Rethinking SSRIs and the Serotonin Theory of Depression

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I. Introduction

For decades, many people have been told that depression is caused by a “chemical imbalance” in the brain, especially a lack of serotonin. This idea was repeated in medical offices, on TV ads, and even in popular culture. The message was simple: if you are depressed, your brain doesn’t make enough serotonin, and antidepressant drugs—especially selective serotonin reuptake inhibitors (SSRIs)—can fix the problem.

But what if this story isn’t true?

Two major scientific reviews published in recent years have examined the evidence behind the serotonin theory and the effectiveness of SSRIs. A 2022 review, led by Joanna Moncrieff and colleagues, examined decades of studies on serotonin itself. Another, led by Janus Jakobsen in 2017, analyzed over 27,000 patients who took SSRIs in clinical trials.

Together, these studies raise serious questions. Does low serotonin really cause depression? And if SSRIs don’t meaningfully correct depression, what are we left to believe?

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II. The Serotonin Theory of Depression (Moncrieff et al. 2022)

The serotonin theory began in the 1960s, when scientists first suggested that mood disorders might come from problems with brain chemicals. When SSRIs like Prozac were released in the 1990s, drug companies promoted them as correcting this imbalance.

The message stuck. Surveys show that more than 80% of the public, and even many doctors, still believe that depression comes from a lack of serotonin.

This simple story also proved highly profitable. Since SSRIs were marketed as the solution to a chemical imbalance, sales of these drugs have risen into the billions of dollars worldwide. The serotonin theory was not only a scientific idea but also a powerful commercial driver.

Moncrieff and her team set out to review all the major areas of serotonin research. Their study pulled together systematic reviews, meta-analyses, and large-scale genetic studies to test the serotonin hypothesis from every angle. Here’s what they found:

A. Serotonin and Its Metabolite (5-HIAA)

• When researchers looked at serotonin levels in the brain and spinal fluid, there was no clear difference between people with depression and those without.
• In fact, some studies showed that lower serotonin levels were linked to antidepressant use, not to depression itself.

B. Serotonin Receptors (5-HT1A)

• Studies of serotonin receptor binding gave weak and inconsistent results.
• In some brain areas, receptor changes suggested more serotonin available, not less—contradicting the low serotonin idea.

C. Serotonin Transporter (SERT)

• Research on the SERT protein, which moves serotonin out of brain cells, was also mixed.
• Any changes could easily be explained by the effects of antidepressants, not depression.

D. Tryptophan Depletion Studies

• Tryptophan is an amino acid needed to make serotonin. Scientists tried lowering it in volunteers to see if their mood worsened.
• Results showed no effect in most healthy people.
• A small effect was seen in those with a family history of depression, but the studies were tiny and unreliable.

E. Genetics and Stress Interaction

• Two of the largest and highest-quality genetic studies ever done found no link between serotonin-related genes and depression.
• They also found no evidence that stressful life events combined with these genes to cause depression.

F. Expanding the Diagnosis of Depression

At the same time as serotonin-based drugs were gaining popularity, the American Psychiatric Association (APA) gradually lowered the diagnostic threshold for depression in its Diagnostic and Statistical Manual of Mental Disorders (DSM). Conditions that once might have been seen as normal sadness or stress could now qualify for a diagnosis of major depressive disorder. This shift meant that more people were labeled as depressed—and more were prescribed SSRIs.

Key DSM changes that widened the net include:

• Shortened duration requirement:
  In earlier DSM editions, depressive symptoms had to last for a longer period before a diagnosis was made. Over time, the minimum duration required for diagnosis was shortened to just two weeks of symptoms. This made it easier to classify temporary sadness or stress as a medical disorder.
• Removal of the bereavement exclusion (DSM-5):
  In previous DSM editions, people grieving a major loss (like the death of a loved one) were not diagnosed with depression unless symptoms lasted beyond a certain period, usually two months. With DSM-5 (2013), this “bereavement exclusion” was eliminated. Now, grief lasting more than two weeks could be diagnosed as major depression. This change blurred the line between normal human grief and clinical illness.
• Broader symptom criteria:
  The DSM also began to allow a wider range of symptoms to be considered in making a diagnosis. For example, symptoms such as fatigue, sleep changes, or appetite changes—often common in everyday stress—could contribute to a depression diagnosis if they persisted.

Impact of these changes:

• More people were eligible for the diagnosis of depression.
• As a result, prescriptions for SSRIs skyrocketed, feeding into the already booming pharmaceutical market.
• What once might have been considered ordinary sadness, stress, or grief became grounds for long-term drug treatment.

G. Overall Conclusion of Moncrieff’s Review

The big picture was clear:

• There is no consistent evidence that depression is caused by low serotonin.
• Some results even suggest that antidepressant use itself may lower serotonin or change the system in other ways.
• The widely accepted “chemical imbalance” story is not supported by science.

This challenges not only how we think about depression but also how we explain it to patients and the public.

III. Clinical Effectiveness of SSRIs (Jakobsen et al. 2017)

While Moncrieff’s team looked at whether serotonin itself causes depression, another group of researchers asked a different question: Do SSRIs really work in practice?

In 2017, Dr. Janus Jakobsen and colleagues published one of the largest systematic reviews and meta-analyses ever done on SSRIs. They examined 131 randomized controlled trials involving over 27,000 adults with major depressive disorder. 

Their goal was not only to determine if SSRIs had a statistically significant effect, but also to assess whether the effect was meaningful for patients.

Here’s what they found:

A. Symptom Reduction

• SSRIs did reduce depression scores on the Hamilton Depression Rating Scale (HDRS), the most common test used in drug trials.
• But the difference was only about 2 points lower than placebo.
• This was below the threshold that researchers had set for being clinically meaningful (a 3-point improvement).
• In other words, while the numbers showed a change, most patients would probably not feel a real-life difference.

B. Remission Rates

• Some trials showed that people on SSRIs were slightly more likely to go into remission (their symptoms dropped below a certain score).
• But when the researchers applied stricter methods, the benefit was not confirmed.

C. Adverse Events

• SSRIs were linked with a higher risk of both serious and non-serious side effects.
• For serious adverse events, about 31 out of every 1,000 people on SSRIs were harmed, compared with 22 out of every 1,000 on placebo.
• The specific serious adverse events reported in the trials included:
  • Suicidal behavior and ideation (suicides, suicide attempts, worsening depression)
  • Cardiovascular problems such as arrhythmia, chest pain, atrial fibrillation, coronary artery occlusion, and even an aortic aneurysm
  • Neurological events like syncope (fainting), confusional states, and agitation with racing thoughts
  • Respiratory issues such as respiratory arrest
  • Severe gastrointestinal events, including bowel obstruction and ruptured ectopic pregnancy
  • Fractures and musculoskeletal problems (ankle fracture, femur fracture, osteoarthritis)
  • Other hospitalizations for conditions such as appendicitis, nephrolithiasis (kidney stones), viral gastroenteritis, and allergic reactions.
• Non-serious side effects, such as digestive problems, sexual dysfunction, and sleep issues, were even more common.

D. Suicidality and Quality of Life

• The review found almost no reliable data on whether SSRIs reduced suicidal thoughts or attempts.
• Data on long-term quality of life were also scarce, leaving a big gap in understanding.

E. Overall Conclusion of Jakobsen’s Review

1. SSRIs may have minor, statistically measurable effects on symptoms.
2. However, these effects are unlikely to significantly impact patients in their daily lives.
3. At the same time, SSRIs increase the risk of side effects, including serious ones.
4. The researchers concluded that the potential benefits of SSRIs might be outweighed by their harms.

IV. Integrating Both Studies

Taken together, the two reviews paint a very different picture of depression and its treatment than what most people have been told.

A. The Theory Doesn’t Hold Up

Moncrieff’s umbrella review showed that there is no consistent evidence that low serotonin levels cause depression. Across multiple areas of research—serotonin levels in the brain and spinal fluid, receptor activity, transporter binding, tryptophan depletion, and genetics—no convincing link was found.

In fact, some data suggested that antidepressant use itself may reduce serotonin or change the brain’s system over time.

B. The Treatment Falls Short

Jakobsen’s systematic review found that SSRIs provide, at best, minor improvements in symptoms, which fall below the threshold of clinical significance. More importantly, they increase the risk of both serious and non-serious adverse effects, raising questions about whether the benefits outweigh the harms.

C. Challenging the Assumptions

For decades, the idea that SSRIs correct a “chemical imbalance” has been used as a central justification for prescribing them. But if depression is not caused by low serotonin, and SSRIs do not meaningfully improve outcomes, then the foundation for this entire treatment model is shaky.

D. A Shift in Perspective

These two studies together challenge both the biological rationale and the clinical justification for SSRIs:

• Biological rationale: The serotonin theory is unsupported.
• Clinical justification: The benefits of SSRIs appear too small to matter, while risks are real.

This doesn’t mean that people should stop their medication abruptly—doing so can cause withdrawal symptoms and should always be done under medical supervision. But it does suggest that the time has come for a broader conversation about how we understand and treat depression.

V. Broader Implications

The findings from Moncrieff and Jakobsen’s studies have consequences that go far beyond the research lab. They affect how patients understand their illness, how doctors prescribe treatments, and how society approaches mental health as a whole.

A. Patient Beliefs and the “Chemical Imbalance” Story

For years, people struggling with depression have been told that their brain is chemically broken. This can create a sense of hopelessness and dependence: if your brain is defective, you may believe you’ll need medication for life.

Moncrieff’s review shows that this belief is not supported by science. Patients deserve honest information so they can make informed decisions about their treatment.

B. Clinical Practice and Transparency

Doctors often prescribe SSRIs as the first-line treatment for depression. But Jakobsen’s review suggests that the real-world benefits are modest, and the risks—both physical and psychological—are often underestimated. This calls for more transparency in how doctors present the pros and cons of SSRIs. Patients should know that improvement is not guaranteed and that side effects are common.

C. Rethinking the Role of SSRIs

These findings do not mean SSRIs should never be used. For some patients, especially those with severe depression, they may provide relief. But they should not be seen as a one-size-fits-all solution.

Other approaches—psychotherapy, exercise, social support, lifestyle changes, and addressing underlying stress—may offer more meaningful, lasting benefits without the risks of long-term drug use.

D. Building a New Model of Care

If depression is not simply a matter of serotonin deficiency, then treatment must look beyond quick chemical fixes. A new model of care should focus on:

• Psychological Resilience: Therapy and Coping Strategies.
• Lifestyle changes: Regular exercise, healthy diet, good sleep, and reduced alcohol or drug use.
• Social connection: Supportive relationships and community.
• Holistic health: Addressing stress, trauma, and physical health conditions that can worsen mood.

E. The Need for Honest Dialogue

Perhaps the most important implication is that patients and doctors need a more open conversation. People should not feel pressured to accept a simple “serotonin imbalance” explanation or a pill as the only option. Instead, they should be empowered to explore multiple paths to recovery.

VI. Conclusion

For decades, the story of depression has been told as one of brain chemicals gone wrong—especially serotonin. This idea shaped how doctors treated patients and how millions of people understood their own struggles. But the science tells a different story.

The umbrella review by Moncrieff and colleagues shows that a serotonin deficiency does not cause depression. The large meta-analysis by Jakobsen and his team shows that SSRIs provide only small improvements that may not be meaningful in everyday life, while increasing the risk of side effects.

Together, these studies challenge both the biological explanation and the clinical justification for SSRIs.

This does not mean antidepressants have no place. Some patients may still find them helpful. But the belief that SSRIs correct a “chemical imbalance” is a myth.

Patients deserve clear, evidence-based information so they can make choices without fear or false promises.

The way forward requires a broader, more holistic approach to depression. This involves examining therapy, lifestyle modifications, community support, and addressing the numerous personal and social factors that influence mental health.

Above all, it means having an honest dialogue—one that respects the complexity of depression and the dignity of those who live with it.

The time has come to move beyond the chemical imbalance myth and towards a future where care for depression is grounded in truth, transparency, and real healing.

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References:

• Jakobsen, Janus Christian, et al. “Selective Serotonin Reuptake Inhibitors versus Placebo in Patients with Major Depressive Disorder: A Systematic Review with Meta-Analysis and Trial Sequential Analysis.” BMC Psychiatry, vol. 17, no. 58, 2017, pp. 1–20. Springer Nature, doi:10.1186/s12888-016-1173-2. https://pubmed.ncbi.nlm.nih.gov/28178949/
• Moncrieff, Joanna, et al. “The Serotonin Theory of Depression: A Systematic Umbrella Review of the Evidence.” Molecular Psychiatry, vol. 28, 2023, pp. 3243–3256. Nature Publishing Group, doi:10.1038/s41380-022-01661-0. https://www.nature.com/articles/s41380-022-01661-0

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