Inflammation appears relevant to bipolar disorder across several important domains. Further research is warranted to parse the reciprocal associations between inflammation and symptoms, comorbidities, and treatments in bipolar disorder. Studies of this topic among youth are needed and may best serve this purpose.

Objective-The present study examined the relationship between medical burden in bipolar disorder and several indicators of illness severity and outcome. It was hypothesized that illnesses of the endocrine/metabolic system would be associated with greater psychiatric symptom burden and would impact the response to treatment with lithium and valproate.Method-Data were analyzed from two studies evaluating lithium and valproate for rapidcycling presentations of bipolar I and II disorder. General medical comorbidity was assessed by the Cumulative Illness Rating Scale (CIRS). Descriptive statistics and logistic regression analyses were conducted to explore the relationships between medical burden, body mass index (BMI), substance use disorder status, and depressive symptom severity.Results-Of 225 patients enrolled, 41.8% had a recent substance use disorder, 50.7% were male, and 69.8% had bipolar I disorder. The mean age of the sample was 36.8 (SD = 10.8) years old. The mean number of comorbid medical disorders per patient was 2.5 (SD = 2.5), and the mean CIRS total score was 4.3 (SD = 3.1). A significant positive correlation was observed between baseline depression severity and the number of organ systems affected by medical illness (p = 0.04). Illnesses of the endocrine/metabolic system were inversely correlated with remission from depressive symptoms (p = 0.02), and obesity was specifically associated with poorer treatment outcome. For every 1-unit increase in BMI, the likelihood of response decreased by 7.5% [odds ratio (OR) = 0.93, 95% confidence interval (CI): 0.87-0.99; p = 0.02] and the likelihood of remission decreased by 7.3% (OR = 0.93, 95% CI: 0.87-0.99; p = 0.03). The effect of comorbid substance use on the likelihood of response differed significantly according to baseline BMI. The presence of a comorbid substance use disorder resulted in a lower odds of response, but only among patients with a BMI ≥ 23 (p = 0.02).Corresponding author: David E. Kemp, M.D., Case Western Reserve University, 10524 Euclid Avenue, 12 th Floor, Cleveland, OH 44106, USA, Fax: 216-844-2875, kemp.david@gmail.com. Disclosures: DEK has acted as a consultant to Bristol-Myers Squibb and has served on a speakers bureau for AstraZeneca and Pfizer. KG has received grant support and/or honoraria from Abbott, AstraZeneca, and GlaxoSmithKline; has served as a consultant to Schering Plough; and has served on a speakers bureau for Pfizer. SJG has received grant support from AstraZeneca and Eli Lilly & Co. RLF receives or has received research support, acted as a consultant, and/or served on a speakers bureau for Abbott, Addrenex, AstraZeneca, Bristol-Myers Squibb, Forest, GlaxoSmithKline, Johnson & Johnson, Eli Lilly & Co., Neuropharm, Novartis, Organon, Otsuka, Pfizer, Sanofi-aventis, Sepracore, Shire, Solvay, Supernus Pharmaceuticals, Validus, and Wyeth. JRC has received research support, acted as a consultant, and/or served on an advisory board for Abbott, AstraZeneca, Bristol-Myers Squibb, France Foundation, GlaxoSmithKline, Janss...

Objectives-Newer atypical antipsychotics have been reported to cause a lower incidence of extrapyramidal side effects (EPS) than conventional agents. This review is to compare antipsychotic-induced EPS relative to placebo in bipolar disorder (BPD) and schizophrenia.Methods-English-language literature cited in Medline was searched with terms antipsychotics, placebo-controlled trial, and bipolar disorder or schizophrenia and then with antipsychotic (generic/brand name), safety, akathisia, EPS, or anticholinergic use, bipolar mania/depression, BPD, or schizophrenia, and randomized clinical trial. Randomized, double-blind, placebocontrolled, monotherapy studies with comparable doses in both BPD and schizophrenia were included. Absolute risk increase and number needed to treat to harm (NNTH) for akathisia, overall EPS, and anticholinergic use relative to placebo were estimated.Results-Eleven trials in mania, 4 in bipolar depression, and 8 in schizophrenia were included. Haloperidol significantly increased the risk for akathisia, overall EPS, and anticholinergic use in both mania and schizophrenia, with a larger magnitude in mania, an NNTH for akathisia of 4 versus 7, EPS of 3 versus 5, and anticholinergic use of 2 versus 4, respectively Among atypical antipsychotics, only ziprasidone significantly increased the risk for overall EPS and anticholinergic use in both mania and schizophrenia, again with larger differences in mania, an NNTH for overall EPS of 11 versus 19, and anticholinergic use of 5 versus 9. In addition, risks were significantly increased for overall EPS (NNTH = 5) and anticholinergic use (NNTH = 5) in risperidone-treated mania, akathisia in aripiprazole-treated mania (NNTH = 9) and bipolar depression (NNTH = 5), and overall EPS (NNTH = 19) in quetiapine-treated bipolar depression.Conclusions-Bipolar patients, especially in depression, were more vulnerable to having acute antipsychotic-induced movement disorders than those with schizophrenia.The matter of bipolar disorder (BPD) as a risk factor for antipsychotic-induced movement disorders is still inconclusive. Some early studies showed that patients with BPD were more vulnerable to developing tardive dyskinesia (TD) as well as acute extrapyramidal side effects (EPS) than those with schizophrenia, 1-3 but others found that they had a similar risk. 4,5 More recently, in a pooled data analysis, Canvazoni et al 6 reported that haloperidoltreated patients with BPD seemed to be more vulnerable to the development of EPS than those with schizophrenia, but not olanzapine-treated patients with BPD. METHODSEnglish-language literature published and cited in Medline through October 31, 2007 was searched using the terms antipsychotics, placebo-controlled trial, and BPD, or mania, or schizophrenia, and then with terms typical antipsychotics, atypical antipsychotics, fluphenazine, haloperidol, perphenazine, pimozide, thiothixene, trifluoperazine, loxapine, molindone, chlorpromazine, mesoridazine, thioridazine, fluspirilene, penfuridol, pipothiazine, flupenthi...

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Objective This study was conducted to examine the safety and efficacy of pioglitazone, a thiazolidinedione insulin sensitizer, in adult outpatients with major depressive disorder. Method In a 12-week, open-label, flexible-dose study, 23 patients with major depressive disorder received pioglitazone monotherapy or adjunctive therapy initiated at 15mg daily. Subjects were required to meet criteria for abdominal obesity (waist circumference >35 in. in women and >40 in. in men) or metabolic syndrome. The primary efficacy measure was the change from baseline to Week 12 on the Inventory of Depressive Symptomatology (IDS) total score. Partial responders (≥25% decrease in IDS total score) were eligible to participate in an optional extension phase for an additional three months. Results Pioglitazone decreased depression symptom severity from a total IDS score of 40.3 ± 1.8 to 19.2 ± 1.8 at week 12 (p<.001). Among partial responders (≥ 25% decrease in IDS total score), an improvement in depressive symptoms was maintained during an additional 3-month extension phase (total duration = 24 weeks) according to IDS total scores (p<.001). Patients experienced a reduction in insulin resistance from baseline to Week 12 according to the log homeostasis model assessment (−0.8 ± 0.75; p<.001) and a significant reduction in inflammation as measured by log highly- sensitive C-reactive protein (−0.87 ± 0.72; p<.001). During the current episode, the majority of participants (74%, n=17), had already failed at least one antidepressant trial. The most common side effects were headache and dizziness; no patient discontinued due to side effects. Limitations These data are limited by a small sample size and an open-label study design with no placebo control. Conclusion Although preliminary, pioglitazone appears to reduce depression severity and improve several markers of cardiometabolic risk, including insulin resistance and inflammation. Larger, placebo-controlled studies are indicated.

The metabolic syndrome and its components are associated with depressive symptomatology. This article discusses the rate of co-occurrence and the points of pathophysiologic commonality between the metabolic syndrome and major depressive disorder.

Background Insulin resistance and other cardiometabolic risk factors predict increased risk of depression and decreased response to antidepressant and mood stabilizer treatments. This proof-of-concept study tested whether administration of an insulin-sensitizing peroxisome proliferator-activated receptor-gamma (PPAR-γ) agonist could reduce bipolar depression symptom severity. A secondary objective determined if levels of highly-sensitive C-reactive protein and Interleukin-6 (IL-6) predicted treatment outcome. Methods Thirty-four patients with bipolar disorder (I, II, or not otherwise specified) and metabolic syndrome/insulin resistance who were currently depressed (Quick Inventory of Depressive Symptoms (QIDS) total score ≥ 16) despite an adequate trial of a mood stabilizer received open-label, adjunctive treatment with the PPAR- γ agonist pioglitazone (15–30 mg/d) for 8 weeks. The majority of participants (76%, n=26) were experiencing treatment-resistant bipolar depression, having already failed two mood stabilizers or the combination of a mood stabilizer and a conventional antidepressant. Results Supporting an association between insulin sensitization and depression severity, pioglitazone treatment was associated with a decrease in the total Inventory of Depressive Symptomatology (IDS-C30) score from 38.7±8.2 at baseline to 21.2±9.2 at week 8 (p<.001). Self-reported depressive symptom severity and clinician-rated anxiety symptom severity significantly improved over 8 weeks as measured by the QIDS (p<.001) and Structured Interview Guide for the Hamilton Anxiety Scale (p<.001), respectively. Functional improvement also occurred as measured by the change in total score on the Sheehan Disability Scale (−17.9±3.6; p<.001). Insulin sensitivity increased from baseline to week 8 as measured by the Insulin Sensitivity Index derived from an oral glucose tolerance test (0.98±0.3; p<.001). Higher baseline levels of IL-6 were associated with greater decrease in depression severity (parameter estimate β=−3.89, SE=1.47, p=0.015). A positive correlation was observed between improvement in IDS-C30 score and change in IL-6 (r=0.44, p<01). Conclusions Open-label administration of the PPAR-γ agonist, pioglitazone, was associated with improvement in depressive symptoms and reduced cardiometabolic risk. Reduction in inflammation may represent a novel mechanism by which pioglitazone modulates mood. (ClinicalTrials.gov Identifier: NCT00835120)

Objective This study examined general medical illnesses and their association with clinical features of bipolar disorder. Methods Data were cross-sectional and derived from the Lithium Treatment – Moderate Dose Use Study (LiTMUS), which randomized symptomatic adults (n=264 with available medical comorbidity scores) with bipolar disorder to moderate doses of lithium plus optimized treatment (OPT) or to OPT alone. Clinically significant high and low medical comorbidity burden were defined as a Cumulative Illness Rating Scale (CIRS) score ≥ 4 and < 4, respectively. Results The baseline prevalence of significant medical comorbidity was 53% (n=139). Patients with high medical burden were more likely to present in a major depressive episode (P=.04), meet criteria for obsessive-compulsive disorder (P=.02), and experience a greater number of lifetime mood episodes (P=0.02). They were also more likely to be prescribed a greater number of psychotropic medications (P=.002). Sixty-nine percent of the sample was overweight or obese as defined by body mass index (BMI), with African-Americans representing the racial group with the highest proportion of stage II obesity (BMI ≥ 35; 31%, n=14). Conclusions The burden of comorbid medical illnesses was high in this generalizable sample of treatment-seeking patients and appears associated with worsened course of illness and psychotropic medication patterns. (Funded by NIMH Contract N01MH80001; ClinicalTrials.gov number NCT00667745).