by Researchers have made significant progress in understanding how antidepressant medications work and why they take several weeks to start showing effects, thanks to a new neuroimaging tool. The most commonly prescribed antidepressants, known as selective serotonin reuptake inhibitors (SSRIs), increase serotonin levels in the brain. However, the “serotonin theory of depression” has long been a topic of debate among scientists. In 2022, a review published in the journal Nature argued against the theory, stating that low serotonin levels are not the cause of depressive mental health conditions.
The delayed onset of action of SSRIs has been a conundrum. According to the prevailing hypothesis, increasing serotonin levels should result in immediate improvements in mood. However, patients typically take four to six weeks to experience any benefits. One theory suggests that SSRIs induce neuroplasticity, resulting in emotional and cognitive improvements over time. But until recently, it has been difficult to investigate neuroplasticity in living humans.
To study neuroplasticity, researchers developed a new tool called SV2A neuroimaging, which uses positron emission tomography (PET) to measure levels of a protein called synaptic vesicle glycoprotein 2A (SV2A) in specific brain areas. SV2A is a proxy for synaptic density, which is linked to neuroplasticity. The researchers conducted a study involving 32 healthy subjects, half of whom received a daily dose of the SSRI escitalopram, while the other half received a placebo.
Initially, there were no significant differences in SV2A density between the two groups. However, further analysis revealed a time-dependent effect in the escitalopram group. Subjects who were imaged closer to the five-week mark showed increased SV2A density compared to those imaged around the three- or four-week mark. This finding suggests that SSRIs increase synaptic density in brain regions related to depression and that the buildup of synapses takes several weeks, explaining the delayed onset of action of antidepressants.
According to Professor Gitte Knudsen from Copenhagen University Hospital, this study provides insights into how antidepressants work and offers a potential target for developing novel drugs against depression. These findings also have implications for research on the relationship between mood disorders and neuroplasticity. In a separate study, the same imaging technique was used to examine SV2A levels in the pig brain after a single dose of the psychedelic drug psilocybin, which also showed increases in hippocampal synaptic density. This suggests that both SSRIs and psychedelic antidepressants may produce their beneficial effects through similar mechanisms.
While this study does not settle the debate on the serotonin hypothesis for depression, it paves the way for future research on the neuroplastic effects of drugs on mood disorders. Novel tools like SV2A imaging are providing scientists with new insights into the mechanisms underlying the effects of antidepressant drugs. Further investigations are needed to determine the optimal timing for PET imaging to capture the effects of drugs on SV2A levels. By understanding these mechanisms better, researchers can potentially develop more effective treatments for depression.
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1. Source: Coherent Market Insights, Public sources, Desk research
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