Experts Clash Over Serotonin's Role in Depression

In June, a group of 36 psychologists published a comment in response to a recent “umbrella review” led by Joanna Moncrieff, MD. The review concluded that the serotonin system is not convincingly linked to depression. 

The serotonin model for depression gained prominence in the 1960s when researchers began exploring the role of neurotransmitters, including serotonin, in mood regulation and mental health disorders. Over the decades, the hypothesis has undergone refinement and revision as new research findings emerged, but has been generally accepted by the scientific community as one of the leading theories explaining the mechanisms of depression.

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Initial Response

The comment, led by Sameer Jauhar, PhD and published by King’s College London, pushed back on the review’s conclusions, saying that they are overstated and pointing to the authors’ use of unclear methodologies and misinterpretations of the studies it analyzed. 

Jauhar noted that the umbrella review did not include any new research. She further stated that many of the signatories of the comment were authors of the original reports included in the umbrella review.

“It was people who’d done the original work asking questions, and we had a dialogue amongst ourselves going through each part of the review, just trying to make sense of what it was the authors were saying to see if that made sense to ourselves,” Jauhar told Psychiatrist.com. 

After parsing through the review in more detail, Jauhar said that the comment writers concluded the review’s criteria for measuring certainty was weak. “It’s not a validated form of criteria; it’s quite arbitrary by nature. And for all of us, that introduced a degree of bias,” he stated.

Methodologies Questioned

Arbitrary criteria was also used in the umbrella analysis of tryptophan depletion studies, the comment asserted. The authors said that it included studies involving healthy volunteers but omitted data acknowledging that in people with major depressive disorder (MDD), tryptophan depletion can cause symptoms to relapse. 

“A more accurate interpretation is that tryptophan depletion studies suggest a role for 5-HT in people vulnerable to depression and in those remitted on SSRI treatment,” the comment stated. 

In a blog post, Moncrieff responded to this particular critique, stating: “The evidence suggests and everyone agrees that tryptophan depletion does not induce depression in people who do not have depression, which is the real test of the hypothesis that low serotonin causes depression.”

The comment further claimed that the umbrella review oversimplified interpretation of molecular imaging data, specifically regarding 5-HT1A receptor and serotonin transporter protein (SERT) binding. It argued that the review overlooked the complexity of the findings it attempts to interpret while failing to acknowledge contradictory evidence and alternative models. 

“Anyone in molecular imaging knows how complicated it is when you find decreased receptor binding. You can’t just draw a very dichotomous conclusion from that,” Jauhar said. “I wish Mother Nature was that simple.” 

The Response Letter

Moncrieff et al. responded to the Jauhar, et al. comment via a letter to the editor of Molecular Psychiatry, writing: “We synthesized all existing studies from the main areas of research on serotonin and depression. The onus is on others to present a convincing case based on other types of research or alternative hypotheses, not on us to disprove every speculation.” 

The letter goes on to say, “We would agree that many brain processes, including the serotonin system likely play a complex, though poorly understood, role in emotion and behaviour, including depression. Yet such ideas are different from the specific claim that depression is caused by low serotonin levels or serotonin activity (often communicated to patients) that our review specifically examines.”

Jauhar said he didn’t feel the response sufficiently answered the questions raised in his comment. “It was more of the same, basically finding some citation in favor of their argument. But when you read through the citation properly, it contrasts with what they say,” he said. “They didn’t address the factual points that we had brought up.”

Key Takeaways

Though his comment critiqued the umbrella review itself, Jauhar doesn’t lay any blame for the mistakes he said he believes were published in it. Instead, he argues it can be an unfortunate part of the editorial process in scientific journals. “It’s very difficult to get reviews solicited and to make sense of them. It’s part of the process, and I think that’s part of why we wrote this,” he said.

Jauhar stressed the importance of using unbiased methodology and accepting that these topics are extremely nuanced. He and his colleagues felt strongly that the review’s conclusion that serotonin has no proven implication in depression was misleading. 

“Getting 36 academics to agree in regard to something like this was a lot of work, and we wouldn’t have gone to all that effort unless we just thought, ‘science corrects itself,’” Jauhar said.

However, Moncrieff continues to stand by the review’s methodology and findings. In a blog post, she reiterated, “No reasonable scientist could conclude that the link between serotonin and depression has been established.” 

Moncrieff did not respond to Psychiatrist.com’s request for comment.