Evidence-Based Reviews

Antidepressants in bipolar disorder: 7 myths and realities

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

References

1. 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.

2. Peet M. Induction of mania with selective serotonin re-uptake inhibitors and tricyclic antidepressants. Br J Psychiatry. 1994;164:549-550.

3. Himmelhoch JM, Thase ME, Mallinger AG, et al. Tranylcypromine versus imipramine in anergic bipolar depression. Am J Psychiatry. 1991;148:910-916.

4. 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.

5. Goldberg JF, Truman CJ. Antidepressant-induced mania: an overview of current controversies. Bipolar Disord. 2003;5:407-420.

6. 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.

7. Tohen M, Frank E, Bowden CL, et al. The International Society for Bipolar Disorders (ISBD) Task Force report on the nomenclature of course and outcome in bipolar disorders. Bipolar Disord. 2009;11:453-473.

8. Ghaemi SN, Rosenquist KJ, Ko JY, et al. Antidepressant treatment in bipolar versus unipolar depression. Am J Psychiatry. 2004;161:163-165.

9. Bottlender R, Rudolf D, Jäger M, et al. Are bipolar I depressive patients less responsive to treatment with antidepressants than unipolar depressive patients? Results from a case control study. Eur Psychiatry. 2002;17:200-205.

10. Möller HJ, Bottlender R, Grunze H, et al. Are antidepressants less effective in the acute treatment of bipolar I compared to unipolar depression? J Affect Disord. 2001;67(1-3):141-146.

11. Amsterdam J. Efficacy and safety of venlafaxine in the treatment of bipolar II major depressive episode. J Clin Psychopharmacol. 1998;18:313-317.

12. Sachs GS, Nierenberg AA, Calabrese JR, et al. Effectiveness of adjunctive antidepressant treatment for bipolar depression. N Engl J Med. 2007;356:1711-1722.

13. 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.

14. 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.

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.

16. Soutullo CA, McElroy SL, Keck PE, Jr. Hypomania associated with mirtazapine augmentation of sertraline. J Clin Psychiatry. 1998;59(6):320.-

17. Bhanji NH, Margolese HC, Saint-Laurent M, et al. Dysphoric mania induced by high-dose mirtazapine: a case for “norepinephrine syndrome”? Int Clin Psychopharmacol. 2002;17(6):319-322.

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

19. Dong J, Blier P. Modification of norepinephrine and serotonin, but not dopamine, neuron firing by sustained bupropion treatment. Psychopharmacol (Berl). 2001;155:52-57.

20. Amsterdam JD, Wang CH, Shwarz M, et al. Venlafaxine versus lithium monotherapy of rapid and non-rapid cycling patients with bipolar II major depressive disorder: a randomized, parallel group, open-label trial. J Affect Disord. 2009;112(1-3):219-230.

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.

22. Henderson TA. Mania induction associated with atomoxetine. J Clin Psychopharmacol. 2004;24(5):567-568.

23. Henderson TA, Hartman K. Aggression, mania, and hypomania induction associated with atomoxetine. Pediatrics. 2004;114(3):895-896.

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.

25. Wehr TA, Sack DA, Rosenthal NE, et al. Rapid cycling affective disorder: contributing factors and treatment responses in 51 patients. Am J Psychiatry. 1988;145:179-184.

26. Coryell W, Solomon D, Turvey C, et al. The long-term course of rapid-cycling bipolar disorder. Arch Gen Psychiatry. 2003;60:914-920.

27. 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.

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.

31. Goldstein TR, Frye MA, Denicoff KD, et al. Antidepressant discontinuation-related mania: critical prospective observation and theoretical implications in bipolar disorder. J Clin Psychiatry. 1999;60(8):563-567.

32. Goldberg JF, Burdick KE, Endick CE. A preliminary randomized, double-blind, placebo-controlled trial of pramipexole added to mood stabilizers for treatment-resistant bipolar depression. Am J Psychiatry. 2004;161:564-566.

33. Zarate CA, Jr, Payne JL, Singh J, et al. Pramipexole for bipolar II depression: a placebo-controlled proof of concept study. Biol Psychiatry. 2004;56:54-60.

34. Frye MA, Grunze H, Suppes T, et al. A placebo-controlled evaluation of adjunctive modafinil in the treatment of bipolar depression. Am J Psychiatry. 2007;164(8):1242-1249.

35. Zarate CA, Jr, Quiroz JA, Singh JB, et al. An open-label trial of the glutamate-modulating agent riluzole in combination with lithium for the treatment of bipolar depression. Biol Psychiatry. 2005;57(4):430-432.

36. Berk M, Copolov DL, Dean O, et al. N-acetyl cysteine for depressive symptoms in bipolar disorder—a double-blind, randomized placebo-controlled trial. Biol Psychiatry. 2008;64(6):468-475.

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 weeks^a	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 placebo^d	Not reported
48% response (monotherapy) in bipolar I (n=24) or bipolar II (N=32) patients over 16 weeks^a	24%
53% response over 8 weeks in 156 bipolar patients (some, but not all, took concomitant mood stabilizers), not significantly different from moclobemide comparator^c	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.

Clinical Point

True antidepressant-induced polarity switches persist even after the medication is discontinued

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 antidepressant^a
Recent mania preceding current depressive episode	Higher risk for antidepressant-associated mania if current depressive episode was preceded by manic phase^b
Bipolar I vs bipolar II subtype	Greater risk for switch in bipolar I^c,d
Comorbid alcohol or substance use disorder	5- to 7-fold increased risk for antidepressant-associated mania^e
Noradrenergic vs serotonergic antidepressants	Possible higher risk for mania induction with TCAs or SNRIs than with bupropionf or SSRIs^g
Concurrent mania symptoms during a depressive episode	Mild or subthreshold mania symptoms during a depressive episode increase risk for mania^h,i
Hyperthymic temperamental traits	Associated with increased likelihood of antidepressant-induced mania^j
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.