REVIEW OF: Barbuti M et al, Eur Neuropsychopharmacol 2023;73:1–15

STUDY TYPE: Systematic review

Some medications are associated with treatment-emergent mania, but less is known about treatment-emergent depression. This analysis looked at switches in both directions. The authors excluded randomized controlled trials and looked only at observational studies, arguing that doing so would better capture the real-world situations our patients face. 

The study included a gamut of 10 prospective and 22 retrospective studies ranging from 1982 to 2020. Each study included 30–3,000 patients with bipolar I or bipolar II disorder from a mix of outpatient and hospital settings. Almost all examined treatment-emergent mania or hypomania (collectively, TEM), and 11 included mixed mood episodes. There were only three studies of treatment-emergent depression (TED). Because of this heterogeneity, the reviewers didn’t quantify their findings, but summarized them qualitatively.

Across the studies, TEM occurred between 17% and 49% of the time. TEM was 7.4 times more likely when antidepressants were involved—especially tricyclics and antidepressant monotherapy. Bupropion was the antidepressant least associated with TEM. In contrast to other reports, bipolar II was more associated with TEM than bipolar I. Hypomania came on more rapidly than mania after starting an antidepressant. Other risk factors for TEM included prior episodes of TEM, history of hospitalizations, rapid cycling, continuous mood episodes, female sex, substance use, younger age of onset, and bipolar disorder that first presented as depression. Atypical antipsychotics and mood stabilizers, particularly lithium, were protective against TEM.

TED was reported 5%–16% of the time in patients with bipolar I disorder (there were no data about TED in bipolar II). First-generation antipsychotics, either as monotherapy or in combination with atypicals, were associated with TED. Other risk factors included more severe mood symptoms, a higher number of prior depressions, more depressions than manias, depressive temperament, and substance use.

While observational data show us what to expect in real-world practice, they tell us nothing about causation. However, controlled trials suggest a causal relationship between first-generation antipsychotics and TED, particularly with haloperidol and perphenazine (Goikolea JM et al, J Affect Disord 2013;144(3):191–198; Zarate CA and Tohen M, Am J Psychiatry 2004;161(1):169–171).

CARLAT TAKE

Switches into mania are common with antidepressants, particularly if they are tricyclics or used as monotherapy. Switches into depression are more common when first-generation antipsychotics are used to treat mania.