Psychiatrist Effort Prompts Retraction of Antidepressant Paper

Eric Ross was listening to a popular psychiatry podcast one day last spring when “some pretty remarkable” research findings caught his attention. 

A team of researchers in Egypt had shown that adding a cheap diabetes drug—metformin—to antidepressant therapy nearly doubled the treatment’s efficacy in people with moderate to severe depression. That meant the drug worked better than electric shock therapy, an option when antidepressants fail. It was a breakthrough.

“I thought, you know, wow, this is something that I’m comfortable prescribing that could make a huge difference for my patients,” said Ross, who at the time was doing his residency in psychiatry at Massachusetts General Hospital.

But when he looked up the study, he discovered several oddities. For instance, the number of patients who experienced an adverse event differed by exactly one for 17 out of 18 single events like fatigue or bloating. That seemed unlikely to have occurred by chance. And all of the scores of statistical tests the authors had done turned out just the way they would have wanted, a dream that rarely comes true in biomedical sciences. 

Perhaps most damningly, many of the numbers in the paper showed a glaring similarity to the numbers in a clinical trial of another add-on drug that the authors had published—as if they had been “rather sloppily copy-pasted” with a digit changed here and there, Ross later wrote. 

That study also had impressive results, suggesting that in just a couple of years, the Egyptian researchers had discovered two treatments—metformin and cilostazol—that outperformed electric shock therapy. 

To Ross, there was no doubt the data was fake, although the corresponding author of the papers, Mahmoud S. Abdallah, a lecturer in clinical pharmacy at the University of Sadat City, vehemently denies this.

“I was fired up,” Ross, now an assistant professor of psychiatry at the University of Vermont, told Retraction Watch. “I was really mad because this is the kind of thing that can immediately affect patient care.”

He decided to share his suspicions with the journals that had published the two studies, Neurotherapeutics and CNS Neuroscience & Therapeutics.

“Research misconduct is damaging in any field, but I am particularly disturbed by these articles,” he told them in an email from March 1, 2022, that Retraction Watch has seen. “Besides its harms to the research community, a fabricated clinical trial with clinically actionable conclusions has the potential to do real and immediate harm to patients.”

Cilostazol, for instance, may cause heart problems and stomach bleeding; metformin is not free of side effects either. Whether or not the drugs work against depression, they can still cause harm.

A first-time sleuth, Ross also pointed to other studies by Abdallah that struck him as suspicious: 

Most unfortunately, the corresponding author appears to be a serial fabulist: he has previously published papers with all the same odd tics (>80% remission rate, multiples of ten evaluated/enrolled, identical numbers of patients discontinuing treatment, no loss to follow-up, and every outcome turning out perfectly) on pentoxifylline for depression (https://pubmed.ncbi.nlm.nih.gov/30205379/) and metformin for rheumatoid arthritis (https://pubmed.ncbi.nlm.nih.gov/33773207/).

In September, Neurotherapeutics pulled the first paper, “The Antidiabetic Metformin as an Adjunct to Antidepressants in Patients with Major Depressive Disorder: A Proof-of-Concept, Randomized, Double-Blind, Placebo-Controlled Trial.” It has been cited 27 times, according to Clarivate’s web of Science.

The retraction note stated:

The response from the authors to these concerns has shown that there are serious issues with the ethical oversight, the reporting and the availability of audited data for this clinical trial. The Editor-in-Chief therefore no longer has confidence in the results and conclusions presented. All authors disagree with this retraction. 

In an email to Retraction Watch, Abdallah denied Ross’ accusations of data fabrication. He added, “The journal retraction decision is based on speculations without any evidence that we have violated ethical oversight.”

Abdallah shared his correspondence with the Committee on Publication Ethics (COPE) and Springer Nature, the publisher of Neurotherapeutics, in which he argued at length against the concerns about his research and also threatened legal action “to protect our reputation.” 

So far, no action has been taken on the cilostazol paper—”Double-blind, randomized, placebo-controlled pilot study of the phosphodiesterase-3 inhibitor cilostazol as an adjunctive to antidepressants in patients with major depressive disorder”—which has been cited three times.

Ross said he was told in January by Wiley, the publisher ofCNS Neuroscience & Therapeutics, that it would contact him “when there is progress.” In response to a request for comment we sent to the journal’s editorial office and its editor-in-chief, a Wiley spokesperson said:

We are grateful to Dr. Ross for bringing this concern to our attention. We have initiated an investigation into these articles in accordance with COPE guidelines.

“It’s been almost a year at this point since I originally raised the issue,” said Ross. “I don’t think this was one where it took a lot of, you know, complex sleuthing, like doing statistical analysis or anything like that, to be very suspicious about these papers. So I certainly would have hoped it would have been done a lot sooner.”

DISCLOSURE: Adam Marcus, a cofounder of Retraction Watch , is an editor at Medscape.

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