Deep Dive Into Mixed Depression Guideline Raises Red Flags

Megan Brooks

February 09, 2018

A recently published guideline on the recognition and management of mixed depression fails to meet standards of trustworthiness and disclosure of conflicts of interest by the majority of the authors, raising serious concerns, say three researchers who took a deep dive into the guideline.

The guideline was published in the April 2017 issue of CNS Spectrums, which was a theme issue devoted to mixed features in mental disorders.

As reported by Medscape Medical News at that time, the guideline writers conclude that one third or more of adults who are diagnosed with major depression have depression with mixed features and probably would derive more benefit by taking an antipsychotic than an antidepressant.

But the guideline raised red flags with Lisa Cosgrove, PhD, of the University of Massachusetts, Boston, Allen Shaughnessy PharmD, of Tufts University School of Medicine, Boston, and Terrence Shaneyfelt, MD, of the University of Alabama, Birmingham.

When they got into "the weeds" of the guideline, they found that four of the seven studies put forth as evidence for recommending antipsychotics for mixed depression were post hoc analyses.

"That's a big no-no. Post hoc analyses should only be used to generate hypotheses for future research — they should not be used as evidence of the efficacy of an intervention," Dr Cosgrove told Medscape Medical News.

The report was published online January 25 in BMJ Evidence-Based Medicine.

A Public Health Issue

The researchers are also concerned about the guideline's frontline recommendation for lurasidone (Latuda, Sunovion Pharmaceuticals) and asenapine (Saphris, Actavis) for mixed depression.

"These are very expensive on-patent drugs, and when we looked at the clinical trial data more closely, it was clear that there weren't enough data to support the recommendation that was made for second-generation antipsychotics for mixed depression," said Dr Cosgrove.

The guideline also runs the risk of widening diagnostic boundaries and unnecessarily exposing people to treatment, the researchers conclude. The guideline expands the diagnostic criteria for depression with mixed features by including criteria that do not appear in the Diagnostic and Statistical of Mental Disorders, Fifth Edition (DSM-5). However, the guideline fails to provide "adequate empirical support for their significant expansion of these criteria," they write.

"Our main concern is the potential for overdiagnosis and therefore overtreatment when you expand diagnostic criteria, which this guideline does, in terms of what constitutes mixed symptoms," said Dr Cosgrove.

They are also concerned that some of the symptoms that the guideline suggests are indicative of mixed depression, such as insomnia, irritability, and rumination, are classic symptoms of unipolar depression.

The guideline also encourages clinicians to look for evidence of subthreshold symptoms and emphasizes that mixed depression is significantly underdiagnosed in clinical practice and is especially common in children and adolescents.

"When you dig into the details, it becomes more apparent how the language in the guideline could really lead to overdiagnosis and overtreatment, particularly in children and adolescents. To us, this is really a public health issue," said Dr Cosgrove.

The lead author of the guideline, Stephen M. Stahl, MD, PhD, of the University of California, San Diego, and chairman, Neuroscience Education Institute, Carlsbad, California, declined multiple requests for comment. Two other guideline authors also did not respond to requests for comment.

Guideline or Industry-Friendly Opinion Piece?

The three researchers also worry that the guideline contains no description of the process used to develop the recommendations, no report of a systematic review of the evidence being used, and no report on how evidence was evaluated for quality (evidence was not graded, and there was no rating of the strength of recommendations). In addition, there does not appear to have been any external review of the guideline prior to publication.

The researchers note that potential financial conflicts of interest (FCOI) abound in this guideline. More than half of the authors disclosed ties to drug companies that manufacture antipsychotic medications recommended in the guideline, and there was no information about the management of FCOI, they note.

Five of the guideline authors served on speakers' bureaus, including the lead author, who serves on the speakers' bureau for Sunovion, the manufacturer of lurasidone. "While any financial arrangement is considered to be a conflict of interest, participation on speakers' bureaus — an extension of the marketing departments of manufacturers — is widely recognized to constitute a significant conflict of interest," they write.

Reached for comment, Claire Neely, MD, chief medical officer, Institute for Clinical Systems Improvement, Bloomington, Minnesota, who was not involved in the guideline review, said, "Relationships to pharmaceutical companies and serving on speakers bureaus are widely considered problematic by guideline producers. Many of us are making significant efforts to avoid these conflicts on our guideline writing panels. We have not allowed panel members with these types of relationships on our guideline working groups for a number of years.

"Likewise, conducting systematic review of the available literature (and showing how authors conducted this review, including how the evidence was graded) is current best practice, as is being clear on the strength of a recommendation and the quality of the supporting evidence," Dr Neely told Medscape Medical News.

She also noted that the National Guideline Clearinghouse (NGC), which is produced by the Agency for Healthcare Research and Quality (AHRQ), is using Institute of Medicine recommendations as they post newly published guidelines, to help the provider community select the best available guidelines for use.

Time For a Centralized Approach?

Also commenting on the guideline for Medscape Medical News, Mary Nix, deputy director, Division of Practice Improvement at the AHRQ, said, "Based on what was submitted, I could not tell that the guideline would meet our criteria for inclusion in the National Guideline Clearinghouse. What we have learned over the 20 years of doing NGC is that guideline developers may have that information in other documents, such as supplemental technical documents or methods manuals."

Nix also noted that on the basis of what is in the guideline document, "it is clear that none of the methods are addressed, so it's not clear that a systematic review of the literature and a synthesis of all that data and evidence were performed. That is one of our criteria for inclusion."

Finally, Nix said that it is also unclear from the guideline document whether it was developed by an organization rather than an individual or group of clinicians. "So without additional information, it would appear that it would not meet our criteria for the guideline developer organization. The NGC would only include a guideline that is developed by an organization."

Dr Cosgrove and her colleagues believe it's time for the United States to consider adopting a national guideline assessment process. Consolidating guideline development efforts would likely improve guidelines, they note.

"We do not need multiple guidelines [often recommending different things] on the same topic developed by multiple groups. Guideline development needs to be prioritized for those diseases with significant practice variability and for which a valid evidence base can guide recommendations. Guideline development should be commissioned to panels with demonstrated technical and clinical expertise."

To achieve this, they say guideline development should be centralized under the guidance of the AHRQ in the United States or similar organizations in other countries.

"Until this happens, we will continue to see the proliferation of industry-friendly opinion pieces, not genuine guidelines, developed by conflicted experts," they conclude.

Dr Cosgrove, Dr Shaughnessy, and Dr Shaneyfelt have disclosed no relevant financial relationships.

Evid Based Med. Published online January 25, 2018. Full text

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