Retinoic acid and affective disorders: the evidence for an association

Abstract

Objective: Isotretinoin (13-cis-retinoic acid), approved by the US Food and Drug Administration for the treatment of acne, carries a black box warning related to the risk of depression, suicide, and psychosis. Retinoic acid, the active form of vitamin A, regulates gene expression in the brain, and isotretinoin is its 13-cis isomer. Retinoids represent a group of compounds derived from vitamin A that perform a large variety of functions in many systems, in particular the central nervous system, and abnormal retinoid levels can have neurologic effects. Although infrequent, proper recognition and treatment of psychiatric side effects in acne patients is critical given the risk of death and disability. This article reviews the evidence for isotretinoin's relationships with depression and suicidality.

Data sources: The PsycINFO, MEDLINE, and PubMed searchable database indexes were searched for articles published in the English language from 1960 to June 2010 using the key words isotretinoin, retinoids, retinoic acid, depression, depressive disorders, and vitamin A. Evidence examined includes (1) case reports; (2) temporal association between onset of depression and exposure to the drug; (3) challenge-rechallenge cases; (4) class effect (other compounds in the same class, like vitamin A, having similar neuropsychiatric effects); (5) dose response; and (6) biologically plausible mechanisms.

Study selection: All articles in the literature related to isotretinoin, depression, and suicide were reviewed, as well as articles related to class effect, dose response, and biologic plausibility.

Data extraction: Information from individual articles in the literature was extracted, including number of episodes of depression, suicidality, suicide, psychosis, violence and aggression, past psychiatric history, time of onset in relation to isotretinoin usage, medication dosage, duration of treatment, and dechallenge and challenge history.

Results: The literature reviewed is consistent with associations of isotretinoin administration with depression and with suicide in a subgroup of vulnerable individuals.

Conclusions: The relationship between isotretinoin and depression may have implications for a greater understanding of the neurobiology of affective disorders.

Figure 1

Cellular retinoic acid signaling. 1. Retinol in the circulation is bound to retinol binding protein (RBP), which itself is bound to transthyretin (TTR). 2. Retinol enters the cells which may be assisted by the membrane protein Stra6. 3. Retinol in the cell is bound by cellular retinol binding protein (CRBP) and can then be oxidized to retinaldehyde by an alcohol dehydrogenase or retinol dehydrogenase in a reversible reaction. 4. Retinaldehyde is oxidized irreversibly to RA by a retinaldehyde dehydrogenase. 5. RA may then enter the nucleus to bind to RA receptors (RAR) to activate transcription or 6. leave the cell to act on adjacent tissue. 7. Alternatively the system may be turned off by further oxidation of RA to oxidative metabolites including 4-oxo RA.

Figure 2

RA synthesis and action in the hypothalamus. A. Transport of retinol into the CSF. 1. Retinol circulates in the blood in a bound complex with retinol binding protein (RBP) and transthyretin (TTR). 2. Retinol is taken up by the choroid plexus. 3. The choroid plexus synthesizes RBP and TTR and these are exported into the CSF with retinol. 4. Retinol in the CSF carried by RBP and TTR is taken up by tanycytes B. Detailed view of RA synthesis by tanycytes and release of RA to act on hypothalamic neurons 5. Stra6 receptors present in the membrane of the tanycyte cell bodies lining the third ventricle facilitate the uptake of retinol into these cells. 6. Intracellular retinol is bound to cellular retinol binding protein (CRBP) and 7. Retinol is converted to retinaldehyde by an alcohol dehydrogenase (ADH). 8. A retinaldehyde dehydrogenase (RALDH) oxidises retinaldehyde to RA and 9. RA is released by the long tanycyte processes into proximal areas of the hypothalamus. 10. RA enters hypothalamic neurons and 11. RA receptors in these neurons convey the RA signal to regulate gene transcription.

Fig. 3

The influence of 13-cis RA on brain glucose metabolism measured by PET FDG. Four months 13-cis RA treatment results in a clear decrease in orbitofrontal cortical function in this representative subject. The same subject had symptoms of headache and slight behavioral change, although not clinical depression.