Elsevier

Biological Psychiatry

Volume 48, Issue 6, 15 September 2000, Pages 558-572
Biological Psychiatry

Therapeutic approach
Bipolar depression: pharmacotherapy and related therapeutic strategies

https://doi.org/10.1016/S0006-3223(00)00980-XGet rights and content

Abstract

The depressed phase of bipolar affective disorder is a significant cause of suffering, disability, and mortality and represents a major challenge to treating clinicians. This article first briefly reviews the phenomenology and clinical correlates of bipolar depression and then focuses on the major pharmacological treatment options. We strongly recommend use of mood stabilizers as the first-line treatment for the type I form of bipolar depression, largely because longer-term preventative therapy with these agents almost certainly will be indicated. Depressive episodes that do not respond to lithium, divalproex, or another mood stabilizer, or episodes that “breakthrough” despite preventive treatment, often warrant treatment with an antidepressant or electroconvulsive therapy. The necessity of mood stabilizers in the type II form of bipolar depression is less certain, aside from the rapid cycling presentation. Both experts and practicing clinicians recommend bupropion and the selective serotonin reuptake inhibitors as coequal initial choices, with venlafaxine and monoamine oxidase inhibitors, such as tranylcypromine, preferred for more resistant cases. The risk of antidepressant-induced hypomania or mania with concomitant mood stabilizer therapy is low, on the order of 5% to 10% during acute phase therapy. Additional therapeutic options and optimal durations of therapy also are discussed.

Introduction

About 90% of people who experience an episode of mania will, at some point, also suffer a major depressive episode (Goodwin and Jamison 1990). For many with this classic form of mental illness, the morbidity and mortality risk of the depressive episodes outstrip the more notorious consequences of mania. Moreover, the hallmark of the type II form of bipolar disorder is that the depressive episodes are more numerous, lengthy, and/or severe than the hypomanias Coryell et al 1987, Dunner 1993. Indiscriminant use of antidepressants can accelerate cycling by inducing manias and mixed states (Altshuler et al 1995), yet failure to treat residual depressive features may reinforce demoralization and weaken the therapeutic alliance. For these reasons, bipolar affective disorder cannot be treated effectively without careful attention to management of depressive episodes. After briefly considering the phenomenology of the disorder, this article will review the major pharmacologic treatment options for bipolar depressive episodes.

Section snippets

Overview

How does bipolar depression differ from other depressive states? At the simplest level, the risk of treatment-emergent mania and the frequent need to combine mood stabilizers and antidepressants distinguish these conditions (Goldberg and Kocsis 1999); however, nearly 60 years before the routine use of antidepressants, Kraepelin (1921) suggested that the phenomenology of manic depression differed from melancholia in several respects, including more pronounced volitional inhibition (i.e.,

Antidepressants

One might assume that the effectiveness of antidepressant medications in bipolar depression is well established because the modern recognition of the disorder (e.g., Perris 1966) is so closely temporally linked to the antidepressant era. To the contrary, not a single antidepressant medication, nor even a particular class of antidepressant, has been demonstrated to be effective in at least two adequately powered, placebo-controlled clinical trials.

There are several reasons that the efficacy of

Mood stabilizers

The mood stabilizers, particularly lithium, divalproex, and carbamazepine, can be viewed as first-line treatments for bipolar I depression for several good reasons. First, virtually all patients with bipolar I disorder will need to be placed on a mood stabilizer anyway for subsequent prophylaxis. Second, these agents, when prescribed as monotherapies, have acute-phase antidepressant response rates of 30%–50% Sachs 1996, Srisurapanont et al 1995. Third, there is virtually no risk of accelerated

Neuroleptics

Like the anticonvulsants, neuroleptics have primarily been studied in mania, with knowledge about efficacy in the depressed phase of bipolar illness limited to clinical observations and case series. Of course, severe psychotic states of bipolar depression often warrant treatment with neuroleptics on clinical grounds, usually in combination with mood stabilizers and/or antidepressants.

Over the past few years the novel or atypical antipsychotics have gained increasing favor over the older

Other adjunctive options

As noted earlier, lithium salts have important antidepressant effects and can be used to augment an inadequate antidepressant response to divalproex, carbamazepine, or lamotrigine. The study by Young et al (2000) reviewed earlier found that the combination of divalproex and lithium was as effective as a mood stabilizer plus paroxetine combination, although less well tolerated. The next most important adjunctive therapeutic option for treatment of bipolar depression is thyroid hormone (Sachs

Other treatment approaches

These strategies can be loosely divided into “somatic” and “nonsomatic,” although it must be recognized that psychotherapies also may affect brain function either directly or indirectly (Thase 2000). The somatic interventions include electroconvulsive therapy (ECT), phototherapy, and sleep deprivation. Nonsomatic interventions include individual psychotherapies, such as cognitive behavior therapy (Basco and Rush 1996) and interpersonal and social rhythm therapy (Frank et al 1994),

Conclusions

The profound suffering, disability, and mortality associated with the depressed phase of bipolar disorder warrants a careful and systematic approach to therapeutics. The strategies recommended herein for treatment of bipolar I depression are largely consistent with recent expert-derived consensus guidelines and emphasize a “mood stabilizer first” approach to therapeutics (Figure 4). The viability of this approach is enhanced by the recent introduction of a number of pharmacologically distinct

Acknowledgements

Preparation of this report was supported in part by Grants Nos. 1N01 MH-80001-01 and MH-30915 (Mental Health Intervention Research Center).

Aspects of this work were presented at the conference “Bipolar Disorder: From Pre-Clinical to Clinical, Facing the New Millennium,” January 19–21, 2000, Scottsdale, Arizona. The conference was sponsored by the Society of Biological Psychiatry through an unrestricted educational grant provided by Eli Lilly and Company.

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