Isotretinoin Use and Risk of Depression, Psychotic Symptoms, Suicide, and Attempted Suicide

Jick, Susan S.; Kremers, Hilal Maradit; Vasilakis‐Scaramozza, Catherine

doi:10.1001/archderm.136.10.1231

Cited by 240 publications

(174 citation statements)

References 30 publications

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“…They did not find that patients were more likely to receive an antidepressant after receiving isotretinoin. Jick and colleagues (Jick et al 2000) looked at 7,195 patients treated with isotretinoin and 13,700 oral antibiotic users with acne from the Saskatchewan Health Database and 340 isotretinoin and 676 antibiotic users from the United Kingdom General Practice Research Database. Prevalence of suicide, attempted suicide, and "neurotic and psychotic disorders" based on computer-recorded histories at 0.5 to 5 years before and more than 5 years after medication use were compared between the groups.…”

Section: Retrospective Analyses Of Databasesmentioning

confidence: 99%

The neurobiology of retinoic acid in affective disorders

Bremner

McCaffery

2008

Progress in Neuro-Psychopharmacology and Biological Psychiatry

144

154

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Current models of affective disorders implicate alterations in norepinephrine, serotonin, dopamine, and CRF/cortisol; however treatments targeted at these neurotransmitters or hormones have led to imperfect resolution of symptoms, suggesting that the neurobiology of affective disorders is incompletely understood. Until now retinoids have not been considered as possible contributors to affective disorders. Retinoids represent a family of compounds derived from Vitamin A that perform a large number of functions, many via the vitamin A product, retinoic acid. This signaling molecule binds to specific retinoic acid receptors in the brain which, like the glucocorticoid and thyroid hormone receptors, are part of the nuclear receptor superfamily and regulate gene transcription. Research in the field of retinoic acid in the CNS has focused on the developing brain, in part stimulated by the observation that isotretinoin (13-cis retinoic acid), an isomer of retinoic acid used in the treatment of acne, is highly teratogenic for the CNS. More recent work has suggested that retinoic acid may influence the adult brain; animal studies indicated that the administration of isotretinoin is associated with alterations in behavior as well as inhibition of neurogenesis in the hippocampus. Clinical evidence for an association between retinoids and depression includes case reports in the literature, studies of health care databases, and other sources. A preliminary PET study in human subjects showed that isotretinoin was associated with a decrease in orbitofrontal metabolism. Several studies have shown that the molecular components required for retinoic acid signaling are expressed in the adult brain ; the overlap of brain areas implicated in retinoic acid function and stress and depression suggest that retinoids could play a role in affective disorders. This report reviews the evidence in this area and describes several systems that may be targets of retinoic acid and which contribute to the pathophysiology of depression.

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Section: Retrospective Analyses Of Databasesmentioning

confidence: 99%

The neurobiology of retinoic acid in affective disorders

Bremner

McCaffery

2008

Progress in Neuro-Psychopharmacology and Biological Psychiatry

144

154

View full text Add to dashboard Cite

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“…Since the mid-1980s, reports in the literature suggest a relationship between 13-cis-RA use and the onset of psychological symptoms including depression, suicidal ideation, and psychosis (Hazen et al, 1983;Bigby and Stern, 1988;Scheinman et al, 1990;Byrne and Hnatko, 1995;Wysowski et al, 2001;Ng and Schweitzer, 2003;O'Connell et al, 2003;Barak et al, 2005). However, there are also studies suggesting that there is no evidence of such a link (Jick et al, 2000;Jacobs et al, 2001;Ferahbas et al, 2004;Chai et al, 2005). One recent study used positron emission tomography to examine brain function in patients with treatment-resistant acne (Bremner et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Chronic Administration of 13-Cis-Retinoic Acid Increases Depression-Related Behavior in Mice

O’Reilly

Shumake

González-Lima

et al. 2006

Neuropsychopharmacol

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Retinoid signaling plays a well-established role in neuronal differentiation, neurite outgrowth, and the patterning of the anteroposterior axis of the developing neural tube. However, there is increasing evidence that nutritional vitamin A status and retinoid signaling play an important role in the function of the adult brain. 13-Cis-retinoic acid (13-cis-RA) (isotretinoin or Accutane), a synthetic retinoid that is an effective oral treatment for severe nodular acne, has been linked with depression and suicide in patients. The purpose of this study was to test the hypothesis that chronic administration of 13-cis-RA would lead to depression-related behaviors in mice. Young, adult male mice received 13-cis-RA (1 mg/kg) by daily intraperitoneal injection for 6 weeks. This treatment paradigm produced plasma levels of 13-cis-RA that are comparable to those reported in human patients taking Accutane. In both the forced swim test and the tail suspension test, we found that 13-cis-RA-treated mice spent significantly more time immobile compared to vehicle-treated controls. In the open field test, there was no change in anxiety-related behavior in 13-cis-RA-treated mice. Furthermore, chronic administration of 13-cis-RA did not impair locomotion in either the open field or the rotarod test. Taken together, these results suggest that administration of 13-cis-RA increases depression-related behaviors in mice.

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“…It is surprising that 13-cis-RA might influence the adult brain, an organ in which there is not extensive proliferation. Certainly, this effect has been considered contentious (5), in large part because no mechanism has been described for such an etiology. Cell proliferation, however, is known to occur in restricted regions of the adult brain.…”

mentioning

confidence: 99%

13- cis -retinoic acid suppresses hippocampal cell division and hippocampal-dependent learning in mice

Crandall

Sakai

Zhang

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

195

170

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The active component of the acne drug Accutane is 13-cis-retinoic acid (RA), and it is highly teratogenic for the developing central nervous system. Very little is known, however, regarding the effect of this drug on the adult brain. Regions of the brain that may be susceptible to RA are those that continue to generate new neurons. In the adult mouse, neurogenesis is maintained in the hippocampus and subventricular zone. This report demonstrates that a clinical dose (1 mg͞kg͞day) of 13-cis-RA in mice significantly reduces cell proliferation in the hippocampus and the subventricular zone, suppresses hippocampal neurogenesis, and severely disrupts capacity to learn a spatial radial maze task. The results demonstrate that the regions of the adult brain where cell proliferation is ongoing are highly sensitive to disruption by a clinical dose of 13-cis-RA.A ccutane, the active component of which is 13-cis-retinoic acid (RA), is the primary treatment for chronic acne. RA induces differentiation and reduces proliferation of stem and progenitor cells, and 13-cis-RA helps control acne by inducing similar events in basal sebocytes (1). These same actions also lead to 13-cis-RA's side effects, and these are directed toward proliferating cells in the adult such as in the skin, gut, and bone (2). However, Accutane has also been reported to modify behavior, sometimes resulting in severe depression with suicidal ideation (2-4). It is surprising that 13-cis-RA might influence the adult brain, an organ in which there is not extensive proliferation. Certainly, this effect has been considered contentious (5), in large part because no mechanism has been described for such an etiology. Cell proliferation, however, is known to occur in restricted regions of the adult brain. New neurons are born and develop in the subgranular zone (SGZ) of the hippocampal formation as well as in the subventricular zone (SVZ) of the forebrain and in its extension via the rostral migratory stream to the olfactory bulb (6). If 13-cis-RA influences the brain, then these proliferating cells would be likely targets. We show, in a mouse model, that 13-cis-RA, at a dose of 1 mg͞kg͞day, reduces both the rate of hippocampal cell birth and the number of newborn neurons. Because the hippocampus is primarily associated with memory processing, and new neuronal birth has been suggested to be required for this task (7), it would also be predicted that 13-cis-RA would result in a decline in hippocampal-dependent memory. In this study, we demonstrate that, by using a radial arm maze test, there is a severe defect in the ability of 13-cis-RA-injected mice to perform this task, suggesting that long-term exposure to 13-cis-RA can disrupt hippocampaldependent behavior. MethodsBrdUrd Treatment. Mice were injected with BrdUrd in two types of experimental paradigms, the first to determine the influence of RA on the rate of cell proliferation in the hippocampus and the second as a cell marker to follow cell survival. To follow cell proliferation (Fig. 1A), RA was injected dail...

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Isotretinoin Use and Risk of Depression, Psychotic Symptoms, Suicide, and Attempted Suicide

Cited by 240 publications

References 30 publications

The neurobiology of retinoic acid in affective disorders

The neurobiology of retinoic acid in affective disorders

Chronic Administration of 13-Cis-Retinoic Acid Increases Depression-Related Behavior in Mice

13- cis -retinoic acid suppresses hippocampal cell division and hippocampal-dependent learning in mice

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