REVIEW OF: Virtanen S et al, JAMA Psychiatry 2024;81(1):25–33

STUDY TYPE: Cohort study using Swedish national health care registers

One of the biggest concerns when prescribing antidepressants to children and adolescents with unipolar depression is the risk of triggering mania. Some studies suggest that antidepressants might unmask an underlying bipolar disorder (BD), while others have found no significant risk. This large-scale study aims to clarify the relationship between antidepressant use and manic episodes in young patients.

Researchers analyzed data from 43,677 children and adolescents (ages 4–17) diagnosed with unipolar depression in Sweden. Patients were divided into a pair of groups: those who started an antidepressant, largely selective serotonin reuptake inhibitors (SSRIs), within 90 days of diagnosis and those who did not. The study tracked these patients for 12 weeks (to assess the risk of treatment-emergent mania) and 52 weeks (to examine longer-term outcomes).

The primary outcome was the onset of mania or hypomania, defined by a new diagnosis or the initiation of a mood stabilizer (eg, lithium, valproate). Researchers used statistical adjustments to account for differences in baseline risk factors, such as prior hospitalizations, parental history of BD, and use of antipsychotic or antiepileptic medications.

At 12 weeks, there was no meaningful difference in the risk of mania/hypomania between those who took antidepressants and those who did not (0.26% vs 0.20%; risk difference 0.06%). At 52 weeks, the antidepressant group had a slightly higher incidence (0.79% vs 0.52%; risk difference 0.28%), but this small increase may reflect the natural course of emerging BD rather than an effect of the medication itself.

Several factors were strongly associated with a higher risk of mania/hypomania:

Psychiatric hospitalization (2x increased risk)

Parental BD (4x increased risk)

Antipsychotic use (4x increased risk)

Antiepileptic use (7x increased risk)

SSRI use was not a significant predictor of mania/hypomania.

CARLAT TAKE

This study did not address the association of behavioral activation to mania, nor did it look at the level of exposure to SSRIs (any use of SSRIs within 90 days of diagnosis was included). Still, it provides reassuring evidence that SSRIs do not trigger manic episodes in children and adolescents with unipolar depression—at least not in the first year. The slight increase in risk observed at 52 weeks may be due to the natural course of progressive underlying mood instability rather than the medication itself.

However, children with a history of hospitalization, a family history of BD, or subsequent use of antipsychotics or antiepileptics may be at higher risk for developing mania and should be followed closely. These patients may require alternative treatment approaches or mood-stabilizing medications alongside SSRIs.