Acne, isotretinoin, depression and suicide risk Anders Sundström Centre for pharmacoepidemiology
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
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
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
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
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
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
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
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
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
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
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
” 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
“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
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
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
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
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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