar I, II or NOS, verified by structured interview. Overall functionality was determined by the Range of Impaired Function Tool (LIFE-RIFT). Stepwise multiple regression analysis tested the non-redundant-independent-association of 28 variables on functioning. Severity of depression symptoms was significantly and uniquely correlated with impaired functioning in the context of a wide variety of demographic and clinical variables, contributing 60.9% to the total variance in overall functioning (ss = 0.254, p = 0.0001). Substantial variance in function remains unexplained. Intensity of depressive symptoms is the major determinant of impaired functioning in bipolar disorder, but longitudinal analyses may further explain the substantial variance in function not explained by this large and comprehensive model. Treatments and outcome assessment for patients with bipolar disorders should consider both functional and symptomatic change.

Two parallel, 8-week double-blind studies compared olanzapine/fluoxetine combination, olanzapine, and fluoxetine in outpatients with treatment-resistant depression (TRD). Treatment-resistant depression was defined as a documented history of current-episode antidepressant failure plus a prospective failure on fluoxetine. Following an 8-week fluoxetine lead-in, 605 nonresponders with DSM-IV major depressive disorder were randomly assigned to olanzapine/fluoxetine combination, olanzapine, or fluoxetine. The primary outcome measure was baseline-to-endpoint mean change on the Montgomery-Asberg Depression Rating Scale (MADRS). The study was conducted from April 2002 to May 2005. After 8 weeks of double-blind treatment, Study 1 revealed no statistically significant therapy differences in MADRS mean change (olanzapine/fluoxetine combination: -11.0, fluoxetine: -9.4, olanzapine: -10.5). In Study 2, olanzapine/fluoxetine combination demonstrated significantly greater MADRS improvement (-14.5) than fluoxetine (-8.6, p < .001) and olanzapine (-7.0, p < .001). Pooled study results revealed significant differences for olanzapine/ fluoxetine combination (-12.7) versus fluoxetine (-9.0, p < .001) and olanzapine (-8.8, p < .001). Pooled remission rates were 27% for olanzapine/ fluoxetine combination, 17% for fluoxetine, and 15% for olanzapine. Adverse events were consistent with previous studies. Cholesterol mean change (mg/dL) was +15.1 for olanzapine/ fluoxetine combination, +0.8 for fluoxetine, and +2.7 for olanzapine. Mean weight change (kg) was +4.9 for olanzapine/fluoxetine combination, +0.4 for fluoxetine, and +5.5 for olanzapine. Nonfasting glucose mean change (mg/dL) was +11.4 for olanzapine/fluoxetine combination, +4.9 for fluoxetine, and +9.9 for olanzapine. Patients with TRD (defined as treatment failure on 2 antidepressants) taking olanzapine/fluoxetine combination demonstrated significantly greater improvement in depressive symptoms than patients taking olanzapine or fluoxetine in 1 of 2 studies and in the pooled analysis. When considered within the context of all available evidence, olanzapine/fluoxetine combination is an efficacious therapy for patients with TRD. ClinicalTrials.gov identifier: NCT00035321.

This study evaluated the efficacy and tolerability of quetiapine monotherapy for depressive episodes in patients with bipolar I or II disorder (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition) who were randomized to 8 weeks of double-blind treatment with quetiapine (300 or 600 mg/d; once daily, evening dosing) or placebo. Patients were assessed weekly using the Montgomery-Asberg Depression Rating Scale (MADRS) and Hamilton Depression Rating Scale (HAM-D). The primary end point was change in MADRS total score from baseline to Week 8 (analysis of covariance/last-observation-carried-forward analysis). Of 509 patients randomized, 59% completed the study. Improvements from baseline in mean MADRS total scores were significantly greater with quetiapine 300 and 600 mg/d than with placebo from first evaluation (Week 1) through Week 8 (both P <or= 0.001 vs. placebo). Therapeutic effect sizes at Week 8 were 0.61 and 0.54 for quetiapine 300 and 600 mg/d, respectively. Improvements in mean HAM-D scores were also significantly greater with both quetiapine doses than with placebo (P < 0.001) as early as Week 1 and throughout the study. The MADRS response and remission rates were also significantly greater in both quetiapine dose groups compared with placebo. Improvements in primary and secondary outcomes were observed with both 300 and 600 mg/d quetiapine without major differences between the doses. Common adverse events included dry mouth, sedation, somnolence, dizziness, and constipation. The incidence of treatment-emergent mania or hypomania was lower with quetiapine treatment than placebo. This study demonstrates that quetiapine monotherapy is an effective and well-tolerated treatment for depressive episodes in bipolar disorder, confirming the results observed from a previous study (BipOLar DEpRession [BOLDER] I).

Depression is increasingly recognized as a highly recurrent and potentially chronic illness that imposes a substantial burden on individuals, families, and society. Evidence indicates that the risks of depressive recurrence, treatment resistance, and chronicity increase as the illness becomes more highly recurrent. Up to 1 year of continuation phase therapy is now recommended for virtually all depressed patients who respond to antidepressants, with a longer course of maintenance phase pharmacotherapy recommended for those who have experienced multiple episodes. Antidepressants, when effective during the acute phase of therapy, reduce the risk of depressive relapse (continuation phase) and recurrence (maintenance phase) by at least 50%. Longer-term antidepressant pharmacotherapy is most effective when the full dose of medication effective during acute-phase treatment is continued. As combined treatment with antidepressants and psychotherapy may improve shorter-term outcomes for patients with more severe recurrent depression, ongoing combined therapy may be indicated, especially for patients at particularly high risk. Approximately 5% to 10% of patients maintained on antidepressants relapse yearly, leading some to implicate tachyphylaxis. However, before attributing relapse or recurrence to diminished responsiveness to antidepressant medication at the neurochemical level, clinicians should ensure that the patient has been adherent to therapy as prescribed and consider other explanations.

Bipolar affective disorder is a virulent illness with high rates of recurrence, disability, social impairment, and suicide. Although the manic or hypomanic episodes define the disorder, the depressions are more numerous and less responsive to treatment. As the initial depressive episodes are commonly misdiagnosed, initiation of therapy with mood stabilizers is often delayed, increasing the likelihood of treatment-emergent affective switches on antidepressant monotherapy. The empirical basis for selecting treatments for people with bipolar depression is weak, and only the combination of olanzapine and fluoxetine has received US Food and Drug Administration (FDA) approval. Conventional mood stabilizers are preferred for first-line therapies, although atypical antipsychotics are increasingly used, and FDA approval of quetiapine is pending. Antidepressants—particularly selective serotonin reuptake inhibitors and bupropion— are indicated when mood stabilizers are ineffective and for “breakthrough“ depressions.

Akiskal and Tohen's Bipolar Psychopharmacotherapy aims to provide an up-to-date and comprehensive review of the principal treatments for bipolar affective disorder. Also known as manic depression, bipolar affective disorder has been ranked by the World Health Organization as the eighth greatest cause of global illness in industrialized nations. The disorder often appears early in life (the median age at onset is 19 years), and although useful therapies have been available for decades, rates of recurrence are high. The disease is chronic and associated with extremely high levels of disability and morbidity, as well as increased risks of death from suicide and cardiovascular disease. The two main forms of bipolar affective disorder (type I and type II, defined according to whether the “up” episodes are manic or hypomanic) affect about 4% of the population of industrialized countries. Moreover, even though the concept of a spectrum of bipolar disorders is still somewhat controversial, up to 50% of persons with so-called unipolar depression have symptoms suggestive of bipolarity. Given the ubiquity of depression and the potential that antidepressants have to worsen unrecognized bipolar disorder, a book that provides authoritative reviews of recent advances in the treatment of bipolar disorder should be of interest to all health care professionals.

This review examines the relationship between sleep and depression. Most depressive disorders are characterized by subjective sleep disturbances, and the regulation of sleep is intricately linked to the same mechanisms that are implicated in the pathophysiology of depression. After briefly reviewing …