This study evaluates types and frequency of psychiatric adverse events that were reported to the US Food and Drug Administration’s Adverse Event Reporting System from 1997 through 2017 for patients taking isotretinoin.
Key Points
Question
What numbers and types of psychiatric adverse events associated with isotretinoin use are reported to the US Food and Drug Administration?
Findings
This study showed 17 829 psychiatric adverse events were reported with isotretinoin use from January 1, 1997, through December 31, 2017. Depressive disorders, emotional lability, and anxiety disorders were most commonly reported.
Meaning
Although adverse event reports submitted to the US Food and Drug Administration indicated that patients taking isotretinoin experienced psychiatric adverse effects, further research is required to determine whether exposure to isotretinoin was causal.
Abstract
Importance
Isotretinoin is a highly effective medication for severe acne. Although no causal link between isotretinoin and psychiatric adverse effects has been established, widespread media reporting of depression and suicidality with use of isotretinoin have raised concerns in both patients and clinicians and generated numerous cases of costly litigation.
Objective
To evaluate reports of psychiatric adverse events associated with isotretinoin use submitted to the US Food and Drug Administration from January 1, 1997, through December 31, 2017.
Design, Setting, and Participants
This retrospective study evaluated reports of psychiatric adverse events with isotretinoin as the primary suspect drug in the US Food and Drug Administration’s Adverse Event Reporting System from 1997 through 2017. Publicly available data on number of patients enrolled in the iPLEDGE program were used to calculate rates of completed suicide per 100 000 patients enrolled in iPLEDGE in 2009 and 2010. All data were analyzed between July 1, 2018, and January 31, 2019.
Main Outcomes and Measures
The main outcomes were frequency and type of psychiatric adverse events in patients taking isotretinoin. Secondary analyses were stratification by age and sex and evaluation of completed suicide rates.
Results
Between 1997 and 2017, 17 829 psychiatric adverse events with isotretinoin use were reported to the US Food and Drug Administration, with depressive disorders, emotional lability, and anxiety disorders reported most frequently. Of these events, 8936 (50.1%) were reported among men and 8362 (46.9%) among women; the sex of the individual was not reported for 531 events (3.0%). Of the 13 553 reports that included patient age, the mean (SD) age was 22.1 (8.6) years. More than half (52.5%) of all events occurred in 10- to 19-year-old individuals. Whereas depression and anxiety were reported equally between sexes, eating disorders were more common in females (58 of 85 [68.2%]), while attention-deficit/hyperactivity disorder (55 of 83 events [66.3%]) and completed suicides (290 of 368 [78.8%]) were more common in males. The rates of completed suicide were 8.4 and 5.6 suicides per 100 000 patients enrolled in iPLEDGE in 2009 and 2010, respectively.
Conclusions and Relevance
Although depressive disorders and suicidality were frequently reported with isotretinoin use, these reports must be considered in the context of elevated rates of depression and suicide among patients with acne at large. These data suggest that the rate of completed suicide in patients taking isotretinoin may be lower than that of the general US population. Many psychiatric adverse events unrelated to depression and suicidality were also reported, but it is unclear if they were a result of isotretinoin therapy. Although no causal link between isotretinoin and psychiatric risk has been established, patients taking the drug appear vulnerable to psychiatric concerns. Mandated monthly iPLEDGE visits may provide an opportunity to screen patients for psychiatric conditions and improve outcomes.
Introduction
Isotretinoin is a highly effective medication for severe refractory acne. Since its approval by the US Food and Drug Administration (FDA) in 1982, isotretinoin has been linked to reports of depression, suicide, and other psychiatric effects, leading to both widespread media coverage and numerous cases of costly litigation.1,2 The isotretinoin package insert was updated in 1998 to include warnings about the risks of depression and suicidality; in addition, several high-profile cases of suicide in the early 2000s resulted in a congressional hearing evaluating the safety of isotretinoin, bringing further national attention to its potential risks.3,4
Although one study highlighted consistent reporting of depression and suicide in patients taking isotretinoin in the United States from 1982 to 2000, few studies have examined reports of psychiatric adverse events at the national level since 2000.5 In addition, few studies have examined the risk of psychiatric adverse events other than depression and suicidality while taking isotretinoin.6 In this study, we evaluated psychiatric adverse events reported in patients taking isotretinoin from January 1, 1997, through December 31, 2017.
Methods
Data Sources
The FDA compiles reports of adverse events submitted by clinicians, pharmacists, and patients in a publicly available database known as the Adverse Event Reporting System. These reports are entered using a coding thesaurus of reaction terms. For this retrospective analysis, we accessed these data using FDAble, a search engine for querying the database.7
We also used data from the iPLEDGE program, a risk management system launched by the FDA in 2006 to eliminate the risk of fetal exposure to isotretinoin. The program requires all male and female patients who initiate isotretinoin therapy to first register with iPLEDGE.8 Under this system, females of childbearing potential must have 2 negative pregnancy tests and must agree to use 2 forms of birth control before they receive the prescription; they then must visit their physician monthly while taking isotretinoin for confirmatory negative pregnancy testing. Males and females who are not of childbearing potential must also visit their physician monthly to confirm proper use of the medication. Data on the number of patients enrolled in iPLEDGE were released in 2009 and 2010, and we used this information to calculate rates of completed suicide per 100 000 patients in iPLEDGE in those years.9 Data from other years have not been released publicly. Because the data used in this study are publicly available, the project was deemed exempt by the Partners Healthcare Institutional Review Board, which also waived the need for patient informed consent because the data were deidentified.
Statistical Analysis
We performed a retrospective study of reports in the Adverse Event Reporting System of psychiatric adverse events with isotretinoin as the primary suspect drug in the United States from 1997 to 2017. We identified 49 discrete psychiatric reaction terms and, given the high redundancy between them, classified the terms into 12 broader adverse event categories (AECs) (Table 1). Twelve reaction terms, accounting for 11.9% of all reports submitted to the FDA during the period evaluated, were excluded because they were less specific than the 37 included terms and did not fit into any AEC.
Table 1. Adverse Event Categories and Reaction Terms Used or Excluded in the Analysis.
| Adverse Event Category | Reaction Terms |
|---|---|
| Attention-deficit/hyperactivity disorder | Attention-deficit/hyperactivity disorder |
| Anxiety disorders | Generalized anxiety disorder; anxiety; panic attack; anxiety NEC; obsessive-compulsive disorder |
| Bipolar and mood disorders | Bipolar disorder; affective disorder |
| Depressive disorders | Depression; depression NEC; depression NOS; major depression; depression aggravated; depressed mood; anhedonia |
| Eating disorders | Bulimia nervosa; eating disorder |
| Emotional lability | Emotional distress; mood swings; mood altered; affect lability; mood alteration NOS; emotional disturbance NOS; irritability |
| Insomnia | Insomnia |
| Psychotic disorders and psychotic symptoms | Psychotic disorder; psychotic disorder NOS; paranoia; hallucination; hallucination, auditory; delusion |
| Self-injurious behavior | Self-injurious ideation; intentional self-injury |
| Suicidal ideation | Suicidal ideation |
| Suicide attempt | Suicide attempt |
| Completed suicide | Completed suicide |
| Excluded | Abnormal behavior; abnormal behavior NOS; social avoidant behavior; personality change; disturbance in attention; stress; nervousness; mental disorder; apathy; aggression; crying; somnolence |
Abbreviations: NEC, not elsewhere classifiable; NOS, not otherwise specified.
When multiple reaction terms from the same AEC were reported for a single individual, that individual was counted only once in the AEC to prevent duplicate reports. Age- and sex-specific analyses excluded reports without an associated age or sex, respectively. We used Python software, version 3.7.2 (Python Software Foundation) for the statistical analysis.
Results
A total of 17 829 psychiatric adverse events with isotretinoin as the primary suspect drug were reported to the FDA from 1997 through 2017 (Table 2); 50.1% of these adverse events occurred in males, 46.9% occurred in females, and 3.0% did not have a reported sex. Depressive disorders (7547 [42.3% of all adverse event reports]), emotional lability (2962 [16.6%]), and anxiety disorders (2412 [13.5%]) were the most commonly reported AECs. In addition, there were 2278 reports of suicidal ideation, 602 reports of attempted suicide, and 368 reports of completed suicide.
Table 2. Frequency of Psychiatric Adverse Events With Use of Isotretinoin Reported to the FDA in 1997-2017 by Sexa.
| Adverse Event Category | Male | Female | Sex Not Reported | Total Events |
|---|---|---|---|---|
| Attention-deficit/hyperactivity disorder | 55 (66.3) | 25 (30.1) | 3 (3.6) | 83 (0.5) |
| Anxiety disorders | 1159 (48.1) | 1145 (47.5) | 108 (4.5) | 2412 (13.5) |
| Bipolar and mood disorders | 131 (50.0) | 127 (48.5) | 4 (1.5) | 262 (1.5) |
| Depressive disorders | 3630 (48.1) | 3762 (49.8) | 155 (2.1) | 7547 (42.3) |
| Eating disorders | 25 (29.4) | 58 (68.2) | 2 (2.4) | 85 (0.5) |
| Emotional lability | 1488 (50.2) | 1425 (48.1) | 49 (1.7) | 2962 (16.6) |
| Insomnia | 299 (50.8) | 279 (47.4) | 11 (1.8) | 589 (3.3) |
| Psychotic disorders and psychotic symptoms | 255 (57.6) | 164 (37.0) | 24 (5.4) | 443 (2.5) |
| Self-injurious behavior | 101 (51.0) | 84 (42.4) | 13 (6.7) | 198 (1.1) |
| Suicidal ideation | 1196 (52.5) | 972 (42.7) | 110 (4.8) | 2278 (12.8) |
| Suicide attempt | 307 (51.0) | 266 (44.2) | 29 (4.8) | 602 (3.4) |
| Completed suicide | 290 (78.8) | 55 (14.9) | 23 (6.2) | 368 (2.1) |
| Total | 8936 (50.1) | 8362 (46.9) | 531 (3.0) | 17 829 (100) |
Abbreviation: FDA, US Food and Drug Administration.
Data are presented as number (percentage). Because of rounding, percentages may not total 100.
Depression and anxiety were reported equally between the sexes, with females representing 49.8% of depressive disorder reports and 47.5% of anxiety disorder reports (Table 2). Sex differences were apparent in eating disorder (68.2% female) and attention-deficit/hyperactivity disorder (66.3% male) reports. Although males accounted for 52.5% and 51.0% of reports of suicidal ideation and suicide attempts, respectively, 78.8% of completed suicides reported occurred in men.
Of the 13 553 (76.0%) reports that included patient age, the mean (SD) age was 22.1 (8.6) years. Among these reports, the 10- to 19-year-old age group accounted for 52.5% of total psychiatric adverse events, the 20- to 29-year-old age group accounted for 30.6%, the 30- to 39-year-old age group accounted for 11.5%, and those 40 years or older accounted for 5.4% (Table 3). The 10- to 19-year-old age group had 164 completed suicides, accounting for 57.7% of completed suicides with age reported.
Table 3. Frequency of Psychiatric Adverse Events With Use of Isotretinoin Reported to the FDA in 1997-2017 by Age Groupa.
| Adverse Event Category | Age Group, y | Total | |||
|---|---|---|---|---|---|
| 10-19 | 20-29 | 30-39 | ≥40 | ||
| Attention-deficit/hyperactivity disorder | 38 (56.7) | 24 (35.8) | 4 (6.0) | 1 (1.5) | 67 (0.5) |
| Anxiety disorders | 832 (47.1) | 629 (35.6) | 218 (12.4) | 86 (4.9) | 1765 (13.0) |
| Bipolar and mood disorders | 107 (52.7) | 67 (33.0) | 17 (8.4) | 12 (5.9) | 203 (1.5) |
| Depressive disorders | 2877 (49.4) | 1795 (30.8) | 760 (13.1) | 390 (6.7) | 5822 (43.0) |
| Eating disorders | 46 (63.9) | 21 (29.2) | 5 (6.9) | 0 (0) | 72 (0.5) |
| Emotional lability | 1213 (55.9) | 624 (28.8) | 226 (10.4) | 106 (4.9) | 2169 (16.0) |
| Insomnia | 237 (48.9) | 177 (36.5) | 52 (10.7) | 19 (3.9) | 485 (3.6) |
| Psychotic disorders | 211 (60.3) | 96 (27.4) | 31 (8.9) | 12 (3.4) | 350 (2.6) |
| Self-injurious behavior | 113 (74.3) | 24 (15.8) | 9 (5.9) | 6 (3.9) | 152 (1.1) |
| Suicidal ideation | 967 (55.9) | 493 (28.5) | 186 (10.8) | 84 (4.9) | 1730 (12.8) |
| Suicide attempt | 309 (68.1) | 90 (19.8) | 40 (8.8) | 15 (3.3) | 454 (3.3) |
| Completed suicide | 164 (57.7) | 106 (37.3) | 11 (3.9) | 3 (1.1) | 284 (2.1) |
| Total | 7114 (52.5) | 4146 (30.6) | 1559 (11.5) | 734 (5.4) | 13 553 (100) |
Abbreviation: FDA, US Food and Drug Administration.
Data are presented as number (percentage). Because of rounding, percentages may not total 100.
In 2009 and 2010, there were 21 and 11 completed suicides, respectively (Table 4), indicating a rate of 8.4 suicides per 100 000 patients enrolled in iPLEDGE in 2009 and 5.6 suicides per 100 000 patients enrolled in 2010.
Table 4. Suicide Reports to the FDA and Rate of Completed Suicide in Patients Enrolled in iPLEDGE in 2009 and 2010.
| 2009 | 2010 | |
|---|---|---|
| Suicidal ideation reports, No. | 110 | 166 |
| Attempted suicide reports, No. | 18 | 31 |
| Completed suicide reports, No. | 21 | 11 |
| Patients enrolled in iPLEDGE, No. | 248 611 | 196 384 |
| Completed suicides per 100 000 patients enrolled in iPLEDGE | 8.4 | 5.6 |
Abbreviation: FDA, US Food and Drug Administration.
Discussion
We evaluated reports to the FDA of depressive disorders, suicidality, and other psychiatric adverse events with isotretinoin as the primary suspect drug from 1997 through 2017. Depressive disorders and suicidal ideation accounted for 55.1% of reported psychiatric adverse events with use of isotretinoin during this period. In addition, 368 completed suicides were reported to the FDA, with men accounting for 78.8% of completed suicides. This sex-specific disparity is consistent with national statistics on completed suicide, which is more common in men.10 The highest number of reported adverse events for all AECs occurred in patients 10 to 19 years old, which could reflect more isotretinoin prescriptions in this age group or may suggest that teenagers are particularly vulnerable to psychiatric adverse events while taking isotretinoin.
Suicidality is one of the most discussed potential adverse events associated with isotretinoin, having received substantial media attention over the past few years.11,12 Our data showed that the reported rates of completed suicide per 100 000 persons enrolled in iPLEDGE in 2009 and 2010 were 8.4 and 5.6, respectively. These rates are lower than reported national suicide rates in the United States for these years, which were 11.8 per 100 000 people in 2009 and 12.1 per 100 000 people in 2010 for the general population and 10.2 per 100 000 people in 2009 and 10.5 per 100 000 people in 2010 for those aged 15 to 24 years.10 Although underreporting to the FDA may contribute partially to the lower rates we observed in this population, this finding suggests that rates of completed suicide among patients taking isotretinoin may not be higher than rates in the general US population.
The risk of psychiatric adverse events in patients taking isotretinoin must be considered in the context of a known increased risk of suicidal ideation in patients with acne independent of isotretinoin therapy.13,14,15 The increased risk is likely a result of the psychosocial effect of severe acne, and it has been shown that this psychiatric burden is experienced in both adolescent and adult patients with acne.16 One prospective study showed no difference in depressive symptoms between patients with acne treated with isotretinoin and those treated with topical therapy or oral antibiotics.17 It has also been shown that initiation of isotretinoin treatment does not necessarily increase the risk of suicide in patients with acne,18 which is consistent with our data on the rate of suicide in this population compared with that of the general population. As such, the risk of depression and suicidality in patients taking isotretinoin may be associated more with the burden of acne itself than with its treatment.
Although depression and suicidality are noted potential adverse events of isotretinoin, our results suggest that other, underappreciated psychiatric adverse events may be linked to its use. Our data showed high numbers of reports of emotional lability, anxiety disorders, insomnia, self-injurious behavior, and psychotic disorders with isotretinoin as the primary suspect drug. Eating disorders and attention-deficit/hyperactivity disorder were also reported, albeit with lower frequencies than the other AECs, and the sex distributions for these disorders reflect the sex differences of the idiopathic forms of these conditions.19,20 It is also important to recognize that some of these adverse events overlap and may represent symptoms of other psychiatric disorders, such as insomnia and depression or emotional lability and bipolar disorder.21 Although it is unclear whether isotretinoin therapy is related to these psychiatric conditions, it is important to note that patients and clinicians reported these adverse events in high numbers, and future inquiries should focus on validating these results.18,22
Although no causal link has been established between isotretinoin and psychiatric adverse events, it is important to recognize that there are data that suggest patients using this drug may be vulnerable to a number of psychiatric conditions.6 In addition, although the iPLEDGE system was designed to reduce fetal exposure to isotretinoin, the required monthly visits for all patients under this system create an ideal opportunity for mental health screening in this population.
Our study builds on prior papers that have called for use of Patient Health Questionnaire-2 or Patient Health Questionnaire-9 to screen for depression in patients taking isotretinoin,23,24,25 and we also advocate for the integration of these screening tools into the existing iPLEDGE infrastructure. These changes to the iPLEDGE system should be evaluated prospectively and in a randomized fashion to determine the benefits vs burdens of an expanded intervention. Improved prospective data collection on top of the existing iPLEDGE infrastructure may shed light on the epidemiology and psychiatric risks of patients taking isotretinoin and determine whether monthly screening is beneficial. Ultimately, although the relationship between severe acne, isotretinoin, and depression has not been firmly established, clinicians should take advantage of monthly appointments to assess patients for psychiatric comorbidity regardless of the root cause.
Limitations
These data must be considered in the context of our study design, which is based on the Adverse Event Reporting System database. These data are limited by reliance on proper reporting by clinicians, although reporting of serious events, such as suicide, may be more likely than reporting of less severe outcomes.26 Although some events may not be reported to or by physicians, it is likely that these reporting behaviors are consistent over time. In addition, although we separated some psychiatric reaction terms, including emotional lability and insomnia, into their own categories, we recognize these may represent symptoms of other psychiatric diagnoses such as depression, anxiety, or bipolar disorder.
Conclusions
Depressive disorders and suicidality were the most frequently reported adverse events associated with isotretinoin use, but these reports must be considered in the context of elevated rates of depression and suicide among patients with acne. Our study suggests that the rate of completed suicide in patients taking isotretinoin may be lower than that of the general US population, but further study is necessary to assess the rate of completed suicide in this population. Mandated monthly visits under the current iPLEDGE infrastructure may provide an opportunity to screen patients for psychiatric conditions and improve patient outcomes.
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