A review of FDA-approved treatment options in bipolar depression.

1 Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada.
CNS spectrums (Impact Factor: 1.3). 11/2013; DOI: 10.1017/S1092852913000746
Source: PubMed

ABSTRACT Objectives/Introduction Herein we review the evidence supporting Food and Drug Administration (FDA) approved and emerging treatments for bipolar depression.
A PubMed search of all English-language articles published up to July 2013 was conducted. The search terms were quetiapine, olanzapine-fluoxetine, olanzapine, lurasidone, ketamine, modafinil/armodafinil, and lamotrigine. The search was augmented with a manual review of relevant article reference lists, as well as posters presented at national and international meetings. Articles selected for review were based on the adequacy of sample size, the use of standardized diagnostic instruments, validated assessment measures, and overall manuscript quality.
Olanzapine-fluoxetine combination (OFC), quetiapine, and lurasidone are FDA-approved for the acute treatment of bipolar depression. Lurasidone is the most recently approved agent for bipolar depression. Olanzapine-fluoxetine combination and quetiapine are approved as single modality therapies while lurasidone is approved as a monotherapy and as an adjunct to lithium or divalproex. The overall effect size of the 3 treatments in mitigating depressive symptoms is similar. Clinically significant weight gain and metabolic disruption as well as sedation are significant limitations of OFC and quetiapine. The minimal propensity for weight gain as well as the metabolic neutrality of lurasidone in the bipolar population is a clinically significant advantage. Evidence also supports lamotrigine with compelling evidence as an adjunct to lithium and in recurrence prevention paradigm; suggested evidence also exists for ketamine and modafinil/armodafinil; notwithstanding, these treatments remain investigational.
Relatively few agents are FDA-approved for bipolar depression. The selection and sequencing of agents in bipolar depression should give primacy to those agents that are FDA-approved. Further refinement of the selection process will need to pay careful attention to the relative hazards of weight gain and metabolic disruption in this highly susceptible population. Other agents with differential mechanisms (eg, ketamine) offer a promising alternative in bipolar depression.

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    ABSTRACT: Bipolar Disorder (BD) is a unique disorder that transcends domains of function since the same patient can exhibit depression or mania, states with polar opposite mood symptoms. During depression, people feel helplessness, reduced energy, and risk aversion, while with mania behaviors include grandiosity, increased energy, less sleep, and risk preference. The neural mechanism(s) underlying each state are gaining clarity, with catecholaminergic disruption seen during mania, and cholinergic dysfunction during depression. The fact that the same patient cycles/switches between these states is the defining characteristic of BD however. Of greater importance therefore, is the mechanism(s) underlying cycling from one state - and its associated neural changes - to another, considered the 'holy grail' of BD research. Herein, we review studies investigating triggers that induce switching to these states. By identifying such triggers, researchers can study neural mechanisms underlying each state and importantly how such mechanistic changes can occur in the same subject. Current animal models of this switch are also discussed, from submissive- and dominant-behaviors to kindling effects. Focus however, is placed on how seasonal changes can induce manic and depressive states in BD sufferers. Importantly, changing photoperiod lengths can induce local switches in neurotransmitter expression in normal animals, from increased catecholaminergic expression during periods of high activity, to increased somatostatin and corticotrophin releasing factor during periods of low activity. Identifying susceptibilities to this switch would enable the development of targeted animal models. From animal models, targeted treatments could be developed and tested that would minimize the likelihood of switching. Copyright © 2015. Published by Elsevier B.V.
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    ABSTRACT: Study objective: this systematic review assessed the safety and efficacy of olanzapine-fluoxetine combination (OFC) for treatment of bipolar depression, specifically in studies of 8 to 12 weeks duration in adults (primary objective) and adolescents (secondary objective). Materials and methods: trials were identified using MEDLINE, EMBASE, Cochrane Library, Web of Knowledge, LILACS, WHOLIS, NEURO, Latindex, and DIALNET (2000 – July 2014). English and Spanish free-text and MeSH terms were used. Searches were supplemented with identified trials (Clinical and congress abstracts. Evidence from randomized controlled trials (RCTs), nonrandomized trials, and meta-analyses were considered. Results: nine publications reporting 5 RCTs (6 publications), 1 nonrandomized trial, and 2 meta-analyses were included. One RCT was conducted in adolescents and one RCT was conducted in a Latin American population. Studies enrolled from 34 to 833 participants, were conducted for 7 to 8 weeks and up to 6 months, and varied in methodological quality and reporting. The efficacy of OFC (depression rating scales, response and remission rates) was greater compared with olanzapine monotherapy, lamotrigine monotherapy, and placebo. OFC was well tolerated in adults and adolescents. However, there was a greater frequency of weight gain, somnolence, nausea, diarrhea, and elevated metabolic parameters in participants receiving OFC versus active comparators or placebo. Conclusions: this systematic review presents findings that OFC is effective and generally well tolerated for acute treatment of bipolar depression in adults and adolescents. Existing evidence suggests that the efficacy and safety profile of OFC in patients from Latin America is not different to Caucasian populations.
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