Unveiling the Complexity of Depression: Moving Beyond the Serotonin Hypothesis

For decades, the narrative surrounding depression has centered on “chemical imbalances” in the brain. When the first antidepressants were discovered, it was unknown how they reduced depression symptoms. Since the medications had notable effects on neurotransmitters, imbalances in serotonin, dopamine and norepinephrine were put forward as a hypothesis as to how they worked. This narrative was further developed with the introduction of Prozac, where the pharmaceutical industry leaned heavily into the idea, marketing Prozac and other serotonin reuptake inhibitors (SSRIs) as a fix for these hypothetical imbalances.

While the serotonin hypothesis was an amazingly successful marketing strategy, the research does not support the idea that depression is a simple serotonin deficiency that can be reversed with medication.

Debunking the Simple Fix for Depression

Delayed Medication Response

One of the first red flags around the idea that a deficiency in serotonin underlies depression comes from the delayed effects of antidepressant medications (Malhi 2020). These medications alter serotonin levels quickly, starting with the first dose. Yet weeks often pass before mood symptoms improve. If low serotonin was the cause of depression, wouldn’t the first dose bring relief? Why are the benefits of antidepressants delayed? This delayed response is highly suggestive of other factors underlying depression symptoms.

Levels of Serotonin

Most of the body’s serotonin is produced in the gut. And serotonin from the bloodstream can’t directly enter the brain (Hardebo 1980). Measuring blood levels of serotonin doesn’t accurately reflect the brain’s levels of the neurotransmitter. As a workaround, researchers have focused on measuring serotonin breakdown products in the cerebrospinal fluid, as these levels more directly reflect brain levels of the chemical.

A meta-analysis of the published human studies on the levels of different metabolites in spinal fluid found no correlation between depression and serotonin (Mousten 2022). In other words, serotonin metabolite levels in depression were not reduced as compared to healthy controls. The idea that an overall deficiency of serotonin is the cause of depression symptoms was not supported.

Serotonin Transporters

In the brain, serotonin transporters clear serotonin from the synapse, decreasing serotonin activity. Blocking these transporters is the main mechanism of SSRI medications like Prozac and Paxil. If low serotonin levels are the cause of depression, transporter activity should be high in depressed patients. Surprisingly, studies reveal the exact opposite: transporter activity is often reduced in depressed patients (Kambeitz 2015).

The finding is counter to what we would expect if low serotonin levels were the cause of depression symptoms.

Serotonin Receptors

In order for serotonin to have a biochemical effect, it needs to interface with a receptor. Serotonin receptors come in multiple flavors. One of the most well-studied receptor types, the 1A receptor, inhibits serotonin release. Increasing the number of 1A receptors would decrease serotonin activity overall. However, research consistently shows a decrease in these receptors in depressed patients, again contradicting the idea that serotonin deficits underlie the condition (Wang 2016).

A Multifaceted Puzzle

Mental health is a complex condition influenced by various factors, including nutritional deficiencies, hormonal levels, inflammation, genetics, chronic infections, toxicity and personal history. While neurotransmitters can impact mood, the “chemical imbalance” narrative is overly simplistic and not well supported by the evidence.

Here at Psychiatry Redefined, we move beyond the serotonin hypothesis and we pursue a more comprehensive understanding of depression. By delving deeper into the contributing factors, and taking a more personalized approach to treatment, we have identified more effective treatments that address the root causes of mental health conditions, not just the symptoms.

If you’re ready to learn about more personalized and effective functional treatments for depression and other mental health conditions, we encourage you to enroll in our Fellowship in Functional & Integrative Psychiatry for mental health providers!