ARCELONA — The typical lag between treatment initiation with selective serotonin reuptake inhibitors (SSRIs) for depression and enhanced mood may be because of the time it takes to increase brain synaptic density, new imaging data suggest.
In a double-blind study, more than 30 volunteers were randomly assigned to the SSRI escitalopram or placebo for 3-5 weeks. Using PET imaging, the investigators found that over time, synaptic density significantly increased significantly in the neocortex and hippocampus but only in patients taking the active drug.
The results point to two conclusions said study investigator Gitta Moos Knudsen, MD, PhD, clinical professor and chief physician at the Department of Clinical Medicine, Neurology, Psychiatry and Sensory Sciences, at Copenhagen University Hospital, Copenhagen, Denmark.
First, they indicate that SSRIs increase synaptic density in brain areas critically involved in depression, a finding that would go some way to indicating that the synaptic density in the brain may be involved in how antidepressants function, "which would give us a target for developing novel drugs against depression," said Knudsen.
"Secondly, our data suggest synapses build up over a period of weeks, which would explain why the effects of these drugs take time to kick-in," she added.
The findings were presented here at the 36th European College of Neuropsychopharmacology (ECNP) Congress, and simultaneously published online in Molecular Psychiatry.
Marked Increase in Synaptic Density
SSRIs are widely used for depression as well as anxiety and obsessive-compulsive disorder. It is thought they act via neuroplasticity and synaptic remodeling to improve cognition and emotion processing. However, the investigators note clinical evidence is lacking.
For the study the researchers randomly assigned healthy individuals to either 20-mg escitalopram or placebo for 3-5 weeks.
They performed PET with the 11C-UCB-J tracer, which allows imaging of the synaptic vesicle glycoprotein 2A (SV2A) in the brain, synaptic density, as well as changes in density over time, in the hippocampus and neocortex.
Between May 2020 and October 2021, 17 individuals were assigned to escitalopram and 15 to placebo. There were no significant differences between two groups in terms of age, sex, and PET-related variables. Serum escitalopram measurements confirmed that all participants in the active drug group were compliant.
When synaptic density was assessed at a single time point, an average of 29 days after the intervention, there were no significant differences between the escitalopram and placebo groups in either the neocortex (P = .41) or in the hippocampus (P = .26).
However, when they performed a secondary analysis of the time-dependent effect on SV2A levels, they found a marked difference between the two study groups.
Compared with the placebo group, participants taking escitalopram had a marked increase in synaptic density in both the neocortex (rp value, 0.58; P = .003) and the hippocampus (rp value, 0.41; P = .048).
In contrast, there were no significant changes in synaptic density in either the neocortex (rp value, -0.01; P = .95) or the hippocampus (rp value, -0.06; P = .62) in the hippocampus.
"That is consistent with our clinical observation that it takes time to evolve synaptic density, along with clinical improvement. Does that mean that the increase in synaptic density is a precondition for improvement in symptoms? We don't know," said Knudsen.
Exciting but Not Conclusive
Session co-chair Oliver Howes, MD, PhD, professor of Molecular Psychiatry, King's College London, London, United Kingdom, agreed that the results do not prove the gradual increase in synaptic density the treatment response lag with SSRIs.
"We definitely don't yet have all the data to know one way or the other," he told Medscape Medical News.
Another potential hypothesis, he said, is that SSRIs are causing shifts in underlying brain circuits that lead to cognitive changes before there is a discernable improvement in mood.
Indeed, Howes suggested increases in synaptic density and cognitive changes related to SSRI use are not necessarily dependent on each other and could even be unrelated.
Also commenting on the research, David Nutt, MD, PhD, Edmond J. Safra Professor of Neuropsychopharmacology at Imperial College London, United Kingdom, said that the "delay in therapeutic action of antidepressants has been a puzzle to psychiatrists ever since they were first discerned over 50 years ago."
"So, these new data in humans, that use cutting edge brain imaging to demonstrate an increase in brain connections developing over the period that the depression lifts, are very exciting."
Nutt added the results provide further evidence that "enhancing serotonin function in the brain can have enduring health benefits."
Funding support was provided by the Danish Council for Independent Research, the Lundbeck Foundation, Rigshospitalet, and the Swedish Research Council. Open access funding provided by Royal Library, Copenhagen University Library.
Knudsen declares relationships with Sage Biogen, H. Lundbeck, Onsero, Pangea, Gilgamesh, Abbvie, and PureTechHealth. Another author declares relationships with Cambridge Cognition, and PopReach via Cambridge Enterprise.
36th European College of Neuropsychopharmacology (ECNP) Congress. Abstract S14.04 and P.0378. Presented October 8 and 9, 2023.