Why It Takes Weeks to See Benefits of SSRI Antidepressants - Explained by Brain Plasticity

Friday - October 13 2023, 19:26 UTC - 1 year ago

A recent study presented on Friday 9th October at the ECNP Conference in Barcelona has revealed that the delayed onset of mental health benefits of SSRI antidepressants may be due to physical changes in the brain leading to greater brain plasticity over the first few weeks of intake. This is due to increased synaptic density, which could also offer a potential target for novel drugs against depression.

Researchers have uncovered that the weeks-long delay in SSRI antidepressant benefits may stem from increased brain plasticity and synapse density over initial weeks of intake, offering new insights into the drug’s workings and onset timing.

SSRI antidepressants normally take a few weeks before any showing mental health benefits, but how come it takes so long? Now a study from a group of clinicians and scientists provides the first human 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. This may also begin to explain one of the mechanisms of how antidepressants work.

This work was presented at the ECNP conference in Barcelona on October 9th. This work is also due to be published (has been accepted) in a peer-reviewed journal.

Doctors have been puzzled as to why Selective Serotonin Reuptake Inhibitors (SSRIs) take time before having an effect. Researchers in Copenhagen, Innsbruck, and University of Cambridge have undertaken a randomized, 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.

17 volunteers were given a 20mg daily dose of the SSRI escitalopram, with 15 volunteers given a placebo. Between 3 and 5 weeks after starting the trial, their brains were scanned with a PET (Positron Emission Tomography) 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 (i.e., greater synaptic density). These scans showed significant between-group differences in how the synapse density evolved over time.

Researcher Professor Gitte Knudsen (of Copenhagen University Hospital) said: "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." .

The neocortex takes up around half of the brain’s volume; it is a complex brain structure that deals with higher functions, such as sensory perception, emotion, and cognition. The hippocampus, which is found deep in the brain, functions with memory and learning.

Professor Knudsen continued, "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. 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." .

Commenting, Professor David Nutt (Imperial College, London) said "The delay in therapeutic action of antidepressants has been a mystery for many years. This study indicates for the first time that it is due to changes in synaptic plasticity, and that this plasticity is likely to be the mechanisms behind SSRI action." .