White matter alterations in antipsychotic- and mood stabilizer-naïve individuals with bipolar II/NOS disorder.

Structural magnetic resonance imaging (MRI) studies using voxel-based morphometry (VBM) and tract-based spatial statistics (TBSS) have been inconsistent in demonstrating impairments in gray matter (GM) and white matter (WM) structures in bipolar disorder (BD). This may be a consequence of significant confounding effects of medication, illness history and selection of controls in existing studies. Study of bipolar II or not-otherwise-specified (BD II/NOS) disorder provides a solution to these confounds and a bridge to unipolar cases across the affective spectrum. Thirty-eight euthymic, antipsychotic- and mood stabilizer-naïve young adults (mean age = 20.9 years) with BD II/NOS and 37 age-, cognitive ability- and gender-matched healthy controls (HCs) underwent MRI. Voxel-wise and regional gray matter volume comparisons were conducted using voxel-based morphometry (VBM). Tract-based spatial statistics (TBSS) were used to assess whole-brain WM, as indexed using fractional anisotropy (FA), mean diffusivity (MD), parallel and perpendicular diffusion values. No between-group differences were observed for whole-brain VBM comparisons. By contrast, in comparison to HCs, participants with BD II/NOS had significant widespread reductions in FA and increased MD and perpendicular diffusion values in virtually all the major cortical white matter tracts. These data suggest pathophysiological involvement of WM microstructures - but not GM macrostructures - in high functioning BD II/NOS patients at an early age and before significant clinical adversity has been recorded. We propose that white matter development is a valid candidate target for understanding genetic and environmental antecedents to bipolar disorder and mood disorder more generally.

Open adjunctive ziprasidone associated with weight loss in obese and overweight bipolar disorder patients.

OBJECTIVE: To assess effectiveness and tolerability of open adjunctive ziprasidone for weight loss in obese/overweight patients with bipolar disorders (BD) in diverse mood states, taking weight gain-implicated psychotropic medications. METHOD: 22 obese and three overweight BD patients (20 female; 10 BD-I, 14 BD-II, 1 BD-NOS) with mean ± SD baseline body mass index (BMI) of 31.8 ± 2.5 kg/m2 received ZIP (mean final dose 190 ± 92 mg/day) for mean of 79.2 ± 23.2 days. Weight was assessed at six weekly and three biweekly visits. Subjects entered the study in diverse mood states. At baseline, 21 were taking second-generation antipsychotics, 7 lithium, and 1 valproate, which could be reduced/discontinued at investigators' discretion. RESULTS: Weight and BMI decreased from baseline to endpoint by 4.5 ± 3.4 kg and 1.6 ± 1.2 kg/m2, respectively, at weekly rates of 0.37 kg and 0.13 kg/m2, respectively (all p < 0.00001). 48% of patients had at least 5% weight loss. Obesity rate decreased from 88% to 35% (p < 0.0001). Waist circumference decreased 1.6 inches (p = 0.0001). Overall, mood did not change. Patients with at least moderate baseline mood symptoms experienced significant mood improvement, despite 72% patients decreasing/discontinuing weight gain-implicated psychotropic medications. Seven patients discontinued ZIP early: 3 for weight loss inefficacy, and 1 each for viral gastroenteritis, loss of consciousness, pneumonia with hypomania, and lost to follow up. CONCLUSION: Open adjunctive ziprasidone may be effective for weight loss in obese/overweight BD patients taking weight gain-implicated psychotropic medications. These preliminary data should be considered with caution due to the open uncontrolled design, small sample size, and brief duration.

Sleep disturbance as transdiagnostic: consideration of neurobiological mechanisms.

Sleep disturbance is increasingly recognized as an important, but understudied, mechanism in the complex and multi-factorial causation of the symptoms and functional disability associated with psychiatric disorders. This review proposes that it is biologically plausible for sleep disturbance to be mechanistically transdiagnostic. More specifically, we propose that sleep disturbance is aetiologically linked to various forms of psychopathology through: its reciprocal relationship with emotion regulation and its shared/interacting neurobiological substrates in (a) genetics--genes known to be important in the generation and regulation of circadian rhythms have been linked to a range of disorders and (b) dopaminergic and serotonergic function--we review evidence for the interplay between these systems and sleep/circadian biology. The clinical implications include potentially powerful and inexpensive interventions including interventions targeting light exposure, dark exposure, the regulation of social rhythms and the reduction of anxiety. We also consider the possibility of developing a 'transdiagnostic' treatment; one treatment that would reduce sleep disturbance across psychiatric disorders.

Altered risk-aversion and risk-seeking behavior in bipolar disorder.

BACKGROUND: Bipolar disorder (BD) is associated with high-risk behaviors, such as gambling and impulsivity. However, little is known about the psychological factors that influence these behaviors or their significance for the development of the disorder. In this study, we investigated the effects of highlighting rewards versus highlighting punishments in the risky decision-making of euthymic individuals with bipolar disorder. METHODS: Twenty euthymic, medication-free men and women with previously undiagnosed bipolar II or bipolar disorder not otherwise specified and 20 age- and IQ-matched healthy men and women completed a computerized risky decision-making task in which mathematically equivalent dilemmas were presented in terms of opportunities to gain rewards ("positively-framed") or to avoid suffering losses ("negatively-framed"). The dependent measures were the proportion of risk-seeking choices (and deliberation times) when making decisions in positively versus negatively framed dilemmas. RESULTS: As expected, healthy control participants made more risky-seeking choices in response to the negatively framed dilemmas compared with the positively framed dilemmas. However, this effect was significantly attenuated in BD participants who also took significantly longer to make risk-averse responses to the positively framed dilemmas. The BD participants overestimated the number of bad outcomes arising out of positively framed dilemmas. CONCLUSIONS: These data demonstrate that risky choice in BD is associated with reduced sensitivity to emotional contexts that highlight rewards or punishments, possibly reflecting altered valuations of prospective gains and losses associated with behavioral options.

Adjunctive zonisamide for weight loss in euthymic bipolar disorder patients: a pilot study.

OBJECTIVE: To assess the effectiveness and tolerability of open adjunctive zonisamide in treatment of obesity in euthymic bipolar disorder (BD) patients. METHOD: Zonisamide was administered to recovered, overweight BD outpatients assessed with the Systematic Treatment Enhancement Program for Bipolar Disorders (STEP-BD) Affective Disorders Evaluation and followed with the STEP-BD Clinical Monitoring Form. Weight changes (Body Mass Index (BMI) and BMI percentage changes) were assessed prospectively at four weekly visits, one bi-weekly visit, and then five monthly visits, for a maximal duration of six months. Weight loss was assessed with random effects modeling to maximize all available data for analysis. RESULTS: Twenty-five BD (10 BD-type I, 15 BD-type II) patients (mean age 41.0+/-10.4 years, 64% female, 96% Caucasian) on a mean of 2.8+/-1.5 prescription psychotropic and 1.3+/-1.4 prescription non-psychotropic medications received zonisamide for a mean duration of 14.2+/-8.5 weeks, with a mean final dose of 375+/-206 (range 75-800) mg/day. Slope of weight loss was 0.078 BMI points per week, and non-zero (p<0.0005). Mean weight loss was 1.2+/-1.9 BMI points (baseline BMI 34.2+/-3.1 to final BMI 33.0+/-3.5, p<0.003). Eighteen patients (72%) discontinued study participation early, 11/25 (44%) due to emergent mood symptoms (eight depression, two mania, one subsyndromal mixed symptoms) requiring treatment intervention, 5/25 (20%) due to adverse physical events, and 2/25 (8%) due to patient choice, but none due to weight loss inefficacy. CONCLUSION: Adjunctive zonisamide appeared effective and generally physically tolerated, but had high rates of mood adverse events, in obese BD patients. Controlled trials are warranted to systematically explore these preliminary naturalistic observations.

Adjunctive aripiprazole in treatment-resistant bipolar depression.

BACKGROUND: There are limited management options for treatment-resistant depression in bipolar disorder (BD) patients. METHOD: Open adjunctive aripiprazole was administered to outpatients with treatment-resistant depression assessed with the Systematic Treatment Enhancement Program for BD (STEP-BD) Affective Disorders Evaluation, and followed with the STEP-BD Clinical Monitoring Form. RESULTS: Thirty BD (11 type I, 15 type II, 4 NOS) patients (mean age 44.4 +/- 17.0 years, 70% female) on a mean of 3.2 +/- 1.6 other psychotropic and 2.3 +/- 1.6 nonpsychotropic prescription medications received aripiprazole for a mean duration of 84 +/- 69 days, with a mean final dose of 15.3 +/- 11.2 (range 2.5-40) mg/day. Fourteen patients (47%) discontinued aripiprazole; due to inefficacy in 5/30 (17%), patient choice in 3/30 (10%), and adverse effects in 6/30 (20%). Aripiprazole yielded improvement in Clinical Global Impression-Severity (CGI-S, 4.4 +/- 1.1 to 3.8 +/- 1.2, p < 0.01), with 8/30 (27%) patients responding (CGI-S improvement > or = 2), including 4/30 (13%) who remitted (final CGI-S < or = 2). Global Assessment of Function, and depressed mood and suicidal ideation ratings also improved. Aripiprazole was generally well tolerated, with no significant change in mean adverse effect ratings or mean weight. CONCLUSION: Aripiprazole appeared effective and generally well tolerated in treatment-resistant bipolar depression. Controlled trials are warranted to systematically explore these preliminary naturalistic observations.

Magnetic resonance spectroscopic measurement of cerebral gamma-aminobutyric acid concentrations in patients with bipolar disorders.

BACKGROUND: Animal models of depression and psychopharmacological mechanisms of action suggest the importance of the gamma-amino butyric acid (GABA) system in the pathophysiology of mood disorders. Mood stabilizers have overlapping effects on GABAergic neurotransmission, and antidepressant use has been associated with alterations in GABAB receptor function. Magnetic resonance spectroscopy (MRS) provides an opportunity to noninvasively assess cerebral GABA concentrations in anterior paralimbic circuits that have been implicated in mood disorders. METHODS: In bipolar disorder patients and healthy control subjects, we used MRS with a modified GABA-edited point resolved spectroscopy sequence (TE 68 ms, TR 1500 ms, 512 averages, total scan time 26 min) to assess GABA in an 18-cm3 occipital voxel. In addition, in another cohort of bipolar disorder patients and healthy control subjects, we similarly assessed GABA in a 12.5-cm3 medial prefrontal/anterior cingulate (MPF/AC) voxel. The concentration of GABA was referenced to creatine (Cr) from unedited spectra. RESULTS: In bipolar patients and controls, we consistently detected 3.0 p.p.m. GABA peaks in occipital lobe and MPF/AC. In 16 bipolar (nine bipolar I and seven bipolar II) disorder patients, compared with six healthy control subjects, mean occipital GABA/Cr concentration was 61% higher. In addition, in 15 bipolar (five bipolar I, nine bipolar II, and one bipolar not otherwise specified) disorder patients, compared with six healthy control subjects, mean MPF/AC GABA/Cr concentration tended to be 41% higher. CONCLUSIONS: Patients with bipolar disorders may have increased cerebral GABA concentrations. Although this was more evident in the occipital lobe, MPC/AC GABA disturbance may be of greater potential interest in view the more established role of MPF/AC in affective processing. Additional studies are warranted to assess changes in GABAergic neurotransmission and the influences of diagnosis, mood state, and medication status in bipolar disorder patients.

Dermatology precautions and slower titration yield low incidence of lamotrigine treatment-emergent rash.

OBJECTIVE: To assess treatment-emergent rash incidence when using dermatology precautions (limited antigen exposure) and slower titration during lamotrigine initiation. METHOD: We assessed rash incidence in 100 patients with DSM-IV bipolar disorder instructed, for their first 3 months taking lamotrigine, to avoid other new medicines and new foods, cosmetics, conditioners, deodorants, detergents, and fabric softeners, as well as sunburn and exposure to poison ivy/oak. Lamotrigine was not started within 2 weeks of a rash, viral syndrome, or vaccination. In addition, lamotrigine was titrated more slowly than in the prescribing information. Patients were monitored for rash and clinical phenomena using the Systematic Treatment Enhancement Program for Bipolar Disorder Clinical Monitoring Form. Descriptive statistics were compiled. RESULTS: No patient had serious rash. Benign rash occurred in 5 patients (5%) and resolved uneventfully in 3 patients discontinuing and 2 patients continuing lamotrigine. Two patients with rash were found to be not adherent to dermatology precautions. Therefore, among the remaining patients, only 3/98 (3.1%) had benign rashes. CONCLUSION: The observed rate of benign rash was lower than the 10% incidence in other clinical studies. The design of this study confounds efforts to determine the relative contributions of slower titration versus dermatology precautions to the low rate of rash. Systematic studies are needed to confirm these preliminary findings, which suggest that adhering to dermatology precautions with slower titration may yield a low incidence of rash with lamotrigine.