Depression and Acitretin: A True Association or a Class Labeling?
April 2011 | Volume 10 | Issue 4 | Original Article | 409 | Copyright © 2011
Jennifer Hayes BAa and John Koo MDb
aDavid Geffen School of Medicine at UCLA, San Francisco, CA bUCSF Psoriasis Skin and Treatment Center, San Francisco, CA
The potential relationship between systemic retinoids used in dermatology and affective disorders is controversial. Acitretin, which is widely used in the treatment of psoriasis is part of this controversy secondary to its chemical relation to isotretinoin, a drug which has been associated with a large number of anecdotal case reports of depression and suicidal ideation. Moreover, an FDA package insert precaution regarding acitretin's association with depression and suicide has elevated the level of concern for patient safety. The objective of this article is to review the evidence in the literature regarding acitretin's association with affective disorders. After 12 years of worldwide use only two cases involving acitretin have been reported in the literature. In addition, despite many anecdotal cases involving isotretinoin, there have been no clinical studies that have proven a causal relationship between isotretinoin and depression or suicidal ideation. For acitretin there have been no systematic clinical studies that examine such a relationship. Moreover, it is notable that the FDA precaution regarding depression and suicide on the package insert of acitretin predates the publication of the aforementioned two cases. This suggests that a relationship between acitretin and affective disorders is a class labeling rather than a scientifically proven association.
J Drugs Dermatol. 2011;10(4):409-412.
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The association between systemic retinoids and the development of affective disorders has been debated for many years. Recent studies have elucidated possible neurological mechanisms by which retinoids might mediate affective disorders. There are numerous case reports associating isotretinoin [Accutane®] and depression. There have also been case reports of depression associated with acitretin [Soriatane ®], a commonly used medication for psoriasis, and its precursor, etretinate [Tigason®]. Acitretin contains a package insert warning of suicidal ideation, which has caused concern amongst doctors and the patient community.1 This paper reviews the scientific basis behind this concern through examining the clinical evidence reported in the literature.
The United States National Library of Medicine's PubMed was used to review English language literature and foreign language articles with English abstracts published between April, 1989 and July, 2009. Keywords included: "acitretin," "etretinate," "isotretinoin" and "retinoic acid" in combination with "depression" and "suicide." Reference lists of identified articles were also searched for additional publications of interest.
Proposed Mechanisms Linking Retinoids and Depression
Retinoids are a class of fat-soluble molecules that include vitamin A as well as other chemically related synthetic and natural derivatives. They are critical for differentiation of organ systems in both the embryo and adult. Endogenous retinoids are known to regulate gene transcription by activating retinoic acid receptors (RARs) and transcribing particular regions of DNA within the nucleus. However the mechanism of action of endogenous and systemic retinoids used in dermatology is incompletely understood.
RARs are widespread in the brain, thus it is reasonable to speculate that retinoic acid may play a role in brain function. Mouse experiments show retinoic acid signaling in many regions of the CNS but these areas become progressively more restricted as the mice mature, particularly in the hippocampus, medial prefrontal cortex, cingulated cortex and retrosplenial areas.2 These areas of the brain demonstrate plasticity-the ability to rearrange neuronal connections-and are important in memory. A study performed in young mice shows that when mice are exposed to excess retinoic acid there is a decrease in neurogenesis3-which may play a role in depression.4,5 The particular strain of mice used in this experiment had relatively high rates of neurogenesis. Further animal studies have shown that 13-cis retinoic acid can affect brain function and behavior. These findings, however, are species specific in that mice demonstrate behavioral changes, while rats do not.6 Moreover, younger animals seem to be more vulnerable to the effects of retinoic acid exposure.6
Bremner, et al. performed a four-month treatment trial on human subjects in which isotretinoin was associated with a decrease in brain functioning in the orbitofrontal cortex, a brain region implicated in depression,7 which was ascertained using positron emission tomography (PET). These changes were not seen after