SSRIs, or Selective Serotonin Reuptake Inhibitors, are the most commonly prescribed antidepressants for anxiety and depression disorders. They usually take a few weeks before ‘kicking in’ — but why?

A representational image of ‘happy pills’ being dispensed from a bottle

• Globally, nearly one billion people live with a mental health disorder, of which anxiety and depression are the most common.
• Antidepressants work by regulating the levels of different neurotransmitters in the brain, like serotonin and dopamine.
• But they take weeks to “kick in” and show effect. A new study may explain this delayed onset.

Mental illness has become endemic worldwide, with the World Health Organization estimating nearly 1 billion people were living with a mental disorder in 2019. Among these, anxiety disorders are the most common, with more than 300 million people affected, closely followed by depression, which affects nearly 280 million people. 

Antidepressants are among the most commonly prescribed medications for the treatment of anxiety and depression. They generally work by affecting levels of neurotransmitters in the brain. 

Antidepressants regulate the levels of chemicals like serotonin, norepinephrine, and dopamine, which play crucial roles in regulating mood and emotion. By influencing the balance of these neurotransmitters, antidepressants aim to alleviate symptoms associated with depressive and anxiety disorders.

SSRIs, or Selective Serotonin Reuptake Inhibitors, belong to a category of antidepressant drugs designed to elevate serotonin levels in the brain. Notable examples of SSRIs include fluoxetine (Prozac), sertraline (Zoloft), and escitalopram (Lexapro).

These medications generally have few unpleasant side effects and can be highly effective in treating various mood disorders, including depression and certain anxiety disorders. However, one significant drawback of SSRIs is the delayed onset of their therapeutic effects — SSRIs often take several weeks to show noticeable improvements in mood.

This extended period before “kicking in” poses challenges for patients and healthcare providers. Yet, the reason behind this lag in action is not well understood.

Now, a new study by scientists from Copenhagen University has explored the impact of the SSRI escitalopram on synaptic density in healthy individuals, focusing on the time-dependent effects and potential reasons behind the delayed therapeutic response of SSRIs. 

“The mode of action of SSRIs is still debated, and people have been wondering why the therapeutic effects against depression set in so late—sometimes weeks after starting the intake,” Dr. Gitte Knudsen, the lead author of the study, told Interesting Engineering. 

The researchers used SV2A, a protein found in the brain, as a marker for presynaptic density. But before we dive into the research and the findings, let us first understand how SSRIs work.

How do SSRIs work?

Antidepressants, including SSRIs, operate by modulating neurotransmitters in the brain, usually targeting serotonin, norepinephrine, and dopamine. These chemicals play pivotal roles in regulating mood and emotional well-being. By influencing their balance, antidepressants aim to alleviate symptoms associated with anxiety and depression.

SSRIs, such as escitalopram (sold under the brand names Lexapro and Cipralex, among others), belong to a class of drugs that selectively target serotonin. Serotonin, referred to as the “feel-good” neurotransmitter, contributes significantly to mood regulation.

Within the brain, neurons communicate through synapses, small gaps between nerve cells. SSRIs enhance serotonin levels by preventing the reabsorption of serotonin by the sending neuron. This mechanism increases the concentration of serotonin in the synaptic cleft, facilitating improved communication between neurons.

The prolonged presence of serotonin in synapses prompts neuroplasticity, the brain’s ability to reorganize and form new connections. This adaptability is crucial for mood stabilization and emotional regulation. By fostering neuroplastic changes, SSRIs aim to create a more resilient and balanced neural environment.

Tracking the SV2A protein 

“There is scientific support to say that the delayed effects may be due to the drugs taking some time to induce brain changes,” said Dr. Knudsen.

To explore these changes, the researchers chose SV2A (synaptic vesicle glycoprotein 2A), a protein found in neurons, as their marker. It is primarily associated with synaptic vesicles, tiny structures within neurons that store and release neurotransmitters. They then measured the impact of escitalopram on synaptic density.

Synaptic density refers to the number and distribution of synapses in the brain. Changes in synaptic density can reflect alterations in the way neurotransmitters such as serotonin are processed in the brain.

In theirdouble-anonymizedd study, the researchers divided 32 healthy participants into two groups: one received 20 milligrams (mg) of escitalopram, and the other received 20 mg of a placebo.

After three to five weeks, researchers used MRI (magnetic resonance imaging) scans to obtain detailed structural images of participants’ brains. PET (positron emission tomography) scans were also performed, employing a radioactive tracer ([11C]UCB-J) to track the presence and distribution of the SV2A protein.

Time-dependent effects of SSRIs

The imaging scans revealed a positive correlation between the radioactive tracer binding and the duration of escitalopram intervention.

“We found that people who took escitalopram (but not those on the placebo) showed a gradual increase in synaptic density over weeks 3-5. The fact that we see a time-dependent increase in SV2A supports the idea that SSRIs take time to work and indeed induce neuroplasticity,” said Dr. Knudsen.

Specifically, the study observed a gradual increase in synaptic density within two crucial brain regions—the neocortex and the hippocampus—among individuals taking SSRIs over time. 

The neocortex, occupying more than half of the brain’s total volume, handles higher cognitive functions, including sensory perception, emotion, and cognition. The hippocampus, located deep within the brain, is integral to memory and learning processes.

The research results imply that synaptic density might play a crucial role in the functioning of antidepressants, presenting a potential target for the development of innovative drugs aimed at treating depression.

This marks the first in vivo evidence supporting the idea that neuroplasticity is a mechanism of action for SSRIs in humans, offering a plausible biological explanation for the delayed treatment response often observed in patients on SSRIs.

However, the exact mechanism of this time dependency is still unclear, with Dr. Knudsen explaining, “We do not know the exact mechanism for how neuroplasticity can help get rid of depressive symptoms. Still, some believe that the drugs change the fixed mode of having ruminating thoughts and behaviors can be changed by neuroplastic effects.”

Effect on patients, doctors & drug development 

Understanding the time-dependence of escitalopram has significant relevance for patients and healthcare providers. However, the study was conducted on healthy individuals, and studying the effects in patients with major depressive disorders could offer more insight, as highlighted by Dr. Knudsen.

For individuals grappling with anxiety and depression, the findings shed light on the prolonged period SSRIs take to manifest therapeutic effects. This awareness can contribute to managing expectations during the initial weeks of treatment, helping patients and their families navigate the often challenging wait for noticeable improvements in mood.

Healthcare providers, especially psychiatrists and general practitioners prescribing SSRIs, can integrate this knowledge into patient consultations.

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via GIPHY

Armed with the understanding that neuroplastic changes induced by SSRIs take time, doctors can also better guide their patients through the treatment process.

Furthermore, the research underscores the need for ongoing exploration into the mechanisms governing the time-dependent effects of SSRIs. This could pave the way for improved treatment strategies, allowing for more targeted interventions and personalized approaches to mental health treatments.

In essence, the study not only contributes to the scientific understanding of SSRIs but also holds practical implications for those directly involved in giving and receiving mental health treatment.

In terms of drug development, the prospect of identifying substances capable of inducing neuroplasticity at an accelerated pace could be a future focal point. Speaking on this matter, Dr. Knudsen said, “If one could identify drugs that induce neuroplasticity, that could be helpful. Animal studies suggest that psychedelics induce neuroplasticity faster.”

Although the research into using psychedelics for various mental health disorders is still new, the findings may have important implications for antidepressant usage and other areas of drug development.