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Over the past four decades, millions of people across the globe have received selective serotonin reuptake inhibitors (SSRIs) to help ease or alleviate the symptoms of depression. This category of antidepressants includes medications such as the following:

  • Escitalopram (which is sold under the brand name Lexapro)
  • Fluoxetine (Prozac)
  • Paroxetine (Paxil)
  • Sertraline (Zoloft)

As the category name suggests, SSRIs affect the body’s production of serotonin. This neurotransmitter affects mood, motivation, memory, and happiness. Although not everyone with depression responds well to SSRIs, these medications are typically one of the first tprescribed to people diagnosed with a depressive disorder.

However, some mental health experts express doubts about the association between serotonin levels and depression. In this post, we’ll take a look at two recent studies that reach conflicting conclusions about the influence of serotonin on risk of developing depression.

The Serotonin Hypothesis

Vittorio Ersparmer, an Italian pharmacologist, identified in the 1930s. Ersparmer originally named this neurotransmitter enteramine. It became widely known as serotonin, the name used by Upjohn Pharmaceutical, the U.S. company that first synthesized it for research. The chemical name for serotonin is 5-hydroxytryptamine, or 5-HT.

Although scientists knew about serotonin, it wasn’t until the 1960s that researchers developed the serotonin hypothesis. This hypothesis links deficient levels of this neurotransmitter with depression.

Here’s a brief summary of this hypothesis from the January 1994 edition of the Jefferson Journal of Psychiatry:

In its simplest form, the serotonin deficiency theory of depression postulates that there is a net reduction in serotonin transmission in depressive illness. The pathophysiological change may result from two different mechanisms.

The first involves a decrease in serotonin (5-HT) availability, which has the consequential effect of compensatory receptor up-regulation or supersensitivity. The second mechanism implies a primary defect in receptor activity and/or signal transduction.

The serotonin hypothesis gained greater popularity in the late 1980s, when fluoxetine (Prozac) became the first selective serotonin reuptake inhibitor approved by the U.S. Food and Drug Administration (FDA) for use as an antidepressant.

Today, mental health professionals understand a variety of genetic, biological, and environmental factors impact risk for depression. Still, many clinicians view serotonin as playing an important role in determining who does and does not develop this disorder.

However, recent research challenges this long-held belief.

A Lack of Persuasive Evidence

In July 2022, the journal Molecular Psychiatry published a review of research into serotonin’s role in depression.

“Although it has been questioned more recently, the serotonin theory of depression remains influential, with principal English language textbooks still giving it qualified support, leading researchers endorsing it, and much empirical research based on it,” wrote the review team’s leader, Joanna Moncrieff.

“Surveys suggest that 80% or more of the general public now believe it is established that depression is caused by a ‘chemical imbalance’,” Moncrieff added. “Many general practitioners also subscribe to this view and popular websites commonly cite the theory.”

Moncrieff’s team identified 361 publications, then narrowied that list to 17 studies that explored serotonin and depression. The studies analyzed:

  • Serotonin and 5-hydroxyindoleacetic acid (5-HIAA)
  • Serotonin receptors
  • The serotonin transporter protein (SERT)
  • Serotonin depletion
  • The SERT gene and gene-stress interactions

As the team reviewed all 17 studies, they rated each one according to the strength of evidence in each area.

Moncrief and his team concluded:

“Our comprehensive review of the major strands of research on serotonin shows there is no convincing evidence that depression is associated with, or caused by, lower serotonin concentrations or activity.”

In a January 2023 article  about the study in Quanta Magazine, writer Joanna Thompson highlighted Moncrieff’s findings:

  • Study subjects with depression did not have lower serotonin activity than people without have depression.
  • Studies that lowered of serotonin levels in volunteers did not consistently result in depression.
  • Research that focused on genes discounted a genetic impact on serotonin and depression

The Moncrieff review, Thompson wrote, is the “death knell for the serotonin hypothesis.”

Support for the Serotonin Hypothesis

As convincing as some found Moncrieff’s review, it did not end the debate over the effect of serotonin on depression.

In October 2022 – just three months after publication of the Moncrief review – the journal Biological Psychiatry published a study from a different UK-based team that reached a different conclusion about serotonin and depression.

Highlights of this study, described in The Guardian, included the following:

  • The study involved:
    • 37 subjects:
    • 17 had major depressive disorder or depression related to Parkinson’s disease
    • 20 had no history of mental illness
    • 31 men and 6 women.
    • Depression group had a mean age of 44
    • Non-depression group had a mean age of 32.
  • The subjects protocol:
    • Patients received PET scans that involved a radioactive tracer to detect levels of serotonin bound to receptors in the frontal cortex.
    • Patients received a 0.5-mg/kg oral dose of d-amphetamine, which prompts the release of serotonin.
    • They then received a second PET scan.
  • The second PET scan noted a reduced serotonin response among members of the depressed group.

“This is the first direct evidence that the release of serotonin is blunted in the brains of people with depression,” said one of the study authors. “People have been debating this question for 60 years, but it’s all been based on indirect measures. So this is a really important step.”

However, the study did not convince everyone. For example, The Guardian quoted clinical psychologist Eiko Fried as noting, “The statistical analyse are inconsistent and do not … establish ‘clear evidence’ for the serotonin theory of depression.”

Also, Joanna Moncrieff told The Guardian that “this study does not provide convincing evidence that a serotonin abnormality is the cause or mechanism underlying depression, or one of the causes or mechanisms.”

Implications for Treatment

It seems safe to say that the debate over the accuracy of the serotonin hypothesis is not close to being resolved. What, then, does this mean for treatment?

First, the use of SSRIs and other prescription medications to treat people who have depression shows no signs of slowing.

  • According to a July 2022 article in The Pharmaceutical Journal, 2021-2022 marked the sixth consecutive year that the annual number of prescriptions for antidepressants increased in England.
  • Over that six-year period, the annual number of prescriptions for selective serotonin reuptake inhibitors increased by more than 35%.
  • In the United States, the Centers for Disease Control and Prevention (CDC) reported that the use of prescription antidepressants among adults rose from 10.6% in 2009-2010 to 13.8% in 2017-2018.

Of course, antidepressants are just one element of a comprehensive approach to treatment for depression. Depending on the nature and severity of a person’s symptoms, residential or outpatient care for someone who has a depressive disorder and any co-occurring mental health concerns may also involve services such as:

  • Acceptance and commitment therapy (ACT)
  • Dialectical behavior therapy (DBT)
  • Cognitive behavioral therapy (CBT)
  • Eye movement desensitization and reprocessing (EMDR) therapy
  • Solution-focused brief therapy (SFBT)
  • Strengths-based therapy

At Crownview Psychiatric Institute, adults who are receiving care for depression may also benefit from having one or more of the following adjunct services included in their treatment plan:

As researchers continue to explore the role of serotonin in depression and the benefits of SSRIs in depression treatment, the CPI team will remain focused on providing comprehensive, community-oriented care that incorporates evidence-based modalities and compassionate wraparound support.

To learn more about treatment for depression and other complex mental health concerns at Crownview Psychiatric Institute, please visit our Contact Us page or call us today.