Low serotonin might not cause depression, but why do SSRIs still work?

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Depression and serotonin levels may not be as closely interlinked as we had thought. Image credit: Aurelien Morissard/Xinhua via Getty Images.
  • Depression is a highly prevalent mental illness. Treatment options for depression are individualized and may include the use of medications and therapy.
  • Researchers have theorized that low serotonin levels cause depression.
  • Data from a recent systematic umbrella review found little evidence linking serotonin levels with depression.

Clinical depression is one of the most common mental illnesses, impacting millions of people worldwide.

While several factors contribute to depression, one common idea is that it is related to chemical imbalances in the brain, particularly low levels of the chemical serotonin.

However, there may be less data supporting this theory than researchers had initially thought.

A recent systematic umbrella review published in Molecular Psychiatry found that there is little evidence to support the notion that depression is associated with low serotonin levels.

Clinical depression is a serious mental illness that impacts quality of life and well-being. The World Health Organization (WHO) notes that about 280 million people worldwide live with depression.

People with depression experience various symptoms that affect their mood, emotions, and ability to go about their daily lives.

The treatment for depression often involves multiple approaches. For example, people with depression might utilize cognitive behavioral therapy (CBT) to help them work through perceptions and thought patterns, or other forms of talking therapy, including counseling and psychotherapy. Other lifestyle changes can also be considered.

Treatment may also include using antidepressants such as selective serotonin reuptake inhibitors (SSRIs). SSRIs increase levels of serotonin in the body.

Serotonin is a neurotransmitter that may impact people’s moods and behaviors, and SSRIs can be effective in treating symptoms of depression.

However, the theory that serotonin levels are inextricably linked to this condition hails back to the 1960s. The review recently published in Molecular Psychiatry now disputes this long-held notion.

The review examined data from systematic reviews, meta-analyses, and large database studies. Researchers did not include animal studies or studies that focused on depression sub-types such as postpartum depression or depression in people with specific physical conditions, such as Parkinson’s.

Their research included 17 studies in their analysis. In one-meta analysis, there was weak evidence that low levels of tryptophan might affect people with family histories of depression.

Tryptophan lowers the amount of serotonin available. However, most of the data suggested that depression is not associated with low serotonin levels or that low serotonin levels cause depression.

Researchers also found some evidence supporting the idea that long-term antidepressant use might actually lower serotonin levels in the body. They note that further research is needed to look into the long-term effects of antidepressants on the body.

They also note that the quality of the reviews included in their own analysis was variable.

Review author Prof. Joanna Moncrieff, from University College London, summarized the results this way:

“The main message of the paper is that scientific evidence accumulated over several decades does not support the theory that depression is caused by a deficiency of serotonin. Since serotonin is the main brain chemical thought to be involved in depression and the one that has been most thoroughly researched in modern times, this means the idea that depression is due to a chemical imbalance is not scientifically established.”

The researchers were thorough in their data collection and analysis methods. However, they note that their review still has several limitations. For example, they point out that some of the non-genetic studies included did not take into account the impact of previous antidepressant use and had small sample sizes.

Their ability to analyze components like confounding was limited based on what was done in the studies, and some data were older, indicating the need for further research.

The data available suggest that low serotonin levels do not cause depression. However, this does not mean that doctors will stop utilizing antidepressants as a treatment option. Instead, it calls for more research about why antidepressants work the way they do.

Prof. Andrea Cipriani, professor of psychiatry at the University of Oxford in the United Kingdom, who was not involved in the study, noted the following to MNT:

“This study tried to answer the question: ‘Do depressed people have different levels of serotonin?’ And the authors suggest the answer is ‘no.’ However, a completely different question is whether antidepressants work. This question was not addressed in the paper, and the problem — and the real danger — is that this study is actually used to answer that second question… The possible role of serotonin in depression is a separate question from the antidepressant effects of selective serotonin reuptake inhibitors, and no current theory of antidepressant action makes the assertion that antidepressants work only by correction of a prior corresponding chemical imbalance.”

Prof. Moncrieff’s view was that:

“Antidepressants were initially suggested to work by rectifying the serotonin abnormality that was thought to underpin depression. As our paper shows, there is no evidence of a serotonin abnormality in depression. This means that we do not actually understand what antidepressants are doing. We need to reevaluate the pros and cons of antidepressant treatment in light of this.”

Furthermore, the research may impact how people view the use of antidepressants. People may come to view antidepressants more as part of a comprehensive approach to treatment rather than a “fix.”

Prof. Moncrieff explained that “[m]any people have been told that their mood problems are due to a chemical imbalance and that they need antidepressants to put them right.”

“This,” she suggested, “has probably contributed to the escalating use of antidepressants over the last three decades. People should be informed that this has not been established, so they can make more informed decisions about whether to use antidepressants.”

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