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Use of the acne medication isotretinoin (Accutane) was not associated with an increased risk of suicide or psychiatric conditions in a meta-analysis of 24 observational studies.

The 1-year pooled absolute risk of completed suicide, suicide attempt, suicide ideation, and self-harm for participants on the drug were each less than 0.5%, Nicole Kye Wen Tan, of the Yong Loo Lin School of Medicine at the National University of Singapore, and colleagues reported in .

Further, after adjustment for age, participants taking isotretinoin were less likely than non-users to attempt suicide at 2 years (relative risk 0.92, 95% CI 0.84-1.00), 3 years (RR 0.86, 95% CI 0.77-0.95), and 4 years (RR 0.85, 95% CI 0.72-1.00), the researchers reported.

"While our findings are reassuring, clinicians should remain vigilant in monitoring patients for signs of psychiatric distress during isotretinoin treatment," they wrote, noting that the "relationship among acne, isotretinoin, and psychiatric disorders is a complex one."

For instance, past "challenge-dechallenge-rechallenge studies have provided strong evidence for a direct causal relationship between isotretinoin use and mood changes in rare individuals, via biological effects on the central nervous system," and that this "may be an idiosyncratic reaction that is difficult to predict."

"However, there may be a second indirect effect of isotretinoin on improved mood, mediated by improved acne and self-image; this is consistent with our meta-analysis, which shows no increased epidemiological risk of suicide or depression among isotretinoin users," they wrote.

"Hence, while clinicians should remain vigilant and provide counseling for rare idiosyncratic mood changes that could increase the risk of suicide, they should be aware that isotretinoin appears to be safe at a population level," the authors added.

Overall, the evidence for an epidemiological link between isotretinoin and the development of psychiatric disorders has been unclear. Still, reported associations with a range of psychiatric disorders, including depression, anxiety, and attempted suicide resulted in the in 2005.

To further clarify the issue, Tan and colleagues analyzed a total of 24 studies involving 1,625,891 participants, where the average age range was 16-38 years and sex distribution ranged from 0% to 100% male. Risk of bias was evaluated using the .

Overall, they found the 1-year absolute risk for those on treatment was 0.07% for completed suicide, 0.14% for suicide attempt, 0.47% for suicide ideation, and 0.35% for self-harm.

Rates were higher for other psychiatric conditions, including depression (3.83%), mood disorder (2.32%), and anxiety (6.67%), and the risk of all psychiatric disorders was 4.57%.

The researchers found no association between isotretinoin use and suicide attempt during treatment or at any other time point, nor was there any risk of all psychiatric disorders, they reported.

However, Tan and colleagues cautioned that their study was limited by "heterogeneity and imprecision." Since there has been increased awareness among patients and physicians of the potential risks of isotretinoin, it's "plausible that patients deemed to be at higher risk of psychiatric illness were less likely to receive isotretinoin, which may have resulted in an underestimation of the psychiatric risks of isotretinoin in these observational studies."

In an , Parker Magin, PhD, of the University of Newcastle in Australia, and Shaun Prentice, PhD, of the University of Adelaide in Australia, noted that the "totality of the findings" taken together with previous evidence are "broadly reassuring."

Still, it's possible that the drug can have an impact in rare instances, so the "challenge ... for clinicians is determining which patients with acne may be at risk of such reactions." Magin and Prentice noted that the study showed that starting the drug at a younger age was tied to a higher risk of depression, and male sex was associated with a higher risk of completed suicide -- though they said "restricting isotretinoin use on the basis of age or sex is not practicable."

Thus, they wrote, "discussing with patients the possible, albeit apparently rare, psychiatric adverse effects of the drug and having a degree of psychiatric monitoring ... for all patients seems a reasonable approach."

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