A randomized controlled trial comparing lithium plus valproic acid versus lithium plus carbamazepine in young patients with type 1 bipolar disorder: the LICAVAL study.

BACKGROUND: Treatment of bipolar disorder (BD) usually requires drug combinations. Combinations of lithium plus valproic acid (Li/VPA) and lithium plus carbamazepine (Li/CBZ) are used in clinical practice but were not previously compared in a head-to-head trial. OBJECTIVE: The objective of this trial was to compare the efficacy and tolerability of Li/VPA versus Li/CBZ in treating type 1 BD in any phase of illness in young individuals. METHODS: LICAVAL was a randomized, unicenter, open-label, parallel-group trial that was conducted from January 2009 to December 2012 in a tertiary hospital in São Paulo, Brazil. Participants were between 18 and 35 years old and were followed up for 2 years. Our primary outcome was the number of participants achieving/maintaining response and remission during the acute and maintenance phases of BD treatment, respectively. Other outcomes assessed were symptom severity and adverse events throughout the study. In the analysis of the primary outcome, we compared groups by using a two-way repeated measures analysis of variance and estimated effect sizes by using Cohen's d. RESULTS: Of our 64 participants, 36 were allocated to Li/VPA and 28 to Li/CBZ. Our sample was composed predominantly of females (66.6%) and the average age was 27.8 years. A total of 27 (45.0%) participants had depression, 17 (28.3%) had mania/hypomania, and 16 (26.7%) had a mixed state. We found no between-group differences in CGI-BP (Clinical Global Impression Scale modified for use in bipolar disorder) scores (P = 0.326) or in any other outcome. Side effects differed significantly between groups only in the first week of treatment (P = 0.021), and there were more side effects in the Li/VPA group. Also, the Li/VPA group gained weight (+2.1 kg) whereas the Li/CBZ group presented slight weight loss (-0.2 kg). CONCLUSION: Our study suggests that Li/VPA and Li/CBZ have similar efficacy and tolerability in BD but that Li/CBZ might have metabolic advantages in the long term. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00976794 . Registered on September 9, 2009.

Antidepressant Efficacy of Adjunctive Aerobic Activity and Associated Biomarkers in Major Depression: A 4-Week, Randomized, Single-Blind, Controlled Clinical Trial.

BACKGROUND: Major depressive disorder (MDD) is a highly prevalent, heterogeneous and systemic medical condition. Treatment options are limited, and recent studies have suggested that physical exercise can play an important role in the therapeutics of MDD. The aim of this study was to evaluate the antidepressant efficacy of adjunctive aerobic activity in association with pharmacotherapy (selective serotonin reuptake inhibitor) in symptomatic MDD as well as its association with physiological biomarkers. METHODS: In this randomized, single-blind, add-on, controlled clinical trial, 57 patients (18-55 years of age) were followed-up for 28 days. All patients were drug-free, had been diagnosed with symptomatic MDD and received flexible dose of sertraline during the trial. Patients were randomized to either a 4-week program (4x/week) of add-on aerobic exercise (exercise group, N = 29) or no activity (control group, N = 28). Depression severity was assessed using the Hamilton Rating Scale for Depression (HAM-D) as the primary outcome. At baseline and endpoint, all patients underwent a comprehensive metabolic/cardiopulmonary exercise testing-including determination of maximal oxygen uptake (VO2max), VO2 at the second ventilatory threshold (VO2-VT2), and oxygen pulse (O2 pulse). RESULTS: Depression scores significantly decreased in both groups after intervention. Importantly, patients in the aerobic exercise group required lower sertraline dose compared to the control group (sertraline monotherapy). The VO2max and O2 pulse parameters increased over time only in the exercise group and remained unchanged in the control group. CONCLUSIONS: The present findings suggest that a 4-week training of aerobic exercise significantly improves functional capacity in patients with MDD and may be associated with antidepressant efficacy. This approach may also decrease the need for higher doses of antidepressants to achieve response. Further studies in unmedicated and treatment-resistant MDD patients are needed in order to confirm the utility of short-term aerobic exercise as an alternative therapeutic approach in MDD. TRIAL REGISTRATION: ClinicalTrials.gov NCT02427789.

Gender effects of the COMT Val 158 Met genotype on verbal fluency in healthy adults.

Cognitive performance in healthy individuals is associated with gender differences in specific tests; a female advantage has been demonstrated in language tests, whereas a male advantage has been demonstrated in spatial relation examinations. The prefrontal cortex (PFC) mediates important cognitive domains and is influenced by dopamine (DA) activity. The single nucleotide polymorphism (SNP) rs4680 in the catechol­O­methyltransferase (COMT) gene results in an amino acid substitution from valine (Val) to methionine (Met). The Met allele has been demonstrated to decrease COMT enzyme activity and improve PFC cognitive function. COMT regulates DA activity in the PFC and exhibits gender effects. The aim of the present study was to investigate the gender­specific effects of the COMT genotype on cognition in healthy young adults. Seventy­six healthy subjects were genotyped for COMT rs4680 and submitted to an extensive range of neuropsychological tests assessing aspects of PFC function. The COMT Met allele influenced the performance of executive function. The results revealed gender effects of the COMT rs4680 Met allele on verbal fluency, with positive effects in males and negative effects in females. This suggested that DA activity affects cognitive function in different ways, according to gender.

The ARIQUELI study: potentiation of quetiapine in bipolar I nonresponders with lithium versus aripiprazole.

BACKGROUND: The treatment of bipolar disorder (BD) remains a challenge due to the complexity of the disease. Current guidelines represent an effort to assist clinicians in routine practice but have several limitations, particularly concerning long-term treatment. The ARIQUELI (efficacy and tolerability of the combination of lithium or aripiprazole in young bipolar non or partial responders to quetiapine monotherapy) study aims to evaluate two different augmentation strategies for quetiapine nonresponders or partial responders in acute and maintenance phases of BD treatment. METHODS/DESIGN: The ARIQUELI study is a single-site, parallel-group, randomized, outcome assessor-blinded trial. BD I patients according to the DSM-IV-TR, in depressive, manic/hypomanic or mixed episode, aged 18 to 40 years, are eligible. After diagnostic assessments, patients initiated treatment in phase I with quetiapine. Nonresponders or partial responders after 8 weeks are allocated into one of two groups, potentiated with either lithium (0.5 to 0.8 mEq/l) or aripiprazole (10 or 15 mg). Patients will be followed up for 8 weeks in phase I (acute treatment), 6 months in phase II (continuation treatment) and 12 months in phase III (maintenance treatment). Outcome assessors are blinded to the treatment. The primary outcome is the evaluation of changes in mean scores on the CGI-BP-M between baseline and the endpoint at the end of each study phase. DISCUSSION: The ARIQUELI study is currently in progress, with patients undergoing acute treatment (phase I), potentiation (phase II) and maintenance (phase III). The study will be extended until January 2015. Trials comparing lithium and aripiprazole with potentiate treatment in young BD I nonresponders to quetiapine in monotherapy can provide relevant information on the safety of these drugs in clinical practice. Long-term treatment is an issue of great importance and should be evaluated further through more in-depth studies given that BD is a chronic disease. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01710163.

Does BDNF genotype influence creative output in bipolar I manic patients?

INTRODUCTION: Creativity is a complex human ability influenced by affective and cognitive components but little is known about its underlying neurobiology. Bipolar Disorder (BD) is highly prevalent among creative individuals. Brain-derived neurotrophic factor (BDNF) is the most widely distributed neurotrophic factor, and has been implicated in the pathophysiology of BD. In contrast to the better functioning of the BDNF polymorphism (Val(66)Met) Val allele, the Met allele decreases BDNF transport and has been associated with worsened performance on several cognitive domains in euthymic BD subjects and controls. We hypothesized that the Val allele is associated with increased creativity in bipolar disorder. MATERIALS AND METHODS: Sixty-six subjects with BD (41 in manic and 25 in depressive episodes) and 78 healthy volunteers were genotyped for BDNF Val(66)Met and tested for creativity using the Barrow Welsh Art Scale (BWAS) and neuropsychological tests. RESULTS: Manic patients with the Val allele (Met-) had higher BWAS scores than Met+ carriers. This relationship was not observed among patients in depressive episodes or among control subjects. BDNF Met allele status showed no association with cognitive function in any of the groups. CONCLUSION: As postulated, these findings suggest that the better functioning allele of BDNF may selectively facilitate creative thinking in subjects with manic episodes, but not in controls or depressives. Further studies exploring the role of BDNF in the neurobiology of creativity in BD and in euthymic phases are warranted.