Evidence-Based Reviews

Antidepressants in bipolar disorder: 7 myths and realities

Current Psychiatry. 2010 May;9(5):41-49

References

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15. 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.

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18. Goyal N, Sinha VK. Mirtazapine-induced manic switch in adolescent unipolar depression. Aust N Z J Psychiatry. 2008;42(12):1070-1071.

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21. Dunner DL, D’Souza DN, Kajdasz DK, et al. Is treatment-associated mania rare with duloxetine: secondary analysis of controlled trials in non-bipolar depression. J Affect Disord. 2005;87:115-119.

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24. 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.

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28. 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.

29. Altshuler LL, Post RM, Hellemann G, et al. Impact of antidepressant continuation after acute positive or partial treatment response for bipolar depression: a blinded, randomized study. J Clin Psychiatry. 2009;70(4):450-457.

30. Ghaemi SN, Ostacher MM, El-Mallakh RS, et al. Antidepressant discontinuation in bipolar depression: a STEP-BD randomized clinical trial of long-term effectiveness and safety. J Clin Psychiatry. In press.

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psychotic features
marked agitation
multiple prior antidepressant nonresponses
high depression recurrence rates regardless of episode duration (ie, cyclicity, irrespective of ≥4 discrete episodes per year).

Table 4

Assessing antidepressant candidacy in bipolar depression

Favors antidepressant use	Discourages antidepressant use
Bipolar II disorder	Bipolar I disorder^a
Depressed (non-mixed) states	Mixed manic and depressive features^b,c
Absence of rapid cycling	Presence of rapid cycling^d,e
Absence of recent mania or hypomania (preceding 2 to 3 months)	Mania or hypomania in past 2 to 3 months^f
Absence of comorbid alcohol or substance use disorder	Presence of comorbid alcohol or substance use disorderg,^h
Prior favorable antidepressant response	Suboptimal responses to prior antidepressants
No history of antidepressant-induced mania or hypomania	History of antidepressant-induced mania or hypomaniaⁱ
Source: References a. 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. b. 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. c. Goldberg JF, Perlis RH, Ghaemi SN, et al. Adjunctive antidepressant use and symptomatic recovery among bipolar depressed patients with concomitant manic symptoms: findings from the STEP-BD. Am J Psychiatry. 2007;164(9):1348-1355. d. Schneck CD, Miklowitz DJ, Miyahara S, et al. The prospective course of rapid-cycling bipolar disorder: findings from the STEP-BD. Am J Psychiatry. 2008;165:370-377. e. Ghaemi SN, Ostacher MM, El-Mallakh RS, et al. Antidepressant discontinuation in bipolar depression: a STEP-BD randomized clinical trial of long-term effectiveness and safety. J Clin Psychiatry. In press. f. 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. g. Goldberg JF, Whiteside JE. The association between substance abuse and antidepressant-induced mania in bipolar disorder: a preliminary study. J Clin Psychiatry. 2002;63:791-795. h. Manwani SG, Pardo TB, Albanese MJ, et al. Substance use disorder and other predictors of antidepressant-induced mania: a retrospective chart review. J Clin Psychiatry. 2006;67:1341-1345. i. 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.

Prospective mood charting may help to establish the latter, in which case recurrence (rather than polarity) may cause waxing and waning depressed mood states.

Psychotropic agents or combinations that have shown to be effective for bipolar depression (supported by at least 1 randomized controlled trial) without destabilizing mood include quetiapine, olanzapine, olanzapine-fluoxetine combination, lamotrigine, and lithium plus lamotrigine. Those with some—but less robustly demonstrated—antidepressant action include lithium, divalproex, and carbamazepine. Other than quetiapine and olanzapine, second-generation antipsychotics have not demonstrated antidepressant effects in bipolar depression.

In general, optimize therapy with 1 or more mood stabilizers with antidepressant properties before deciding it is necessary to add antidepressants.

Clinical Point

In general, optimize therapy with 1 or more mood stabilizers before deciding it is necessary to add antidepressants

Step 3: Use antidepressants in suitable patients. For patients with no risk factors for mood destabilization from antidepressants (Table 3), these drugs may be worth incorporating, keeping in mind the following guiding principles:

In patients with bipolar I depression, it is preferable to add an antidepressant to an antimanic mood stabilizer (ie, lithium, divalproex, carbamazepine, or an antipsychotic) rather than prescribing antidepressant monotherapy. There is greater diversity of opinion about the safety of antidepressant monotherapy for bipolar II depression.
Consider using antidepressants that have at least 1 positive randomized controlled trial in bipolar disorder and low risk for mood destabilization (bupropion,^12,14 sertraline,¹⁴ fluoxetine,^4,5 tranylcypromine,^3,28 or venlafaxine in bipolar II depression²⁰) before using those with reported increased risk for inducing mania or hypomania (TCAs^1,2 or venlafaxine in bipolar I depression¹⁴), multiple negative controlled trials (paroxetine^12,13), or no controlled data in bipolar depression (citalopram, escitalopram, fluvoxamine, mirtazapine, duloxetine, desvenlafaxine, nefazodone, and selegiline transdermal). Combinations of antidepressants have not been adequately studied in bipolar depression.

Clinical Point

Under certain circumstances it is reasonable to continue an antidepressant until new hypomania or mania signs emerge

The optimal duration of antidepressant therapy is unknown. However, longer-term treatment may be worthwhile in patients who show robust acute antidepressant response and experience infrequent mania or hypomania. Long-term antidepressant use is less compelling in patients with a poor initial response²⁹ or rapid cycling.³⁰ Abrupt antidepressant cessation also may induce mania, potentially by disrupting homeostasis.³¹ In the absence of rapid cycling, manic/hypomanic features, or worsening suicidal features, and in the presence of an unequivocal acute response and a greater predisposition to depression than mania, it is reasonable to continue an antidepressant indefinitely until new signs of mania or hypomania emerge.
Emerging signs of mania or hypomania should signal the need to discontinue the antidepressant. Dosage reductions alone may not diminish emerging manic or hypomanic symptoms, and “counterbalancing” maneuvers (ie, adding antimanic agents while continuing an antidepressant) may not effectively stabilize mood.