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Impact of the FDA Black Box Warning on Physician Antidepressant Prescribing and Practice Patterns: Opening Pandora's Suicide Box

      To the Editor: After a decade-long decline, annual suicide rates in American children and adolescents increased in 2004. A report released in February 2007 described an 18% increase in the suicide rate in persons aged 1 through 19 years between 2003 and 2004.
      • Hamilton BE
      • Minino AM
      • Martin JA
      • Kochanek KD
      • Strobino DM
      • Guyer B
      Annual summary of vital statistics: 2005.
      The incidence of suicide, the third-leading cause of death in 15- to 19-year-old Americans, increased from 7.3 to 8.2 per 100,000 persons in 2004.
      This increase in suicides directly parallels the US Food and Drug Administration (FDA) recommendation for caution in prescribing antidepressants to children and adolescents. A March 2004 FDA advisory warned that antidepressants could cause worsening depression and increased suicidality. Within a month, the number of antidepressant prescriptions filled for children nationally declined 10%.
      • Rosack J
      New data show declines in antidepressant prescribing.
      In October 2004, after public committee hearings held in September, the FDA issued a black box warning (BBW),
      • US Food and Drug Administration
      FDA public health advisory: suicidality in children and adolescents being treated with antidepressant medications. October 15, 2004.
      its most serious warning, for children and adolescents (defined as ≤18 years, making no clear distinction between adolescents and children), on all antidepressants marketed in the United States. Although the FDA encouraged prescribers to “balance this risk with the clinical need,”
      • US Food and Drug Administration
      Class suicidality labeling language for antidepressants.
      prescriptions filled for children and adolescents had decreased an additional 10% by June 2005,
      • Rosack J
      New data show declines in antidepressant prescribing.
      2 months after the labeling appeared.
      Testimony at FDA hearings raised concern that a BBW could create unintended barriers to care if generalist physicians became reluctant to prescribe antidepressants. This is especially critical because visits to nonpsychiatric generalist (primary care) physicians account nationally for more than 60% of physician visits for depression.
      • Stafford RS
      • MacDonald EA
      • Finkelstein SN
      National patterns of medication treatment for depression, 1987 to 2001.
      The FDA panel's decision-making process has been hotly debated in the media and academic literature. Remarkably, not one child or adolescent among the 4400 cases the FDA reviewed completed suicide. Furthermore, the FDA inveighed against “suicidality”—a vague clinical concept encompassing everything from passive death wishes to near-lethal suicide attempts. Meanwhile, untreated depression is the single most widely recognized risk factor for suicide at all ages, even as depression in children is underrecognized and undertreated in a nation with woefully inadequate numbers of child and adolescent psychiatrists. Thus, family practitioners and pediatricians write most antidepressant prescriptions for young Americans. Large observational pharmacoepidemiological studies link increasing rates of selective serotonin reuptake inhibitor antidepressant prescriptions and decreased national suicide rates.
      • Olfson M
      • Shaffer D
      • Marcus SC
      • Greenberg T
      Relationship between antidepressant medication treatment and suicide in adolescents.
      • Gibbons RD
      • Hur K
      • Bhaumik DK
      • Mann JJ
      The relationship between antidepressant medication use and rate of suicide.
      In contrast, decreased antidepressant prescribing by primary care physicians could lead to increased suicide rates, an effect opposite the FDA's intent.
      Mayo Clinic Survey. The reasons for the 20% decrease in prescriptions filled for children and adolescents by June 2005 remain unclear. Similarly unclear is whether a subsequent expansion of the upper age limit within the BBW will have additional impact on physicians' prescribing practices. Specifically, in December 2006, an FDA panel voted 6 to 2 to expand the warning to include adults through age 24,
      • Young D
      Antidepressant black-box warning should include young adults, panel urges. ASHP Web site. January 15, 2007.
      a group at high risk for both initial episodes of depression and suicide, particularly in men. To gain insight into antidepressant drug use across all ages, we conducted an anonymous Web survey of physicians at the Mayo Clinic in Rochester, Minn, between November 2005 and January 2006. About half of the sample that responded prescribe for both adults and children and the other half for adults only. Most questionnaire items could be answered only by those actually prescribing antidepressants at some point in their careers.
      Of the 1433 doctoral-level health care professionals surveyed, 344 (24%) responded, including 44 (64%) of 69 psychiatry and psychology department members, 89 (32%) of 275 generalists, and 211 (19%) of 1089 specialists. Of the 344 respondents, 324 (94%) indicated that they were currently treating patients. Two of the survey respondents did not answer the question regarding age groups treated. Twenty-one (7%) of the remaining 322 respondents treated exclusively children and adolescents, 152 (47%) treated only adults, and 149 (46%) treated both groups. Of the 324 respondents who were currently treating patients, 247 (76%) indicated that they prescribed antidepressants, including 37 psychiatrists, 79 generalists, and 131 specialists.
      Of the 247 respondents who prescribed antidepressants, 233 (94%) had heard about the BBW, including all 37 psychiatrists and 78 (99%) of the 79 generalists vs 118 (90%) of the 131 specialists. Overall, 176 (76%) of the 233 physicianswho were aware of the BBW reported continuing to prescribe at the same rate, whereas 57 (24%) had decreased or stopped prescribing antidepressants. (One generalist did not respond to the question specifically addressing age groups treated, which resulted in a sample size of 232). Figure 1 shows the changes in prescribing patterns by physician group.
      Figure thumbnail gr1
      FIGURE 1Impact of antidepressant prescribing behavior by patient age among physicians aware of the BBW (N-232). Adol = adolescents and children.
      Decreased prescribing in response to the BBW was particularly marked for generalists seeing children and adolescents only, with 82% (9/11) indicating that they had decreased or stopped antidepressant prescribing vs only 28% (9/32) of generalists treating exclusively adults and 18% (6/34) seeing both adults and children. Psychiatrists did not report notable decreases in prescribing—the 8% decline reported in psychiatrists treating both adults and children appears to be related to less willingness of patients or guardians to accept medication. Whether they treated adults only or adults and children, 25% of specialists decreased or stopped prescribing antidepressants to patients in any age group. No physician group in our survey increased prescribing of antidepressants.
      In addition to rates of antidepressant prescribing, the survey collected information on practice pattern response after the BBW across the 3 physician groups. The data included in Table 1 are from all respondents who prescribed antidepressants, whether or not they had heard of the BBW (n=247). All physician groups reported changes in practice patterns, with 35% of psychiatrists, 12% of generalists, and 9% of specialists spending more time reviewing the treatment plan at the initial meeting. In addition, 11% of psychiatrists, 15% of generalists, and 4% of specialists saw or contacted patients sooner after the first appointment, and 4% of specialists said they would try counseling patients first before prescribing antidepressants. In the largest practice pattern change, we found that a total of 43% (23% + 20%) of specialists and 26% (17% + 9%) of generalists reported increasing their referrals to a psychiatrist or other mental health specialist for consultation.
      TABLE 1Most Common Practice Pattern Responses
      Not all practice pattern changes are listed. The electronic survey allowed selection of only 1 practice pattern response, with all responses totaling 100%.
      After FDA Black Box Warning, by Physician Group (N=247)
      FDA = Food and Drug Administration.
      Psychiatrists (n=37)Generalists (n=79)Other specialists (n=131)
      No change in practice (41%)No change in practice (30%)No change in practice (32%)
      Spend more time explaining treatment to patients and families (19%)More likely to refer patients to a mental health specialist for consultation (17%)More likely to refer patients to a mental health specialist for consultation (23%)
      Spend more time explaining rationale for prescribing antidepressants (16%)See patients sooner or contact them personally after initial appointment (15%)Less likely to prescribe antidepressants and will refer patients to a psychiatrist for antidepressant prescriptions (20%)
      See patients sooner or contact them personally after initial appointment (11%)Spend more time explaining rationale for prescribing antidepressants (12%)Spend more time explaining rationale for prescribing antidepressants (9%)
      Patients/families less willing to agree with antidepressant prescription (8%)Less likely to prescribe antidepressants themselves and will refer patients to a psychiatrist for antidepressant prescriptions (9%)More likely to counsel patients themselves first before prescribing antidepressants (4%) and see patients sooner or contact them personally after initial appointment (4%)
      An equal number of specialists chose these 2 responses.
      Other (5%)Other (17%)Other (8%)
      * Not all practice pattern changes are listed. The electronic survey allowed selection of only 1 practice pattern response, with all responses totaling 100%.
      FDA = Food and Drug Administration.
      An equal number of specialists chose these 2 responses.
      Discussion. The FDA intended the BBW to improve physician-patient communication and encourage closer physician monitoring. Although our research suggests that this expectation was realistic, the FDA did not adequately take into account the implications of nonpsychiatric physicians ceasing to prescribe. We found that large numbers of both generalists and nonpsychiatric specialists who formerly would have written antidepressant prescriptions themselves are choosing instead to refer patients to psychiatrists or other mental health specialists.
      The FDA panel should have known from existing research that FDA warnings are linked to decreased prescribing.
      • Lasser KE
      • Allen PD
      • Woolhandler SJ
      • Himmelstein DU
      • Wolfe SM
      • Bor DH
      Timing of new black box warnings and withdrawals for prescription medications.
      Our findings underscore the impact of a BBW on physician prescribing and practice patterns across all age groups. Although the results of our survey showed that nonpsychiatrists were less likely to prescribe antidepressants to any age group, the decreased prescribing was particularly marked in children. Despite the limitations of our pilot research, including low response rates, a possibly nonrepresentative academic medical center setting, and an inability to correlate physician self-report with actual prescribing, our study results suggest that the FDA's BBW markedly altered physician prescribing and practice patterns.
      In addition, the FDA BBW mandates closer follow-up of patients taking antidepressants without addressing the stark realities of the current mental health system,
      • US Department of Health and Human Services
      Mental Health: A Report of the Surgeon General. Chapter 6: Organizing and Financing Mental Health Services.
      including (1) insurance plans with poor or absent mental health coverage, (2) increased copayments for individual mental health visits, (3) strict limits on outpatient mental health visits and inpatient psychiatric care, and (4) limited access to mental health providers. Current shortages—particularly of child and adolescent psychiatrists—are not expected to reverse in the near future. Despite FDA expectations of increased medication monitoring, patients cannot afford and physicians cannot provide the recommended contacts, let alone the gold standard of combined medication and counseling.
      • March J
      • Silva S
      • Petrycki S
      • et al.
      Fluoxetine, cognitive-behavioral therapy, and their combination for adolescents with depression: treatment for adolescents with depression study (TADS) randomized controlled trial.
      In terms of increasing physician-patient communication, our results indicate that the BBW may have selectively succeeded in obtaining one of the FDA's goals, providing earlier contact and more communication, which was noted in all physician groups and particularly in psychiatrists. As antidepressant experts with nowhere to refer patients, more than a third of our psychiatrists reported talking to patients more, as did smaller proportions of both generalists and specialists. Of concern in the current environment of limited psychiatric resources, many generalists and specialists are choosing to no longer prescribe antidepressants themselves and instead refer their patients to mental health specialists for care that may not be available in a timely fashion, if at all.
      Given that reduced prescribing by generalists in our survey was most marked in children and adolescents, we fear that decreased antidepressant prescribing due to BBW concerns may underlie increasing youth suicide rates.
      • Hamilton BE
      • Minino AM
      • Martin JA
      • Kochanek KD
      • Strobino DM
      • Guyer B
      Annual summary of vital statistics: 2005.
      Disconcertingly, a warning of increased “suicidality”—in the absence of any actual suicides—could conceivably have driven increased suicide rates already observed in American youths in 2004, the year the BBW took effect. An argument can be made that the BBW did not take effect until late 2004. However, as we described previously, antidepressant prescriptions filled for children and adolescents had decreased by 10%
      • Rosack J
      New data show declines in antidepressant prescribing.
      in April 2004, 1 month after the initial FDA public advisory.
      We fear that the correlation seen between declining youth antidepressant prescription rates and increasing suicide rates could soon be seen in older populations, particularly with the FDA currently considering its panel's recommendation to extend the BBW to young adults. Further research is needed to clarify why nonpsychiatrists have decreased antidepressant prescribing, opting instead for referrals to limited psychiatry resources already unable to handle the demand. If further research confirms the BBW's role in reduced antidepressant prescribing and increased suicide rates, revising the BBW and getting generalists and nonpsychiatric specialists to prescribe these drugs again should become public health priorities.

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