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Vol.21, No.8, August 2005 - Drug Safety: New Data on Accutane - Is there a link between Accutane and depression?

Findings from a new pilot study1 indicate that Accutane (isotretinoin), an acne medication, is associated with decreased brain metabolism in the orbitofrontal cortex, an area of the brain that is believed to mediate symptoms of depression.

Based on the results of positron emission tomography (PET) and magnetic resonance imaging (MRI), researchers J. Douglas Bremner, M.D., Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, Georgia, and colleagues, conclude that there may be a biological mechanism by which treatment with Accutane may lead to depression in a minority of vulnerable patients with acne. These results are similar to those of other brain imaging studies which, according to Bremner, "have led to the hypothesis that retinoids play a role in the development of psychiatric disorders."

Accutane, chemically similar to the retinoid vitamin A (a fat-soluble vitamin that is stored in high concentrations in the liver), has been the subject of controversy over its possible role in the development of suicide and depression. Studies examining the content and toxicity of bear and seal liver have demonstrated the biological effects on explorers in Arctic regions feeding on polar bear liver who developed symptoms of psychosis and confusion. Symptoms of vitamin A toxicity, documented in published case reports, include personality changes, aggression, poor concentration, depression, psychotic symptoms and guilty rumination. Bremner and colleagues note that "Case reports in the literature describe depression that developed in conjunction with [Accutane] treatment, resolved with discontinuation of the medication, and in some cases returned when the medication was restarted."

Causal relationship?
There is no consensus, however, on a causal relationship between Accutane and development of depression and suicide, and the issue remains controversial, although the FDA (5/05) issued an alert that patients on the medication should be monitored for these symptoms. In one epidemiological study2 based on large population-based cohort trials in Canada and the United Kingdom, results showed no significantly increased risk for suicide in Accutane-treated patients. Still, Bremner suggests that due to the high incidence of depression in the general population, identifying small increases specifically related to one additional factor, such as Accutane treatment, is difficult.

According to a study by Y. Barak, M.D., and colleagues, published in International Clinical Psychopharmacology,3 Accutane ranks in the top 10 of the FDA's database of drugs associated with reports of depression and suicide attempts. The association is still controversial, however, because up to 5.6% of patients with moderate cases of acne may have pre-existing suicidal ideations. Also, improvement of acne may often reduce associated depression. The study showed that in 500 Israeli soldiers who were evaluated by a dermatologist for severe acne over a period of one year, there were five cases of psychosis linked to Accutane. Manic irritability was noted in all cases. All patients had either a personal or family history of psychiatric or neurological morbidity. The authors conclude that "screening and identifying those patients who are at high risk of psychopathology is carried out before [Accutane] administration is undertaken..."

Bremner and colleagues indicate that although some studies have shown improvements in patient's feelings of well-being or self-image following Accutane treatment, the findings were related more to improvements in measures of patient satisfaction than with the clinical symptoms of depression.

In order to establish a causal relationship between Accutane and development of depression and suicide, Bremner and his team hypothesized that treatment with Accutane, but not antibiotic, would be associated with a decreased brain metabolism in the orbitofrontal cortex, an area of the brain that is believed to mediate symptoms of depression.

Study details
The study participants, recruited through advertisements, included 28 healthy men and women (ages 18-50 years) with antibiotic-resistant acne. They were not randomly assigned to Accutane treatment or placebo but, together with their physicians, decided to take either a second trial with antibiotics or Accutane. It was not possible to blind the subjects or raters to treatment conditions because of the obvious side effects (severe skin dryness) of Accutane.

All subjects received a PET brain scan at baseline and again after 4 months of treatment. Subjects were treated by their outpatient physicians and were given either Accutane 1 mg/kg (N=13) or a standard 4-month course of acne treatment with an antibiotic.

In the Accutane group, none of the subjects had a current or past psychiatric disorder. In the antibiotic group, 2 subjects had a history of psychiatric problems including major depression, and bulimia and alcohol dependence. There were no subjects with current alcohol or substance abuse or dependence in either group.

Behavioral assessment was carried out at baseline and every month following initiation of treatment using the Hamilton Rating Scale for Depression (HRSD). A clinician- administered questionnaire was used to assess severity of acne, and Skindex, a 16-item self-report questionnaire, was used to assess emotional, functional and symptomatic aspects of their skin condition. There were no differences between the 2 groups based on HDRS and Skindex assessments.

Results showed significantly decreased orbitofrontal cortical metabolism after 4 months of treatment with Accutane (-21%) versus antibiotic (2%) (p<0.001). In the Accutane group, 5 patients had headache symptoms and "subtle changes" in irritability and/or mood. These subjects all had decreased brain metabolism but did not show clinically significant depression. Two subjects (one in each group) had a clinically significant increase in depression (>9 point increase on the HDRS). In both groups, there were no clinically significant Hamilton depression scores and no significant differences between the 2 groups.

Although these findings are limited by the small sample, this trial is the first to study the effects of Accutane on human brain functioning. Bremner and colleagues say that more definitive results than the current study could be achieved through a randomized, placebo-controlled study.

Conclusion
Patients undergoing Accutane treatment need to be monitored for behavioral changes, some of which may not be reported by the patient. "It has been my personal observation that patients treated with Accutane don't just develop classic melancholic depression, but also develop changes in mood and behavior that they are not necessarily aware of, but that are reported by family and friends," said Bremner. "Also, some individuals have problems in school and may drop out for these reasons. Diagnostically, they can be evaluated with [screening tools]. We are planning additional research studies to look at measures of impulsivity and aggression to see if these are more sensitive." "In some extreme cases, children have developed bizarre hallucinations [with Accutane]," Bremner says. However, he suggests that "these types of behavior are more like a combination of impulsivity, psychosis and depression, than the classic melancholic depression with suicidal ideation."

Supported by funding from Liam Grant, director of the Roaccutane Action Group (80%), and by lawyers involved in Accutane litigation (20%).

References
1 Bremner JD, Fani N, Ashraf A, et al.: Functional brain imaging alterations in acne patients treated with isotretinoin. Am J Psychiatry 2005; 162(5):983-991. E-mail: jdbremn@emory.edu.
2 Jick SS, Kremers HM, Vasilakis-Scaramozza C: Isotretinoin use and risk of depression: Psychotic symptoms, suicide and attempted suicide. Arch Dermatol 2000; 136(10):1231-1236.
3 Barak Y, Wohl Y, Greenberg Y, et al.: Affective psychosis following Accutane (isotretinoin) treatment. Intl Clin Psychopharmacol 2005; 20(1):39-41.


FDA Accutane Alert
FDA continues to assess reports of suicide or suicide attempts associated with the use of Accutane. All patients treated with Accutane should be observed closely for symptoms of depression or suicidal thoughts, such as sad mood, irritability, anger, loss of pleasure or interest in social or sports activities, sleeping too much or too little, changes in weight or appetite, school or work performance going down, or trouble concentrating.
This information reflects the FDA's preliminary analysis of data concerning this drug. The FDA is considering, but has not reached a final conclusion about, this information. The FDA intends to update this sheet when additional information or analyses become available.
Isotretinoin is marketed under the names of Accutane, Amnesteem, Claravis and Sotret. See the FDA website for more information: http://www.fda.gov/

Accutane is an FDA-approved treatment for cystic acne. Roche Laboratories, manufacturers of Accutane, warn that "Accutane may cause depression, psychosis and, rarely, suicidal ideation, suicide attempts, suicide and aggressive and/or violent behaviors. Discontinuation of Accutane therapy may be insufficient; further evaluation may be necessary. No mechanism of action has been established for these events."

The Brown University Child and Adolescent Behavior Letter, August 2005
Reproduced with permission of Manisses Communications Group, Inc
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