Association studies of bipolar disorder

Association studies in outbred populations represent an important paradigm for investigation of complex traits, such as bipolar disorder, both to follow-up regions of interest from linkage studies (by systematic linkage disequilibrium mapping and positional candidate studies) and for pure functional studies. The advantages of the association method include its relative robustness to genetic heterogeneity and the ability to detect much smaller effect sizes than are detectable using feasible sample sizes in linkage studies. The candidate gene approach is potentially very powerful, particularly when used within the context of a VAPSE (variation affecting protein structure or expression) paradigm, but a major problem is that the efficiency in the choice of candidates is inevitably a function of the level of previous understanding of disease pathophysiology. To date, most candidate gene studies in bipolar disorder have focussed on the major neurotransmitter systems that are influenced by medication used in clinical management of the disorder. Early studies often used anonymous markers in the hope of detecting linkage disequilibrium but recently direct examination of polymorphisms of known or presumed functional relevance has become more usual. Most studies in the literature have been of the unrelated case–control design with samples rarely exceeding 200–300 subjects. No definitive findings have yet emerged although there have been some interesting preliminary findings including those with polymorphisms within the genes encoding catechol- o -methyl transferase (COMT), monoamine oxidase A (MAOA) and the serotonin transporter (hSERT; 5-HTT). In this article we critically review the current status of the literature within the context of the important methodological issues and limitations inherent in the use of association studies for genetic dissection of bipolar disorder. We conclude by examining likely future directions and developments in the field.     

Cigarette smoking in the early course of bipolar disorder: association with ages-at-onset of alcohol and marijuana use

Objectives: Despite the high prevalence of smoking among individuals with bipolar disorder, few studies have attempted to identify correlates of smoking status in this group. We examined illness characteristics of bipolar disorder as well as co-occurring alcohol and marijuana use as correlates of cigarette smoking, including the developmental timing of the onset of regular alcohol and cannabis use (i.e., three or more times per week for a month or more). Methods: Demographic and clinical characteristics of 134 patients with bipolar I disorder, the majority of whom were adolescents, who were hospitalized for their first manic episode were analyzed to identify correlates of smoking status. Results: A total of 61 (45.5%) of the patients were smokers at the time of their first hospitalization. Smokers were significantly more likely than nonsmokers to report recent use of marijuana (55.7% versus 18.1%) and alcohol (67.2% versus 25.4%). Among those who had ever used marijuana (48.5%) or alcohol (45.5%) regularly, current cigarette smokers reported a significantly earlier age-at-onset of regular use of both substances than reported by nonsmokers. Earlier age-at-onset of marijuana use was the only significant predictor of current smoking in a multivariate analysis. None of the bipolar disorder characteristics examined (i.e., symptom severity, age-at-onset of illness, rapid cycling, and psychosis) were correlated with smoking status. Conclusions: Smoking status in the early course of bipolar disorder is related to both current and past alcohol and marijuana use, but not to characteristics of bipolar illness. Earlier initiation of regular marijuana use is associated with an increased risk of smoking cigarettes.     

A retrospective study of symptom patterns of cannabis-induced psychosis

The aim of this study was to find out whether there are any similarities between cannabis psychosis on the one hand and schizophrenia and mania on the other, and to delineate any consistency in the pattern of clinical symptoms of cannabis psychosis. Relevant data were collected from patient's case-notes depicting biographical information and the frequencies of mental symptoms. Age and duration in hospital agreed between the 3 groups. Although several significant differences were recorded in the distribution of mental symptoms, it was not possible to demonstrate a consistent pattern of symptoms typical of cannabis psychosis.     

Rates, types, and psychosocial correlates of legal charges in adolescents with newly diagnosed bipolar disorder

OBJECTIVES: To examine the rates, types, and psychosocial correlates of legal charges in adolescents with newly diagnosed bipolar disorder (BD). METHODS: Adolescents (n = 80), between the ages of 12 and 21 years (mean = 15.6, standard deviation = 2.3), hospitalized for their initial manic or mixed episode of BD, were evaluated for the incidence of prior juvenile offending (i.e., legal charges). We examined potential psychosocial correlates associated with legal charges using chi-square, t-tests, and discriminant function analyses to determine if there were differences between adolescents who did and did not offend prior to their first manic episode. RESULTS: Juvenile antisocial behaviors were common (55%) for adolescents with newly diagnosed BD. Discriminant function analysis revealed that older age at first treatment (p < 0.01), sexual activity over the previous month (p < 0.05), therapeutic use of stimulants (p < 0.05), and anxiety disorders were the most significant factors to differentiate between bipolar adolescents who offended and those who did not (Wilks' lambda = 0.80, p < 0.005). CONCLUSIONS: Our findings indicate that there are identifiable psychosocial correlates associated with antisocial behaviors in adolescents with newly diagnosed BD that may improve our understanding of juvenile antisocial behaviors.     

Phenomenology of mixed states: a principal component analysis study

OBJECTIVES: To contribute to the definition of external and internal limits of mixed states and study the place of dysphoric symptoms in the psychopathology of mixed states. METHODS: One hundred and sixty-five inpatients with major mood episodes were diagnosed as presenting with either pure depression, mixed depression (depression plus at least three manic symptoms), full mixed state (full depression and full mania), mixed mania (mania plus at least three depressive symptoms) or pure mania, using an adapted version of the Mini International Neuropsychiatric Interview (DSM-IV version). They were evaluated using a 33-item inventory of depressive, manic and mixed affective signs and symptoms. RESULTS: Principal component analysis without rotation yielded three components that together explained 43.6% of the variance. The first component (24.3% of the variance) contrasted typical depressive symptoms with typical euphoric, manic symptoms. The second component, labeled 'dysphoria', (13.8%) had strong positive loadings for irritability, distressing sensitivity to light and noise, impulsivity and inner tension. The third component (5.5%) included symptoms of insomnia. Median scores for the first component significantly decreased from the pure depression group to the pure mania group. For the dysphoria component, scores were highest among patients with full mixed states and decreased towards both patients with pure depression and those with pure mania. CONCLUSIONS: Principal component analysis revealed that dysphoria represents an important dimension of mixed states.     

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

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.