Effect of age on the response to serotonergic and noradrenergic antidepressants: A systematic review, meta-regression and individual participant data pooled analysis

It is known that the serotonin and norepinephrine systems change with age. Consequently, response to antidepressants having different effects on these two systems may vary between patients of different ages. We systematically searched Embase/Medline/PsychINFO until December 2024 for randomised controlled trials (RCT) in patients with unipolar major depressive disorder comparing response rates to serotonergic versus noradrenergic antidepressants (PROSPERO pre-registration #CRD42020145386). Our primary outcome was to assess the effect of age on response rates to serotonergic versus noradrenergic antidepressants in unipolar depression. We then performed a pooled analysis of individual participant data (IPD). Seventy-four RCTs with a total of 8981 participants (4488 with serotonergic and 4493 with noradrenergic antidepressants) were included in the meta-analysis. We found no differences in the response rates to the two antidepressants, although the improvement in depressive symptoms was greater in the noradrenergic arm (subset of n = 31 studies, z = -2.61; p = 0.009); younger age was associated with a greater response to serotonergic than noradrenergic agents both in terms of response rates (estimate = -0.011; p-value = 0.041) and symptom improvement (estimate = -0.016; p-value<0.0001), even after controlling for year of publication, study design, baseline severity, type of noradrenergic medication, inpatients, and dropout rates. The effect of age on antidepressant response was also confirmed in the IPD pooled analysis (n = 339), in which responders to serotonergic antidepressants were significantly younger than non-responders (p-value = 0.028) and than responders to noradrenergic antidepressants (p-value = 0.034). Our study highlights the importance of age when considering the efficacy of serotonergic versus noradrenergic antidepressants as part of a precision psychiatry-oriented approach.