Affective disorders as potential complication of anti-acne treatment with isotretinoin: A case series

doi:10.1016/j.jad.2016.06.048

Journal of Affective Disorders

Volume 204, 1 November 2016, Pages 154-158

https://doi.org/10.1016/j.jad.2016.06.048 Get rights and content

Highlights

•
Temporal relationship between affective disorders (AD) and use of isotretinoin was certain while causal association was possible.
•
A family history of AD and a prior episode of mental disorders predicted affective symptoms.
•
Onset of AD was preceded by prodromal symptoms: headaches, sleep disorders, fatigue, drowsiness, general weakness.
•
Psychiatrists should pay special attention to isotretinoin as a drug that may trigger episodes of AD.

Abstract

Objective

To analyse cases of 9 patients (18-27 yo) who were consequently admitted to our department and treated with affective disorders (AD) while undergoing isotretinoin (INN) therapy.

Methods

A semi-structured questionnaire designed by the authors was used to analyse many variables related to demographic characteristics, dermatologic and psychiatrics symptoms, AD course and treatment, family history of mental disorders, building on medical histories of patients and their families, and available medical records.

Results

Patients were diagnosed (DSM-IV-TR) with: a major depressive episode (4 patients), a recurrent major depressive episode (3), a bipolar mixed episode (1), and rapid cycling bipolar I disorder (1). The mean time from the first use of INN to: I. the onset of mental disorders was approximately 2 months (1–6 months), II. a visit with a psychiatrist was about 12 months (1–38 months). The predictors of occurrence of AD included a family history of AD and a prior episode of mental disorders. The onset of AD was in most cases preceded by prodromal symptoms such as headaches, sleep disorders, fatigue, drowsiness, or general weakness. Five patients reported suicidal ideation, four patients showed suicidal tendencies, and two persons attempted to commit suicide during the treatment.

Conclusions

Psychiatrists should pay special attention to isotretinoin as a drug that may trigger episodes of AD, particularly in patients with a family history of AD or prior episodes of mental disorders. Isotretinoin therapy of patients with acne and a family history of AD or prior episodes of mental disorders requires special care and, if symptoms of depression develop or worsen during the INN treatment, collaboration between a dermatologist and a psychiatrist is needed.

Introduction

The introduction of isotretinoin preparations for acne therapy (MHRA, 2014) in the 1980s is considered to have been an undoubted breakthrough in the treatment of this disease. Despite their efficacy, however, there has been ongoing discussion of the potential side effects of those preparations related to the possible development of psychiatric disorders, including affective disorders (AD) (Azoulay et al., 2008). A review of the literature indicates that isotretinoin can affect a patient's mental state in two opposing ways (Bachmann et al., 2007; Yesilova et al., 2012). Isotretinoin has a clear antidepressive effect, probably associated with improved self-esteem resulting from the effectiveness of acne treatment (Cyrulnik et al., 2012). However, there are reports on an increased risk of development of AD in patients treated with retinoids (Azoulay et al., 2008), connected with the side effect profile of this group of medications (vitamin A derivatives); information on such hazards was introduced in the patient information leaflet in 1998 due to an increase in the number of reported adverse reactions of this type (MHRA, 2014).

The aim of the present study was to analyse the cases of nine patients (Table 1) with regard to the relationship between isotretinoin use and the occurrence of AD, and to assess predictors of the occurrence of these disorders.

Section snippets

Material and method

In the years 2011–2014, units of the Department of Psychiatry at the Medical University of Lublin recorded nine patients (seven women and two men), aged 18-27 years, who were diagnosed with AD temporally associated with the use of isotretinoin preparations (Table 1).

An analysis was performed on the patients’ sociodemographic characteristics, the route of administration and the dose of isotretinoin used, the duration of treatment, and the total dose received. Estimates were made of the time

Results

The average daily dose of isotretinoin used in the anti-acne treatment was 38.75 mg (range: 20–80 mg) and the mean total dose was 10.725 g (3–42 g). In eight cases, the drug was administered orally. In one case, the medicine was applied externally to the large area of skin, including the face, the neck and the back.

None of the patients used dietary supplements containing vitamin A or other medications affecting its metabolism. The mean time from the first use of isotretinoin to the onset of mental

Discussion

The introduction of isotretinoin as a second line agent was undoubtedly a milestone in the treatment of severe acne and cases unresponsive to conventional acne therapies, including oral and/or topical anti-infectives (Bremner et al., 2012). The use of oral isotretinoin preparations in the most severe forms of acne usually marks a turning point in the treatment of this disease and is often regarded as the only possibility of restoring and maintaining the patient's health (Blasiak et al., 2013).

Conclusions

1.
The mean time from the first use of INN to: I. the onset of mental disorders was approximately 2 months (1-6 months), II. a visit with a psychiatrist was about 12 months (1-38 months).
2.
The temporal relationship between the occurrence of affective disorders and the use of isotretinoin preparations in the cases presented here was certain, while the causal association cannot be ruled out.
3.
The predictors of the occurrence of affective symptoms associated with isotretinoin use included a family

Disclosures

The authors of this paper do not have any commercial associations that might pose a conflict of interest in connection with this manuscript.

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Isotretinoin and neuropsychiatric side effects: Continued vigilance is needed
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Citation Excerpt :
Campos-Muñoz et al reported on treatment of severe acne in transgender boys, who are at high risk of depression. Two out of four boys (50%) developed severe depression after initiation of treatment (Campos-Muñoz et al., 2020) Hannah et al reported on a series of nine cases referred for psychiatric hospitalization for depression following treatment with isotretinoin (Karakula-Juchnowicz et al., 2016) Isotretinoin administration has also been associated with mania, psychosis, violence, aggression, and anxiety (Bigby and Stern, 1988; Cott and Wisner, 1999; Villalobos et al., 1989).
Isotretinoin (13-cis-retinoic acid, marketed under the names Accutane, Roaccutane, and others) is an effective treatment for acne that has been on the market for over 30 years, although reports of neuropsychiatric side effects continue to be reported. Isotretinoin is an isomer of the active form of Vitamin A, 13-trans-retinoic acid, which has known psychiatric side effects when given in excessive doses, and is part of the family of compounds called retinoids, which have multiple functions in the central nervous system.
The literature was reviewed in pubmed and psychinfo for research related to isotretinoin and neuropsychiatric side effects including depression, suicidal thoughts, suicide, mania, anxiety, impulsivity, emotional lability, violence, aggression, and psychosis.
Multiple case series have shown that successful treatment of acne with isotretinoin results in improvements in measures of quality of life and self esteem However, studies show individual cases of clinically significant depression and other neuropsychiatric events that, although not common, are persistent in the literature. Since the original cases of depression were reported to the United States Food and Drug Administration, numerous cases have been reported to regulatory agencies in the United Kingdom, France, Ireland, Denmark, Australia, Canada, and other countries, making isotretinoin one of the top five medications in the world associated with depression and other neuropsychiatric side effects. Clinicians are advised to warn patients of the risks of neuropsychiatric side effects with isotretinoin which may arise from the medication itself, and not just as a side effect of acne or youth.
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Also, some patients with psychiatric symptoms have reported a history of present or past treatment with ITT (Ludot et al., 2015). The abundant studies that have demonstrated increased risks to develop depression, psychosis or suicidal ideation following ITT treatment (Hanna et al., 2016; Ludot et al., 2015) combined with a growing number of reported cases of depressive disorder associated with ITT use in patients with acne, has raised awareness and warnings. Below, we review the accumulated clinical evidence of associations between ITT treatment and depressive symptoms from clinical case reports, data-base studies and government reports.
The retinoid family members, including vitamin A and derivatives like 13-cis-retinoic acid (ITT) and all-trans retinoic acid (ATRA), are essential for normal functioning of the developing and adult brain. When vitamin A intake is excessive, however, or after ITT treatment, increased risks have been reported for depression and suicidal ideation.
Here, we review pre-clinical and clinical evidences supporting association between retinoids and depressive disorders and discuss several possible underlying neurobiological mechanisms. Clinical evidences include case reports and studies from healthcare databases and government agency sources. Preclinical studies further confirmed that RA treatment induces hyperactivity of the hypothalamus-pituitary-adrenal (HPA) axis and typical depressive-like behaviors. Notably, the molecular components of the RA signaling are widely expressed throughout adult brain. We further discuss three most important brain systems, hippocampus, hypothalamus and orbitofrontal cortex, as major brain targets of RA. Finally, we highlight altered monoamine systems in the pathophysiology of RA-associated depression. A better understanding of the neurobiological mechanisms underlying RA-associated depression will provide new insights in its etiology and development of effective intervention strategies.
Psychiatric and Developmental Effects of Isotretinoin (Retinoid) Treatment for Acne Vulgaris
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In the United States in 2015, isotretinoin ranked in the top 10 of the FDA's database of drugs associated with reports of depression and suicide attempts.60 However, numerous authors have suggested either no association with depression, or instead an amelioration of depressive or anxious symptoms with treatment, prompting suggestions that idiosyncratically susceptible patients may exist, or that individuals with a family history or personal history of mental illness may be susceptible.61–76 Isotretinoin is contraindicated in psychosis because it worsens the course of the disease.77
An association between isotretinoin (13-cis-retinoic acid, sold under trade names including Accutane [Hoffmann-La Roche Inc, Basel, Switzerland]) and birth defects, depression, and suicide is well documented but controversial. A link to psychosis and exacerbation of bipolar symptoms is less extensively addressed in the literature.
Given recent conceptualization of psychotic disorders as neurodevelopmental, and current interest in possible shared etiology of different neurodevelopmental disorders such as psychosis, autism, and intellectual disability, this review concurrently examines the literature on developmental (primarily teratogenic) and psychiatric side effects of isotretinoin exposure. The goal of concurrent review is to identify shared mechanisms in the literature that may inform future efforts to clarify the neurocognitive and psychiatric effects of isotretinoin exposure at different developmental stages or given different genetic backgrounds.
Literature was obtained by PubMed search for the term isotretinoin in combination with each of the terms psychosis, psychiatric, and teratogenic. Resulting articles met inclusion criteria for review if they addressed psychiatric side effects of isotretinoin treatment or the neurobehavioral teratology of isotretinoin.
The association of isotretinoin exposure with prenatal developmental toxicity is well established. Although numerous reports also link isotretinoin treatment with psychiatric side effects, this association remains controversial.
The extent to which isotretinoin influences pediatric and adult development and cognition, and whether and why certain individuals may be susceptible to psychiatric side effects, remains to be clarified. Curr Ther Res Clin Exp. 2019; 80:XXX–XXX)
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2021, Journal of Drugs in Dermatology
Isotretinoin Induced Psychotic Mania: A Case Report
2021, Turk Psikiyatri Dergisi

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Short communicationAffective disorders as potential complication of anti-acne treatment with isotretinoin: A case series

Highlights

Abstract

Objective

Methods

Results

Conclusions

Introduction

Section snippets

Material and method

Results

Discussion

Conclusions

Disclosures

Prog. Neuropsychopharmacol. Biol. Psychiatry

Eur. Neuropsychopharmacol.

Prog. Neuropsychopharmacol. Biol. Psychiatry

J. Affect. Disord.

J. Am. Acad. Dermatol.

Isotretinoin and the risk of depression in patients with acne vulgaris: a case-crossover study

J. Clin. Psychiatry

Isotretinoin, depression and suicide ideation in an adolescent boy

Pharmacopsychiatry

Affective psychosis following Accutane (isotretinoin) treatment

Int. Clin. Psychopharmacol.

High-dose isotretinoin treatment and the rate of retrial, relapse, and adverse effects in patients with acne vulgaris

JAMA Dermatol.

Functional brain imaging alterations in acne patients treated with isotretinoin

Am. J. Psychiatry

Retinoic acid and affective disorders: the evidence for an association

J. Clin. Psychiatry

Adverse effects of isotretinoin therapy

Cutis

No association found between patients receiving isotretinoin for acne and the development of depression in a Canadian prospective cohort

Can. J. Clin. Pharmacol.

High-dose isotretinoin in acne vulgaris: improved treatment outcomes and quality of life

Int. J. Dermatol.

Short communication
Affective disorders as potential complication of anti-acne treatment with isotretinoin: A case series