Anti-anhedonic effect of ketamine and its neural correlates in treatment-resistant bipolar depression.

Anhedonia--which is defined as diminished pleasure from, or interest in, previously rewarding activities-is one of two cardinal symptoms of a major depressive episode. However, evidence suggests that standard treatments for depression do little to alleviate the symptoms of anhedonia and may cause reward blunting. Indeed, no therapeutics are currently approved for the treatment of anhedonia. Notably, over half of patients diagnosed with bipolar disorder experience significant levels of anhedonia during a depressive episode. Recent research into novel and rapid-acting therapeutics for depression, particularly the noncompetitive N-Methyl-D-aspartate receptor antagonist ketamine, has highlighted the role of the glutamatergic system in the treatment of depression; however, it is unknown whether ketamine specifically improves anhedonic symptoms. The present study used a randomized, placebo-controlled, double-blind crossover design to examine whether a single ketamine infusion could reduce anhedonia levels in 36 patients with treatment-resistant bipolar depression. The study also used positron emission tomography imaging in a subset of patients to explore the neurobiological mechanisms underpinning ketamine's anti-anhedonic effects. We found that ketamine rapidly reduced the levels of anhedonia. Furthermore, this reduction occurred independently from reductions in general depressive symptoms. Anti-anhedonic effects were specifically related to increased glucose metabolism in the dorsal anterior cingulate cortex and putamen. Our study emphasizes the importance of the glutamatergic system in treatment-refractory bipolar depression, particularly in the treatment of symptoms such as anhedonia

Evidence for genetic association of RORB with bipolar disorder

<p>Abstract</p> <p>Background</p> <p>Bipolar disorder, particularly in children, is characterized by rapid cycling and switching, making circadian clock genes plausible molecular underpinnings for bipolar disorder. We previously reported work establishing mice lacking the clock gene D-box binding protein (<it>DBP</it>) as a stress-reactive genetic animal model of bipolar disorder. Microarray studies revealed that expression of two closely related clock genes, <it>RAR</it>-related orphan receptors alpha (<it>RORA</it>) and beta (<it>RORB</it>), was altered in these mice. These retinoid-related receptors are involved in a number of pathways including neurogenesis, stress response, and modulation of circadian rhythms. Here we report association studies between bipolar disorder and single-nucleotide polymorphisms (SNPs) in <it>RORA </it>and <it>RORB</it>.</p> <p>Methods</p> <p>We genotyped 355 <it>RORA </it>and <it>RORB </it>SNPs in a pediatric cohort consisting of a family-based sample of 153 trios and an independent, non-overlapping case-control sample of 152 cases and 140 controls. Bipolar disorder in children and adolescents is characterized by increased stress reactivity and frequent episodes of shorter duration; thus our cohort provides a potentially enriched sample for identifying genes involved in cycling and switching.</p> <p>Results</p> <p>We report that four intronic <it>RORB </it>SNPs showed positive associations with the pediatric bipolar phenotype that survived Bonferroni correction for multiple comparisons in the case-control sample. Three <it>RORB </it>haplotype blocks implicating an additional 11 SNPs were also associated with the disease in the case-control sample. However, these significant associations were not replicated in the sample of trios. There was no evidence for association between pediatric bipolar disorder and any <it>RORA </it>SNPs or haplotype blocks after multiple-test correction. In addition, we found no strong evidence for association between the age-at-onset of bipolar disorder with any <it>RORA </it>or <it>RORB </it>SNPs.</p> <p>Conclusion</p> <p>Our findings suggest that clock genes in general and <it>RORB </it>in particular may be important candidates for further investigation in the search for the molecular basis of bipolar disorder.</p

Rapid and non-rapid cycling bipolar disorder:A meta-analysis of clinical studies

Background: Rapid cycling, defined as 4 or more mood episodes per year, is a course specifier of bipolar disorder associated with relative treatment resistance. Several risk factors have been suggested to be associated with rapid cycling. The purpose of this meta-analysis was to compare clinical studies for the evidence of discriminating factors between rapid and non-rapid cycling. Data Sources and Selection: We searched MEDLINE and reference lists of articles and book chapters and selected all of the clinical studies published from 1974 to 2002 comparing subjects with rapid and non-rapid cycling bipolar disorder. Prevalence rates and mean random effect sizes for 18 potential risk factors that were reported by at least 3 studies were calculated. In addition, we differentiated between current and lifetime diagnoses of rapid cycling. Data Synthesis: Twenty studies were identified. Rapid cycling was present in 16.3% of 2054 bipolar patients in 8 studies that included patients who were consecutively admitted to an inpatient or outpatient facility, without a priori selection of rapid cyclers and without matching the numbers of rapid cyclers to non-rapid cycling controls. Female gender and bipolar II subtype both had a small, but statistically significant, effect (p <.000 for female gender, p <.001 for bipolar 11 subtype). The further absence of recurrences with lithium prophylaxis was reported in 34% of rapid cyclers compared with 47% of non-rapid cyclers, a nearly significant difference, and a partial response was present in 59% and 65% of patients, respectively. The effect of hypothyroidism was significant (p <.01) in studies using current, but not lifetime, definitions of rapid cycling. In 46% of cases, a rapid cycling course was preceded by treatment with antidepressants, but systematic data on their causal role are lacking. Conclusion: Rapid cycling is slightly more prevalent in women and in patients with bipolar II subtype. In contrast to common opinion, lithium prophylaxis has at least partial efficacy in a considerable number of rapid cyclers, especially when antidepressants are avoided. Hypothyroidism may be associated with mood destabilization in vulnerable patients

Preliminary observations on the effectiveness of levetiracetam in the open adjunctive treatment of refractory bipolar disorder

Objective: Levetiracetam is a recently approved, well-tolerated anticonvulsant with a unique mechanism of action yielding efficacy in treatment-refractory seizure disorders and positive effects in an animal model of mania. Given the effectiveness of a range of other anticonvulsants in bipolar disorder, we sought to evaluate levetiracetam in patients with treatment-resistant illness. Method: Thirty-four patients received 500 to 1000 mg of levetiracetam titrated to a target dose of 2000 mg/day (maximum dose = 3000 mg/day) as open, adjunctive treatment for clinically significant symptoms of depression (N = 13), mania (N = 7), or cycling (N = 14) despite ongoing treatment with mood stabilizers. Inventory for Depressive Symptomatology-Clinician version (IDS-C), Young Mania Rating Scale (YMRS), and Clinical Global Impressions scale for use in Bipolar Illness ratings were completed at each visit for 8 weeks, and partial responders were offered continuation treatment. Data were collected from July 2001 to December 2002. Results: Five of 16 (31%; 13 depressed, 3 cycling) patients with initial depressive symptoms met the criterion for remission (IDS-C score of: 13) at last observation. All of these patients were less severely ill at baseline, whereas none of those more severely depressed at baseline responded. The majority of the 16 patients (7 manic, 9 cycling) with manic symptoms at baseline showed improvement in the YMRS in the first 2 weeks. While 7 of the 16 (44%) patients met the criterion for manic response and remission at last observation, 4 showed intervening periods of moderate to marked exacerbation. Levetiracetam was weight neutral. Conclusion: Other pilot trials should explore possible areas of psychotropic action of levetiracetam prior to the conduct of more controlled clinical trials

Comparison of rapid-cycling and non-rapid-cycling bipolar disorder based on prospective mood ratings in 539 outpatients

Objective: To detect risk factors for rapid cycling in bipolar disorder, the authors compared characteristics of rapid-cycling and non-rapid-cycling patients both from a categorical and a dimensional perspective. Method: Outpatients with bipolar I disorder (N = 419), bipolar II disorder (N = 104), and bipolar disorder not otherwise specified (N = 16) were prospectively evaluated with daily mood ratings for 1 year. Subjects were classified as having rapid cycling (defined by the DSM-IV criterion of four or more manic or depressive episodes within 1 year) or not having rapid cycling, and the two groups' demographic and retrospective and prospective illness characteristics were compared. Associated factors were also evaluated in relationship to episode frequency. Results: Patients with rapid cycling (N = 206; 38.2%) significantly differed from those without rapid cycling (N = 333) with respect to the following independent variables: history of childhood physical and/or sexual abuse, bipolar I disorder subtype, number of lifetime manic or depressive episodes, history of rapid cycling, and history of drug abuse. The prevalence of these characteristics increased progressively with episode frequency. The proportion of women was greater than the proportion of men only among patients with eight or more episodes per year. The average time spent manic/hypomanic increased as a function of episode frequency, but the average time spent depressed was comparable in patients with one episode and in those with more than one episode. Brief episodes were as frequent as full-duration DSM-IV-defined episodes. Conclusions: A number of heterogeneous risk factors were progressively associated with increasing episode frequency. Depression predominated in all bipolar disorder patients, but patients with rapid cycling were more likely to be characterized by manic features. The findings overall suggest that rapid cycling is a dimensional course specifier arbitrarily defined on a continuum of episode frequency