Why do antidepressants take so long to kick in?

Selective serotonin reuptake inhibitor (SSRI) antidepressants normally take a few weeks before any showing mental health benefits, but why is this the case? Researchers in Denmark, Austria and the UK have now provided evidence that this is due to physical changes in the brain, leading to greater brain plasticity developing over the first few weeks of SSRI intake.

Seeking to answer the question of why SSRIs take time before having an effect, the research team undertook a randomised, double-blind, placebo-controlled study in a group of healthy volunteers which shows a gradual difference in how many nerve cell connections (synapses) the brain cells have between those taking the antidepressants and a control group, depending on how long the treatment lasts. Their work was presented at the 36th ECNP Congress, held in Barcelona earlier this month, and has also been published in the journal Molecular Psychiatry.

Seventeen volunteers were given a 20 mg daily dose of the SSRI escitalopram, while 15 were given a placebo. Between three and five weeks after starting the trial, the participants’ brains were scanned with a PET scanner, which showed the amount of synaptic vesicle glycoprotein 2A in the brain: this is an indicator of the presence of synapses, so the more of the protein is found in an area, the more synapses are present in that area (ie, greater synaptic density). These scans showed significant between-group differences in how the synapse density evolved over time.

“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,” said Professor Gitte Knudsen, of Copenhagen University Hospital. The neocortex is a complex brain structure that deals with higher functions, such as sensory perception, emotion and cognition, while the hippocampus, which is found deep in the brain, functions with memory and learning.

“This points towards two main conclusions,” Knudsen said. “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. The second point is that our data suggest that synapses build up over a period of weeks, which would explain why the effects of these drugs take time to kick in.”

Imperial College London’s Professor David Nutt, who was not involved in the study, commented, “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. Also, they provide more evidence [that] enhancing serotonin function in the brain can have enduring health benefits.”

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