So-called black box warnings on prescription medications are supposed to alert people to the possibility that using the medication can cause serious or life-threatening events. They often, but not always, do this well.
The dangerous, outdated black box warning on all antidepressants, including newer, safer SSRI antidepressants (Prozac was the first of these) represents one of the failures of this process. These strident warnings about teens and young adults are required on every container of antidepressants and advertisements for them. The often-exaggerated media reports of the dangers of these antidepressants give them the air of incontestable truth.
More than a decade’s worth of studies have revealed that the warnings on these antidepressants aimed at teens and young adults, which are intended to alert clinicians to be on the lookout for young people having thoughts of suicide at the start of treatment, have actually discouraged teens and young adults from seeking needed care. But their effects have spilled over to older adults.
These studies show precipitous drops in diagnoses of depression, mental health visits, use of antidepressants, and even decreases in monitoring depressed patients, which is especially ironic because the FDA warnings called for increased monitoring. The irony becomes tragic because the drop in depression care appears to have increased suicide attempts.
The FDA’s refusal to remove or tone down these warnings — even in the face of mounting evidence of their dangers — can be traced in part to a blatant conflict of interest hidden from the public: Dr. Marc Stone, the FDA’s deputy director for safety in the psychiatric products division, who had a major role in developing the boxed warnings, published vitriolic critiques of research questioning the warnings’ safety without disclosing his role in the process.
A study published Wednesday based on 28 years of U.S. death certificate data beginning in 1990 suggests how the FDA’s warning increased suicides, potentially by many thousands, at least for the first several years. It uses actual suicide deaths, not just suicidal thoughts and attempts. As one of us (S.S.) and colleagues reported in the journal Psychiatric Research and Clinical Practice, suicide rates began declining after 1990. That trend was reversed in 2004 following the first FDA warnings about a link between use of these antidepressants and the onset of suicidal thoughts. The rate of suicide continued to increase as the FDA escalated the severity of the warnings, implementing the most severe black box warning in 2005 and then extending it from children and adolescents to young adults in 2007.
Most people are aware of financial conflicts of interest, such as when Dr. Jose Baselga at Memorial Sloan Kettering Cancer Center in New York failed to disclose millions of dollars in payments from pharmaceutical companies in research articles evaluating the companies’ products. But here the conflict is the intransigence of those who developed the warnings. This is a nonfinancial conflict of interest. Such conflicts often go undetected, but they are common and insidious.
A study conducted by Academy Health, the largest U.S. professional organization of health services researchers, found that government funders were at least as likely to censor or manipulate research results as private industry. Such censorship was mostly due to personal or political — meaning nonfinancial — considerations, such as state health agencies censoring researchers reporting negative effects of state health insurance policies.
Scientific journals often require that authors disclose nonfinancial conflicts of interest as well as financial ones. These policies are only useful, however, if they are enforced or if individuals are honest. In 2010, the New England Journal of Medicine added a question to its standard conflict-of-interest form for authors to disclose nonfinancial conflicts: Are there other relationships or activities that readers could perceive to have influenced, or that give the appearance of potentially influencing, what you wrote in the submitted work?
Yet in an editorial analyzing studies about the antidepressant warnings in NEJM, Stone failed to disclose his obvious nonfinancial conflict in response to this question.
For policymakers and the public to evaluate scientific findings, academics and representatives of government and corporations should disclose all conflicts of interest when they participate in scientific conversations. The case of black-box antidepressant warnings provides an example of an undisclosed nonfinancial conflict that produced a biased, inaccurate analysis and an unscientific and dismissive response to rigorous and important safety studies. FDA officials’ refusal to consider the overwhelming evidence and their unprofessional defensiveness likely reduced essential care and increased suicides among America’s youth.
The problem of nonfinancial conflicts of interest is far from limited to the FDA, with political leaders distorting and influencing reports on everything from the severity of Covid-19 to progress on treatments and vaccines. When this happens, we sacrifice the essential health and biomedical principles that have dramatically improved health and well-being in much of the world. These nonfinancial conflicts are eroding our ability to escape the current health and economic crises.
Resolving this issue matters today. The Covid-19 pandemic is impairing the mental health of many Americans. The young are especially affected: Recent national studies find that 1 in 4 of those between the ages of 18 and 24 have seriously considered suicide since the beginning of the pandemic. To make things worse, mental health care in the U.S. has decreased during this crisis, as patients lose insurance or avoid medical facilities.
At a time like this, policymakers should respond by doing everything possible to ensure people get the mental health care they need. As suicides mount and the Covid-19 pandemic heightens that danger, the FDA should set aside its intransigence and commission outside reviews of all studies that have shown adverse effects of its antidepressant warnings.
In the meantime, it should strongly consider demoting the ill-advised black box warnings on SSRI antidepressants to the long list of less-severe warnings contained in the product labelling.
Most FDA warnings about medication dangers are essential to patient safety. But ignoring the effects of ill-considered warnings — especially in light of overwhelming evidence of their harms — can also be dangerous.
Stephen Soumerai is professor of population medicine at Harvard Medical School and the founding and former director of Harvard’s Division of Health Policy and Insurance Research. Ross Koppel is professor of biomedical informatics and adjunct professor of sociology at the University of Pennsylvania, a senior fellow at Penn’s Leonard Davis Institute of Healthcare Economics, and professor of biomedical informatics at the University at Buffalo (SUNY).
I enter here a relevant example.
In 2013, my team and I published: Zivin K, Pfeiffer PN, Bohnert ASB, Ganoczy D, Blow FC, Nallamothu BK, Kales HC. Evaluation of the FDA warning against prescribing citalopram at doses exceeding 40 mg. American Journal of Psychiatry.
This study assessed relationships between citalopram use and ventricular arrhythmias and mortality in light of the 2011-2012 FDA drug safety warnings, which cautioned that citalopram dosages exceeding 40 mg/day may cause abnormal heart rhythms, including torsade de pointes. This large study in the Department of Veterans Affairs (N>1,000,000) found no elevated risks of these outcomes associated with elevated citalopram dosages. This study generated significant clinical, policy, and media attention. It was selected as one of the top ten articles in 2013 by the New England Journal of Medicine Journal Watch Psychiatry, and invited oral presentation at the American Journal of Psychiatry Forum at the 2014 American Psychiatric Association annual meeting.
In 2014, Dr. Stone’s team wrote a rebuttal to our piece: Bird ST, Crentsil V, Temple R, Pinheiro S, Demczar D, Stone M. Cardiac Safety Concerns Remain for Citalopram at Dosages Above 40 mg/Day. American Journal of Psychiatry.
We responded in the same journal issue in 2014: Zivin K, Pfeiffer PN, Bohnert AS, Ganoczy D, Blow FC, Nallamothu BK, Kales HC. Safety of high-dosage citalopram. American Journal of Psychiatry.
In 2016, a separate team of Department of Veterans Affairs researchers found that: Reduction of prescribed citalopram dosages to a new safety limit was associated with a higher rate of hospitalization in a large patient population who had been treated with substantially higher dosages. Stipulating a safety limit for citalopram dosages before the benefits and risks of doing so were firmly established appears to have had unintended clinical consequences. Rector TS, Adabag S, Cunningham F, Nelson D, Dieperink E. Outcomes of Citalopram Dosage Risk Mitigation in a Veteran Population. American Journal of Psychiatry.
In the spirit of transparency, Stephen Soumerai served on my health policy dissertation committee at Harvard University (2002-2004) and as a mentor during my postdoctoral fellowship at Harvard Medical School (2004-2006).
Kara Zivin, PhD, MS, MA
Professor of Psychiatry
Professor of Health Management and Policy
University of Michigan
The linked article contains more charts and scores of references
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