Masoud Kamali

A high-risk study of bipolar disorder. Childhood clinical phenotypes as precursors of major mood disorders.

CONTEXT The childhood precursors of adult bipolar disorder (BP) are still a matter of controversy. OBJECTIVE To report the lifetime prevalence and early clinical predictors of psychiatric disorders in offspring from families of probands with DSM-IV BP compared with offspring of control subjects. DESIGN A longitudinal, prospective study of individuals at risk for BP and related disorders. We report initial (cross-sectional and retrospective) diagnostic and clinical characteristics following best-estimate procedures. SETTING Assessment was performed at 4 university medical centers in the United States between June 1, 2006, and September 30, 2009. PARTICIPANTS Offspring aged 12 to 21 years in families with a proband with BP (n = 141, designated as cases) and similarly aged offspring of control parents (n = 91). MAIN OUTCOME MEASURE Lifetime DSM-IV diagnosis of a major affective disorder (BP type I; schizoaffective disorder, bipolar type; BP type II; or major depression). RESULTS At a mean age of 17 years, cases showed a 23.4% lifetime prevalence of major affective disorders compared with 4.4% in controls (P = .002, adjusting for age, sex, ethnicity, and correlation between siblings). The prevalence of BP in cases was 8.5% vs 0% in controls (adjusted P = .007). No significant difference was seen in the prevalence of other affective, anxiety, disruptive behavior, or substance use disorders. Among case subjects manifesting major affective disorders (n = 33), there was an increased risk of anxiety and externalizing disorders compared with cases without mood disorder. In cases but not controls, a childhood diagnosis of an anxiety disorder (relative risk = 2.6; 95% CI, 1.1-6.3; P = .04) or an externalizing disorder (3.6; 1.4-9.0; P = .007) was predictive of later onset of major affective disorders. CONCLUSIONS Childhood anxiety and externalizing diagnoses predict major affective illness in adolescent offspring in families with probands with BP.

Differential executive functioning performance by phase of bipolar disorder

Ryan KA, Vederman AC, McFadden EM, Weldon AL, Kamali M, Langenecker SA, McInnis MG. Differential executive functioning performance by phase of bipolar disorder. Bipolar Disord 2012: 14: 527–536.

Association of exercise with quality of life and mood symptoms in a comparative effectiveness study of bipolar disorder

BACKGROUND Individuals with bipolar disorder lead a sedentary lifestyle associated with worse course of illness and recurrence of symptoms. Identifying potentially modifiable predictors of exercise frequency could lead to interventions with powerful consequences on the course of illness and overall health. METHODS The present study examines baseline reports of exercise frequency of bipolar patients in a multi-site comparative effectiveness study of a second generation antipsychotic (quetiapine) versus a classic mood stabilizer (lithium). Demographics, quality of life, functioning, and mood symptoms were assessed. RESULTS Approximately 40% of participants reported not exercising regularly (at least once per week). Less frequent weekly exercise was associated with higher BMI, more time depressed, more depressive symptoms, and lower quality of life and functioning. In contrast, more frequent exercise was associated with experiencing more mania in the past year and more current manic symptoms. LIMITATIONS Exercise frequency was measured by self-report and details of the exercise were not collected. Analyses rely on baseline data, allowing only for association analyses. Directionality and predictive validity cannot be determined. Data were collected in the context of a clinical trial and thus, it is possible that the generalizability of the findings could be limited. CONCLUSION There appears to be a mood-specific relationship between exercise frequency and polarity such that depression is associated with less exercise and mania with more exercise in individuals with bipolar disorder. This suggests that increasing or decreasing exercise could be a targeted intervention for patients with depressive or mood elevation symptoms, respectively.

Associations between suicide attempts and elevated bedtime salivary cortisol levels in bipolar disorder

BACKGROUND Hypothalamic-pituitary-adrenal (HPA) axis abnormalities have been reported in bipolar disorder and also in suicidal behavior, but few studies have examined the relationship between suicidal behaviors and the HPA axis function in bipolar disorder, attending to and minimizing confounding factors. We compare HPA axis activity in bipolar individuals with and without suicidal behavior and unaffected healthy controls through measurement of salivary cortisol. METHOD Salivary cortisol was collected for three consecutive days in 29 controls, 80 bipolar individuals without a history of suicide and 56 bipolar individuals with a past history of suicide. Clinical factors that affect salivary cortisol were also examined. RESULTS A past history of suicide was associated with a 7.4% higher bedtime salivary cortisol level in bipolar individuals. There was no statistical difference between non-suicidal bipolar individuals and controls in bedtime salivary cortisol and awakening salivary cortisol was not different between the three groups. LIMITATIONS The measure of salivary cortisol was a home based collection by the study subjects and the retrospective clinical data was primarily based on their historical account. CONCLUSIONS Bipolar individuals with a past history of suicidal behavior exhibit hyperactivity in the HPA axis. This biological marker remains significant regardless of demographic factors, mood state, severity and course of illness. This finding in bipolar disorder is consistent with the evidence for altered HPA axis functioning in suicide and mood disorders and is associated with a clinical subgroup of bipolar patients at elevated risk for suicide based on their history, and in need of further attention and study.

Medical burden in bipolar disorder: findings from the Clinical and Health Outcomes Initiative in Comparative Effectiveness for Bipolar Disorder study (Bipolar CHOICE)

OBJECTIVES Individuals with bipolar disorder have high rates of other medical comorbidity, which is associated with higher mortality rates and worse course of illness. The present study examined common predictors of medical comorbidity. METHODS The Clinical and Health Outcomes Initiative in Comparative Effectiveness for Bipolar Disorder study (Bipolar CHOICE) enrolled 482 participants with bipolar I or bipolar II disorder in a six-month, randomized comparative effectiveness trial. Baseline assessments included current and lifetime DSM-IV-TR diagnoses, demographic information, psychiatric and medical history, severity of psychiatric symptoms, level of functioning, and a fasting blood draw. Medical comorbidities were categorized into two groups: cardiometabolic (e.g., diabetes, hyperlipidemia, and metabolic syndrome) and non-cardiovascular (e.g., seizures, asthma, and cancer). Additionally, we looked at comorbid substance use (e.g., smoking and drug dependence). RESULTS We found that 96.3% of participants had at least one other medical comorbidity. Older age predicted a greater likelihood of having a cardiometabolic condition. Early age of onset of bipolar symptoms was associated with a lower chance of having a cardiometabolic condition, but a greater chance of having other types of medical comorbidity. Additional predictors of other medical comorbidities in bipolar disorder included more time spent depressed, less time spent manic/hypomanic, and longer duration of illness. Medications associated with weight gain were associated with low high-density lipoprotein and abnormal triglycerides. CONCLUSIONS There appears to be a substantial medical burden associated with bipolar disorder, highlighting the need for collaborative care among psychiatric and general medical providers to address both psychiatric and other medical needs concomitantly in this group of patients.

Gender differences, clinical correlates, and longitudinal outcome of bipolar disorder with comorbid migraine.

OBJECTIVE Migraine is a common comorbidity of bipolar disorder and is more prevalent in women than men. We hypothesized comorbid migraine would be associated with features of illness and psychosocial risk factors that would differ by gender and impact outcome. METHOD A retrospective analysis was conducted to assess association between self-reported, physician-diagnosed migraine, clinical variables of interest, and mood outcome in subjects with DSM-IV bipolar disorder (N = 412) and healthy controls (N = 157) from the Prechter Longitudinal Study of Bipolar Disorder, 2005-2010. Informed consent was obtained from all participants. RESULTS Migraine was more common in subjects with bipolar disorder (31%) than in healthy controls (6%) and had elevated risk in bipolar disorder women compared to men (OR = 3.5; 95% CI, 2.1-5.8). In men, migraine was associated with bipolar II disorder (OR = 9.9; 95% CI, 2.3-41.9) and mixed symptoms (OR = 3.5; 95% CI, 1.0-11.9). In comparison to absence of migraine, presence of migraine was associated with an earlier age at onset of bipolar disorder by 2 years, more severe depression (β = .13, P = .03), and more frequent depression longitudinally (β = .13, P = .03). Migraine was correlated with childhood emotional abuse (P = .01), sexual abuse (P = 4 × 10⁻³), emotional neglect (P = .01), and high neuroticism (P = 2 × 10⁻³). Protective factors included high extraversion (P = .02) and high family adaptability at the trend level (P = .08). CONCLUSIONS Migraine is a common comorbidity with bipolar disorder and may impact long-term outcome of bipolar disorder, particularly depression. Clinicians should be alert for migraine comorbidity in women and in men with bipolar II disorder. Effective treatment of migraine may impact mood outcome in bipolar disorder as well as headache outcome. Joint pathophysiologic mechanisms between migraine and bipolar disorder may be important pathways for future study of treatments for both disorders.

Bipolar CHOICE (clinical health outcomes initiative in comparative effectiveness): A pragmatic 6-month trial of lithium versus quetiapine for Bipolar disorder

BACKGROUND Bipolar disorder is among the 10 most disabling medical conditions worldwide. While lithium has been used extensively for bipolar disorder since the 1970s, second-generation antipsychotics (SGAs) have supplanted lithium since 1998. To date, no randomized comparative-effectiveness study has compared lithium and any SGA. METHOD Within the duration of the study (September 2010-September 2013), participants with bipolar I or II disorder (DSM-IV-TR) were randomized for 6 months to receive lithium (n = 240) or quetiapine (n = 242). Lithium and quetiapine were combined with other medications for bipolar disorder consistent with typical clinical practice (adjunctive personalized treatment [APT], excluding any SGA for the lithium + APT group and excluding lithium or any other SGA for the quetiapine + APT group). Coprimary outcome measures included Clinical Global Impressions-Efficacy Index (CGI-EI) and necessary clinical adjustments, which measured number of changes in adjunctive personalized treatment. Secondary measures included a full range of symptoms, cardiovascular risk, functioning, quality of life, suicidal ideation and behavior, and adverse events. RESULTS Participants improved across all measures, and over 20% had a sustained response. Primary (CGI-EI, P = .59; necessary clinical adjustments, P = .15) and secondary outcome changes were not statistically significantly different between the 2 groups. For participants with greater manic/hypomanic symptoms, CGI-EI changes were significantly more favorable with quetiapine + APT (P = .02). Among those with anxiety, the lithium + APT group had fewer necessary clinical adjustments per month (P = .02). Lithium was better tolerated than quetiapine in terms of the burden of side effects frequency (P = .05), intensity (P = .01), and impairment (P = .01). CONCLUSIONS Despite adequate power to detect clinically meaningful differences, we found outcomes with lithium + APT and quetiapine + APT were not significantly different across 6 months of treatment for bipolar disorder. TRIAL REGISTRATION ClinicalTrials.gov identifier for the Bipolar CHOICE study: NCT01331304.

Fats and Factors: Lipid Profiles Associate with Personality Factors and Suicidal History in Bipolar Subjects

Polyunsaturated fatty acids (PUFA) have shown efficacy in the treatment of bipolar disorder, however their specific role in treating the illness is unclear. Serum PUFA and dietary intakes of PUFA associate with suicidal behavior in epidemiological studies. The objective of this study was to assess serum n-3 and n-6 PUFA levels in bipolar subjects and determine possible associations with suicidal risk, including suicidal history and relevant personality factors that have been associated with suicidality. We studied 27 bipolar subjects using the NEO-PI to assess the big five personality factors, structured interviews to verify diagnosis and assess suicidal history, and lipomics to quantify n-3 and n-6 PUFA in serum. We found positive associations between personality factors and ratios of n-3 PUFA, suggesting that conversion of short chain to long chain n-3s and the activity of enzymes in this pathway may associate with measures of personality. Thus, ratios of docosahexaenoic acid (DHA) to alpha linolenic acid (ALA) and the activity of fatty acid desaturase 2 (FADS2) involved in the conversion of ALA to DHA were positively associated with openness factor scores. Ratios of eicosapentaenoic acid (EPA) to ALA and ratios of EPA to DHA were positively associated with agreeableness factor scores. Finally, serum concentrations of the n-6, arachidonic acid (AA), were significantly lower in subjects with a history of suicide attempt compared to non-attempters. The data suggest that specific lipid profiles, which are controlled by an interaction between diet and genetics, correlate with suicidal history and personality factors related to suicidal risk. This study provides preliminary data for future studies to determine whether manipulation of PUFA profiles (through diet or supplementation) can affect personality measures and disease outcome in bipolar subjects and supports the need for further investigations into individualized specific modulations of lipid profiles to add adjunctive value to treatment paradigms.

Modality-specific alterations in the perception of emotional stimuli in Bipolar Disorder compared to Healthy Controls and Major Depressive Disorder

OBJECTIVES Affect identification accuracy paradigms have increasingly been utilized to understand psychiatric illness including Bipolar Disorder (BD) and Major Depressive Disorder (MDD). This investigation focused on perceptual accuracy in affect identification in both visual and auditory domains among patients with BD, relative to Healthy Controls (HC) and patients with MDD. Demographic and clinical variables, in addition to medications were also investigated. METHOD The visual Facial Emotion Perception Test (FEPT) and auditory Emotional Perception Test (EPT) were administered to adults with BD (n=119) and MDD (n=78) as well as HC (n=66). RESULTS Performance on the FEPT was significantly stronger than on the EPT irrespective of group. Performance on the EPT did not significantly differentiate the groups. On the FEPT, BD samples had the greatest difficulty relative to HC in identification of sad and fearful faces. BD participants also had greater difficulty identifying sad faces relative to MDD participants though not after controlling for severity of illness factors. For the BD (but not MDD) sample several clinical variables were also correlated with FEPT performance. CONCLUSIONS The findings suggest that disruptions in identification of negative emotions such as sadness and fear may be a characteristic trait of BD. However, this effect may be moderated by greater illness severity found in our BD sample.

The double burden of age and disease on cognition and quality of life in bipolar disorder

Bipolar disorder (BPD) and normal aging are known to impact cognitive skills and health‐related quality of life (HRQOL). This study investigated how aging and disease interact in predicting cognitive and psychosocial outcomes.