Antidepressants and suicidality in younger adults – is bipolar illness the missing link?

In 2007, the FDA reported an increase in suicidal acts and suicidal ideations in patients below the age of 25 receiving antidepressants compared with placebo-treated patients (OR 2.3; 95% CI 1.04–5.09) leading to the extensively discussed black-box warnings for antidepressants in young adults aged 18–24 years during initial treatment (1). In contrast, a significant suicide-protective effect emerged for patients above the age of 65 treated with antidepressant as compared with placebo (OR 0.06; 95% CI 0.01–0.58) (1). The reasons for this phenomenon are unknown, but it has been suggested that this difference might indicate that depression is a stronger risk factor for suicide in the elderly and that the suicide-preventive potential of antidepressants is consequently stronger in this patient population (2). However, the increased risk of suicide in patients below 25 years receiving antidepressants may also have to do with the fact that different types or even entities of depression account for different effects on medication on suicidality across age. There is growing evidence that bipolar illness could account for this age difference in suicide risk associated with antidepressants (3, 4). Bipolar disorder has a significantly earlier mean age of onset of 21 (5), with about 74% of all bipolar patients experiencing their first symptoms between the age of 5 and 25 (6). In contrast, in unipolar depression, the mean age of onset is around the age of 30 (5, 7). Thus, populations treated for depression below 25 years are enriched with patients being at high risk for having or developing bipolar illness. Accordingly, elderly populations are enriched with patients suffering from unipolar depression. In addition, a major presentation of bipolar illness during early age or adolescence is a mixed state which often fulfills the diagnostic criteria for a major depressive episode (8), is closely linked to suicidality, but may not respond to antidepressants. In fact, according to almost all treatment guidelines antidepressants may even worsen the outcome in this patient population and should be generally avoided (9–12). In conclusion, the signal of a suicidality promoting effect of antidepressants in the age group below 25 years might be due to antidepressants in a population being at high risk for bipolar disorder. Consequently, antidepressants might have a suicidepreventing effect in unipolar depression but may increase suicidality in patients with (undiagnosed) bipolar depression treated with antidepressant monotherapy.