Psychiatric Adverse Events in Patients Taking Isotretinoin as Reported in a Food and Drug Administration Database From 1997 to 2017 | Acne | JAMA Dermatology | JAMA Network
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Table 1.  Adverse Event Categories and Reaction Terms Used or Excluded in the Analysis
Adverse Event Categories and Reaction Terms Used or Excluded in the Analysis
Table 2.  Frequency of Psychiatric Adverse Events With Use of Isotretinoin Reported to the FDA in 1997-2017 by Sexa
Frequency of Psychiatric Adverse Events With Use of Isotretinoin Reported to the FDA in 1997-2017 by Sexa
Table 3.  Frequency of Psychiatric Adverse Events With Use of Isotretinoin Reported to the FDA in 1997-2017 by Age Groupa
Frequency of Psychiatric Adverse Events With Use of Isotretinoin Reported to the FDA in 1997-2017 by Age Groupa
Table 4.  Suicide Reports to the FDA and Rate of Completed Suicide in Patients Enrolled in iPLEDGE in 2009 and 2010
Suicide Reports to the FDA and Rate of Completed Suicide in Patients Enrolled in iPLEDGE in 2009 and 2010
1.
Huang  Y-C, Cheng  Y-C.  Isotretinoin treatment for acne and risk of depression: a systematic review and meta-analysis.  J Am Acad Dermatol. 2017;76(6):1068-1076.e9. doi:10.1016/j.jaad.2016.12.028PubMedGoogle Scholar
2.
Acne drug maker sued over Florida suicide. New York Times. https://www.nytimes.com/2002/04/16/national/acne-drug-maker-sued-over-florida-suicide.html. Published April 16, 2002. Accessed March 24, 2019.
3.
Wysowski  DK, Pitts  M, Beitz  J.  Depression and suicide in patients treated with isotretinoin.  N Engl J Med. 2001;344(6):460. doi:10.1056/NEJM200102083440616PubMedGoogle Scholar
4.
Hearing Before the Committee on Government Reform, House of Representatives, 106th Cong, 2nd Sess (2000). https://www.govinfo.gov/content/pkg/CHRG-106hhrg73924/html/CHRG-106hhrg73924.htm. Accessed May 31, 2019.
5.
Wysowski  DK, Pitts  M, Beitz  J.  An analysis of reports of depression and suicide in patients treated with isotretinoin.  J Am Acad Dermatol. 2001;45(4):515-519. doi:10.1067/mjd.2001.117730PubMedGoogle Scholar
6.
Brzezinski  P, Borowska  K, Chiriac  A, Smigielski  J.  Adverse effects of isotretinoin: a large, retrospective review.  Dermatol Ther. 2017;30(4):e12483. doi:10.1111/dth.12483PubMedGoogle Scholar
7.
Pratt  LA, Danese  PN.  More eyeballs on AERS.  Nat Biotechnol. 2009;27(7):601-602. doi:10.1038/nbt0709-601PubMedGoogle Scholar
8.
About iPLEDGE. iPLEDGE Program website. https://www.ipledgeprogram.com/iPledgeUI/aboutProgram.u. Accessed March 24, 2019.
9.
Drug Safety and Risk Management Advisory Committee. Dermatologic and Opthalmic [sic] Drugs Advisory Committee. Briefing Document for iPLEDGE. https://wayback.archive-it.org/7993/20170114004041/http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/DermatologicandOphthalmicDrugsAdvisoryCommittee/UCM281376.pdf. Published 2011. Accessed December 16, 2018.
10.
Centers for Disease Control and Prevention. Web-based Injury Statistics Query and Reporting System (WISQARS). 2002. https://www.cdc.gov/injury/wisqars/index.html. Last reviewed March 21, 2019. Accessed January 13, 2019.
11.
Accutane killed my son. CBS News. https://www.cbsnews.com/news/accutane-killed-my-son/. Published October 5, 2000. Accessed February 24, 2019.
12.
Dixon H. Controversial acne drug blamed for a number of suicides. Telegraph. https://www.telegraph.co.uk/news/health/10160484/Controversial-acne-drug-blamed-for-a-number-of-suicides.html. Published July 4, 2013. Accessed February 24, 2019.
13.
Vallerand  IA, Lewinson  RT, Parsons  LM,  et al.  Risk of depression among patients with acne in the U.K.: a population-based cohort study.  Br J Dermatol. 2018;178(3):e194-e195. doi:10.1111/bjd.16099PubMedGoogle Scholar
14.
Purvis  D, Robinson  E, Merry  S, Watson  P.  Acne, anxiety, depression and suicide in teenagers: a cross-sectional survey of New Zealand secondary school students.  J Paediatr Child Health. 2006;42(12):793-796. doi:10.1111/j.1440-1754.2006.00979.xPubMedGoogle Scholar
15.
Uhlenhake  E, Yentzer  BA, Feldman  SR.  Acne vulgaris and depression: a retrospective examination.  J Cosmet Dermatol. 2010;9(1):59-63. doi:10.1111/j.1473-2165.2010.00478.xPubMedGoogle Scholar
16.
Gupta  MA, Gupta  AK.  Depression and suicidal ideation in dermatology patients with acne, alopecia areata, atopic dermatitis and psoriasis.  Br J Dermatol. 1998;139(5):846-850. doi:10.1046/j.1365-2133.1998.02511.xPubMedGoogle Scholar
17.
Ng  CH, Tam  MM, Celi  E, Tate  B, Schweitzer  I.  Prospective study of depressive symptoms and quality of life in acne vulgaris patients treated with isotretinoin compared to antibiotic and topical therapy.  Australas J Dermatol. 2002;43(4):262-268. doi:10.1046/j.1440-0960.2002.00612.xPubMedGoogle Scholar
18.
Sundström  A, Alfredsson  L, Sjölin-Forsberg  G, Gerdén  B, Bergman  U, Jokinen  J.  Association of suicide attempts with acne and treatment with isotretinoin: retrospective Swedish cohort study.  BMJ. 2010;341:c5812. doi:10.1136/bmj.c5812PubMedGoogle Scholar
19.
Gaub  M, Carlson  CL.  Gender differences in ADHD: a meta-analysis and critical review.  J Am Acad Child Adolesc Psychiatry. 1997;36(8):1036-1045. doi:10.1097/00004583-199708000-00011PubMedGoogle Scholar
20.
Kjelsås  E, Bjørnstrøm  C, Götestam  KG.  Prevalence of eating disorders in female and male adolescents (14-15 years).  Eat Behav. 2004;5(1):13-25. doi:10.1016/S1471-0153(03)00057-6PubMedGoogle Scholar
21.
Truitt  JM, Reichenberg  JS, Sharghi  KG, Sampson  SM, Roenigk  RK, Magid  M.  Isotretinoin: the ups are just as troubling as the downs.  G Ital Dermatol Venereol. 2018;153(4):535-539.PubMedGoogle Scholar
22.
Strahan  JE, Raimer  S.  Isotretinoin and the controversy of psychiatric adverse effects.  Int J Dermatol. 2006;45(7):789-799. doi:10.1111/j.1365-4632.2006.02660.xPubMedGoogle Scholar
23.
Schrom  K, Nagy  T, Mostow  E.  Depression screening using health questionnaires in patients receiving oral isotretinoin for acne vulgaris.  J Am Acad Dermatol. 2016;75(1):237-239. doi:10.1016/j.jaad.2016.02.1148PubMedGoogle Scholar
24.
McDonald  K, Shelley  A, Jafferany  M.  The PHQ-2 in dermatology—standardized screening for depression and suicidal ideation.  JAMA Dermatol. 2018;154(2):139-141. doi:10.1001/jamadermatol.2017.5540PubMedGoogle Scholar
25.
Schrom  KP, Mostow  EN, Nagy  T.  Depression screening in dermatology—think isotretinoin.  JAMA Dermatol. 2018;154(5):629-630. doi:10.1001/jamadermatol.2018.0085PubMedGoogle Scholar
26.
Hazell  L, Shakir  SA.  Under-reporting of adverse drug reactions: a systematic review.  Drug Saf. 2006;29(5):385-396. doi:10.2165/00002018-200629050-00003PubMedGoogle Scholar
Original Investigation
July 3, 2019

Psychiatric Adverse Events in Patients Taking Isotretinoin as Reported in a Food and Drug Administration Database From 1997 to 2017

Author Affiliations
  • 1Medical student, Harvard Medical School, Boston, Massachusetts
  • 2Department of Dermatology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
  • 3Medical student, University of Massachusetts Medical School, Worcester
  • 4Department of Dermatology, University of Pennsylvania Perelman School of Medicine, Philadelphia
JAMA Dermatol. 2019;155(10):1162-1166. doi:10.1001/jamadermatol.2019.1416
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.

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.

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.

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.

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.13-15 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,23-25 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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Article Information

Accepted for Publication: April 8, 2019.

Corresponding Author: Arash Mostaghimi, MD, MPA, MPH, Department of Dermatology, Brigham and Women’s Hospital, 221 Longwood Ave, Boston, MA 02115 (amostaghimi@bwh.harvard.edu).

Published Online: July 3, 2019. doi:10.1001/jamadermatol.2019.1416

Author Contributions: Mr Singer and Ms Tkachenko are considered co–first authors. Mr Singer and Dr Mostaghimi had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Singer, Tkachenko.

Acquisition, analysis, or interpretation of data: Singer, Tkachenko, Sharma, Barbieri.

Drafting of the manuscript: Singer, Tkachenko.

Critical revision of the manuscript for important intellectual content: Singer, Tkachenko, Sharma, Barbieri.

Statistical analysis: Sharma.

Administrative, technical, or material support: Singer, Tkachenko, Sharma.

Conflict of Interest Disclosures: Dr Mostaghimi reported receiving personal fees from Pfizer and personal fees from hims outside the submitted work. No other disclosures were reported.

Funding/Support: Dr Barbieri is supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health under grant T32-AR-007465 and receives partial salary support through a Pfizer Fellowship in Dermatology Patient-Oriented Research grant to the trustees of the University of Pennsylvania.

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

References
1.
Huang  Y-C, Cheng  Y-C.  Isotretinoin treatment for acne and risk of depression: a systematic review and meta-analysis.  J Am Acad Dermatol. 2017;76(6):1068-1076.e9. doi:10.1016/j.jaad.2016.12.028PubMedGoogle Scholar
2.
Acne drug maker sued over Florida suicide. New York Times. https://www.nytimes.com/2002/04/16/national/acne-drug-maker-sued-over-florida-suicide.html. Published April 16, 2002. Accessed March 24, 2019.
3.
Wysowski  DK, Pitts  M, Beitz  J.  Depression and suicide in patients treated with isotretinoin.  N Engl J Med. 2001;344(6):460. doi:10.1056/NEJM200102083440616PubMedGoogle Scholar
4.
Hearing Before the Committee on Government Reform, House of Representatives, 106th Cong, 2nd Sess (2000). https://www.govinfo.gov/content/pkg/CHRG-106hhrg73924/html/CHRG-106hhrg73924.htm. Accessed May 31, 2019.
5.
Wysowski  DK, Pitts  M, Beitz  J.  An analysis of reports of depression and suicide in patients treated with isotretinoin.  J Am Acad Dermatol. 2001;45(4):515-519. doi:10.1067/mjd.2001.117730PubMedGoogle Scholar
6.
Brzezinski  P, Borowska  K, Chiriac  A, Smigielski  J.  Adverse effects of isotretinoin: a large, retrospective review.  Dermatol Ther. 2017;30(4):e12483. doi:10.1111/dth.12483PubMedGoogle Scholar
7.
Pratt  LA, Danese  PN.  More eyeballs on AERS.  Nat Biotechnol. 2009;27(7):601-602. doi:10.1038/nbt0709-601PubMedGoogle Scholar
8.
About iPLEDGE. iPLEDGE Program website. https://www.ipledgeprogram.com/iPledgeUI/aboutProgram.u. Accessed March 24, 2019.
9.
Drug Safety and Risk Management Advisory Committee. Dermatologic and Opthalmic [sic] Drugs Advisory Committee. Briefing Document for iPLEDGE. https://wayback.archive-it.org/7993/20170114004041/http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/DermatologicandOphthalmicDrugsAdvisoryCommittee/UCM281376.pdf. Published 2011. Accessed December 16, 2018.
10.
Centers for Disease Control and Prevention. Web-based Injury Statistics Query and Reporting System (WISQARS). 2002. https://www.cdc.gov/injury/wisqars/index.html. Last reviewed March 21, 2019. Accessed January 13, 2019.
11.
Accutane killed my son. CBS News. https://www.cbsnews.com/news/accutane-killed-my-son/. Published October 5, 2000. Accessed February 24, 2019.
12.
Dixon H. Controversial acne drug blamed for a number of suicides. Telegraph. https://www.telegraph.co.uk/news/health/10160484/Controversial-acne-drug-blamed-for-a-number-of-suicides.html. Published July 4, 2013. Accessed February 24, 2019.
13.
Vallerand  IA, Lewinson  RT, Parsons  LM,  et al.  Risk of depression among patients with acne in the U.K.: a population-based cohort study.  Br J Dermatol. 2018;178(3):e194-e195. doi:10.1111/bjd.16099PubMedGoogle Scholar
14.
Purvis  D, Robinson  E, Merry  S, Watson  P.  Acne, anxiety, depression and suicide in teenagers: a cross-sectional survey of New Zealand secondary school students.  J Paediatr Child Health. 2006;42(12):793-796. doi:10.1111/j.1440-1754.2006.00979.xPubMedGoogle Scholar
15.
Uhlenhake  E, Yentzer  BA, Feldman  SR.  Acne vulgaris and depression: a retrospective examination.  J Cosmet Dermatol. 2010;9(1):59-63. doi:10.1111/j.1473-2165.2010.00478.xPubMedGoogle Scholar
16.
Gupta  MA, Gupta  AK.  Depression and suicidal ideation in dermatology patients with acne, alopecia areata, atopic dermatitis and psoriasis.  Br J Dermatol. 1998;139(5):846-850. doi:10.1046/j.1365-2133.1998.02511.xPubMedGoogle Scholar
17.
Ng  CH, Tam  MM, Celi  E, Tate  B, Schweitzer  I.  Prospective study of depressive symptoms and quality of life in acne vulgaris patients treated with isotretinoin compared to antibiotic and topical therapy.  Australas J Dermatol. 2002;43(4):262-268. doi:10.1046/j.1440-0960.2002.00612.xPubMedGoogle Scholar
18.
Sundström  A, Alfredsson  L, Sjölin-Forsberg  G, Gerdén  B, Bergman  U, Jokinen  J.  Association of suicide attempts with acne and treatment with isotretinoin: retrospective Swedish cohort study.  BMJ. 2010;341:c5812. doi:10.1136/bmj.c5812PubMedGoogle Scholar
19.
Gaub  M, Carlson  CL.  Gender differences in ADHD: a meta-analysis and critical review.  J Am Acad Child Adolesc Psychiatry. 1997;36(8):1036-1045. doi:10.1097/00004583-199708000-00011PubMedGoogle Scholar
20.
Kjelsås  E, Bjørnstrøm  C, Götestam  KG.  Prevalence of eating disorders in female and male adolescents (14-15 years).  Eat Behav. 2004;5(1):13-25. doi:10.1016/S1471-0153(03)00057-6PubMedGoogle Scholar
21.
Truitt  JM, Reichenberg  JS, Sharghi  KG, Sampson  SM, Roenigk  RK, Magid  M.  Isotretinoin: the ups are just as troubling as the downs.  G Ital Dermatol Venereol. 2018;153(4):535-539.PubMedGoogle Scholar
22.
Strahan  JE, Raimer  S.  Isotretinoin and the controversy of psychiatric adverse effects.  Int J Dermatol. 2006;45(7):789-799. doi:10.1111/j.1365-4632.2006.02660.xPubMedGoogle Scholar
23.
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