In a highly publicized article published in the British Medical Journal (BMJ) on June 18, 2014, “Changes in antidepressant use by young people and suicidal behavior after FDA warnings and media coverage: quasi-experimental study,” Dr. Lu and colleagues suggest the FDA’s warnings regarding an increased risk of suicidality in children and adolescents taking antidepressants caused antidepressant prescriptions to drop and simultaneously increased suicide attempts in youths. However, according to Baum Hedlund attorney Bijan Esfandiari, “The article’s rhetoric is not supported by the actual data. Ironically, Lu’s admonition about how media coverage of the FDA suicide warnings caused undue alarm is precisely what the unwarranted conclusions and resulting publicity from her study will likely generate.”
Here are some of the flaws
- A quasi-experimental study such as this cannot convincingly demonstrate a causal link between treatment and observed outcome, particularly when confounding factors cannot be controlled or accounted for.
- The conclusion of the study that: “Safety warnings about antidepressants and widespread media coverage decreased antidepressant use, and there were simultaneous increases in suicide attempts amongst young people” does not state the two are causally related because it cannot, just as ice cream sales and murders going up in the summer does not mean ice cream causes murder.
- The authors incorrectly describe the FDA’s analysis of suicidality in children and adolescents and subsequent call for a black box warning as based on “inconclusive evidence.” Anyone who attended the FDA advisory committee meetings or has read the data analyses and the interchange between the numerous scientists during the FDA meetings on February 2, 2004, and September 13 and 14, 2004, which culminated in the black box warnings, would likely disagree with Lu. Related articles and documents:
- Reason Magazine Perpetuates False Information About Safety and Efficacy of Antidepressants
- February 2, 2004, FDA Hearing Transcript: Psychopharmacologic Drugs Advisory Committee with the Pediatric Subcommittee of the Anti-Infective Drugs Advisory Committee Department of Health And Human Services, Food And Drug Administration Center For Drug Evaluation And Research
- September 13, 2004, FDA Hearing Transcript: Joint Meeting of the CDER Psychopharmacologic Drugs Advisory Committee and the FDA Pediatric Advisory Committee, Department of Health and Human Services, Food and Drug Administration Center for Drug Evaluation and Research
- September 14, 2004, FDA Hearing Transcript: Joint Meeting of the CDER Psychopharmacologic Drugs Advisory Committee and the FDA Pediatric Advisory Committee, Department of Health and Human Services, Food and Drug Administration Center for Drug Evaluation and Research
- In fact, the FDA analysis of double-blind placebo-controlled trials of antidepressants found a statistically significant increased risk of suicidality in pediatric patients taking antidepressants:
- FDA Memo: Background on Suicidality Associated with Antidepressant Drug Treatment
- FDA Warning: Suicidality in Children and Adolescents Being Treated With Antidepressant Medications
- After reviewing the FDA analysis, a panel of FDA experts voted 25 to 1 that the data “support the conclusion that [antidepressants] increase the risk of suicidality in pediatric patients.”
- February 2, 2004, Summary Minutes of the Psychopharmacologic Drugs Advisory Committee Meeting and the Pediatric Subcommittee of the Anti-Infective Drugs Advisory Committee, FDA Center for Drug Evaluation and Research
- Explanation of FDA antidepressant warnings regarding suicide
- One voting member, Dr. Thomas Newman, an epidemiologist from the University of San Francisco, pointed out that the higher rates of suicidality that emerged from the clinical trials is “striking” and “such a dramatic result would be expected to occur by chance only 1 time in 20,000.” He further stated: “The fact that an association emerged from the meta-analysis … for an outcome that the sponsors of the trials were not looking for, and presumably did not wish to find, was quite convincing.”
- The FDA itself “concluded that suicidal thinking or behavior may increase in pediatric patients treated with any type of antidepressant, especially early in treatment. Increases in suicidal thinking or behavior due to drug can be expected in about 1 out of 50 treated pediatric patients.”
- Lu and colleagues also completely ignore the overwhelming evidence that the drugs lack efficacy in treating child and adolescent depression, not to mention adult depression. As Dr. Newman stated, “We have I think very strong evidence of harm and really not very good evidence of efficacy.”
- A Black-Box Warning for Antidepressants in Children? Thomas B. Newman, M.D., M.P.H
- Wishful thinking: antidepressant drugs in childhood depression, The British Journal of Psychiatry (2005). Authors: Anne Tonkin and Jon Jureidini
- The Lu analysis only looked at psychotropic drug poisonings resulting in hospitalization. Excluding a code for actual suicide attempts and instead of using a proxy that may or may not even be related to suicide attempts fatally flaws the study.
- Read the Response to the Lu analysis by Peter C Gøtzsche, Professor Nordic Cochrane Centre, Rigshospitalet, Copenhagen
- Olfson (Columbia) and Schoenbaum (NIMH) explain in response to the Lu study that “acute care visits for psychotropic drug poisoning is clearly an unreliable measure of suicide attempts” and they question whether the data support the authors’ conclusions: “A more plausible explanation for the reported findings … is that the FDA warnings slowed prior growth in the rate of antidepressant treatment [and] in the following years, there was substantial – but likely unrelated – increase in emergency department visits and hospital admissions by young people in the United States related to the non-medical use of benzodiazapines [ ], stimulants [ ], and other psychotropic agents,” most of which “do not represent suicide attempts.”
- According to Dr. David Healy, limiting the analysis to self-poisoning is flawed for another reason. Since SSRIs and SNRIs hit the market, the proportion of self-inflicted deaths due to hanging has increased over 50% and evidence indicates that suicides linked to SSRIs involve marked violence as opposed to self-poisoning. He also points out that the suicide attempts reported in Lu’s analysis parallel the increase in prescriptions of atypical antipsychotics (such as Risperdal and Zyprexa), the clinical trials of which show almost exactly the same increases in suicidal acts over placebo as antidepressants. According to Dr. Healy, there is little basis from the underlying study data to make the argument being made in the paper, and the paper is better evidence of an agenda by the authors than an effect of warnings on suicide attempt rates. Read Dr. Healy’s response in BMJ to the Lu study
- A senior medical reviewer at the FDA, Marc Stone, stated of the study: “It’s a stretch to say that the people that are committing suicide or the increase in suicide attempts has to do with the prescription of antidepressants,” Stone said in a telephone interview. “There’s absolutely nothing in the study to say that these are the people who would have been prescribed the antidepressants if it weren’t for the warnings.”
- Dr. David Juurlink, a drug safety specialist and head of clinical pharmacology and toxicology at Sunnybrook Health Sciences Centre, stated: “It’s important that people not infer that the warnings, which clearly led to a reduction in the prescribing of antidepressants, were the cause of deliberate overdoses in the same population.” The increase in overdoses could come from any number of factors, he said.
- According to Thomas J. Moore, Drug Safety Research, Institute for Safe Medication Practices, any one of the numerous flaws in the Lu study “would be fatal to the authors’ premise.”
- Meanwhile, Lu does not advocate removing the black box warning, “because it alerts people to a real, if small, risk and emphasizes the importance of monitoring and the hazards of undertreatment.”
- Read: “Study finds rise in suicide attempts after FDA warning,” The Boston Globe, June 18, 2014
And, the FDA said in an e-mailed statement that it has no plans to reconsider the black box warnings. “At this time, nothing indicates a need for change in the boxed warning on these drugs, which urges attention to patients starting treatment, which the FDA feels is still good advice,” wrote FDA spokeswoman Sandy Walsh. “The warnings on the drugs … say suicidality is a risk in young people, and so the clinician should monitor the young patient when starting, or increasing the dose, of these drugs.” Source: Bloomberg
- The authors began the analysis with the preconceived assumption that “decreasing rates of overall antidepressant treatment after the warnings would be associated with a net increase in suicide attempts among young people.”
- The authors admit: “In adolescents and young adults, initiation of antidepressant treatment may precipitate short term increases in suicidal ideation and behavior.”
- The authors “did not observe changes in completed suicides amongst adolescents.”
- The authors “did not detect changes in poisonings by any drugs after the warnings among young adults.”
- The authors “did not observe discontinuities in completed suicides when [they] combined the data from adolescents and young adults.”
- The authors “did not find changes in poisonings by any drugs after the warnings among adults. There was no change in completed suicides.”
- The authors state that, although they “found substantial reductions in antidepressant use,” they only found “small increases in psychotropic poisonings” and “even with large sample sizes we observed no changes in suicides after the warnings.”
Baum Hedlund has litigated antidepressant suicide and suicide attempt cases for over 20 years. As a result, the firm (in conjunction with research consultants and leading experts in psychopharmacology) have conducted a great deal of research on the issues presented in the Lu paper. The firm has also obtained confidential pharmaceutical company documents which shed further light on the issues. Baum Hedlund is currently litigating a high-profile adult antidepressant suicide case in Chicago. The firm believes it is important to continue to share our knowledge base when we become aware of research that could mislead the public.