Heightened reactivity in the amygdala measured by functional magnetic resonance imaging during emotional processing is considered a potential biomarker for clinical depression. Still, it is unknown whether this is also true for depressive symptoms in the general population, and – when in remission after recurrent depressive episodes – it is associated with future episodes.

Using the UK Biobank population study (n = 11,334), we investigated the association of amygdala reactivity during negative facial stimuli, focusing on lifetime depression (trait), depressive symptoms (state), and the modulating effect of antidepressant (AD) treatment thereof. We employed normative modeling (NM) to better incorporate population heterogeneity of the amygdala activity.

In line with a previous study, depressive symptoms (state) over the last 2 weeks were not associated with the amygdala reactivity signal. Rather, our results indicate a significant positive association (p = 0.03, ω2 = 0.001) between amygdala response and the recurrence of depressive episodes (trait). Longitudinal analysis revealed that the group that had experienced a single depressive episode before showed a significantly increased amygdala response after additional episodes (p = 0.03, ω2 = 0.017). ADs were not associated with amygdala response directly, but decreased associations within episode recurrence severity.

The amygdala response to negative stimuli was associated with an individual’s risk of recurrence of depressive episodes, and AD treatment reduced these associations. This study highlights the relevance of amygdala reactivity as a trait, but not a state biomarker for (recurrent) depression. Moreover, it demonstrates the benefit of applying NM in the context of population data.