Antidepressant Warnings Research Articles

Intended And Unintended Outcomes After FDA Pediatric Antidepressant Warnings: A Systematic Review.

Since 2003, the Food and Drug Administration (FDA) has warned that antidepressants may be associated with suicidal thoughts and behaviors among youth. An FDA advisory in 2003 and a black-box warning in 2005 focused on children and adolescents younger than age eighteen. The FDA expanded the black-box warning in 2007 to include young adults. Both warnings were intended to increase physician monitoring of suicidal thoughts and behaviors. Our systematic review identified thirty-four studies of depression and suicide-related outcomes after these warnings; eleven of these studies met research design criteria established to reduce biases. The eleven studies examined monitoring for suicidal thoughts and behaviors, physician visits for depression, depression diagnoses, psychotherapy visits, antidepressant treatment and use, and psychotropic drug poisonings (a proxy for suicide attempts) and suicide deaths. We assessed possible spillover to adults not targeted by the warnings. The one study that measured intended physician monitoring of suicidal thoughts and behaviors did not find evidence of an increase. Multiple studies found significant unintended reductions in mental health care after the warnings. After these reductions, there were marked increases in psychotropic drug poisonings and suicide deaths. These findings support reevaluation of risks and benefits of the FDA's black-box antidepressant warnings.

Youth Suicides Increased After FDA Required Antidepressant Warnings

Back to table of contents Previous article Next article Clinical & ResearchFull AccessYouth Suicides Increased After FDA Required Antidepressant WarningsTerri D'ArrigoTerri D'ArrigoSearch for more papers by this authorPublished Online:1 Dec 2020https://doi.org/10.1176/appi.pn.2020.11b31AbstractDepression diagnoses and treatment declined in the wake of the FDA warnings, disrupting a previously downward trend in suicide among adolescents and young adults.Suicide deaths among adolescents and young adults increased after the U.S. Food and Drug Administration (FDA) issued warnings about antidepressant use and possible suicidal ideation in these populations, a study in Psychiatric Research and Clinical Practice has found. The researchers buttressed their findings by including results from more than a decade of prior research suggesting that the warnings also reduced care seeking, depression diagnoses, psychotherapy visits, antidepressant treatment, and monitoring of patients who take antidepressants and may have led to increased suicide attempts.The FDA should consider downgrading its warnings about antidepressants and suicidal ideation in adolescents and young adults, says Stephen B. Soumerai, Sc.D.Harvard Pilgrim Health Care Institute/Elisif Andrews Brandon“It is surprising that a warning could set off a chain of events that are important intermediate outcomes in health care that could influence suicide,” senior author Stephen B. Soumerai, Sc.D., a professor of population medicine at Harvard Medical School and Harvard Pilgrim Health Care Institute, told Psychiatric News. “The warnings had unintended consequences of fear and stigma, not just among youth but among parents and clinicians.”Soumerai and colleagues analyzed data on suicide deaths by people aged 10 to 24 years from the Centers for Disease Control and Prevention’s WONDER database, which contains mortality counts for U.S. residents based on birth certificates. They analyzed suicide rates for the following three time segments:1990 to 2002, a 13-year span before the FDA issued its first warning, a public health advisory that children and adolescents who took antidepressants were at increased risk of suicidal ideation and behavior2003 and 2004 as a transition period after the initial advisory2005 to 2017, after the FDA required a boxed warning, effective in January 2005, for children and adolescents taking antidepressants, a warning that was expanded to include young adults in 2007Before the warnings, suicide deaths in youth had been on a downward trend. From 1990 to 2002, suicide deaths among adolescents aged 10 to 19 years dropped from 6.4 to 4.2 per 100,000 per year. For the same time frame, suicide deaths had decreased in young adults aged 20 to 24 years from 15.1 to 12.3 per 100,000 per year.However, almost immediately after the FDA issued its first black-box warning on antidepressants, depression care began to decline and suicide deaths began to climb in both groups. Between 2005 and 2017, suicide deaths among adolescents rose from 4.4 to 7.2 per 100,000 people a year. At the same time, suicide deaths among young adults rose from 12.4 to 17.0 per 100,000 people a year.“A mechanism for this association is clear: The FDA antidepressant ‘warning,’ accompanied by exaggerated media coverage, stigmatized depression care for young people and fostered reluctance by providers to initiate antidepressant treatment. Thus, the warnings reduced diagnosis of major depression and drug and nondrug mental health treatment,” the researchers wrote.“Not all young people with depression should be treated with medication. Research demonstrates that many will do well with structured forms of therapy such as CBT [cognitive-behavioral therapy],” said David Fassler, M.D., a clinical professor of psychiatry at the University of Vermont’s Larner College of Medicine, who was not involved in the research. “The real tragedy is that following the black-box warnings and the related media coverage, so many adolescents and young adults received no treatment at all.“This [study] represents a significant contribution to the ongoing dialogue concerning the impact of the FDA’s black-box warnings,” Fassler added. “Hopefully, it will help inform clinical practice, public policy, and future research initiatives.”Soumerai believes that the FDA should consider downgrading its warnings on antidepressants.“At the very least, take them out of the box,” he said. “We’re not saying these drugs don’t have the potential to harm. All drugs have the potential to harm if they are used inappropriately. Antibiotics have significant risks. Nonsteroidal anti-inflammatory medications can put people with certain risk factors into kidney dialysis. But undertreatment of depression can be harmful [and] result in suicidal behaviors and death.”Several of the researchers were supported in part by a cooperative agreement with the National Institute of Mental Health. ■“Increases in Suicide Deaths Among Adolescents and Young Adults Following U.S. Food and Drug Administration Boxed Warnings and Declines in Depression Care” is posted here. ISSUES NewArchived

Increases in Suicide Deaths Among Adolescents and Young Adults Following US Food and Drug Administration Antidepressant Boxed Warnings and Declines in Depression Care.

ObjectiveStudies show decreased depression diagnosis, psychotherapy, and medications and increased suicide attempts following US Food and Drug Administration antidepressant warnings regarding suicidality risk among youth. Effects on care spilled over to older adults. This study investigated whether suicide deaths increased following the warnings and declines in depression care.MethodsWe conducted an interrupted time series study of validated death data (1990–2017) to estimate changes in trends of US suicide deaths per 100,000 adolescents (ages 10–19) and young adults (ages 20–24) after the warnings, controlling for baseline trends.ResultsBefore the warnings (1990–2002), suicide deaths decreased markedly. After the warnings (2005–2017) and abrupt declines in treatment, this downward trend reversed. There was an immediate increase of 0.49 suicides per 100,000 adolescents, 95% confidence interval [CI]: 0.12, 0.86) and a trend increase of 0.03 suicides per 100,000 adolescents per year (95% CI: 0.026, 0.031). Similarly, there was an immediate increase of 2.07 suicides per 100,000 young adults (95% CI: 1.04, 3.10) and a trend increase of 0.05 suicides per 100,000 young adults per year (95% CI: 0.04, 0.06). Assuming baseline trends continued, there may have been 5958 excess suicides nationally by 2010 among yearly cohorts of 43 million adolescents and 21 million young adults.ConclusionsWe observed increases in suicide deaths among youth following the warnings and declines in depression care. Alternative explanations were explored, including substance use, economic recessions, smart phone use, and unintentional injury deaths. Additional factors may have contributed to continued increases in youth suicide during the last decade. Combined with previous research on declining treatment, these results call for re‐evaluation of the antidepressant warnings.

Increases in youth suicide deaths after FDA antidepressant warnings

Increases in youth suicide deaths after FDA antidepressant warnings

A decline in depression treatment following FDA antidepressant warnings largely explains racial/ethnic disparities in prescription fills.

The Food and Drug Administration's 2004 antidepressant warning was followed by decreases in antidepressant prescribing for youth. This was due to declines in all types of depression treatment, not just the intended changes in antidepressant prescribing patterns. Little is known about how these patterns varied by race/ethnicity. Data are Medicaid claims from four U.S. states (2002-2009) for youth ages 5-17. Interrupted time series analyses measured changes due to the warning in levels and trends, by race/ethnicity, of three outcomes: antidepressant prescription fills, depression treatment visits, and incident fluoxetine prescription fills. Prewarning, antidepressant fills were increasing across all racial/ethnic groups, fastest for White youth. Postwarning, there was an immediate drop and continued decline in the rate of fills among White youth, more than double the decline in the rate among Black and Latino youth. Prewarning, depression treatment visits were increasing for White and Latino youth. Postwarning, depression treatment stabilized among Latinos, but declined among White youth. Prewarning, incident fluoxetine fills were increasing for all groups. Postwarning, immediate increases and increasing trends of fluoxetine fills were identified for all groups. Antidepressant prescription fills declined most postwarning for White youth, suggesting that risk information may have diffused less rapidly to prescribers or caregivers of minorities. Decreases in depression treatment visits help to explain the declines in antidepressant prescribing and were largest for White youth. An increase in incident fluoxetine fills, the only medication indicated for pediatric depression at the time, suggests that the warning may have shifted prescribing practices.

Are FDA Antidepressant Warnings Linked to Rise in Youth Suicides?

Back to table of contents Previous article Next article Clinical and Research NewsFull AccessAre FDA Antidepressant Warnings Linked to Rise in Youth Suicides?Vabren WattsVabren WattsSearch for more papers by this authorPublished Online:17 Jul 2014https://doi.org/10.1176/appi.pn.2014.7b18AbstractA study on the effects of the FDA’s warnings about antidepressants’ increased risk of suicidality leads to different interpretations.The warnings issued by the Food and Drug Administration (FDA) about the increased risk of suicidality (suicidal ideation and behavior) in young people taking antidepressants may have led to unintended consequences, reported a study published June 18 in BMJ. Martin Novak/ShutterstockFrom 2003 to 2007, the FDA issued several health advisories and a black-box warning that children, adolescents, and young adults taking antidepressants were at increased risk for suicidal behavior—leading to intense media attention. Some experts have since attributed the steep decline in the number of antidepressant prescriptions to youth to these FDA warnings.“These drugs can save lives,” stated the study’s senior author Stephen Soumerai, Sc.D., a professor of population medicine at Harvard Pilgrim Health Care Institute, but in reporting about the FDA antidepressant warning, “The media concentrated more on the relatively small risk than on the significant upside,” he said.The risk of suicidality cited by the FDA was approximately 1 percent for youth treated with antidepressants. A 2007 study published in the American Journal of Psychiatry reported that the use of antidepressants by youth and young adults dropped quickly by 20 percent, without a reciprocal increase in treatment alternatives such as psychotherapy or atypical antipsychotics (Psychiatric News, June 15, 2007). These findings prompted Soumerai and colleagues to investigate whether a link exists between the FDA warnings about antidepressants and a gradual increase in suicidality among youth in the years after the warning.To assess whether such a correlation exists, the researchers collected data from 2000 to 2010 on 7.5 million patients aged 10 to 64. Patients were assessed on changes in antidepressant use, suicide attempts, and deaths by suicide before and after the FDA’s highly publicized black-box warning was issued in 2004.The analysis showed that in the second year after the warning was issued, use of antidepressants had dropped 31 percent among adolescents, 24.3 percent among young adults, and 14.5 percent among older adults. Simultaneously, there was a 21.7 percent increase in suicide attempts by psychotropic drug poisoning among adolescents and a 33.7 percent increase in attempts among young adults. The number of deaths by suicide did not change for any age group.“Our study provides the first evidence that suicide attempts increased rather than decreased after the warnings,” noted the authors. “[The] data are consistent with the Centers for Disease Control and Prevention report that showed gradual increases in completed suicides between 1999 and 2010 . . . among people aged 10 to 34 years.”Mark Olfson, M.D., M.P.H., a professor of psychiatry at Columbia University Medical Center and an expert in mood disorders, told Psychiatric News that the interpretation of the current findings should be taken with caution. “The new findings shed little light on the complex associations between anxiety and depressive disorders, antidepressant treatment, and the risk of self-harm and suicide. The measure of suicide attempts used in this study, psychotropic poisonings, is only loosely related to suicide attempts. Most suicide attempts in young people do not involve poisoning by psychotropic drugs, and most intoxications do not represent suicide attempts.”Because of the recent substantial increase in unintentional poisonings from stimulants, Olfson stated that the increase in psychotropic overdose could be a result of an underlying substance use disorder rather than suicide. “This trend [of psychotropic overuse by youth], which may be driven by complex societal factors, deserves study and clinical attention,” Olfson concluded.The current study was funded by the National Institute of Mental Health. ■An abstract of “Changes in Antidepressant Use by Young People and Suicidal Behavior After FDA Warnings and Media Coverage: Quasi-Experimental Study” can be accessed here. ISSUES NewArchived

The FDA And ABCs: Unintended Consequences Of Antidepressant Warnings On Human Capital.

Using annual cross-sectional data on over 100,000 adolescents aged 12-17, we studied academic and behavioral outcomes among those who were and were not likely affected by FDA warnings regarding the safety of antidepressants. Compared to other adolescents, adolescents with probable depression experienced a relative decline in grade point average of .14 points following the FDA warnings. The FDA warnings also coincided with increased delinquency, use of tobacco and use of illicit drugs. Together, our results stress the importance of mental health and its treatment as an input into cognitive and non-cognitive aspects of human capital.

Impact of Food and Drug Administration (FDA) paediatric antidepressant warnings on stock prices of pharmaceutical manufacturers

Objectives The objective was to investigate the impact of the Food and Drug Administration (FDA) paediatric antidepressant warnings in 2004 on the magnitude and the systematic risk associated with stock returns of antidepressant manufacturers. Methods Center for Research in Security Prices (CRSP) daily stock-price data for 2003–2006 were used to examine the FDA warning impact. The beta coefficient from the capital asset pricing model was used as a measure of systematic risk. The CRSP New York Stock Exchange 500 value-weighted daily return was used as the market return. A multivariate regression model framework was employed in which an equation was estimated simultaneously for each of the five firms (Eli Lilly, Forest Laboratories, GlaxoSmithKline, Pfizer and Wyeth) affected by the warnings. The periods 2 February to 23 March 2004 and 14 September to 18 October 2004 were defined as the warning periods. A seemingly unrelated regression model was used with daily stock return as the dependent variable and warning period as the primary independent variable. The unit of analysis was each trading day between 1 January 2003 and 31 December 2006. Key findings In the period of uncertainty and warnings (2003–2004) the beta coefficient increased by an average of 0.296 (95% confidence interval 0.103, 0.489) across the five firms. The FDA warnings had no significant impact on the magnitude of the stock returns. Conclusions The 2004 FDA warnings on antidepressant use in children led to an increase in the systematic risk associated with antidepressant drug manufacturers' stocks with no corresponding change in stock returns, suggesting that investors did not change their perception of the value of these firms, but did perceive increased risk. This increase in risk makes it more costly for the manufacturers to raise capital.

Antidepressant Warnings May Have Caused Drop in New Rx

Antidepressant Warnings May Have Caused Drop in New Rx

Table of Contents

AbstractCognitive Therapy Equal to Medication in Augmentation for Citalopram‐Resistant DepressionNew Analysis of Second‐Generation Anti‐Depressants and Suicide Risk in Young PatientsComparative Effect of Duloxetine, Escitalopram and Sertraline on CYP2D6Effects of Risperidone Tablet‐SplittingComorbid Anxiety and Treatment Response in Late‐Life DepressionFew Patients Accept all Second‐Step Depression TreatmentsPsychotherapeutic Drug Spending ClimbsDuloxetine for Role Impairment/Quality of Life in GADSuicide Attempt with TopiramateNew Antidepressant Warning: Suicidality in Young AdultsProduct Withdrawal: PergolideApproved: Low Dose Risperidone

Table of Contents

AbstractMedicare Study Cites Medication Access Problems for Part D BeneficiariesVirginia Tech Tragedy Spurs Calls for Funding, Services on CampusMagellan Officials Report ‘Robust’ First‐Quarter EarningsSenate Parity Bill: Strong Legislation That Will Help Consumers and FamiliesFDA Proposes Expanding Antidepressant Warning to Young AdultsFDA Products Affected by Proposed Labeling ChangesState WatchResourcesNames in the NewsComing up

The Effect of Antidepressant Warnings on Prescribing Trends in Ontario, Canada

We studied whether 5 regulatory agency advisories concerning the possible increased risk of suicidal behavior during antidepressant therapy had an effect on antidepressant prescription trends in Ontario. We conducted a population-based, time-series analysis of new monthly antidepressant prescriptions dispensed by the Ontario Drug Benefits program in 3 age groups (younger than 20 years, 20-65 years old, and older than 65 years) over a 7-year period (April 1998 to March 2005). The impact of five advisories about the possible risk of suicide during antidepressant therapy was also analyzed. The number of new prescriptions for selective serotonin reuptake inhibitors as a group did not change after any antidepressant warning in any age group. However, the rate of new paroxetine prescriptions in patients younger than 20 years declined by 54% immediately after the first warning for paroxetine was issued in the United Kingdom in June 2003. That same warning had no effect on new paroxetine prescriptions in the other age categories. The warning about paroxetine use in depressed patients younger than 18 years that was issued in the United Kingdom led to a significant decrease in new paroxetine prescriptions for young patients in this country. By contrast, warnings in North America did not influence new antidepressant prescription rates in any patient group.

Pediatric Primary Care Providers and Adolescent Depression: A Qualitative Study of Barriers to Treatment and the Effect of the Black Box Warning

Purpose The recent black box warning on antidepressants has drawn attention to controversies regarding the treatment of adolescent depression in primary care settings, but little is known about how providers decide to treat depressed youth and what resources are employed. Methods We conducted focus groups with 35 providers and staff in nine community-based pediatric practices in rural and urban settings of western Washington State. Discussion topics included perceived barriers to the treatment of depression in youth, how providers addressed these barriers, and the impact of the recent Federal Drug Administration (FDA) black-box warning. Focus groups were audiotaped and professionally transcribed. Qualitative content analysis was conducted using Atlas ti software and differences in coding were resolved via discussion by three independent reviewers. Results Based on analysis of interviews, a conceptual model was developed detailing factors influencing primary care providers’ (PCP) decisions about depression treatment. The three key themes that influenced doctors’ decisions about treating depression were lack of availability of mental health resources in the community, feeling responsible for helping based on long-standing relationships with patients and families, and patient and family beliefs and preferences regarding treatment. Most of the approaches to address barriers were not systemized and were physician dependent. Most providers expressed concern about recent antidepressant warnings, but many continued to treat and none had developed new strategies for closer monitoring of youth initiating treatment with antidepressants. Conclusion The decision of when and how PCPs decide to treat adolescent depression is strongly influenced by PCP perceptions of their role in treatment, availability of other treatment resources, and family and patient preferences and resources. Few practices have developed changes in the approach to practice needed to meet FDA black-box recommendations regarding close monitoring of response to medications.

Antidepressant black-box warning should include young adults, panel urges

Balancing the advice from a panel of experts with federal regulatory rules is often quite difficult and sometimes takes some profound pondering, said Robert Temple, director of medical policy at FDA. On December 13, 2006, the agency asked its Psychopharmacologic Drugs Advisory Committee to discuss

Antidepressant Warning Focuses Attention on Unmet Need for Child Psychiatrists

The controversial black-box warning for antidepressants describing the possible link between use of these drugs and suicide in adolescents has sparked an active debate regarding the appropriate treatment of depression in younger patients. The warning, required in the labeling of at least 32 commonly prescribed antidepressants, not only focuses attention on concerns about these medications for pediatric patients but also highlights a widening gap between the needs of the approximately 2.7 million US children and adolescents with significant depression and the nation's relatively small number of trained child psychiatrists. However, a growing recognition of this unmet need is driving new efforts to address the problem. Primary care pediatricians, family medicine practitioners, and psychiatrists are collaborating to formulate and promote guidelines and other measures.

US FDA antidepressant warning has created unnecessary confusion

US FDA antidepressant warning has created unnecessary confusion

US FDA antidepressant warning has created unnecessary confusion

US FDA antidepressant warning has created unnecessary confusion

Dr. Teicher and Associates Reply

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