Synaptic density (SV2A) tracks illness chronicity rather than symptom severity in major depressive disorder

Synaptic loss has been proposed as a key mechanism in major depressive disorder (MDD). Positron emission tomography with [¹¹C]UCB-J enables in vivo quantification of synaptic vesicle glycoprotein 2A (SV2A), a proxy marker of synaptic density. A landmark study by Holmes et al reported an inverse association between depression severity and SV2A binding in frontolimbic regions. As a replication, we examined this association in [¹¹C]UCB-J PET data from 34 unmedicated individuals with MDD, focusing on the dorsolateral prefrontal cortex, anterior cingulate cortex, and hippocampus. We found no support of an association between MADRS scores and SV2A binding in the primary regions of interest (r = 0.18–0.26, all p ≥ 0.15). Findings were similar in unadjusted and age- and sex-adjusted models. However, adjustment for duration of the current depressive episode and lifetime depressive episodes yielded positive associations across primary regions. In post hoc analyses, longer current episode duration, but not lifetime depressive episodes, was negatively associated with SV2A binding across primary regions. Thus, our findings did not support an association between depression severity and synaptic density, contrary to a previous report; instead, the exploratory findings suggest that SV2A binding may be related to episode duration rather than current symptom burden.