Acne, isotretinoin, depression and suicide risk Anders Sundstrm - - PowerPoint PPT Presentation

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Acne, isotretinoin, depression and suicide risk Anders Sundstrm - - PowerPoint PPT Presentation

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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

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Anders Sundström

Centre for pharmacoepidemiology

Acne, isotretinoin, depression and suicide risk

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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?

Acne and Rosacea Evidence Based Update 10 May 2012 A Sundström 2

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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?

Acne and Rosacea Evidence Based Update 10 May 2012 A Sundström 3

Källen B. Restriction of the Use of Drugs With Teratogenic Properties: Swedish Experiences With Isotretinoin.Teratology 60:53 (1999)

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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.

Acne and Rosacea Evidence Based Update 10 May 2012 A Sundström 4

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The Swedish isotretinoin cohort characteristics

Acne and Rosacea Evidence Based Update 10 May 2012 A Sundström 5

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

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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.

Acne and Rosacea Evidence Based Update 10 May 2012 A Sundström 6

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Acne and Rosacea Evidence Based Update 10 May 2012 7 A Sundström

Distribution of sex and age: then and now

0% 10% 20% 30% 40% 50% 60% 10-14 15-19 20-24 25-29 30-34 35-39 40-44 45-49 Proportion of population Age Females 80ies Females 2008 Males 80ies Males 2008

63% males 54% males 37% females 46% females

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The Swedish isotretinoin cohort Who should be controls?

  • Severe acne → psychiatric morbidity
  • Other treatments as control? → different severity of

acne

Acne and Rosacea Evidence Based Update 10 May 2012 A Sundström 8

5,756 patients starting treatment (Tx)

1981 1989

National Patient Register – Cause of Death Register

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Population before Treatment: its own control

”Cohort Cross-Over”:

First prescription Acne, tetracycline Severe acne Unexposed Treatment w Roaccutan Severe acne Exposed Time after treatment Long-term effects after exposure?

Acne and Rosacea Evidence Based Update 10 May 2012 9 A Sundström

Person-time after Tx (87,000 py) Person-time

  • n Tx (2,900)

Up to 15 years after Tx (2001-12-31)

Person-time before Tx (17,000 py)

Up to 3 years before

”Cohort Cross-Over”:

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Hospitalizations for suicide attempt

Acne and Rosacea Evidence Based Update 10 May 2012 A Sundström 10

Ever before treatment During treatment plus 1 year > 1 to 15 Y after treatment Number of individuals

32 20 76

Subsequent suicides*: Previous attempts

3 4 6

No previous attempt

11

128 individuals (2.2%) 210 hospitalizations

*) Completed suicides at any time during follow-up; N=24

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Rates of first and all suicide attempts

per 1000 person-years before, during and after Tx

Acne and Rosacea Evidence Based Update 10 May 2012 A Sundström 11

27 21 14 8 17 24 28 20 16 10 6 15 20 22 0.0 0.5 1.0 1.5 2.0 2.5 3.0

  • 3 Y
  • 2 Y
  • 1 Y

On Tx Tx + 6 M Tx + 1 Y Tx + 2 Y

Rates /1000 P.Y.

first attempts total

RD 0.8/1000 (-0.9; 2.4) IRR 1.4 (0.6 ; 3.6)

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Rates of first and all suicide attempts

per 1000 person-years before, during and after Tx

Acne and Rosacea Evidence Based Update 10 May 2012 A Sundström 12

27 21 14 8 17 24 28 20 16 10 6 15 20 22 0.0 0.5 1.0 1.5 2.0 2.5 3.0

  • 3 Y
  • 2 Y
  • 1 Y

On Tx Tx + 6 M Tx + 1 Y Tx + 2 Y

Rates /1000 P.Y.

first attempts total

RD 0.40/1000 (-1.5 ; 2.2) IRR 1.2 (0.5 ; 2.5) RD 0.8/1000 (-0.9; 2.4) IRR 1.4 (0.6 ; 3.6)

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”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.

Acne and Rosacea Evidence Based Update 10 May 2012 A Sundström 13

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0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 3y prior 2Y prior 1Y prior On Tx +6M +1Y +2Y +3Y +4Y +5Y +6Y +7Y +8Y +9Y +10Y +11Y +12Y +13Y +14Y +15Y

SIR

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

“Standardized Incidence Rates” of first suicide attempts standardized by age, sex and calendar-year

Acne and Rosacea Evidence Based Update 10 May 2012 A Sundström 14

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0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 3y prior 2Y prior 1Y prior On Tx +6M +1Y +2Y +3Y +4Y +5Y +6Y +7Y +8Y +9Y +10Y +11Y +12Y +13Y +14Y +15Y

SIR

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

Standardized Incidence Rates of first and all suicide attempts standardized by age, sex and calendar-year

Acne and Rosacea Evidence Based Update 10 May 2012 A Sundström 15

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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?

Acne and Rosacea Evidence Based Update 10 May 2012 A Sundström 16

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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

Acne and Rosacea Evidence Based Update 10 May 2012 A Sundström 17

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Thank you!

Acknowledgment to my co-authors Lars Alfredsson Gunilla Sjölin-Forsberg Barbro Gerdén Ulf Bergman Jussi Jokinen Anders.Sundstrom@Ki.se

Acne and Rosacea Evidence Based Update 10 May 2012 A Sundström 18