Exploring escitalopram

New international research has explored the mechanisms behind the effective operation of the SSRI escitalopram, explaining why the medication normally takes a few weeks before showing any mental health benefits.

The study, published this week in Molecular Psychiatry by a team from the Copenhagen University Hospital, led by Professor Gitte Knudson – one of the leading figures in global neuroscience – has provided the first evidence that this delayed effect was due to physical changes in the brain leading to greater brain plasticity developing over the first few weeks of SSRI intake.  

The team noted that this may also begin to explain one of the mechanisms of how antidepressants work, and their findings were presented at the ECNP conference in Barcelona on 9th October. 

“Drugs targeting the serotonin system, specifically the serotonin transporter, have long been the primary pharmacological treatment for affective and anxiety-related disorders, and the most widely used group is the selective serotonin reuptake inhibitors (SSRIs), presumed to work by increasing serotonergic neurotransmission,” Professor Knudson explained. 

“In this study, we examined the effects of the SSRI escitalopram on brain synaptic density in SSRI-naïve healthy volunteers, as indexed by SV2A density – the amount of synaptic vesicle glycoprotein 2A in the brain is an indicator of the presence of synapses, so the more of this protein that is found in an area, the more synapses are present and the greater synaptic density. 

“We found that with those taking the SSRI, over time there was a gradual increase in synapses in the neocortex and the hippocampus of the brain, compared to those taking placebo. We did not see any effect in those taking placebo”. 

Researchers from Copenhagen, Innsbruck, and the University of Cambridge gave 17 volunteers a daily 20mg dose of the SSRI antidepressant escitalopram, and 15 volunteers a placebo.  

Between three and five weeks after starting the trial, their brains were PET scanned, revealing significant between-group differences in how the synapse density evolved over time, with those taking SSRIs were found to have a gradual increase in brain connections in the neocortex and hippocampus – critical areas involved in sensory perception, emotion, cognition, and memory. 

The mean (SD) hippocampus volume was 4,572 (389) mm3 in the escitalopram group versus 4,767 (329) mm3 in the placebo group, and when compared using a linear regression model controlling for age, sex, and intracranial volume the estimated difference was reduced to −97mm3. 

Linear regression models with age and sex as covariates showed no difference in cortical thickness between the escitalopram group compared to the placebo group for the neocortical subregions, but when the team modelled the drug-specific effect of the duration of escitalopram intervention the neocortex during secondary analysis, they found a positive effect of time for the escitalopram group: at +0.41 mL/cm3 per day compared to −0.12 mL/cm3 per day for the placebo group. 

“This points towards two main conclusions. Firstly, it indicates that SSRIs increase synaptic density in the brain areas critically involved in depression. This would go some way to indicating that the synaptic density in the brain may be involved in how these antidepressants function, which would give us a target for developing novel drugs against depression.,” Professor Knudson explained.  

“The second point is that our data suggest that synapses build up over a period of weeks and offers a biological explanation for the delayed response commonly observed in patients treated with SSRIs. “While we found no statistically significant group difference in SV2A, our secondary analyses suggested that escitalopram has a time-dependent effect on cerebral SV2A, that is, over 3–5 weeks escitalopram induces synaptic neuroplasticity in the human brain. 

“This also provides more evidence that enhancing serotonin function in the brain can have enduring health benefits.”