Using a new neuroimaging tool, researchers have uncovered evidence that helps explain how antidepressant drugs work and why they take weeks to take effect. Over the past few decades, the most commonly used antidepressants have been a class of drugs called SSRIs (selective serotonin reuptake inhibitors). This class of drugs increases levels of the neurotransmitter serotonin in the brain, a mechanism through which antidepressants are thought to produce their mental health benefits.

However, the so-called "serotonin theory of depression" has been a source of debate among scientists for years. In 2022, a large review published in the journal Nature concluded that SSRIs are overprescribed and there is no convincing evidence that low serotonin levels are the root cause of depressive mental illness.

One problem with the serotonin theory of depression is that if low levels of the neurotransmitter are the cause of the mood disorder, SSRIs should relieve symptoms relatively quickly. The drug works almost immediately, but it is known that it generally takes at least four to six weeks for patients to start feeling the effects.

So why do SSRI antidepressants take so long to start working?

The prevailing hypothesis is that increased serotonin levels induce downstream effects of neuroplasticity, and it is this mechanism that ultimately leads to improvements in mood and cognitive performance over the course of weeks. Of course, proving this hypothesis has been a challenge because until recently, studying neuroplasticity in living humans was nearly impossible.

Professor Gitte Knudsen of Copenhagen University Hospital said in an email to New Atlas: "Many scientists have speculated that neuroplasticity is a driver of antidepressant effects, but this speculation is mostly (entirely) based on animal studies, where you would doubt whether this speculation would apply to humans. With the new tool (SV2A neuroimaging function), we are interested to know whether this mechanism can be found in healthy brains."

Recently developed tools use positron emission tomography (PET) to measure levels of a protein called synaptic vesicle glycoprotein 2A (SV2A) in specific brain regions. This protein has been shown to be an effective surrogate for synaptic density. So basically, the higher the SV2A levels, the greater the neuroplasticity.

Knudson and colleagues collected 32 healthy subjects for the experiment. About half of the subjects received a daily dose of escitalopram, a common SSRI, and the other half received a placebo. Three to five weeks later, each subject was scanned for SV2A density in the hippocampus and neocortex, areas critical for cognitive and emotional processes.

Preliminary results are disappointing. The researchers were unable to identify any statistically significant differences in SV2A density between the SSRI and placebo groups. However, upon closer inspection, an interesting time-dependent effect emerged in the data.

Escitalopram subjects who were imaged closer to five weeks had significantly increased SV2A density compared with escitalopram subjects who were imaged around three or four weeks. Knutson believes this finding provides clues about how antidepressant drugs work and why they take at least a month to take effect.


"First, this shows that SSRIs increase synaptic density in areas of the brain that are strongly associated with depression," Knutson said. "This suggests, in part, that synaptic density in the brain may be related to the way these antidepressants work, which would provide a target for us to develop new antidepressant drugs. Second, our data show that synapses take weeks to form, which explains why the effects of these drugs take a while to kick in."

Aside from a small ketamine study, this is the first time a drug's effect on SV2A levels has been investigated in humans. Perhaps most interesting is the implications of these findings for other researchers studying the relationship between mood disorders and neuroplasticity.

A recent study by Knutson and colleagues used the same novel imaging technique to look at SV2A levels in pig brains after a single dose of psychedelic drugs. The study found that hippocampal synaptic density increased significantly 24 hours after taking the drug. This suggests that both SSRIs and the newer wave of psychedelic antidepressants may have beneficial effects through similar mechanisms. Knutson noted that the key for future research will be to ensure that PET imaging is performed at the right time to discover the drug's effect on SV2A levels.

"Can we determine the best time to do follow-up scans after taking psychedelics?" Knudsen added. "This will be a very similar question to our escitalopram data, but it's also important to make sure we catch the signal at the right time."

The new findings are by no means the end of the debate over the serotonin hypothesis of depression, but they do provide tantalizing clues for future research into the neuroplastic effects of drugs in mood disorders. New tools like SV2A imaging are giving scientists new insights into how drugs we've used for decades actually work.

The new study was published in the journal Molecular Psychiatry.