The most widely prescribed class of antidepressant has – at long last – been shown to increase connections in the human brain.

The discovery offers a plausible biological explanation for the medication's delayed treatment response and could help develop new targeted treatments.

It's been unclear why it takes so long – usually a few weeks – for selective serotonin reuptake inhibitors (SSRIs) to achieve noticeable benefits. Understanding the delay could help medical professionals encourage patients to continue treatment, and provide hope to the millions affected by the devastating condition.

In the first human study of its kind, a global team measured physical changes in neuron connections (synapses) after SSRI treatment in healthy adults.

"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," says neuroscientist Gitte Knudsen of Copenhagen University Hospital in Denmark.

An increase in brain levels of the neurotransmitter serotonin is responsible for SSRIs' mood-boosting effects. Unfortunately they don't work for everyone, and scientists don't yet know their precise mechanism of action.

It has been hypothesized that SSRIs increase synaptic plasticity in the human brain. This ability of synapses to strengthen or weaken over time is thought to be important for learning, memory, and mood regulation.

To test the hypothesis, a double-blind, semi-randomized controlled trial was conducted on 32 adults without a history of depression. Participants were randomly assigned to take daily doses of 20 milligrams of either escitalopram (an SSRI) or a placebo for up to 5 weeks.

The researchers used positron emission tomography (PET) scanning to measure brain levels of a protein called synaptic vesicle glycoprotein 2A (SV2A). The level of SV2A protein in the brain indicates synapse presence. Higher levels in a specific area signify a greater density of synapses in that region.

The scans revealed significant differences between groups in the progression of synaptic density. People who had taken escitalopram presented higher levels of SV2A in their neocortex and hippocampus compared to those who took a placebo.

The neocortex, which occupies roughly half of our brain's volume, is an intricate structure responsible for higher-level mental processes like emotion, sensory perception, and cognition. Those on escitalopram presented smaller increases in levels of SV2A in the hippocampus, an area deep within our brains that helps us remember and learn.

"It indicates that SSRIs increase synaptic density in the brain areas critically involved in depression," Knudsen says.

"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."

Importantly, it took some time for these differences to appear. For context, there were no significant differences in SV2A density between the escitalopram and placebo groups after an average of 29 days.

And analysis showed that increase in synaptic density was greater in people who took escitalopram for longer periods of time.

"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," explains Knudsen. "We did not see any effect in those taking placebo."

Enlisting subjects without diagnoses made it possible to study the potential effects of SSRIs on synaptic plasticity without interference from clinical symptoms or brain pathology. More research is needed to find out if this also happens in people with depression and if it's linked to clinical improvement.

"The delay in therapeutic action of antidepressants has been a puzzle to psychiatrists ever since they were first discerned over 50 years ago," says David Nutt, a neuropsychopharmacologist from Imperial College, London, who was not involved in the research.

"So these new data in humans that uses cutting edge brain imaging to demonstrate an increase in brain connections developing over the period that the depression lifts are very exciting."

The study has been accepted for publication in a peer-reviewed journal and was presented at the European College of Neuropsychopharmacology conference.