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Evidence-Based Reviews


Antidepressants in bipolar disorder: 7 myths and realities

Dispelling misconceptions leads to rationale-based steps for treating bipolar depression

Vol. 9, No. 5 / May 2010

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.

Early suspicions

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.

Table 1

Antidepressants for bipolar depression: SSRIs and SNRIs*

Acute efficacy

Reported switch risk

Fluoxetine (SSRI)

86% response rate after 3 weeks in 6-week double-blind randomized comparison with imipramine or placeboa

0%

38% response rate after 8 weeks of placebo-controlled monotherapy in bipolar II or NOS subjectsb

0%

56% response rate over 8 weeks in combination with olanzapine; significantly better than placebo plus olanzapine (30%)c

6%

Paroxetine (SSRI)

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

7%

Same as divalproex plus lithium when coadministered with divalproex or lithium over 6 weeks (actual response rates not reported)f

0%

43% response (coadministered with lithium, divalproex, or carbamazepine) over 6 weeksg

3% (not statistically significantly different from venlafaxine comparison arm)

Sertraline (SSRI)

41% improved (comparable to rates seen with bupropion [33%] or venlafaxine [36%] when coadministered with a mood stabilizer over 10 weeks)h

12%

Venlafaxine (SNRI)

36% improved (comparable to rates seen with bupropion [33%] or sertraline [41%]) when coadministered with a mood stabilizer over 10 weeksh

6%

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

Source:
References
a. Cohn JB, Collins G, Ashbrook E, et al. A comparison of fluoxetine, imipramine and placebo in patients with bipolar depressive disorder. Int Clin Psychopharmaol. 1989;4:313-322.
b. Amsterdam JD, Shults J. Fluoxetine monotherapy of bipolar type II and bipolar NOS major depression: a double-blind, placebo-substitution, continuation study. Int Clin Psychopharmacol. 2005;20:257-264.
c. Tohen M, Vieta E, Calabrese J, et al. Efficacy of olanzapine and olanzapine-fluoxetine combination in the treatment of bipolar I depression. Arch Gen Psychiatry. 2003;60:1079-1088.
d. Sachs GS, Nierenberg AA, Calabrese JR, et al. Effectiveness of adjunctive antidepressant treatment for bipolar depression. N Engl J Med. 2007;356:1711-1722.
e. Nemeroff CB, Evans DL, Gyulai L, et al. Double-blind, placebo-controlled comparison of imipramine and paroxetine in the treatment of bipolar depression. Am J Psychiatry. 2001;158:906-912.
f. Young LT, Joffe RT, Robb JC, et al. Double-blind comparison of addition of a second mood stabilizer versus an antidepressant to an initial mood stabilizer for treatment of patients with bipolar depression. Am J Psychiatry. 2000;157:124-126.
g. Vieta E, Martinez-Aran A, Goikolea JM. A randomized trial comparing paroxetine and venlafaxine in the treatment of bipolar depressed patients taking mood stabilizers. J Clin Psychiatry. 2002;63:508-512.
h. Leverich GS, Altshuler LL, Frye MA, et al. Risk of switch in mood polarity to hypomania or mania in patients with bipolar depression during acute and continuation trials of venlafaxine, sertraline, and bupropion as adjuncts to mood stabilizers. Am J Psychiatry. 2006;163:232-239.


Table 2

Antidepressants for bipolar depression: MAOIs, TCAs, and bupropion*

Acute efficacy

Reported switch risk

Tranylcypromine (MAOI)

81% response (monotherapy) in bipolar I (n=24) or bipolar II (n=32) patients over 16 weeksa

21%

75% response among imipramine nonresponders (n=12)b

17%

Moclobemide (MAOI)

46% response over 8 weeks in 156 bipolar patients (some, but not all, took concomitant mood stabilizers), not significantly different from imipramine comparatorc

4%

Imipramine (TCA)

57% response rate after 3 weeks in a 6-week double-blind randomized comparison with fluoxetine or placebod

Not reported

48% response (monotherapy) in bipolar I (n=24) or bipolar II (N=32) patients over 16 weeksa

24%

53% response over 8 weeks in 156 bipolar patients (some, but not all, took concomitant mood stabilizers), not significantly different from moclobemide comparatorc

11%

41% (coadministered with therapeutically dosed lithium)e

8%

Desipramine (TCA)

50% (5/10) response rate (coadministered with a mood stabilizer over 8 weeks)f

50%

Bupropion

55% response (5/9) (coadministered with a mood stabilizer over 8 weeks)f

11%

33% response rate (coadministered with mood stabilizers over 10 weeks)g

20%

*No data are available for isocarboxazid, mirtazapine, nefazodone, phenelzine, or selegiline transdermal

MAOI: monoamine oxidase inhibitor; TCA: tricyclic antidepressant

Source:
References
a. Himmelhoch JM, Thase ME, Mallinger AG, et al. Tranylcypromine versus imipramine in anergic bipolar depression. Am J Psychiatry. 1991;148:910-916.
b. Thase ME, Malinger AG, McKnight D, et al. Treatment of imipramine-resistant recurrent depressions, IV: a double-blind crossover study of tranylcypromine for anergic bipolar depression. Am J Psychiatry. 1992;149:195-198.
c. Silverstone T. Moclobemide vs. imipramine in bipolar depression: a multicentre double-blind clinical trial. Acta Psychiatr Scand. 2001;104:104-109.
d. Cohn JB, Collins G, Ashbrook E, et al. A comparison of fluoxetine, imipramine and placebo in patients with bipolar depressive disorder. Int Clin Psychopharmaol. 1989;4:313-322.
e. Nemeroff CB, Evans DL, Gyulai L, et al. Double-blind, placebo-controlled comparison of imipramine and paroxetine in the treatment of bipolar depression. Am J Psychiatry. 2001;158:906-912.
f. Sachs GS, Lafer B, Stoll AL, et al. A double blind trial of bupropion versus desipramine for bipolar depression. J Clin Psychiatry. 1994;55:391-393.
g. Leverich GS, Altshuler LL, Frye MA, et al. Risk of switch in mood polarity to hypomania or mania in patients with bipolar depression during acute and continuation trials of venlafaxine, sertraline, and bupropion as adjuncts to mood stabilizers. Am J Psychiatry. 2006;163:232-239.

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).

Table 3

What increases risk of antidepressant-induced mania?

Factor

Findings

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

Source:
References
a. Truman CJ, Goldberg JF, Ghaemi SN, et al. Self-reported history of manic/hypomanic switch associated with antidepressant use: data from the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD). J Clin Psychiatry. 2007;68:1472-1479.
b. MacQueen GM, Young LT, Marriott M, et al. Previous mood state predicts response and switch rates in patients with bipolar depression. Acta Psychiatr Scand. 2002;105:414-418.
c. Himmelhoch JM, Thase ME, Mallinger AG, et al. Tranylcypromine versus imipramine in anergic bipolar depression. Am J Psychiatry. 1991;148:910-916.
d. Altshuler LL, Suppes T, Black DO, et al. Lower switch rate in depressed patients with bipolar II than bipolar I disorder treated adjunctively with second-generation antidepressants. Am J Psychiatry. 2006;163:313-315.
e. Goldberg JF, Truman CJ. Antidepressant-induced mania: an overview of current controversies. Bipolar Disord. 2003;5:407-420.
f. Sachs GS, Lafer B, Stoll AL, et al. A double blind trial of bupropion versus desipramine for bipolar depression. J Clin Psychiatry. 1994;55:391-393.
g. Peet M. Induction of mania with selective serotonin re-uptake inhibitors and tricyclic antidepressants. Br J Psychiatry. 1994;164:549-550.
h. Frye MA, Hellmann G, McElroy SL, et al. Correlates of treatment-emergent mania associated with antidepressant treatment in bipolar depression. Am J Psychiatry. 2009;166:164-172.
i. Bottlender R, Rudolf D, Strauss A, et al. Mood-stabilisers reduce the risk of developing antidepressant-induced maniform states in acute treatment of bipolar I depressed patients. J Affect Disord. 2001;63:79-83.
j. Henry C, Sorbara F, Lacoste J, et al. Antidepressant-induced mania in bipolar patients: identification of risk factors. J Clin Psychiatry. 2001;62:249-255.

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

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