Review of a new mixed depression guideline reveals financial bias of guideline developers and lack of evidence supporting recommendations for prescribing of antipsychotics

An in-depth review of the “first” guideline for the recognition and management of major depression with mixed features, which recommended antipsychotics as a first-line treatment, found that it fails to meet any of the Institute of Medicine standards for guidelines. The three researchers who investigated the guideline found that its authors had close ties to industry; that they urged clinicians to use industry-friendly criteria for diagnosing the disorder; and that there was a lack of clinical evidence to support their recommendations.

The review, which was published in BMJ Evidence-Based Medicine, was conducted by Lisa Cosgrove of the University of Massachusetts Boston, Allen Shaughnessy of Tufts Medical School, and Terrence Shaneyfelt of the University of Alabama. Their deconstruction of the guideline, they wrote, provides “a case example of the economies of influence that contribute to the development and dissemination of untrustworthy guidelines.”

Financial conflicts of interest

Institute of Medicine standards state that guideline developers should be independent of industry. At a minimum, neither the chair nor the majority of members should have financial conflicts of interest.

In this case, the lead author of the guideline, Stephen Stahl, from the University of California, San Diego, is a member of the speaker’s bureau for Sunovion, the manufacturer of lurasidone (Latuda), which was one of two antipsychotics the guideline recommended as a preferred treatment. Stahl is also the editor-in-chief of CNS Spectrums, the journal that published the guideline. Finally, the guideline was published “in association with the Neuroscience Education Institute, a for-profit company, founded by Stahl, that provides continuing medical education for psychiatric disorders.

Of the 19 other guideline authors, at least 12 had ties to manufacturers of antipsychotics, and four in this group, like Stahl, were on Sunovion’s speaker’s bureau.

“Pharmaceutical companies refer to individuals who serve on speakers’ bureaus as ‘key opinion leaders’ because they are seen as essential to the marketing of new disorders as well as the drugs to treat them,” Cosgrove and colleagues wrote.

Expanding the market for industry

In their guideline, Stahl and his co-authors recommended that the criteria for recognizing “mixed depression” should be expanded beyond the criteria in DSM-5. They listed additional “non-DSM criteria” for making the diagnosis, without “providing adequate empirical support” for doing so, Cosgrove and her colleagues found.

The guideline also urges clinicians to “look for evidence of subthreshold symptoms,” recommending (and writing in bold) that they “ask every patient. Every time.” The guideline “emphasized that ‘mixed depression’ is significantly underdiagnosed in clinical practice and is ‘especially common in children and adolescents.”

This guideline, Cosgrove and colleagues wrote, “runs the risk of widening diagnostic boundaries and unnecessarily exposing people to treatment.”

No good clinical evidence

The guideline authors cited seven studies as evidence for recommending antipsychotics for mixed depression. Four of the seven were post-hoc analyses, rather than reports of the studies’ primary outcomes. Such analyses, Cosgrove and colleagues noted, “should only be used to generate hypotheses for future research” and not “as evidence of the efficacy of an intervention.”

The fifth study was a clinical trial for a different condition, not depression. That left two randomized clinical trials that the guideline authors reviewed.

One was of lurasidone. All of the investigators in that trial had commercial ties to the manufacturer, including six who were company employees. The second trial was of ziprasidone; six of the authors of that study, which was funded by Pfizer, the manufacturer of ziprasidone, had ties to industry.

Stahl and his guideline co-authors recommended lurasidone (Latuda) and asenaphine (Saphris) as the antipsychotics of choice for mixed depression. The authors did not list any RCT evidence to support their recommendation of asenaphine. Both of these medications are unavailable as generics and cost more than $1000 a month and $500 a month respectively.

An industry-friendly guideline

In conclusion, Cosgrove and her colleagues write:

“The ‘first ever’ guideline on the recognition and management of mixed depression highlights ongoing problems in guideline development, namely, that poorly developed, untrustworthy guidelines continue to be produced and conflicts of interest are still a major problem in guideline development.”

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Cosgrove L, Shaughnessy AF, Shaneyfelt, T. (2018). “When is a guideline not a guideline? The devil is in the details.” BMJ Evidence-Based Medicine 23:33-36. (Link)