Antidepressants in bipolar disorder: 7 myths and realities
Dispelling misconceptions leads to rationale-based steps for treating bipolar depression
Few topics are as controversial as the role of antidepressants for patients with bipolar disorder. Although depression usually is the predominant, most enduring mood state in bipolar disorder, clinicians often face uncertainty about using antidepressants because of concerns about safety and efficacy. Whether and when to use antidepressants for bipolar depression hinges on complex parameters that preclude any single, simple rule.
Rather than asking if antidepressants are useful or detrimental for depressed patients with bipolar disorder, a more practical question might be: Under what circumstances are antidepressants likely to be beneficial, deleterious, or ineffective for an individual patient? Because “real world” patients often have idiosyncrasies that defy practice guidelines’ generic treatment recommendations, clinicians who practice in the proverbial trenches need strategies to tailor treatments to each patient that are informed—but not dictated—by evidence-based research.
Concerns that antidepressants might precipitate mania were first described with tricyclic antidepressant (TCA) use in Europe in the 1960s. After bupropion and selective serotonin reuptake inhibitors (SSRIs) emerged, some clinicians believed they posed a lesser risk for this phenomenon compared with TCAs1,2 or monoamine oxidase inhibitors (MAOIs).3
Antidepressants’ potential to induce short-term mania/hypomania following acute exposure has been weighed against the longer-term risk for worsening illness course by increasing frequency of subsequent episodes (so-called cycle acceleration). In the 1980s, some researchers suggested that rapid cycling might—at least in some instances—represent an iatrogenic phenomenon caused by long-term antidepressant use. These issues remain controversial, but more than 20 years of research suggest that antidepressants induce mania or accelerate cycling in a smaller minority of bipolar disorder patients than was once thought.
Table 1 and Table 2 summarize findings from randomized controlled studies that have examined antidepressants’ efficacy for acute bipolar depression. Except for a study of fluoxetine plus olanzapine,4 no large-scale placebo-controlled trial has demonstrated superior antidepressant response to a mood stabilizer plus antidepressant compared with a mood stabilizer alone.
Antidepressants for bipolar depression: SSRIs and SNRIs*
Reported switch risk
86% response rate after 3 weeks in 6-week double-blind randomized comparison with imipramine or placeboa
38% response rate after 8 weeks of placebo-controlled monotherapy in bipolar II or NOS subjectsb
56% response rate over 8 weeks in combination with olanzapine; significantly better than placebo plus olanzapine (30%)c
Same as placebo when added to an antimanic drug (STEP-BD) for up to 26 weeksd
10.1% (reported only jointly for paroxetine or bupropion)
36% response rate (no different from placebo) when coadministered with therapeutically dosed lithium over 10 weekse
Same as divalproex plus lithium when coadministered with divalproex or lithium over 6 weeks (actual response rates not reported)f
43% response (coadministered with lithium, divalproex, or carbamazepine) over 6 weeksg
3% (not statistically significantly different from venlafaxine comparison arm)
41% improved (comparable to rates seen with bupropion [33%] or venlafaxine [36%] when coadministered with a mood stabilizer over 10 weeks)h
36% improved (comparable to rates seen with bupropion [33%] or sertraline [41%]) when coadministered with a mood stabilizer over 10 weeksh
48% response (coadministered with lithium, divalproex, or carbamazepine) over 6 weeksg
13% (not statistically significantly different from paroxetine comparison arm)
*No data are available for citalopram, desvenlafaxine, duloxetine, escitalopram, fluvoxamine, or milnacipran
NOS: not otherwise specified; SNRI: serotonin/norepinephrine reuptake inhibitor; SSRI: selective serotonin reuptake inhibitor; STEP-BD: Systematic Treatment Enhancement Program for Bipolar Disorder
Antidepressants for bipolar depression: MAOIs, TCAs, and bupropion*
Reported switch risk
81% response (monotherapy) in bipolar I (n=24) or bipolar II (n=32) patients over 16 weeksa
75% response among imipramine nonresponders (n=12)b
46% response over 8 weeks in 156 bipolar patients (some, but not all, took concomitant mood stabilizers), not significantly different from imipramine comparatorc
57% response rate after 3 weeks in a 6-week double-blind randomized comparison with fluoxetine or placebod
48% response (monotherapy) in bipolar I (n=24) or bipolar II (N=32) patients over 16 weeksa
53% response over 8 weeks in 156 bipolar patients (some, but not all, took concomitant mood stabilizers), not significantly different from moclobemide comparatorc
41% (coadministered with therapeutically dosed lithium)e
50% (5/10) response rate (coadministered with a mood stabilizer over 8 weeks)f
55% response (5/9) (coadministered with a mood stabilizer over 8 weeks)f
33% response rate (coadministered with mood stabilizers over 10 weeks)g
*No data are available for isocarboxazid, mirtazapine, nefazodone, phenelzine, or selegiline transdermal
MAOI: monoamine oxidase inhibitor; TCA: tricyclic antidepressant
MYTH 1: Antidepressant-induced mania is a highly prevalent, widespread problem.
Reality: Although some might argue that the precise relative risk of antidepressant-induced mania or hypomania is unknown (eg, considering intervening factors such as the natural illness course), recent literature suggests that the emergence of mania or hypomania can be reasonably attributed to antidepressant use in no more than 10% to 25% of patients with bipolar disorder.5,6 Part of the difficulty in estimating the true prevalence of antidepressant-induced mania involves variability and inconsistency in defining mania induction.
A recent consensus statement proposed a graduated series of definitions for treatment-emergent affective switch:7
- “Definite” switch involves fulfilling DSM-IV syndromic criteria for a manic, hypomanic, or mixed episode for at least 2 days, within 8 weeks of antidepressant introduction.
- “Likely” switches call for at least 2 DSM-IV mania or hypomania symptoms plus a Young Mania Rating Scale (YMRS) score >12, occurring for at least 2 days, within 12 weeks of antidepressant introduction.
- “Possible” switches require a “clear change” in mood or energy with a YMRS score >8, persisting ≥4 hours over 2 days, occurring within 12 weeks of antidepressant initiation.
Adverse effects such as agitation typically diminish or remit with dosage reductions or drug cessation, whereas true antidepressant-induced polarity switches persist even after the medication is discontinued. Moreover, it is often difficult—if not impossible—to know with certainty when a polarity switch results from treatment effects vs the natural illness course. In my experience, true manic or hypomanic syndromes soon after antidepressant exposure are less common than heterogeneous, nonspecific symptoms such as agitation, anxiety, insomnia, or worsening depression (ie, lack of efficacy).
MYTH 2: Antidepressant response rates are lower in bipolar depression.
Reality: It is difficult to draw broad conclusions about antidepressant response rates in unipolar vs bipolar depression because:
- few direct comparisons have been reported
- all relevant studies are retrospective
- small sample sizes in most studies may not have satisfactorily controlled for factors that could predispose to mood destabilization (Table 3).
What increases risk of antidepressant-induced mania?
History of antidepressant-induced mania or hypomania
Confers an approximate 2- to 5-fold increased risk for subsequent antidepressant-induced mania/hypomania, regardless of antidepressanta
Recent mania preceding current depressive episode
Higher risk for antidepressant-associated mania if current depressive episode was preceded by manic phaseb
Bipolar I vs bipolar II subtype
Greater risk for switch in bipolar Ic,d
Comorbid alcohol or substance use disorder
5- to 7-fold increased risk for antidepressant-associated maniae
Noradrenergic vs serotonergic antidepressants
Possible higher risk for mania induction with TCAs or SNRIs than with bupropionf or SSRIsg
Concurrent mania symptoms during a depressive episode
Mild or subthreshold mania symptoms during a depressive episode increase risk for maniah,i
Hyperthymic temperamental traits
Associated with increased likelihood of antidepressant-induced maniaj
SNRIs: serotonin/norepinephrine reuptake inhibitors; SSRIs: selective serotonin reuptake inhibitors; TCAs: tricyclic antidepressants
A retrospective review of bipolar (n=41) and unipolar (n=37) depressed patients by Ghaemi et al8 found no significant difference in acute nonresponse rates between the groups. Similarly, Bottlender et al9 found no differences in treatment response when comparing naturalistic antidepressant outcomes for 50 unipolar and 50 bipolar patients matched for age, sex, and illness duration. Comparable antidepressant response outcomes also were reported in a retrospective study of 2,032 unipolar and bipolar inpatients conducted by Möller et al,10 and between unipolar (n=31) vs bipolar II (n=17) depressed patients receiving venlafaxine monotherapy for 6 weeks.11