Efficacy and tolerability of treatments for bipolar depression

doi:10.1016/j.jad.2015.05.016

Journal of Affective Disorders

Volume 183, 1 September 2015, Pages 258-262

https://doi.org/10.1016/j.jad.2015.05.016 Get rights and content

Highlights

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Treatments for acute bipolar depression were rated by number-needed-to-treat or harm (NNT, NNH).
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Older antidepressants were more effective than modern agents (NNT=4.5 vs. 7.4).
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Carbamazepine, valproate, lamotrigine were effective (NNT<6).
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Lamotrigine was especially well-tolerated (NNH>20).
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Olanzapine+fluoxetine, lurasidone and quetiapine were most effective antipsychotics (NNT<6).
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Olanzapine, aripiprazole, and ziprasidone were less effective (NNT>10).
•
Lurasidone was the best-tolerated antipsychotic (NNH>20).

Abstract

Background

Depression in bipolar disorder is a major therapeutic challenge associated with disability and excess mortality.

Methods

We reviewed findings from randomized placebo-controlled trials concerning efficacy and adverse effects of treatments for acute bipolar depression, including anticonvulsants, antidepressants, lithium, and modern antipsychotics, to compare numbers-needed-to-treat (NNT) versus -to-harm (NNH).

Results

Included were data from 22 reports involving 33 drug-placebo pairs. Antidepressants (especially modern drugs) had the most favorable (highest) risk/benefit ratio (pooled NNH/NNT=18.1). Anticonvulsants were effective agents (pooled NNT=5.06), but carbamazepine and valproate were not as well tolerated (NNH<10) as lamotrigine, and they had an unfavorable pooled NNH/NNT (3.75). Some antipsychotics (lurasidone, olanzapine+fluoxetine, and quetiapine (NNT all < 10) were effective though aripiprazole and ziprasidone were not (NNT≥45); olanzapine alone was weakly effective (NNT=11.3), and all but lurasidone (NNH=20.2) were not well tolerated (NNH≤4.18). Lithium appeared to be poorly effective but well tolerated in only one trial.

Conclusions

Some anticonvulsants and antipsychotics seemed effective for acute bipolar depression, but most antipsychotics were not well tolerated. Antidepressants were effective and well-tolerated; lithium remains inadequately tested.

Limitations

There are remarkably few short-term treatment trials (2.75/12 treatments), and fewer long-term trials for bipolar depression, possibly arising from exaggerated concerns about inducing mania.

Introduction

Bipolar disorder (BD) is a disabling, episodic or recurrent illness associated with potentially severe functional impairment, co-occurring psychiatric and somatic morbidity, and premature mortality from both suicide and medical illnesses (Sanders and Goodwin, 2010). Lifetime prevalence of BD, as types I (with mania) and II (with hypomania), is at least 1–2% of the general population, and higher if broad diagnostic criteria include recurrent major depression with minor hypomanic features (Zimmermann et al., 2009). Major mood disorders produce unusually high illness burdens (Ferrari et al., 2010; WHO, 2012). Depressive, dysthymic, and dysphoric-agitated mixed-states contribute particularly strongly to morbidity, disability, and excess mortality (Baldessarini 2013), and depressive components of BD are not well controlled by current clinical treatment (Martínez-Arán et al., 2004; Forte. et al., 2015).

Modern antidepressants have become the leading form of treatment provided to BD patients, regardless of current clinical state (Baldessarini et al., 2008), and despite ongoing controversy about their efficacy and risk of mood-switching, especially without mood-stabilizing treatment (Tohen et al., 2003, Tondo et al., 2010, Pacchiarotti et al., 2013). Yet, adequate assessment of treatments for bipolar depression is greatly constrained by the limited and inconsistent research-based information available despite more than a half-century of research and clinical use of mood-altering drugs (Ghaemi et al., 2008, Baldessarini, 2013, Tondo et al., 2013, Vázquez et al., 2013, Selle et al., 2014). Particularly striking is the rarity of studies of effects of lithium on acute bipolar depression (Young et al., 2010), despite its prolonged clinical use and expert support as a first-line treatment (Yatham et al., 2013). This general lack of therapeutics research on such a prevalent, disabling and potentially lethal disorder is remarkable.

Given the lack of clarity regarding the comparative efficacy and tolerability of treatments for bipolar depression, we reviewed reports of controlled trials testing short-term efficacy and indications of relative tolerability of available treatments in acute bipolar depression. Comparisons are based on meta-analytically estimated number-needed-to-treat (NNT) to indicate efficacy, and of number-needed-to-harm (NNH) by common clinically encountered adverse effects as an indication of tolerability—both in comparison to placebo-treatment. These convenient and readily grasped measures express relative cost-benefit relationships as the NNH/NNT ratio (Cookson et al., 2007, Citrome et al., 2014).

Section snippets

Methods

Comprehensive literature searching of several computerized databases (PubMed, Google Scholar, and Medline) through December 2014 used combinations of the search terms “bipolar depression”, “controlled”, “randomized”, “clinical trial”, and “efficacy”. Studies included were randomized, nominally double-blinded trials of treatments (antidepressants, anticonvulsants, lithium, and modern antipsychotic–antimanic drugs) for acute depression in adults diagnosed with BD by modern criteria; all were

Overall findings

Of the 22 included trials, 11 had more than one drug-arm, to yield a total of 10 trials of anticonvulsants, 8 of antidepressants (separated into older (imipramine, phenelzine) and newer agents (fluoxetine, paroxetine, bupropion)), 14 for antipsychotics, and only 1 for lithium carbonate, or a total of 33 drug-placebo pairs. There were 7846 unique subjects (adjusted from 8566 subjects for 720 placebo-treated participants in two-comparisons trials): 4770 randomized to a drug and 3076 to placebo.

Discussion

Despite severe clinical and economic burdens associated with bipolar depression, it remains extraordinarily little-studied. This review summarizes the rather meager available research evidence concerning four plausible types of treatment options, based on the relationship of meta-analytically computed NNH to NNT as indicators of efficacy and tolerability, respectively.

Antidepressants appeared to be effective in the studies reviewed (NNT=4.52–7.43), and they were among the best-tolerated agents

Role of the funding source

Funding sources cited below had no role in the conduct or reporting of the present study.

Conflict of interest

No author or any immediate family member has financial relationships with commercial entities that might represent potential conflicts of interest in this work.

Acknowledgments

Supported in part by an award from the Aretæus Foundation of Rome and Centro Bini Private Donors (to LT), and by the Bruce J Anderson Foundation and the McLean Private Donors Research Fund (to RJB).

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Brief reportEfficacy and tolerability of treatments for bipolar depression

Highlights

Abstract

Background

Methods

Results

Conclusions

Limitations

Introduction

Section snippets

Methods

Overall findings

Discussion

Role of the funding source

Conflict of interest

Acknowledgments

J. Affect. Disord.

J. Affect. Disord.

J. Affect. Disord.

J. Affect. Disord.

Efficacy and safety of antidepressant monotherapy in the treatment of bipolar-II depression

Int. Clin. Psychopharmacol.

Chemotherapy in Psychiatry

Psychotropic medications for patients with bipolar disorder in the United States: polytherapy and adherence

Psychiatr. Serv.

Seven-week, randomized, double-blind trial of olanzapine/fluoxetine combination versus lamotrigine in the treatment of bipolar I depression

J. Clin. Psychiatry

A double-blind placebo-controlled study of lamotrigine monotherapy in outpatients with bipolar I depression

J. Clin. Psychiatry

A randomized, double-blind, placebo-controlled trial of quetiapine in the treatment of bipolar I or II depression

Am. J. Psychiatry

A comparison of fluoxetine imipramine and placebo in patients with bipolar depressive disorder

Int. Clin. Psychopharmacol.

Number needed to treat and time to response/remission for quetiapine monotherapy efficacy in acute bipolar depression: evidence from a large, randomized, placebo-controlled study

Int. Clin. Psychopharmacol.

Burden of depressive disorders by country, sex, age, and year: findings from the global burden of disease study 2010

PLoS Med.

Long term morbidity in bipolar I, bipolar II, and unipolar major depressive disorders

J. Affect. Disord.

Divalproex in the treatment of acute bipolar depression: a preliminary double-blind, randomized, placebo-controlled pilot study

J. Clin. Psychiatry

Long-term antidepressant treatment in bipolar disorder: meta-analyses of benefits and risks

Acta Psychiatr. Scand.

Lurasidone monotherapy in the treatment of bipolar I depression: a randomized, double-blind, placebo-controlled study

Am. J. Psychiatry

Lurasidone as adjunctive therapy with Lithium or Valproate for the treatment of bipolar I depression: a randomized, double-blind, placebo-controlled study

Am. J. Psychiatry

Two 6-week, randomized, double-blind, placebo-controlled studies of Ziprasidone in outpatients with bipolar I depression

J. Clin. Psychopharmacol.

Cognitive impairment in euthymic bipolar patients: implications for clinical and functional outcome

Bipolar Disord.

Brief report
Efficacy and tolerability of treatments for bipolar depression