Why Antidepressants Take Weeks to Start Working?

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Why Antidepressants Take Weeks to Start Working?

Why Antidepressants Take Weeks to Start Working?

Using a novel neural imaging tool, researchers have uncovered evidence that helps explain how antidepressants work and why they take weeks to become effective.

For decades, the most commonly used antidepressants have been a class of drugs known as SSRIs (Selective Serotonin Reuptake Inhibitors).

These drugs are believed to elevate serotonin levels in the brain, and it’s thought that this mechanism produces the mental health benefits associated with antidepressants.

However, the so-called “serotonin theory of depression” has been a point of contention among scientists for years. In 2022, a large review published in the journal “Nature” argued that SSRIs are overprescribed, and there is no convincing evidence that low serotonin levels are the root cause of depressive mental disorders.

One issue with the serotonin depression theory is that if low neurotransmitter levels are the cause of mood imbalances, then SSRIs should alleviate symptoms relatively quickly. These drugs can have an almost immediate effect, yet it’s well known that patients typically need at least four to six weeks to start feeling the benefits.

So, why do SSRIs, the class of antidepressants, take so long to become effective?

The prevailing hypothesis is that the increase in serotonin levels triggers downstream effects of neuroplasticity, and over a period of several weeks, this mechanism ultimately leads to improvements in mood and cognitive abilities. Of course, proving this hypothesis has been a challenge because studying neuroplasticity in live humans was nearly impossible until recently.

Professor Gitte Knudsen at the Copenhagen University Hospital stated in an email to “The New Atlas,” “Many scientists have speculated that neuroplasticity is a driving factor for the antidepressant effect, but this speculation has largely been based on animal studies, where you might question whether it applies to humans. With the new tool (SV2A neural imaging function), we are eager to find out if we can identify this mechanism in the healthy human brain.”

The recently developed tool uses Positron Emission Tomography (PET) to measure the protein levels of Synaptic Vesicle Glycoprotein 2A (SV2A) in specific brain regions. This protein has been shown to be an effective surrogate for synaptic density. Essentially, the higher the SV2A levels, the stronger the neuroplasticity.

Knudsen and her colleagues collected 32 healthy volunteers for the experiment. Approximately half of the participants took a daily dose of the common SSRI escitalopram, while the other half received a placebo. After three to five weeks, scans of SV2A density in the hippocampus and neocortex, regions crucial to cognitive and emotional processes, were conducted for each participant.

The initial analysis results were disappointing. Researchers couldn’t establish any statistically significant differences in SV2A density between the SSRI group and the placebo group. However, upon closer examination, an intriguing time-dependent effect emerged from the data.

Compared to escitalopram participants who underwent imaging at around three to four weeks, those imaged close to five weeks showed a significant increase in SV2A density. Knudsen believes this finding offers a clue to understanding the mechanism behind antidepressant drugs and why they take at least a month to become effective.

Why Antidepressants Take Weeks to Start Working?

“This firstly indicates that SSRIs can increase synaptic density in brain regions closely associated with depression,” Knudsen said. “This suggests that synaptic density in the brain may be related to the mechanism of action of these antidepressant drugs, providing a target for the development of new antidepressants. Secondly, our data suggests that synaptic formation takes several weeks, explaining why these drugs take time to become effective.”

Apart from a small ketamine study, this is the first investigation into the impact of drugs on SV2A levels in the human body. Perhaps most interestingly, these findings have implications for researchers studying the relationship between mood disorders and neuroplasticity.

Knudsen and her colleagues recently used the same novel imaging technology to observe SV2A levels in pig brains after a single dose of a psychedelic drug. The study found a significant increase in hippocampal synaptic density 24 hours after drug administration. This suggests that SSRIs and the next generation of psychedelic antidepressants may produce beneficial effects through similar mechanisms. Knudsen pointed out that a key aspect of future research is to determine the optimal time for PET imaging after taking psychedelic drugs.

“Can we establish the best time for follow-up scans after taking psychedelic drugs?” Knudsen added. “This will be a question very similar to our escitalopram data, but equally important is to ensure that we capture the signal at the right time.”

These new findings do not put an end to the debate over the serotonin theory of depression, but they do provide intriguing clues for future research on how drugs affect neuroplasticity in mood disorders. Tools like SV2A imaging offer scientists a new perspective on understanding how the drugs we’ve been using for decades actually work.

This new study was published in the “Molecular Psychiatry” journal.