Discussion
depression, psychiatric, neurodegenerative and, cocaine-use disorder
SECONDARY, DISORDERS
In this study, we examine the effects of the SSRI escitalopram on brain synaptic density in SSRI-naïve healthy volunteers, as indexed by SV2A density measured with [This positive association with escitalopram intervention duration suggests that a reason why we do not find a group difference in the primary analysis could be that an average of 28 days of escitalopram intervention is too short for synaptic effects to fully emerge. Delayed effects of the escitalopram intervention align with the clinical observations that when SSRIs are used for treating, e.g., depression, at least 2–4 weeks of treatment is required before effects on symptoms can be expected [The reason for the delay in symptom relief following the initiation of SSRI treatment is unclear, although both biological and neuropsychological hypotheses have been proposed, e.g., affective bias and reward sensitivity [Aside from the intervention duration, the drug dose is also an important aspect to consider. Despite substantial variation in drug concentration, we saw no association between [Few other studies have investigated the effect of drug interventions on SV2A quantified with radioligand techniques. Using [So far, most other SV2A PET imaging studies have been cross-sectional case-control studies of neurodegenerative and psychiatric disorders for which causal relationships cannot be determined. Yet, indications of how modifiable SV2A is in the human brain may potentially be derived indirectly: A study on SV2A binding in cocaine-use disorder by Angarita et al. [Some methodological aspects of the current study should be considered. First, the use of SV2A as a proxy for pre-synaptic density. Although SV2A is ubiquitously expressed throughout the brain, it cannot be excluded that SSRI induced changes (or lack thereof) in SV2A binding estimates could have several different causes, such as a number of vesicles per synapse or differential effects on excitatory and inhibitory synapses. Preclinical studies comparing in vivo SV2A PET imaging with in vitro methods will help advance our understanding and interpretations of SV2A imaging studies.Second, we chose Third, as our study did not include baseline [Finally, the sample size was targeted to detect larger effect sizes, which limits us in detecting subtler differences and subgroup differences (e.g., sex). As such, the study should be replicated in an independent sample, ideally with a longer range in the intervention period and in more subjects, to confirm the results and map the temporal dynamics more closely.In summary, this is the first study to investigate the effect of an SSRI intervention, using clinically relevant doses and duration (i.e., 3–5 weeks), on pre-synaptic density in the human brain. Whereas we find no statistically significant group difference in SV2A, our secondary analyses suggest that escitalopram has a time-dependent effect on cerebral SV2A, i.e., that over 3–5 weeks, escitalopram induces synaptic neuroplasticity in the human brain. This offers a biological explanation for the delayed response commonly observed in patients treated with SSRIs. While replication of the findings is warranted, these results have important implications for future studies investigating the effects of SSRIs, especially concerning the duration of intervention studies. As such, our study adds a novel perspective to the growing literature on synaptic alterations in neuropsychiatric conditions.