Showing papers in "Bipolar Disorders in 2009"

Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) collaborative update of CANMAT guidelines for the management of patients with bipolar disorder: update 2009.

Abstract: The Canadian Network for Mood and Anxiety Treatments (CANMAT) published guidelines for the management of bipolar disorder in 2005, with a 2007 update. This second update, in conjunction with the International Society for Bipolar Disorders (ISBD), reviews new evidence and is designed to be used in conjunction with the previous publications. The recommendations for the management of acute mania remain mostly unchanged. Lithium, valproate, and several atypical antipsychotics continue to be first-line treatments for acute mania. Tamoxifen is now suggested as a third-line augmentation option. The combination of olanzapine and carbamazepine is not recommended. For the management of bipolar depression, lithium, lamotrigine, and quetiapine monotherapy, olanzapine plus selective serotonin reuptake inhibitor (SSRI), and lithium or divalproex plus SSRI/bupropion remain first-line options. New data support the use of adjunctive modafinil as a second-line option, but also indicate that aripiprazole should not be used as monotherapy for bipolar depression. Lithium, lamotrigine, valproate, and olanzapine continue to be first-line options for maintenance treatment of bipolar disorder. New data support the use of quetiapine monotherapy and adjunctive therapy for the prevention of manic and depressive events, aripiprazole monotherapy for the prevention of manic events, and risperidone long-acting injection monotherapy and adjunctive therapy, and adjunctive ziprasidone for the prevention of mood events. Bipolar II disorder is frequently overlooked in treatment guidelines, but has an important clinical impact on patients' lives. This update provides an expanded look at bipolar II disorder.

Bipolar disorder risk allele at CACNA1C also confers risk to recurrent major depression and to schizophrenia

Abstract: Molecular genetic analysis offers opportunities to advance our understanding of the nosological relationship between psychiatric diagnostic categories in general, and the mood and psychotic disorders in particular. Strong evidence (P=7.0 × 10−7) of association at the polymorphism rs1006737 (within CACNA1C, the gene encoding the α-1C subunit of the L-type voltage-gated calcium channel) with the risk of bipolar disorder (BD) has recently been reported in a meta-analysis of three genome-wide association studies of BD, including our BD sample (N=1868) studied within the Wellcome Trust Case Control Consortium. Here, we have used our UK case samples of recurrent major depression (N=1196) and schizophrenia (N=479) and UK non-psychiatric comparison groups (N=15316) to examine the spectrum of phenotypic effect of the bipolar risk allele at rs1006737. We found that the risk allele conferred increased risk for schizophrenia (P=0.034) and recurrent major depression (P=0.013) with similar effect sizes to those previously observed in BD (allelic odds ratio ∼1.15). Our findings are evidence of some degree of overlap in the biological underpinnings of susceptibility to mental illness across the clinical spectrum of mood and psychotic disorders, and show that at least some loci can have a relatively general effect on susceptibility to diagnostic categories, as currently defined. Our findings will contribute to a better understanding of the pathogenesis of major psychiatric illness, and such knowledge should be useful in providing an etiological rationale for shaping psychiatric nosology, which is currently reliant entirely on descriptive clinical data.

The International Society for Bipolar Disorders (ISBD) Task Force report on the nomenclature of course and outcome in bipolar disorders

Abstract: Objectives: Via an international panel of experts, this paper attempts to document, review, interpret, and propose operational definitions used to describe the course of bipolar disorders for worldwide use, and to disseminate consensus opinion, supported by the existing literature, in order to better predict course and treatment outcomes. Methods: Under the auspices of the International Society for Bipolar Disorders, a task force was convened to examine, report, discuss, and integrate findings from the scientific literature related to observational and clinical trial studies in order to reach consensus and propose terminology describing course and outcome in bipolar disorders. Results: Consensus opinion was reached regarding the definition of nine terms (response, remission, recovery, relapse, recurrence, subsyndromal states, predominant polarity, switch, and functional outcome) commonly used to describe course and outcomes in bipolar disorders. Further studies are needed to validate the proposed definitions. Conclusion: Determination and dissemination of a consensus nomenclature serve as the first step toward producing a validated and standardized system to define course and outcome in bipolar disorders in order to identify predictors of outcome and effects of treatment. The task force acknowledges that there is limited validity to the proposed terms, as for the most part they represent a consensus opinion. These definitions need to be validated in existing databases and in future studies, and the primary goals of the task force are to stimulate research on the validity of proposed concepts and further standardize the technical nomenclature.

The role of lithium in the treatment of bipolar disorder: convergent evidence for neurotrophic effects as a unifying hypothesis

Abstract: Lithium has been and continues to be the mainstay of bipolar disorder (BD) pharmacotherapy for acute mood episodes, switch prevention, prophylactic treatment, and suicide prevention. Lithium is also the definitive proof-of-concept agent in BD, although it has recently been studied in other psychoses as well as diverse neurodegenerative disorders. Its neurotrophic effects can be viewed as a unifying model to explain several integrated aspects of the pathophysiology of mood disorders and putative therapeutics for those disorders. Enhancing neuroprotection (which directly involves neurotrophic effects) is a therapeutic strategy intended to slow or halt the progression of neuronal loss, thus producing long-term benefits by favorably influencing outcome and preventing either the onset of disease or clinical decline. The present article: (i) reviews what has been learned regarding lithium's neurotrophic effects since Cade's original studies with this compound; (ii) presents human data supporting the presence of cellular atrophy and death in BD as well as neurotrophic effects associated with lithium in human studies; (iii) describes key direct targets of lithium involved in these neurotrophic effects, including neurotrophins, glycogen synthase kinase 3 (GSK-3), and mitochondrial/endoplasmic reticulum key proteins; and (iv) discusses lithium's neurotrophic effects in models of apoptosis and excitotoxicity as well as its potential neurotrophic effects in models of neurological disorders. Taken together, the evidence reviewed here suggests that lithium's neurotrophic effects in BD are an example of an old molecule acting as a new proof-of-concept agent. Continued work to decipher lithium's molecular actions will likely lead to the development of not only improved therapeutics for BD, but to neurotrophic enhancers that could prove useful in the treatment of many other illnesses.

The role of dopamine in bipolar disorder.

Abstract: Objective: Despite effective pharmacological treatments for bipolar disorder, we still lack a comprehensive pathophysiological model of the illness. Recent neurobiological research has implicated a number of key brain regions and neuronal components in the behavioural and cognitive manifestations of bipolar disorder. Dopamine has previously been investigated in some depth in bipolar disorder, but of late has not been a primary focus of attention. This article examines the role of dopamine in bipolar disorder, incorporating recent advances into established models where possible. Methods: A critical evaluation of the literature was undertaken, including a review of behavioural, neurochemical, receptor, and imaging studies, as well as genetic studies focusing on dopamine receptors and related metabolic pathways. In addition, pharmacologic manipulation of the central dopaminergic pathways and comparisons with other disease states such as schizophrenia were considered, principally as a means of exploring the hypothesised models. Results: Multiple lines of evidence, including data from pharmacological interventions and structural and functional magnetic resonance imaging studies, suggest that the dopaminergic system may play a central role in bipolar disorder. Conclusion: Future research into the pathophysiological mechanisms of bipolar disorder and the development of new treatments for bipolar disorder should focus on the dopaminergic system.

White matter abnormalities in bipolar disorder and schizophrenia detected using diffusion tensor magnetic resonance imaging

Abstract: OBJECTIVES: Strong qualitative and quantitative evidence exists of white matter abnormalities in both schizophrenia and bipolar disorder (BD). Diffusion tensor imaging (DTI) studies suggest altered connectivity in both disorders. We aim to address the diagnostic specificity of white matter abnormalities in these disorders. METHODS: DTI was used to assess white matter integrity in clinically stable patients with familial BD (n = 42) and familial schizophrenia (n = 28), and in controls (n = 38). Differences in fractional anisotropy (FA) were measured using voxel-based morphometry and automated region of interest analysis. RESULTS: Reduced FA was found in the anterior limb of the internal capsule (ALIC), anterior thalamic radiation (ATR), and in the region of the uncinate fasciculus in patients with BD and those with schizophrenia compared with controls. A direct comparison between patient groups found no significant differences in these regions. None of the findings were associated with psychotropic medication. CONCLUSIONS: Reduced integrity of the ALIC, uncinate fasciculus, and ATR regions is common to both schizophrenia and BD. These results imply an overlap in white matter pathology, possibly relating to risk factors common to both disorders.

Neurocognitive impairment in bipolar disorder patients: functional implications

Abstract: Background: Functional recovery among treated bipolar disorder (BPD) patients is far less likely than syndromal and even symptomatic recovery. We hypothesized that increasingly well-documented aspects of cognitive impairment may contribute to poor functional outcomes in BPD patients, and reviewed the available research on the topic. Methods: Computerized literature searching identified 12 studies with 13 comparisons that simultaneously evaluated cognitive and functional status in euthymic (n = 8) or non-euthymic (n = 5 comparisons) adult BPD patients versus otherwise similar healthy controls. Results: In 6/8 studies of euthymic BPD patients and 5/5 studies of non-euthymic BPD patients, neurocognitive impairment was significantly associated with impaired psychosocial functioning, even after adjusting for residual mood symptoms and relevant demographic and clinical variables. Cognitive status was consistently assessed with standardized, performance-based neuropsychological tests, but functional status usually was based on subjective self-appraisals. Approximately 55% of BPD patients were unemployed. Conclusions: Available studies are limited by subjective assessments of functional status rather than objective, performance-based measures. Nevertheless, they support the hypothesis that enduring aspects of cognitive impairment found even in euthymic BPD patients are associated with inferior functioning. These findings encourage further studies with better assessment methods and greater rehabilitative efforts in BPD patients.

Retrospective age-at-onset of bipolar disorder and outcome during two-year follow-up: results from the STEP-BD study

Abstract: In a large, population-based survey of adults, about half of psychiatric disorders exhibited an onset by age 14 and 75% by age 24 (1). In particular, the retrospective onset of bipolar disorder in childhood and adolescence is increasingly recognized (2, 3), and has been associated with poorer outcomes, and particularly with high rates of recurrence (3–7). However, little is known about the course of bipolar disorder among adults who experience childhood onset of symptoms. This feature of illness has both clinical and nosological importance. From a clinical perspective, it is of great interest whether early onset has prognostic significance once these individuals reach adulthood, particularly as many individuals with childhood onset do not enter treatment until that time (8, 9). More generally, understanding the adult course may be informative about the continuity—or lack thereof —between the diagnosis made in children and that in adults, given that the clinical presentation among children often differs from that in adults (10). Specifically, children and adolescents with bipolar disorder have been described as having a primarily mixed presentation, high rates of rapid cycling, longer episodes, and frequent switches of polarity (5, 7). One recent prospective cohort study found that 44% of children diagnosed with bipolar I disorder went on to have manic episodes as young adults (11). Initial studies in adults utilized retrospective assessment of both onset age and illness course (3, 12, 13). To date, two studies have examined prospective outcomes of retrospectively obtained childhood-onset bipolar disorder in adults. The two studies included fewer than 25 subjects and 67 subjects, respectively, with onset before age 13 (8, 14). Importantly, neither study accounted for the potential confounding effects of time since first episode or described recurrences, functional impairment, or quality of life. Furthermore, no study has examined the length of euthymic intervals, which may be especially important in defining a more pernicious course. The Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) study included longitudinal assessments of mood state and functional status in over 3,500 individuals with bipolar I and II disorder, with up to two years of follow-up (15, 16). We sought to extend cross-sectional findings of a more severe course among individuals with retrospectively obtained childhood onset by examining the prospective course of childhood-, adolescent-, and adult-onset bipolar patients in this cohort. We hypothesized that bipolar patients with childhood onset of mood symptoms would experience shorter periods of euthymia prior to recurrence compared with those with adult-onset symptoms. We further hypothesized that childhood-onset patients would experience a more chronic course, marked by a smaller proportion of days euthymic as well as greater functional impairment during follow-up (17).

Cardiovascular disease and hypertension among adults with bipolar I disorder in the United States

Abstract: Objective Despite ample evidence of excess cardiovascular mortality in bipolar disorder (BD), few studies have demonstrated increased prevalence of cardiovascular disease (CVD) and/or hypertension (HTN) in BD. We therefore examined this topic in a representative epidemiologic sample.

Increased oxidative stress in the anterior cingulate cortex of subjects with bipolar disorder and schizophrenia.

Abstract: Background: Recent studies indicate the presence of mitochondrial dysfunction in brains of subjects with bipolar disorder (BD). Because the mitochondrial electron transport chain is a major source for production of reactive oxygen species that cause oxidative stress, we sought to determine in the present study if BD is associated with oxidative stress. Methods: Postmortem anterior cingulate brain sections from subjects with BD, major depressive disorder (MDD), or schizophrenia, and from nonpsychiatric, non-neurologic comparison controls were generously provided by the Stanley Foundation Neuropathology Consortium. Oxidative stress was determined by analyzing 4-hydroxynonenal (4-HNE), a major product of lipid peroxidation. The level of 4-HNE was determined by measuring 4-HNE protein adducts using immunohistochemistry. Results: We found that 4-HNE levels were significantly increased by 59% in BD subjects and by 47% in schizophrenia subjects, but not in MDD subjects, when compared with controls. Levels of 4-HNE were negatively correlated with pH in all 60 subjects. When pH was used as covariate, 4-HNE levels were still significantly increased in BD subjects when compared with controls. Further, 4-HNE levels were significantly correlated with pH values only in BD subjects, but not in MDD, schizophrenia, or control subjects. Conclusions: Oxidative damage in the brain may contribute in part to the pathological process in BD and schizophrenia. This finding also suggests antioxidative stress as a probable alternative approach to the pharmacological treatment of these psychiatric disorders.

Increased trait-like impulsivity and course of illness in bipolar disorder

Abstract: Impulsivity results from dysregulation of the initiation of action (1, 2), an integral part of bipolar disorder (3). Operationalized as a predisposition to action without reflection or without regard for consequences (2), impulsivity is increased in bipolar disorder (4–6). Potential consequences of this increased impulsivity include substance abuse (7, 8), suicidal behavior (9–11), and other serious behavioral problems (12). Impulsivity has interacting state- and trait-like characteristics (5, 13). Trait impulsivity, as measured by the Barratt Impulsiveness Scale (BIS-11) (1), is increased in bipolar disorder, even when patients are euthymic (4, 13, 14). Impulsivity may also be related differentially to mania, depression, and anxiety (13, 15, 16). Increased impulsivity is consistent with many characteristics of bipolar disorder (6), but there is relatively little evidence directly linking measurements of impulsivity to specific illness-course characteristics of bipolar disorder. Patients with bipolar disorder vary substantially in their course of illness. Early onset and more frequent episodes are associated with susceptibility to mixed states (17) and with resistance to lithium treatment (18–20). Trait impulsivity is potentially related to the long-term course of bipolar disorder, whether as a consequence of unstable illness or as an expression of biological factors predisposing to a severe course (17), and may further worsen course of illness by contributing to substance abuse (8) and nonadherence to treatment (21). Patients with early-onset or highly recurrent bipolar disorder have characteristics consistent with impulsivity, including substance use disorders, aggression, and suicide attempts (22–24), but there is little direct evidence about impulsivity in these patients. Education and age can influence impulsivity and may confound the interpretation of variations in impulsivity relative to illness course; for example, either severe bipolar disorder or impulsive behavior could interfere with completion of education, while education could potentially provide cognitive tools for counteracting impulsivity (25, 26). We examined trait impulsivity in bipolar disorder in relation to demographic characteristics, symptoms, and course of illness. After characterizing relationships to age, education, and gender, we investigated relationships between trait-like impulsivity and age of onset, frequency of episodes, substance use disorders, and suicidal behavior.

The history of lithium therapy

Abstract: The use of lithium in psychiatry goes back to the mid-19th century. Early work, however, was soon forgotten, and John Cade is credited with reintroducing lithium to psychiatry for mania in 1949. Mogens Schou undertook a randomly controlled trial for mania in 1954, and in the course of that study became curious about lithium as a prophylactic for depressive illness. In 1970, the United States became the 50th country to admit lithium to the marketplace. Meanwhile, interest in lithium for the prophylaxis of depression was growing apace and today the agent is widely prescribed for that indication, even though it has not been accepted by the Food and Drug Administration. Lithium was almost derailed by a small group of opponents from the Maudsley Hospital and its status today is threatened by the "mood stabilizers."

Tobacco smoking behaviors in bipolar disorder: a comparison of the general population, schizophrenia, and major depression.

Abstract: Objectives: This study compared the prevalence of tobacco smoking behaviors in patients with bipolar disorder with normal and psychiatric (schizophrenia and major depression) controls. The main goal was to establish that bipolar patients smoke more than normal controls. Differences with psychiatric controls were explored. Methods: Samples of 424 patients (99 bipolar, 258 schizophrenia and 67 major depression) and 402 volunteer controls were collected in Central Kentucky. Smoking data for Kentucky’s general population were available. Odds ratios (ORs) and their 95% confidence intervals (CIs) were used to establish the strength of associations. Logistic regression was used to adjust ORs for confounding variables. Results: Using epidemiological definitions of smoking behaviors and the general population as controls provided bipolar disorder unadjusted ORs of 5.0 (95% CI: 3.3–7.8) for current cigarette smoking, 2.6 (95% CI: 1.7–4.4) for ever cigarette smoking, and 0.13 (95% CI: 0.03–0.24) for smoking cessation. Using a clinical definition and volunteers as controls provided respective bipolar disorder adjusted ORs of 7.3 (95% CI: 4.3–12.4), 4.0 (95% CI: 2.4–6.7), and 0.15 (95% CI: 0.06–0.36). Prevalences of current daily smoking for patients with major depression, bipolar disorder, and schizophrenia were 57%, 66%, and 74%, respectively. Conclusions: Bipolar disorder was associated with significantly higher prevalences of tobacco smoking behaviors compared with the general population or volunteer controls, independently of the definition used. It is possible that smoking behaviors in bipolar disorder may have intermediate prevalences between major depression and schizophrenia, but larger samples or a combination of multiple studies (meta-analysis) will be needed to establish whether this hypothesis is correct.

A 3-week, randomized, placebo-controlled trial of asenapine in the treatment of acute mania in bipolar mania and mixed states.

Abstract: Objective: Asenapine is approved for bipolar disorder and schizophrenia. This was a 3-week, randomized, double-blind, placebo-controlled trial of asenapine for treating acute bipolar mania. Methods: After a single-blind placebo run-in period, adults (n = 488) experiencing manic or mixed episodes were randomized to flexible-dose sublingual asenapine (10 mg BID on day 1; 5 or 10 mg BID thereafter; n = 194), placebo (n = 104), or oral olanzapine (15 mg BID on day 1; 5–20 mg QD thereafter; n = 191). Primary efficacy, change in Young Mania Rating Scale (YMRS) total score from baseline to day 21, was assessed using analysis of covariance with last observation carried forward [(LOCF); primary analysis]. A mixed model for repeated measures [(MMRM); prespecified secondary analysis] was also used to assess efficacy. Tolerability and safety assessments included adverse events, physical examinations, extrapyramidal symptom ratings, and laboratory values. Results: Mean daily dosages were asenapine 18.2 mg and olanzapine 15.8 mg. Significantly greater least squares (LS) mean ± SE changes in YMRS scores were observed on day 2 with asenapine (−3.0 ± 0.4) and olanzapine (−3.4 ± 0.4) versus placebo (−1.5 ± 0.5, both p < 0.01) and were maintained until day 21 (−10.8 ± 0.8 with asenapine, −12.6 ± 0.8 with olanzapine; both p ≤ 0.0001 versus placebo, −5.5 ± 1.1) with LOCF. The results of MMRM analyses were consistent with those of LOCF. Asenapine had a modest impact on weight and metabolic measures. Conclusions: These results indicate that asenapine is rapidly acting, efficacious, and well tolerated for patients with bipolar I disorder experiencing an acute manic episode.

Clinical predictors of functional outcome of bipolar patients in remission.

Abstract: Objectives: A number of studies have now shown that subjects with bipolar disorder (BD) have significant psychosocial impairment during interepisode intervals. This study was carried out to assess the level of functioning as well as to identify potential predictors of functioning in a well-defined, euthymic bipolar sample. Methods: The study included 71 euthymic bipolar patients and 61 healthy controls. The Functioning Assessment Short Test (FAST) was used to assess multiple areas of functioning such as autonomy, occupational functioning, cognitive functioning, interpersonal relationships, financial issues, and leisure time. Multivariate analysis was used to determine the global and specific clinical predictors of outcome. Results: Sixty percent (n = 42) of the patients had overall functional impairment (defined as a FAST total score > 11) compared to 13.1% (n = 8) of the control group (p = 0.001). Bipolar patients showed a worse functioning in all the areas of the FAST. Only four variables-older age, depressive symptoms, number of previous mixed episodes, and number of previous hospitalizations-were associated with poor functioning, on a linear regression model, which accounted for 44% of the variance (F - 12.54, df = 58, p < 0.001). Conclusions: A substantial proportion of bipolar patients experience unfavorable functioning, suggesting that there is a significant degree of morbidity and dysfunction associated with BD, even during remission periods. Previous mixed episodes, current subclinical depressive symptoms, previous hospitalizations, and older age were identified as significant potential clinical predictors of functional impairment.

Identifying and treating cognitive impairment in bipolar disorder

Abstract: 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.

The International Society for Bipolar Disorders (ISBD) consensus guidelines for the safety monitoring of bipolar disorder treatments

Abstract: Objectives: Safety monitoring is an important aspect of bipolar disorder treatment, as mood-stabilising medications have potentially serious side effects, some of which may also aggravate existing medical comorbidities. This paper sets out the International Society for Bipolar Disorders (ISBD) guidelines for the safety monitoring of widely used agents in the treatment of bipolar disorder. These guidelines aim to provide recommendations that take into consideration the balance between safety and cost-effectiveness, to highlight iatrogenic and preventive clinical issues, and to facilitate the broad implementation of therapeutic safety monitoring as a standard component of treatment for bipolar disorder. Methods: These guidelines were developed by an ISBD workgroup, headed by the senior author (MB), through an iterative process of serial consensus-based revisions. After this, feedback from a multidisciplinary group of health professionals on the applicability of these guidelines was sought to develop the final recommendations. Results: General safety monitoring recommendations for all bipolar disorder patients receiving treatment and specific monitoring recommendations for individual agents are outlined. Conclusions: These guidelines are derived from evolving and often indirect data, with minimal empirical cost-effectiveness data available to provide guidance. These guidelines will therefore need to be modified to adapt to different clinical settings and health resources. Clinical acumen and vigilance remain critical ingredients for safe treatment practice.

Psychosocial treatments for bipolar disorder: cost-effectiveness, mediating mechanisms, and future directions.

Abstract: Objectives: Randomized trials of adjunctive psychotherapy for bipolar disorder are reviewed, in tandem with discussion of cost-effectiveness, mediating mechanisms, and moderators of effects. Methods: Systematic searches of the MEDLINE and PSYCHLIT databases yielded 19 randomized controlled trials of individual family and group therapies. Outcome variables included time to recovery, relapse or recurrence, symptom severity, medication adherence, and psychosocial functioning. Results: Meta-analyses consistently show that disorder-specific psychotherapies [cognitive-behavioral therapy (CBT), interpersonal, family, and group] augment mood stabilizers in reducing rates of relapse (OR = 0.57; 95% CI: 0.39–0.82) over 1–2 years. Specific mediating mechanisms include, but are not limited to, increasing medication adherence, teaching self-monitoring and early intervention with emergent episodes, and enhancing interpersonal functioning and family communication. All therapies have strengths and weaknesses. One group psychoeducation trial, demonstrated effect sizes for recurrence that are at least equivalent to individual therapies, but findings await replication. Family interventions have been successfully administered in both single and multi-family formats, but no studies report the comparative cost-effectiveness of these formats. The best-studied psychotherapy modality, CBT, can have beneficial effects on depression, but findings are inconsistent across studies and vary with sample characteristics and comparison treatments. Conclusions: Adjunctive psychotherapies can be cost-effective when weighed against observed reductions in recurrence, hospitalization and functional impairments. Future trials need to (i) clarify which populations are most likely to benefit from which strategies; (ii) identify putative mechanisms of action; (iii) systematically evaluate costs, benefits, and generalizability; and (iv) record adverse effects. The application of psychosocial interventions to young-onset populations deserves further study.

Association study of 21 circadian genes with bipolar I disorder, schizoaffective disorder, and schizophrenia

Abstract: Objective Published studies suggest associations between circadian gene polymorphisms and bipolar I disorder (BPI), as well as schizoaffective disorder (SZA) and schizophrenia (SZ). The results are plausible, based on prior studies of circadian abnormalities. As replications have not been attempted uniformly, we evaluated representative, common polymorphisms in all three disorders.

Risperidone for the treatment of acute mania in children and adolescents with bipolar disorder: a randomized, double-blind, placebo-controlled study.

Abstract: Objectives: To evaluate the efficacy, safety, and tolerability of risperidone monotherapy for the treatment of an acute mixed or manic episode in children and adolescents with bipolar I disorder. Methods: This randomized, placebo-controlled, double-blind, 3-arm study (N = 169) included children and adolescents (ages 10–17 years) with a DSM-IV diagnosis of bipolar I disorder, experiencing a manic or mixed episode. Study participants were randomized to placebo (n = 58), risperidone 0.5–2.5 mg/day (n = 50), or risperidone 3–6 mg/day (n = 61) for 3 weeks. The primary efficacy measure was change in Young Mania Rating Scale (YMRS) total score from baseline to end point. Safety assessments included adverse event (AE) monitoring and scores on extrapyramidal symptom rating scales. Results: Improvement in mean YMRS total score was significantly greater in risperidone-treated subjects than in placebo-treated subjects [mean change (SD) −9.1 (11.0) for placebo; −18.5 (9.7) for risperidone 0.5–2.5 mg (p < 0.001); −16.5 (10.3) for risperidone 3–6 mg (p < 0.001)]. The most common risperidone-associated AEs were somnolence, headache, and fatigue. Mean (SD) weight gain was 0.7 (1.9) kg, 1.9 (1.7) kg, and 1.4 (2.4) kg in the placebo, risperidone 0.5–2.5 mg, and risperidone 3–6 mg groups, respectively, during this 3-week study. Conclusions: At daily doses of 0.5–2.5 mg and 3–6 mg, risperidone was effective and well tolerated in children and adolescents experiencing acute manic or mixed episodes of bipolar I disorder. Results indicate that risperidone 0.5–2.5 mg has a better benefit–risk profile than risperidone 3–6 mg.

Conceptualizing impulsivity and risk taking in bipolar disorder: importance of history of alcohol abuse.

Abstract: Individuals with bipolar disorder (BD) tend to be impulsive and engage in risky behaviors—pleasurable activities with high potential for negative consequences. Indeed, increased risk taking is one of several diagnostic criteria for a manic episode (1). Impulsivity can be conceptualized as a personality trait, characterized by acting quickly and without planning in order to satisfy a desire (2). As such, impulsivity is a complex, multifaceted construct that includes cognitive components, personality / motivational dimensions, and behavioral components; related traits and behaviors include risk taking, sensation seeking, and behavioral disinhibition (3, 4). Among the most popular self-report indices of impulsivity is the Barratt Impulsiveness Scale (BIS) (5), which incorporates three dimensions of impulsivity: attentional, motor, and non-planning. Based on research with this instrument, there is growing evidence that impulsivity is a stable trait characteristic of BD (6) and appears to represent a core feature of the illness (7). Elevated levels of impulsivity have been found in BD patients during manic (8, 9), depressive (10), and euthymic (9, 10) periods. Additionally, increased impulsivity has been linked to a more severe suicide attempt history in BD (11). Impulsivity and risk-taking propensity are thought to be highly correlated, yet not synonymous, constructs. Elevated levels of impulsivity are often present among those psychiatric disorders characterized by risk-taking behavior (e.g., bipolar disorder, personality disorders, and substance use disorders) (12). In general, impulsivity refers to a predisposition and an overall pattern of behavior, whereas risk taking encompasses specific, situationally determined behaviors that may or may not result from a deficit in impulse control (2). Although risk taking is often part of the clinical presentation of BD, very few studies have formally assessed risk-taking propensity in BD patients. A better understanding of the relationship between impulsivity and risk-taking behavior in BD has implications for the development of appropriate treatment strategies. Impulsivity and risk taking are also constructs of central importance for addictive disorders. For example, higher levels of impulsivity are seen in early-onset versus late-onset alcoholics (13). Increased impulsivity has also been associated with early experimentation with illicit substances and a high susceptibility to developing substance use disorders (14). One commonly used behavioral measure of risk taking in research related to addictive disorders is the computerized Balloon Analogue Risk Task (BART) (15). Numerous studies have found performance on the BART to be related to self-report of substance use and other risk behaviors (15–19). To our knowledge, this is the first study to apply this task in patients with BD. An estimated 56% of patients with bipolar I disorder experience alcohol abuse and 38% experience alcohol dependence during their lifetimes (20). There is increasing evidence that alcoholism phenomenologically changes illness presentation in bipolar disorder and can lead to increased chronicity and symptom severity [see (21) for a review]. Because problems with alcohol use are so common in BD, any conceptualization of impulsivity and risk taking in BD must include an understanding of the effect of comorbid alcohol use disorders. In the current study, we used the BIS and the BART to better conceptualize impulsivity and risk propensity, respectively, in patients with BD with and without a history of alcohol use disorders. Based on the existing literature, we predicted that patients with BD overall would have elevated levels of both impulsivity and risk taking compared to demographically matched healthy control (HC) subjects. Additionally, we expected patients with BD with a history of alcohol abuse or dependence (BD-A) to have exaggerated levels of impulsivity and risk taking compared to their counterparts without a history of alcohol abuse or dependence (BD-N). Further, consistent with the notion that these measures reflect trait dimensions of BD, we predicted that performance would not be related to clinical symptoms.

Can body mass index help predict outcome in patients with bipolar disorder

Abstract: Obesity is common in patients with bipolar disor- der (BD), with a prevalence of 20% to 49% (1-3), compared to 18% in the general US population (4). There are a number of possible causes of obesity in BD, including lifestyle, medication exposure, binge-eating comorbidity, neuroendocrine and neurotransmitter dysfunctions, comorbid meta- bolic syndrome, and genetic predisposition. The growing evidence of obesity in patients with BD and its correlation with increased morbidity and mortality led us to study the association between the two disorders more systematically, with the hypothesis that body mass index (BMI) is related to prognosis and outcome. In this paper, we examine differences in sociodemographic, clinical, and medical characteristics of BD patients with elevated BMI. Calkin C, van de Velde C, RuzickovaM, Slaney C, Garnham J, Hajek T, ODonovan C, Alda M. Can body mass index help predict outcome in patients with bipolar disorder? Bipolar Disord 2009: 11: 650-656. a 2009 The Authors. Journal compilation a 2009 John Wiley & A ⁄ S. Objective: Several studies have reported higher prevalence of obesity in patients suffering from bipolar disorder (BD). To study the relation of elevated body mass index (BMI) in patients with BD more closely, we investigated differences in sociodemographic, clinical, and medical characteristics with respect to BMI, with the hypothesis that BMI is related to prognosis and outcome. Methods: We measured the BMI of 276 subjects of a tertiary care sample from the Maritime Bipolar Registry. Subjects were 16 to 83 years old, with psychiatric diagnoses of bipolar I disorder (n = 186), bipolar II disorder (n = 85), and BD not otherwise specified (n = 5). The registry included basic demographic data and details of the clinical presentation. We first examined the variables showing a significant association with BMI; subsequently, we modeled the relationship between BMI and psychiatric outcome using structural equation analysis. Results: The prevalence of obesity in our sample was 39.1%. We found higher BMI in subjects with a chronic course (p < 0.001) and longer duration of illness (p = 0.02), lower scores on the Global Assessment of Functioning Scale (p = 0.02), and on disability (p = 0.002). Overweight patients had more frequent comorbid subthreshold social (p = 0.02) and generalized anxiety disorders (p = 0.05), diabetes mellitus type II (p < 0.001), and hypertension (p = 0.001). Subjects who achieved complete remission of symptoms on lithium showed significantly lower BMI (p = 0.01). Conclusions: Our findings suggest that BMI is associated with the prognosis and outcome of BD. Whether this association is causal remains to be determined.

Similar immune profile in bipolar disorder and schizophrenia: selective increase in soluble tumor necrosis factor receptor I and von Willebrand factor.

Abstract: Background: Alterations in the inflammatory system have been associated with schizophrenia and major depression, while bipolar disorder has been less studied. Most previous studies examined small samples, and the literature is inconsistent with regard to specific underlying immune mechanisms. In the present study, we examined markers representing different inflammatory pathways, and the aim was to investigate whether the levels of inflammatory parameters in a representative sample of bipolar disorder and schizophrenia are elevated compared to healthy controls, and to investigate whether the inflammatory profile is different between the groups. Methods: Plasma levels of soluble tumor necrosis factor receptor 1 (sTNF-R1), interleukin-1 receptor antagonist (IL-1Ra), interleukin-6 (IL-6), high-sensitivity CRP (hs-CRP), soluble CD40L ligand (sCD40L), and von Willebrand factor (vWf) were measured with ELISA techniques in a catchment area based sample of consecutively referred patients with severe mental disorders [N = 311, comprising bipolar disorder (n = 125) and schizophrenia (n = 186)] and in healthy volunteers (n = 244). Results: Plasma levels of sTNF-R1 and vWf were statistically significantly increased in both bipolar disorder and schizophrenia compared to controls (p < 0.00001), and were also increased in unmedicated patients, but there were no major differences between the two diagnostic groups. Controlling for age, gender, ethnicity, cardiovascular disorders, kidney and liver function, and other confounders did not affect the results. There were no differences in other inflammation factors between the groups. Conclusion: The present results indicate specific alterations of endothelium-related inflammation processes in both bipolar disorder and schizophrenia.

Mood episodes and mood disorders: patterns of incidence and conversion in the first three decades of life

Abstract: In the traditional nosology of manic-depressive illness/bipolar disorder (BD), depression and mania are viewed as part of a unitary illness, reflecting dysregulation along a mood dimension (1). The frequency of (hypo)manic episodes without lifetime episodes of depression remains controversial; prevalence data among all bipolar patients range from 1.1 to 47.2% (2). Less controversial is the observation that individuals with unipolar depressive disorder might subsequently develop (hypo)manic episodes, thus converting to BD. The question remains what proportion will convert and whether it is feasible to predict conversion, e.g., by characteristics of the initial depressive episode. The answers to these questions would inform nosology and facilitate early recognition and intervention (3). While there are a substantial number of large, community-based surveys, most are limited by their cross-sectional nature and inclusion of a broad age spectrum, spanning adolescence (age 16+) to late adulthood (4–9). Thus, these studies may be subject to notable recall bias and they typically do not provide an adequately powered sample to estimate the prevalence and incidence of mood episodes in restricted age ranges, such as adolescence and young adulthood. Yet these studies suggest that the highest incidence of mood episodes occurs between ages 15–25 (9–14). Ages of first onset may date back to childhood (15, 16), but childhood studies often differ from those in adolescents and adults in terms of diagnostic criteria and assessment instruments (e.g., self versus parental report). Thus, it is difficult to draw firm conclusions about the frequency of hypomania and mania in childhood and adolescence. Furthermore, little information is available about the probability of longitudinal transitions from depressive to (hypo)manic episodes, and also the reverse direction, in this time period. Beyond major depression, considering minor depression (potential ‘counterparts’ of hypomanic episodes) is important given significant functional impairment (17). Using data from a prospective, longitudinal community sample of adolescents and young adults, we examined the following questions: What is the cumulative incidence of manic episodes (ME), hypomanic episodes (HE), major depressive episodes (MDE), and minor depressive episodes (MinDE), as well as of unipolar and bipolar mood disorders, in the first three decades of life? What is the risk for first onset of major or minor depression among individuals with a previous history of HE/ME? And what is the risk for first onset of HE/ME among individuals with a preceding MDE or MinDE? What clinical and treatment features characterize subjects with unipolar and bipolar mood disorders?

A randomized, double‐blind, placebo‐controlled study of maintenance treatment with adjunctive risperidone long‐acting therapy in patients with bipolar I disorder who relapse frequently

Abstract: Objective: No large controlled trials have evaluated adjunctive maintenance treatment with long-acting injectable antipsychotics in patients with bipolar disorder. This study assessed whether adjunctive maintenance treatment with risperidone long-acting therapy (RLAT), added to treatment-as-usual (TAU) medications for bipolar disorder, delays relapse in patients with bipolar disorder type I. Methods: This study included patients with bipolar disorder type I with ≥ four mood episodes in the 12 months prior to study entry. Following a 16-week, open-label stabilization phase with RLAT plus TAU, remitted patients entered a 52-week, double-blind, placebo-controlled, relapse-prevention phase. Randomized patients continued treatment with adjunctive RLAT (25–50 mg every two weeks) plus TAU (n = 65) or switched to adjunctive placebo injection plus TAU (n = 59). The primary outcome measure was time to relapse to any mood episode. Results: Of 240 enrolled patients, 124 entered double-blind treatment. Time to relapse was longer in patients receiving adjunctive RLAT (p = 0.010). Relapse rates were 23.1% (n = 15) with adjunctive RLAT versus 45.8% (n = 27) with adjunctive placebo; relative relapse risk was 2.3-fold higher with adjunctive placebo (p = 0.011). Completion rates were: adjunctive RLAT, 60.0% (n = 39) and adjunctive placebo, 42.4% (n = 25; p = 0.050). Adverse event (AE)-related discontinuations were 4.6% (n = 3) and 1.7% (n = 1), respectively. Common AEs (adjunctive RLAT versus adjunctive placebo) were: tremor (24.6% versus 10.2%), insomnia (20.0% versus 18.6%), muscle rigidity (12.3% versus 5.1%), weight increased (6.2% versus 1.7%), and hypokinesia (7.7% versus 0.0%). Conclusions: Adjunctive RLAT significantly delayed time to relapse in patients with bipolar disorder type I who relapse frequently. Safety and tolerability of RLAT were generally consistent with that previously observed.

Augmentative repetitive navigated transcranial magnetic stimulation (rTMS) in drug-resistant bipolar depression.

Abstract: Objectives: The efficacy of transcranial magnetic stimulation (TMS) has been poorly investigated in bipolar depression. The present study aimed to assess the efficacy of low-frequency repetitive TMS (rTMS) of the right dorsolateral prefrontal cortex (DLPFC) combined with brain navigation in a sample of bipolar depressed subjects. Methods: Eleven subjects with bipolar I or bipolar II disorder and major depressive episode who did not respond to previous pharmacological treatment were treated with three weeks of open-label rTMS at 1 Hz, 110% of motor threshold, 300 stimuli/day. Results: All subjects completed the trial showing a statistically significant improvement on the 21-item Hamilton Depression Rating Scale (HAM-D), Montgomery-Asberg Depression Rating Scale, and Clinical Global Impression severity of illness scale (ANOVAs with repeated measures: F = 22.36, p < 0.0001; F = 12.66, p < 0.0001; and F = 10.41, p < 0.0001, respectively). In addition, stimulation response, defined as an endpoint HAM-D score reduction of ≥50% compared to baseline, was achieved by 6 out of 11 subjects, 4 of whom were considered remitters (HAM-D endpoint score ≤ 8). Partial response (endpoint HAM-D score reduction between 25% and 50%) was achieved by 3/11 patients. No manic/hypomanic activation was detected during the treatment according to Young Mania Rating Scale scores (ANOVAs with repeated measures: F = 0.62, p = 0.61). Side effects were slight and were limited to the first days of treatment. Conclusions: Augmentative low-frequency rTMS of the right DLPFC combined with brain navigation was effective and well tolerated in a small sample of drug-resistant bipolar depressive patients, even though the lack of a sham controlled group limits confidence in the results.

Gray matter, white matter, brain, and intracranial volumes in first‐episode bipolar disorder: a meta‐analysis of magnetic resonance imaging studies

Abstract: Objectives: To perform a comprehensive quantitative analysis of the existing magnetic resonance imaging (MRI) studies of the brain conducted on patients with first-episode bipolar disorder (BD). Methods: A systematic search was performed of MRI studies that reported quantitative measurements of brain volumes of first-episode bipolar patients and healthy controls. Four meta-analyses were performed for four cerebral regions. Results: Significant overall effect sizes were demonstrated, with a reduction detected in patients with BD for total intracranial and white matter volumes, but not for gray matter and whole brain volumes. Conclusions: The available MRI literature indicates that specific structural brain abnormalities are already present in first-episode bipolar patients. These do not overlap with those emerging from previous meta-analyses performed in patients with chronic BD. These findings support the hypothesis of different patterns of changes in brain morphology over the time course of bipolar disorder.

A double-blind, placebo-controlled pilot study of quetiapine for depressed adolescents with bipolar disorder

Abstract: Objective: To conduct a pilot study comparing the effects of quetiapine and placebo for the treatment of depressive episodes in adolescents with bipolar I disorder. Method: Thirty-two adolescents (ages 12–18 years) with a depressive episode associated with bipolar I disorder were randomized to eight weeks of double-blind treatment with quetiapine, 300–600 mg/day, or placebo. This two-site study was conducted from March 2006 through August 2007. The primary efficacy measure was change in Children’s Depression Rating Scale–Revised Version (CDRS-R) scores from baseline to endpoint. Secondary efficacy measures included change in CDRS-R scores over the eight-week study period (PROC MIXED), changes from baseline to endpoint in Hamilton Anxiety Rating Scale (HAM-A), Young Mania Rating Scale (YMRS), and Clinical Global Impression–Bipolar Version Severity (CGI-BP-S) scores, as well as response and remission rates. Safety and tolerability were assessed weekly. Results: There was no statistically significant treatment group difference in change in CDRS-R scores from baseline to endpoint (p = 0.89, effect size =−0.05, 95% confidence interval: −0.77–0.68), nor in the average rate of change over the eight weeks of the study (p = 0.95). Additionally, there were no statistically significant differences in response (placebo =67% versus quetiapine = 71%) or remission (placebo = 40% versus quetiapine = 35%) rates, or change in HAM-A, YMRS, or CGI-BP-S scores (all p > 0.7) between treatment groups. Dizziness was more commonly reported in the quetiapine (41%) than in the placebo (7%) group (Fisher’s exact test, p = 0.04). Conclusions: The results suggest that quetiapine monotherapy is no more effective than placebo for the treatment of depression in adolescents with bipolar disorder. However, limitations of the study, including the high placebo response rate, may have contributed to our findings and should be considered in the design of future investigations of pharmacological interventions for this population.

The longitudinal course of cognition in older adults with bipolar disorder.

Abstract: More than 30 cross-sectional studies have revealed cognitive impairments in mixed-aged adults with bipolar disorder (BD) that are present even with symptomatic recovery (1–4). Deficits have been identified in multiple cognitive domains, including information processing speed (5, 6), executive function (5–10), memory (7, 11–14), attention/concentration (15, 16), and visual-spatial abilities (17, 18). In turn, cognitive impairment has been associated with impairment in functional abilities (5, 6, 13). Epidemiologic studies have suggested that BD is associated with increased risk of developing dementia (19–21). Despite the large number of cross-sectional studies, to our knowledge, there have been just six published studies on the longitudinal course of cognitive function in BD patients of any age (22–27), with only one study focused on older adults (23). This study by Dhingra and Rabins (23) used the Mini-Mental State Exam (MMSE) (28) to follow older patients for 5–7 years after they were hospitalized for mania. The investigators found that 8 (32%) of the 25 BD subjects followed-up experienced a decline in their MMSE to a score below 24 (indicating significant cognitive impairment), including 5 subjects (20%) who became so cognitively impaired that they required nursing home placement. Although no control group was included, this is ten-fold higher than the 1–2% expected incidence rate of dementia, given the age of these patients. Furthermore, the MMSE may have underestimated the level of cognitive dysfunction present in their subjects, since the instrument has low sensitivity to detect cognitive impairment in older adults with mood disorders (29). More recently, Depp and colleagues (26) examined the ‘short-term’ course of neuropsychological abilities in middle-aged and older adults with BD. They examined 35 community-dwelling outpatients with BD (mean age 58 years) with a battery of neurocognitive tests, repeated once (1–3 years after baseline), comparing the performance with that of demographically matched samples of normal comparison subjects (n = 35) and patients with schizophrenia (n = 35). They found that patients with BD did not differ from normal comparators or patients with schizophrenia in the mean trajectory of change between time-points, but that the patients with BD showed more intra-individual variability over time than either comparison group. In their study, although subjects with BD or schizophrenia had mild/minimal levels of psychopathology, they were not specifically tested when stable or symptom-free. The reports from middle-aged adults with BD present a mixed picture of stability or decline of cognition over longitudinal follow-up (22, 24, 25, 27). The reports from Engelsmann et al. (24) and Balanza-Martinez et al. (22) in midlife subjects showed that impairments in cognitive function were present in memory (24) or overall cognitive function (22); however, no significant decline was evident over the three to six years of follow-up. When assessed in euthymic states, Mur and colleagues (27) observed stable cognitive deficits in executive function and information processing speed over two-year follow-up in patients treated with lithium as their primary mood stabilizer. In contrast, in Moorhead et al.’s study (25), 20 patients with bipolar I disorder (BD I) (mean age: 42 ± 9) and 21 controls (group-matched for age, gender, and premorbid IQ) underwent cognitive assessment and had MRI brain scans at baseline and four years later. Patients with BD showed a larger decline in hippocampal, fusiform, and cerebellar gray matter density over four years than control subjects. Reductions in temporal lobe gray matter correlated with decline in cognitive function (verbal IQ) and number of mood episodes during the follow-up period. Taken together, the reports from middle or older age suggest that cognitive impairments may manifest in early life, but significant decline may not be apparent until late middle or older age. Not surprisingly, cognitive function is strongly associated with performance of ‘cognitive’ instrumental activities of daily living (IADLs) (e.g., medication management, managing finances, or home safety) and the ability to live independently (6). Determining whether elders with BD genuinely exhibit accelerated cognitive decline is critical for investigators to design or optimize treatments targeting specific factors or subgroups of patients with BD. For instance, patients with BD who exhibit a specific pattern of cognitive impairment or a cluster of risk factors indicating a very high risk of further cognitive decline may be candidates for cognitive remediation or interventions designed to enhance cognitive function or halt decline. To clarify whether cognitive decline is ‘accelerated’ in older adults with BD, we have assessed a group of patients with BD over several years with the Dementia Rating Scale (DRS) (30), along with a group of age-equated, mentally healthy comparators. We decided to include both BD I and bipolar II disorder (BD II) in our investigation to describe the cognitive course of BD in older adults that may generalize to individuals in the community. Based on our prior research in bipolar and major depressive disorders (6, 31, 32), we hypothesized that subjects with BD would exhibit cognitive deficits in relation to age-matched, mentally healthy comparators and that they would exhibit faster decline over longitudinal follow-up. We secondarily examined whether the profile of cognitive function across the DRS subscales revealed greater levels of impairment or decline in attention, executive function, or memory in patients with BD.

Lithium-induced enhancement of mitochondrial oxidative phosphorylation in human brain tissue

Abstract: Objectives: Extensive preclinical and clinical evidence suggests mitochondrial dysfunction in bipolar disorder. Studies of brain energy metabolism in bipolar disorder suggest an impairment of energy generation by mitochondrial oxidative phosphorylation. Lithium is an effective drug widely used in treating bipolar disorder, but its mechanism of action has remained uncertain. The aim of this study was to clarify the effect of lithium on mitochondrial oxidative phosphorylation. Methods: We spectrophotometrically determined the activities of the respiratory chain complexes I + III [antimycin A-sensitive nicotinamide adenine dinucleotide (NADH) cytochrome c oxidorductase], complexes II + III (succinate cytochrome c oxidoreductase), succinate dehydrogenase, and complex IV [cytochrome c oxidase (COX)], and of the mitochondrial matrix enzyme citrate synthase in postmortem human brain cortex homogenates following exposure to lithium (up to 10 mM). Results: Activities of complexes I + III and of complexes II + III were dose-dependently increased by lithium with maximum values at 1 mM (165%, p = 0.03, and 146%, p = 0.00002, of controls). Activity of succinate dehydrogenase remained unchanged up to 2 mM, but was raised at higher drug concentrations (maximum 220%, p = 0.01, of controls). In contrast, activity of COX was not significantly affected by the drug (decrease of 12% at 1 mM, p = 0.4). Conclusions: Our study suggests that lithium stimulates mitochondrial respiratory chain enzyme activities at clinically relevant concentrations. Lithium’s effect on the mitochondrial respiratory chain presents further evidence of the pathophysiological significance of mitochondrial dysfunction in bipolar disorder. The effect may be relevant to the therapeutic efficacy of the drug by potentially reversing a disease-related alteration.