Bipolar disorder often presents initially with one or more episodes of major depression, and an episode of mania or hypomania may first occur during treatment with an antidepressant, stimulant, or other agent with mood-elevating effects. Such “switching” of mood into mania, a mixed-state, or psychosis can be dangerous. This switching is particularly prevalent among juveniles and young adults exposed to treatment with an antidepressant or stimulant for a depressive, anxiety, or attention disorder.1 Such pathological shifts of mood and behavior may represent adverse drug actions or a manifestation of undiagnosed bipolar disorder.
DSM-5 now considers that mood elevation with antidepressants justifies the diagnosis of bipolar disorder, whereas earlier editions considered it a drug-induced reaction. Before the development of modern psychopharmacology, distinctions between recurrent unipolar depression and bipolar disorder within a broad “manic-depressive” concept may not have been critical. Currently, however, the diagnostic distinction has considerable clinical significance for prognosis and clinical treatment, including, notably, when and how long to use antidepressants and mood-stabilizing agents.
Recently, we systematically reviewed available research pertaining to antidepressant-associated mood switches and changes of diagnosis from unipolar depression to bipolar disorder, supported by spontaneous mood elevations not associated with treatment.2 Previously, we evaluated rates of spontaneous and antidepressant-associated mood switching among patients with bipolar disorder or unipolar depression.3 Computerized literature searching identified 51 relevant reports involving nearly 100,000 patients with MDD without a history of mania or hypomania who were treated with an antidepressant.2 Mood switching occurred in 8.2% within an average of 2.4 years of treatment, or 3.4% per year. Cumulative risk of mood switching increased up to 24 months of antidepressant treatment. Switching rates were 4.3 times greater among juveniles than adults. Risks tended to be similar the years observed (1968 - 2012), although other findings indicate higher risks with older TCAs than with most newer antidepressants.2
We considered 12 studies of patients initially thought to have unipolar MDD who required a new diagnosis of bipolar disorder, usually with verification by occurrence of spontaneous mania or hypomania. Such diagnostic changes occurred in 3.3% within 5.4 years, or 5.6 times less than the rate of mood switching with antidepressants. If the relatively low rates of new bipolar diagnoses are not due to under-reporting, their marked difference from rates of antidepressant-associated mood switching leaves open the possibility that direct pharmacological, mood-elevating actions of antidepressants may be involved in mood switching, in addition to hypothesized “uncovering” or perhaps even “causing” of bipolar disorder. Of particular concern is that these ambiguous possibilities leave specifically uncertain the potential value of long-term treatment with antimanic or putative mood-stabilizing agents.
In general, our findings indicate that mood switching is not uncommon; it occurs in approximately 6% to 8% of patients with unipolar MDD who receive treatment with an antidepressant.2,3 Switching was much more prevalent in depressed juveniles than in depressed adults, probably because adults with bipolar disorder are more likely to have been recognized and excluded. A particularly intriguing finding was the large apparent excess of antidepressant-associated switching over reported spontaneous diagnostic changes to bipolar disorder. This raises questions about the diagnostic, prognostic, and therapeutic implications of antidepressant-associated reactions.
Depressed patients who become manic during antidepressant treatment appear likely to have other characteristics of bipolar disorder, and prudence requires that they be monitored closely if future trials of antidepressants are considered. Even a single occurrence of mood switching with antidepressant treatment can support a DSM-5 diagnosis of bipolar disorder but may not be sufficient to support indefinitely continued treatment aimed at mood stabilization.4 Indeed, it is not even proved that drugs considered to be mood-stabilizing are highly protective against antidepressant-associated mood switching, although such protection is widely assumed.3,4 Moreover, there is very limited evidence that prolonged antidepressant treatment provides substantial protection against recurrences of bipolar depression and that it might contribute to emotional instability or rapid cycling.4
Our findings also underscore the need for caution in starting antidepressant treatment in a new patient with depression. Several clinical factors may suggest increased risk of either drug-induced switching or spontaneous mania-like responses in depressed patients. They include a family history of bipolar disorder or psychosis, onset before age 25, multiple recurrences of depression within several years, particular temperamental traits (cyclothymic, hyperthymic, or irritable), previous postpartum disorder, psychomotor-retarded depression with hypersomnia and increased appetite, previous excessive activation with a mood-elevating drug, current agitated-dysphoric features, a possible comorbid substance use disorder, and treatment with a TCA or venlafaxine.4
An additional clinical implication of switching from depression to mania in patients with bipolar disorder is that following a depression before mania course pattern (versus mania before depression) is associated with less favorable responses to mood-stabilizing agents. This predicts an excess of future depression episodes, with associated risks of substance abuse, disability, and excess mortality from suicide or, later, an intercurrent medical illness.5,6
From the International Consortium for Bipolar Disorder Research, based at McLean Hospital and Harvard Medical School, Boston.
1. Offidani E, Fava GA, Tomba E, Baldessarini RJ. Excessive mood elevation and behavioral activation with antidepressant treatment of juvenile depressive and anxiety disorders: systematic review. Psychother Psychosom. 2013;82:132-141.
2. Baldessarini RJ, Faedda GL, Offidani E, et al. Antidepressant-associated mood-switching and transition from unipolar major depression to bipolar disorder: a review. J Affect Disord. 2013;148:129-135.
3. Tondo L,Vázquez GH, Baldessarini RJ. Mania associated with antidepressant treatment: comprehensive meta-analytic review. Acta Psychiatr Scand. 2010;121:404-414.
4. Baldessarini RJ. Chemotherapy in Psychiatry. 3rd ed. New York: Springer Press; 2013.
5. Koukopoulos A, Reginaldi D, Tondo L, et al. Course sequences in bipolar disorder: depressions preceding or following manias or hypomanias. J Affect Disord. 2013;151:105-110.
6. Baldessarini RJ, Undurraga J, Vázquez GH, et al. Predominant recurrence polarity among 928 adult international bipolar I disorder patients. Acta Psychiatr Scand. 2012;125:293-302.