Using a new kind of neuroimaging tool, researchers have uncovered evidence to help explain how antidepressant medications work, and why they take so many weeks to kick in.
For the last few decades the most commonly prescribed antidepressant drug has been a class of medicines called SSRIs (selective serotonin reuptake inhibitors). The drugs increase levels of the neurotransmitter serotonin in the brain, and it’s through this mechanism that antidepressants are thought to generate their mental health benefits.
The so-called ‘serotonin theory of depression’ has, however, been a constant source of debate amongst scientists for years. In 2022 a large umbrella review published in the journal Nature argued SSRIs are overprescribed and there is no convincing evidence that low levels of serotonin are the source of depressive mental health conditions.
One problem with the serotonin theory of depression is that if low levels of the neurotransmitter were the cause of mood disorders then SSRI drugs should alleviate symptoms relatively quickly. The drugs work almost immediately yet it is well-known that patients generally take at least four to six weeks to begin feeling benefits.
So why do SSRI antidepressants take so long to start working?
The prevailing hypothesis has been that increasing serotonin levels induces downstream effects on neuroplasticity, and over the course of several weeks it is this mechanism that ultimately results in emotional and cognitive improvements. Of course, proving this hypothesis has been challenging because, until recently, it has been virtually impossible to investigate neuroplasticity in living humans.
“Many scientists have speculated that neuroplasticity is what drives the antidepressant effects, but this has mostly (as in entirely) been based on animal studies where you notoriously wonder if it applies to humans,” said Professor Gitte Knudsen, from Copenhagen University Hospital, in an email to New Atlas. “With a new tool at hand (SV2A neuroimaging enabled) we were excited to learn if we could identify this mechanism in the healthy brain.”
The recently developed tool uses Positron Emission Tomography (PET) to measure levels of a protein called synaptic vesicle glycoprotein 2A (SV2A) in specific brain areas. This protein has been shown to serve as an effective proxy for synaptic density. So basically, greater levels of SV2A can offer clues to increased neuroplasticity.
Knudsen and colleagues gathered 32 healthy subjects for an experiment. Around half the cohort were given a daily dose of common SSRI escitalopram, and the other half were given a placebo. After between three and five weeks, each subject was scanned for SV2A density in the hippocampus and neocortex, brain regions that are crucial for cognitive and emotional processes.
On first analysis the results were disappointing. The researchers couldn’t identify any statistically significant difference in SV2A density between the SSRI and placebo groups. However, on closer examination an interesting time-dependent effect in the data appeared.
The escitalopram subjects who were imaged closer to the five-week point showed noticeable increases in SV2A density compared to the escitalopram subjects imaged around the three- or four-week point. According to Knudsen, this finding offers clues to how antidepressants work, and why they maybe take at least a month to kick in.
“Firstly, 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. 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.”
Apart from a small ketamine study, this is the first in-human investigation into the effects of a drug on SV2A levels. Perhaps most interesting are the implications of the findings for other researchers looking at the relationship between mood disorders and neuroplasticity.
A recent study by Knudsen and colleagues used the same novel imaging technique to look at SV2A levels in a pig brain following a single dose of the psychedelic drug psilocybin. That study saw notable increases in hippocampal synaptic density just 24 hours after the drug dose. This suggests both SSRIs and the new wave of psychedelic antidepressants could be generating their beneficial effects through similar mechanisms. Knudsen notes the key to future investigations will be in making sure PET imaging is conducted at the right time to pick up any pharmaceutical effect on SV2A levels.
“Can we identify a good time to do follow-up scans after psilocybin?" Knudsen adds. "That will be a question quite similar to our escitalopram data, but also important to make sure we pick up the signal at the right time.”
The new findings are by no means the end of the debate over the serotonin hypothesis for depression, but they do offer enticing clues for future research into the neuroplastic effects of drugs on mood disorders. Novel tools such as SV2A imaging are offering scientists new insights into how drugs we have been using for decades actually work.
The new study was published in the journal Molecular Psychiatry.
