Depression and Acitretin: A True Association or a Class Labeling?
April 2011 | Volume 10 | Issue 4 | Original Article | 409 | Copyright © April 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.
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