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Acne, isotretinoin, depression and suicide risk Anders Sundstrm Centre for pharmacoepidemiology Isotretinoin and suicide attempts: Background Systemic treatment severe acne since early 1980ies Highly teratogenic Not licensed in


  1. Acne, isotretinoin, depression and suicide risk Anders Sundström Centre for pharmacoepidemiology

  2. Isotretinoin and suicide attempts: Background  Systemic treatment severe acne since early 1980ies  Highly teratogenic  Not licensed in Sweden – compassionate use  Cohort established late 1980ies  Exposure during pregnacy?  Malformations?  Late 1990ies: psychiatric side-effects? A Sundström Acne and Rosacea Evidence Based 2 Update 10 May 2012

  3. Isotretinoin and suicide attempts: Background  Systemic treatment severe acne since early 1980ies  Highly teratogenic  Not licensed in Sweden – compassionate use  Cohort established late 1980ies  Exposure during pregnacy?  Malformations? Källen B. Restriction of the Use of Drugs With Teratogenic Properties: Swedish Experiences  Late 1990ies: psychiatric side-effects? With Isotretinoin. Teratology 60:53 (1999) A Sundström Acne and Rosacea Evidence Based 3 Update 10 May 2012

  4. Psychiatric side effects – evidence  Case reports (Hazen 1983)  Spontaneous ADR-reports  Animal studies  Decreased metabolism in orbitofrontal cortex in humans:  No differences in depressive symptoms between isotretinoin-group (n=13) and antibiotics-group (n=15) before and after treatment.  Observational studies. A Sundström Acne and Rosacea Evidence Based 4 Update 10 May 2012

  5. The Swedish isotretinoin cohort characteristics Males Females Patients, N (%) 3613 (63%) 2143 (37%) Age (years) at first prescription Mean 22.3 27.1 Duration of treatment (months) Mean 6.0 6.1 Total number of person-years on treatment 1819 1091 A Sundström Acne and Rosacea Evidence Based 5 Update 10 May 2012

  6. The Swedish isotretinoin cohort highly selected  Prescription by dermatologists only  Requirement for prescription:  Treatment with antibiotics for up to 6 months without improvement  Selection of those with the worst acne, that also managed to pass through the health- care system to a specialist. A Sundström Acne and Rosacea Evidence Based 6 Update 10 May 2012

  7. Distribution of sex and age: then and now 60% Proportion of population 50% Females 80ies 40% Females 2008 Males 80ies 30% Males 2008 20% 10% 0% 10-14 15-19 20-24 25-29 30-34 35-39 40-44 45-49 Age 63% males 37% females 54% males 46% females A Sundström Acne and Rosacea Evidence Based 7 Update 10 May 2012

  8. The Swedish isotretinoin cohort Who should be controls?  Severe acne → psychiatric morbidity  Other treatments as control? → different severity of acne 1981 1989 5,756 patients starting treatment (Tx) National Patient Register – Cause of Death Register A Sundström Acne and Rosacea Evidence Based 8 Update 10 May 2012

  9. Population before Treatment: its own control ”Cohort Cross - Over”: First prescription Acne, tetracycline Treatment w Roaccutan Time after treatment Severe acne Long-term effects Severe acne Exposed after exposure? Unexposed ” Cohort Cross-Over ”: Person-time Person-time after Tx Person-time before Tx (87,000 py) on Tx (2,900) (17,000 py) Up to 3 years before Up to 15 years after Tx (2001-12-31) A Sundström Acne and Rosacea Evidence Based 9 Update 10 May 2012

  10. Hospitalizations for suicide attempt 128 individuals (2.2%) 210 hospitalizations Ever before During treatment > 1 to 15 Y after treatment plus 1 year treatment Number of 32 20 76 individuals Subsequent suicides*: 3 4 6 Previous attempts No previous 11 attempt *) Completed suicides at any time during follow-up; N=24 A Sundström Acne and Rosacea Evidence Based 10 Update 10 May 2012

  11. Rates of first and all suicide attempts per 1000 person-years before, during and after Tx 3.0 2.5 Rates /1000 P.Y. 2.0 RD 0.8/1000 1.5 (-0.9; 2.4) IRR 1.4 (0.6 ; 3.6) 1.0 0.5 27 21 14 24 8 17 28 22 20 16 15 10 6 20 0.0 -3 Y -2 Y -1 Y On Tx Tx + 6 M Tx + 1 Y Tx + 2 Y first attempts total A Sundström Acne and Rosacea Evidence Based 11 Update 10 May 2012

  12. Rates of first and all suicide attempts per 1000 person-years before, during and after Tx RD 0.40/1000 (-1.5 ; 2.2) IRR 1.2 (0.5 ; 2.5) 3.0 2.5 Rates /1000 P.Y. 2.0 RD 0.8/1000 1.5 (-0.9; 2.4) IRR 1.4 (0.6 ; 3.6) 1.0 0.5 27 21 14 24 8 17 28 22 20 16 15 10 6 20 0.0 -3 Y -2 Y -1 Y On Tx Tx + 6 M Tx + 1 Y Tx + 2 Y first attempts total A Sundström Acne and Rosacea Evidence Based 12 Update 10 May 2012

  13. ” Number needed to harm” Number of new six-months ’ treatments per year needed for one additional suicide attempt to occurr:  2300 (first suicide attempt)  5000 (repeat attempt) Assuming that the entire additional risk could be attributed to the treatment. Rates and rate differences were higher for female patients than for male patients. A Sundström Acne and Rosacea Evidence Based 13 Update 10 May 2012

  14. “Standardized Incidence Rates” of first suicide attempts standardized by age, sex and calendar-year 3.5 3.0 2.5 2.0 SIR 1.5 1.0 0.5 0.0 3y 2Y 1Y On Tx +6M +1Y +2Y +3Y +4Y +5Y +6Y +7Y +8Y +9Y +10Y +11Y +12Y +13Y +14Y +15Y prior prior prior Acc N 1st 20 16 10 6 15 20 22 28 37 44 49 56 60 68 77 84 86 90 92 94 Total 27 21 14 8 17 24 28 38 52 65 71 85 92 106 119 136 143 149 155 161 A Sundström Acne and Rosacea Evidence Based 14 Update 10 May 2012

  15. Standardized Incidence Rates of first and all suicide attempts standardized by age, sex and calendar-year 3.5 3.0 2.5 2.0 SIR 1.5 1.0 0.5 0.0 3y 2Y 1Y On Tx +6M +1Y +2Y +3Y +4Y +5Y +6Y +7Y +8Y +9Y +10Y +11Y +12Y +13Y +14Y +15Y prior prior prior Acc N 1st 20 16 10 6 15 20 22 28 37 44 49 56 60 68 77 84 86 90 92 94 Total 27 21 14 8 17 24 28 38 52 65 71 85 92 106 119 136 143 149 155 161 A Sundström Acne and Rosacea Evidence Based 15 Update 10 May 2012

  16. Interpretation  Increasing frequency of suicide attempts already before treatment  No definite additional risk attributable to isotretinoin, on the population level  No long-term effects on initiating suicidal behavior  Certain individuals more sensitive to isotretinoin?  Different risk patterns for females compared to males: higher vulnerability to acne and/or to isotretinoin ? A Sundström Acne and Rosacea Evidence Based 16 Update 10 May 2012

  17. No ” reinforced ” behaviour – but sensitive individuals?  32 patients made a first attempt before treatment:  12 (38%) (95% CI: 21% to 54%) made new attempt during follow-up  14 patients made a first suicide attempt during treatment or within six months thereafter:  10 (71%) (95% CI: 48% to 95%) made a new attempt during follow-up A Sundström Acne and Rosacea Evidence Based 17 Update 10 May 2012

  18. Thank you! Acknowledgment to my co-authors Lars Alfredsson Gunilla Sjölin-Forsberg Barbro Gerdén Ulf Bergman Jussi Jokinen Anders.Sundstrom@Ki.se A Sundström Acne and Rosacea Evidence Based 18 Update 10 May 2012

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