Serotonin’s Role in Depression

Learn what serotonin is and discover the role it plays in depression. Explore SSRIs and their effect on serotonin levels and the symptoms of depression.

Serotonin is a chemical messenger that plays a role in mood, sleep and emotional balance, but its connection to depression may be more complex than once believed.

For decades, serotonin has been viewed as one of the primary chemicals involved in mood regulation and emotional well-being. Many antidepressants, particularly selective serotonin reuptake inhibitors, are designed to increase serotonin availability in the brain. But a growing body of research suggests that low serotonin levels may not be the sole, or even primary, cause of depression.

So what is serotonin, what does it do and what’s the real story behind its role in mental health?

What Is Serotonin?

Serotonin is a neurotransmitter — a chemical that helps transmit signals in the brain and throughout the body. It plays an important role in regulating:

• Mood
• Sleep
• Digestion
• Blood clotting
• Appetite
• Emotional response

While serotonin is widely associated with the brain, about 90% of the body’s serotonin is actually found in the gut. Only a small portion exists in the brain, where it helps regulate mood and emotional stability.

When serotonin reaches its target receptors, it’s eventually reabsorbed by neurons through a process called reuptake. Antidepressants such as SSRIs work by blocking this reuptake, allowing more serotonin to remain available in the brain for longer periods.

The Traditional “Chemical Imbalance” Theory

In the 1960s, researchers began promoting the idea that depression was caused by a chemical imbalance, particularly a deficiency in serotonin. This theory became widely accepted and influenced how depression has been treated for decades.

SSRIs, such as Prozac, Lexapro, Zoloft, Paxil and Celexa, became standard treatment options, and many people found relief through these medications. However, more recent research suggests this theory may oversimplify what’s really going on in the brain.

What the Research Now Shows

A Landmark Review Challenges the Serotonin Hypothesis

A 2022 umbrella review published in Molecular Psychiatry examined data from 17 major studies related to serotonin and depression. The researchers found no consistent evidence that low serotonin levels cause depression. This includes findings from:

• Serotonin level studies in blood and brain fluid
• Imaging studies examining serotonin activity in the brain
• Genetic studies of serotonin transporter genes
• Tryptophan depletion studies

While some evidence suggested a modest effect of tryptophan depletion in individuals with a family history of depression, the overall quality of evidence was rated as very low.

Criticism and Context

Other scientists have responded to the review, noting that while serotonin may not be the sole cause of depression, it still plays a role in a much more complex system of neurotransmitters and brain functions. Researchers from King’s College London pointed out that the review may have selectively interpreted data and downplayed the limitations of some studies.

SSRIs and Their Effect on the Brain

Despite questions about serotonin’s role, SSRIs continue to help many people with depression. These medications work by blocking the reabsorption of serotonin in the brain, allowing more of the chemical to remain active.

For many, this results in improved mood, energy and focus. However, SSRIs don’t work for everyone. Researchers believe their effectiveness may have more to do with how they affect neuroplasticity — the brain’s ability to reorganize and form new connections.

Neuroplasticity and Depression

Some scientists now suggest that reduced neuroplasticity may play a key role in depression. Stress and trauma can impair the brain’s ability to adapt, rewire and learn — leading to stagnation in mood and behavior.

SSRIs may help by promoting the growth of new synaptic connections, allowing the brain to adapt and recover. This theory could help explain why these medications are still effective for many, even if serotonin levels aren’t the root cause of their symptoms.

Serotonin Syndrome: When There’s Too Much

While most people worry about having too little serotonin, it’s also possible to have too much — especially when taking multiple medications that affect serotonin levels.

Serotonin syndrome can be a serious, even life-threatening, condition. Symptoms may include:

• Confusion or disorientation
• High fever
• Rapid heartbeat
• High blood pressure
• Muscle rigidity or tremors
• Seizures
• Fainting

If you notice symptoms such as nausea, diarrhea, agitation or tremors while taking medication, speak to a health care provider right away.

A Broader View of Depression

As of 2021, approximately 21 million American adults had experienced a major depressive episode, which is 8.3% of the U.S. adult population. Current research suggests depression is caused not by a single chemical deficiency but rather a multifaceted interplay of:

• Neurotransmitters (serotonin, dopamine, glutamate)
• Hormonal regulation
• Brain inflammation
• Neuroplasticity
• Life experiences and trauma
• Genetic predispositions

One 2024 imaging study even found that people with depression may show reduced serotonin release under stress, highlighting a more dynamic view of serotonin’s involvement.

Frequently Asked Questions