ISOTRETINOIN AND POTENTIAL PSYCHIATRIC SIDE EFFECTS
ISOTRETINOIN (13-cis-retinoic acid, or 13-cis-RA) (Accutane) is a medication for the treatment of acne that has been associated with psychiatric side effects, including depression, suicide, aggression, and psychosis. Isotretinoin is a retinoid that occurs naturally in the body; retinoids are a group of molecules derived from vitamin A that are essential in regulating the function of multiple organ systems in the embryonic and adult mammal. The majority of these functions are performed by the vitamin A metabolite all-trans-retinoic acid (RA), which binds to retinoid receptors to control gene transcription. RA has a number of functions, which include regulation of brain development in utero; thus administration of retinoids (including isotretinoin) during pregnancy is associated with neurological side effects.
Isotretinoin works for the treatment of acne in part by inhibiting sebaceous gland function, as well as decreasing keratinization, and suppressing the inflammatory response. The Food and Drug Administration (FDA) has approved this drug for the treatment of cystic and nodular acne that is not responsive to other forms of treatment. Isotretinoin is the same molecule as the transcriptionally active form of RA, all-trans RA, but is altered subtly in shape (i.e. is an isomer) by having one of its double bonds, at the 13th carbon, in cis conformation. 13-cis RA is an endogenous isomer of RA, and can be present at similar concentrations in the plasma as all-trans RA. It is the all-trans isomer of RA that has a high affinity for the RA receptor to regulate transcription and the bioactivity of 13-cis RA is most likely achieved via isomerization in tissue to all-trans RA. Although this implies the activity of 13-cis RA is less than that of the all-trans isomer, 13-cis RA is more resistant to catabolism and has an elimination half-life of 20 hours, in contrast to only 0.9 hours for all-trans RA, and the peak plasma concentrations for 13-cis RA are reached 2-4 hours after oral dosage. The side effect profile of isotretinoin led it originally to be approved only for severe nodular or cystic acne, however dermatologists in the US have frequently prescribed it for less severe acne. For instance, in 1999, of patients treated with isotretinoin only around 8% suffered severe acne, while the majority had mild to moderate acne.
Recently there has been increased attention to the potential psychiatric side effects of isotretinoin. This is related to the increase in warnings since its first introduction, including the application of a black box warning for suicide, depression, aggression and psychosis, as well as the institution of the IPLEDGE program, a required registry of manufacturers, pharmacists, patients and doctors, established by the FDA in 2005. Very important is the evidence for an association between isotretinoin and depression.
(”Retinoic Acid and Affective Disorders: The Evidence for an Association. 2012”)
Drug Induced Depression
Major depression is a common disorder that is associated with substantial loss of productivity. Major depression is defined by the Diagnostic and Statistical Manual–IV (DSM-IV) as depressed mood most of the day, nearly every day, with markedly diminished interest or pleasure in activities most of the day. This is associated with contradictory symptoms of significant weight loss or weight gain, decrease or increase in appetite, insomnia or hypersomnia, psychomotor agitation or retardation, fatigue or loss of energy, feelings of worthlessness or excessive or inappropriate guilt, diminished ability to think or concentrate, recurrent thoughts of death, and recurrent suicidal ideation or suicide attempts. About 30,000 people in the US kill themselves every year, with depression being a common cause of suicide. Drug-induced depression is defined as a depression that occurs in the context of administration of a medication or substance, can likely be attributed to the use of that medication, and which resolves with discontinuation of the medication. Several drugs have been shown to cause symptoms of depression including corticosteroids. These are in a similar class as retinoids, binding to members of the nuclear receptor superfamily, and promoting gene transcription through activation of specific promoters. Isotretinoin is the only non-psychotropic drug in the top 10 list of drugs most commonly reported to be associated with depression.
Evidence on an Association between Isotretinoin, Depression and Suicidality
Factors that assess the causative effects of a drug on an adverse event such as depression include: 1) class effect; 2) evidence from case reports and a review of the literature; 3) temporal association of drug administration and the event; 4) challenge/dechallenge (and rechallenge) cases; 5) dose response; and; 6) biological plausibility. These factors as they relate to isotretinoin and depression and suicide are reviewed below.
1.Class Effect: Neuropsychiatric Effects of Vitamin A
If a drug in the same chemical class as isotretinoin had a similar side effect to the latter then this would provide evidence that isotretinoin was associated with this adverse event. Vitamin A is such a chemical, which is in the same retinoid class as isotretinoin. Because Vitamin A is the parent compound of RA increased amounts of this substrate would be expected to result in elevated levels of RA. Thus it would be predicted that many of the adverse side effects of isotretinoin will be similar to those of patients taking high doses of Vitamin A although, since it requires several metabolic steps for vitamin A to be converted to RA and several alternative pathways also exist into which vitamin A may be channeled, vitamin A would not be expected to be as potent as RA. Indeed, large doses of vitamin A can have a number of other neurological and mental effects including nausea, vomiting, weakness, fatigue, irritability, drowsiness, loss of appetite, ataxia, decreased interest, headache, and diplopia (double vision); These effects appear to be more common in children and adolescents. There have been multiple cases of psychiatric consequences of Vitamin A intoxication reported in the literature. These include cases of aggression and depression, depression and psychosis. Further evidence of class effect comes from other retinoids that are used therapeutically.
2.Case Reports and Review of the Literature Related to Suicide and Depression with Isotretinoin
A significant number of case reports exist in the literature that describe depression, suicidality, psychosis, violence and aggression developing in conjunction with isotretinoin treatment. Some of the cases used the Hamilton Depression Scale (Ham-D), a clinician administered rating scale that quantitates the severity of depression. A score of greater than 15 is considered clinically significant depression. Most of the cases had a dose of 0.5-1 mg/kg/day, which for the typical 70 kg person translates into 40 or 80 mg per day, respectively, based on the available doses of isotretinoin. Byrne and colleagues reported on 3 cases of depression associated with isotretinoin use, none of whom had a family or personal prior psychiatric history. All were evaluated with the Hamilton Depression Scale and found to have clinically significant increases in depressive symptoms.
(”The Neurobiology of Retinoic Acid in Affective Disorders. 2009”)
For example, one patient was an 18 year-old man who developed depressed mood, loss of interest, apathy, insomnia, anergia, anhedonia, and irritability, with feelings of guilt and loss of work and social function after two months of isotretinoin treatment. This patient attempted suicide on the fifth month of isotretinoin treatment. At the time of psychiatric evaluation his HAM-D score was 31, representing clinically significant depression. He had been receiving trazodone for the prior six weeks without benefit, and was still on isotretinoin at the time of the suicide attempt. After discontinuation of isotretinoin and administration of fluoxetine, there was an improvement in mood over 4 weeks with a Ham D score of five at follow up. A second patient was a 20 year old women treated with isotretinoin who developed depression, tearfulness, suicidal ideation, feelings of worthlessness and agitation, anergia and anhedonia, irritability and anger.
Her HAM-D score was 29. The patient also had symptoms of headache. Following supposed discontinuation of isotretinoin and treatment with imipramine and several other antidepressants there was a poor response. She later revealed that she had been surreptitiously continuing the isotretinoin, but after she finally stopped, and fluoxetine was started, she had a reduction of symptoms within two weeks and a follow-up HAM-D score of 8. Bravard et al described a 17 year old with a prior history of depression treated with isotretinoin at 0.5 mg/kg/day. At the time of treatment initiation he was free of signs of depression. However, following a further four months of treatment he tried to commit suicide by shooting himself. He reported that before the suicide attempt he had two months of fatigue, insomnia, and unhappy thoughts. In another case a 17 year-old man without prior psychiatric history who was treated with isotretinoin at 1 mg/kg/day developed growing fatigue which forced him to stop sports, and after four months he developed unhappy thoughts and asked to stop treatment. It was later learned that he committed suicide three months after stopping treatment. Another young woman with no psychiatric history began having crying spells after three months of isotretinoin treatment that lead to cessation of treatment.
Not all cases of depression concurrent with isotretinoin treatment are associated with suicidal ideation, but can include a multiplicity of unusual, sometimes extreme, behaviors. For instance, a 15-year-old girl who was previously without psychiatric history developed strange behavior one month after initiating treatment with 1 mg/kg/day of isotretinoin, including cutting the hair off of one side of her head, showing personality changes to her family, and leaving home. At that time she developed sleep disturbances and irritability, and became sullen and withdrawn. At that point the medication was stopped because of symptoms of depression. Two days later she threatened to cut her wrists and set fire to her clothes. After several months of being off of the medication she was reported to be normal again. The authors reported another case of depression that alleviated with cessation of the drug. A number of other cases, most of which resolved with discontinuation of treatment (de-challenge) and some that returned with re-challenge, are described in the literature about depression.
Isotretinoin has also been associated with symptoms of mania and psychosis. There are many examples: two male and three female acne patients with no prior history of psychiatric diagnosis and with a mean age of 19 reported “manic psychosis” with their symptoms developing after a mean of eight months [range 3-11 months] following start of treatment with isotretinoin. Four patients had an improvement in symptoms with antipsychotic treatment while one was treated with antipsychotics without a response. Three patients attempted suicide at some time after initiation of treatment. This drug may also exacerbate pre-existing psychiatric conditions; for instance, Schaffer et alexamined the charts of 300 patients with bipolar disorder. Ten of the patients were found to have been treated with isotretinoin. Of those, 9/10 had an exacerbation of their psychiatric symptoms with treatment, and three developed suicidal ideation. In the 9 patients, 6 had a mixed depressive and manic response, 1 was hypomanic, and 2 depressed. Symptoms began from 4-20 weeks after initiation of therapy, and resolved with discontinuation in all but one.
The evidence from the literature hence shows that isotretinoin treatment affects individuals in differing ways, but even though the diversity and severity of symptoms vary, all have adverse effects on the mental well being of these individuals. The physiological effects of isotretinoin are presumably on pathways that are part of the pathology of these psychiatric conditions, but with the most prominent effects being on those pathways that engender depression.
3.The temporal relationship between isotretinoin treatment and depression
The fact that the development of depression is temporally related to the initiation of treatment with isotretinoin supports the causal role that isotretinoin plays in the development of depression. Most cases of isotretinoin associated depression developed after 1-2 months of treatment. In other cases depression or suicide occurred at later stages of treatment, around 2-4 months after drug commencement. Depression and suicide do not follow immediately after treatment but commonly 1-2 months after commencement, sometimes with a longer delay. This suggests that the biological mechanism may not be via immediate influence of 13-cis RA on a crucial neurotransmitter or other signal pathway but may be through a secondary system or possibly alteration of neuroplasticity or metabolic process known to be influenced by RA, as previously described and discussed below in section 3.3. Alternatively, changes in neurochemical systems may occur more rapidly, but it may take weeks or months before a behavioral effect is seen, as is the case with the mechanism of action of antidepressants.
4.Cases of Challenge/Dechallenge Related to Isotretinoin and Depression and Suicide
There have been multiple reports in the literature of depression associated with isotretinoin use that resolved after discontinuation of the drug, and in some cases returned with re-introduction of the drug. For instance, the FDA have 41 reports of positive challenge/dechallenge/rechallenge with isotretinoin and 67% of these are not associated with a psychiatric history. In one series of seven cases of depression associated with isotretinoin treatment symptoms resolved in all cases after discontinuation of medication within 2-7 days. One patient of this series returned to isotretinoin treatment and, within 3 months of this, exhibited a recurrence of depression. In another series several cases were described, including a 19 year old with no psychiatric history who during a 3-4 month course of isotretinoin therapy developed personality changes, mood swings, and depression. After completion of treatment he returned to normal. The patient started a second course of isotretinoin treatment at a later date. Again he experienced the same symptoms, but returned to normal at the end of four months of treatment. Sometime later he started a third course of treatment. This time his symptoms recurred and persisted after the end of isotretinoin treatment. A year later he was referred for counseling. In a second case an 18 year old man with no history of mental disorder received 1.1 mg/kg/day of isotretinoin. After 29 days he experienced depression, loss of interest in daily activities, and decreased school performance. Isotretinoin was stopped and symptoms cleared in 8 days. The drug was started at 0.5 mg/kg/day and the symptoms returned after five days. Isotretinoin was stopped and the symptoms cleared in 7 days. He later was treated at the lower dose without recurrence of symptoms. The report concluded that multiple lines of evidence pointed to an association between isotretinoin treatment and depression.
These examples of depression resulting from isotretinoin use, remission on discontinuation of the drug and in some cases the return of depression on re-introduction of isotretinoin, make for a very strong case for their link in some individuals. It also implies that, although the promotion of depression by isotretinoin is relatively slow, the biological change can, in some cases, be restored to normal when the drug is removed.
5.Dose Response between Isotretinoin and Depression and Suicide
The fact that higher doses of isotretinoin are associated with a greater risk of depression is further indication that isotretinoin is responsible for the development of depression. For example, when doses were as high as 3 mg/kg/day, which is 3-6 times higher than the standard dose, then 25% of patients exhibited depression, contrasting with the 3-4% that is described in several other reports. One case involved a lawyer who was no longer able to argue cases in court, and a man who precipitously divorced his wife. The author concluded that the “psychological changes may be dose related.” It would also be predicted that a decrease in isotretinoin dose would reduce symptoms of depression and a “possible dose response” was evident in six cases where isotretinoin dose was reduced and depression symptoms declined. In another study higher doses of isotretinoin were associated with symptoms of depression including depressed libido (9% of high dose versus 2% of low dose), impotence (2% versus 0%), and weight loss (7% versus 0%). These symptoms were higher than a group of acne patients not on isotretinoin, who reported none of these symptoms. These studies provide some evidence for a dose response effect for isotretinoin and psychiatric side effects, where higher doses are associated with more side effects.
In order for a drug to cause a particular adverse event, there needs to be a plausible mechanism of action. Since depression is a disorder that is based in the brain, isotretinoin must have an effect on brain function.
• Retinoic acid signaling
all-trans RA is an endogenous regulator of gene expression acting via specific receptors that function as ligand (in this case RA) activated transcription factors. The dietary substrate of RA is vitamin A, stored as a reservoir of retinyl esters in the liver. These retinyl esters can be hydrolyzed and the resulting retinol released, circulating bound to retinol binding protein (RBP) and transthyretin (TTR). The events lead to activation of gene expression in a cell. Uptake of retinol by target cells is facilitated by the RBP receptor Stra6. Intracellular retinol is bound to cellular retinol binding protein (CRBP) before being oxidized to retinal by the ubiquitous enzymes alcohol dehydrogenase or retinol dehydrogenase. Retinal is further oxidized to RA by retinaldehyde dehydrogenase (RALDH) an enzyme that is only expressed in regions where RA is required. RA is bound to cellular retinoic acid binding protein (CRABP) and translocates to the nucleus where it binds to retinoic acid receptors ( RAR) that form heterodimers with retinoid X receptors ( RXR). These ligand-receptor complexes are bound to the retinoic acid response elements (RARE) located in the promoter regions of certain genes and promote transcription. This signaling system can be inactivated by the P450 enzyme CYP26 that generates further oxidized derivatives including 4-oxo RA. A balance of RA synthesis and catabolism in the cell maintains the correct levels of RA regulated transcription. Exposure of the cells to isotretinoin, which is isomerized in tissue to the active all-_trans_ RA, will destabilize this balance and result in inappropriate gene transcription.
• Retinoic acid function in the hypothalamus
Brain regions that are endogenously regulated by RA, and which may be disrupted by isotretinoin to potentially promote depression include the striatum, hippocampus and frontal cortex. An area of the brain, however, that has been little considered for retinoid action is the hypothalamus. The hypothalamus is the hormone regulatory center of the brain and, as part of the hypothalamus/pituitary/adrenal (HPA) axis, is a central component in the response to stress. Hyperactivity of this system is a reproducible finding in depression.
One particular RA regulated gene in the hypothalamus that may provide a link between RA and depression is corticotrophin-releasing hormone (CRH) a key regulatory factor in the HPA axiswhich may contribute to HPA axis hyperactivity in depression. Chen et al have described increased density of RARα expressing cells in the paraventricular nucleus (PVN) of patients with affective disorder and this receptor colocalized with those neurons expressing CRH.
• Metabolic effects of isotretinoin and depression
Isotretinoin administration has also been shown to affect metabolic pathways, alterations of which have been linked to depression; two examples are given below involving biotin and homocysteine. Biotin, a member of the B vitamin family (vitamin B-7) is a required nutrient that is involved in the biosynthesis of fatty acids, gluconeogenesis, and metabolism of amino acids. Side effects of biotin deficiency include hair loss, conjunctivitis, neuromuscular dysfunction, skin changes, neurological dysfunction, and of note for this review, depression. One mechanism by which biotin is recycled in the body, maintaining its availability, is supported by the enzyme biotinidase. Mutations in this enzyme result in biotin deficiency. Isotretinoin administration to human subjects is associated with a decrease of biotinidase, and the presumed decrease in biotin that would result from this may contribute to depression. Homocysteine is a sulphur containing amino acid that is involved in carbon transfer reactions. Homocysteine can receive a methyl group from 5′-methyltetrahydrofolate and become re-methylated to methionine, the immediate precursor of S-adenosylmethionine (SAM), a donor of methylation reactions involved in the synthesis of DNA, proteins, phospholipids, neurotransmitters and polyamines. SAM is involved in the synthesis in the brain of dopamine, norepinephrine and serotonin, neurotransmitters that have been linked to depression, and many studies have found a relationship between elevated homocysteine levels, lower folate concentrations, and depression. Increased concentrations of homocysteine have also been associated with attacks of violent anger. Isotretinoin administration to human subjects was shown to be associated with increased concentrations of homocysteine, as well as decreases in 5-methyl-tetrahydrofolate, providing a potential metabolic mechanism by which isotretinoin may promote depression. (”Retinoic Acid and Affective Disorders: The Evidence for an Association. 2012”)
• RA and the Frontal Cortex
The orbitofrontal cortex is another brain region that may mediate the effects of RA on symptoms of depression and the mammalian frontal cortex is one of the few regions of the adult brain where RA is synthesized. Human subjects with lesions of the medial prefrontal cortex (including orbitofrontal cortex) such as the famous case of Phineas Gage, who had a railroad spike pass through these areas of medial prefrontal cortex, show dysfunction of normal emotions and an inability to relate in social situations that require correct interpretation of the emotional expressions of others, while speech and cognition are intact. Patients with orbitofrontal damage also have impairments in impulse control with increased violent aggression and impairments in emotional regulation. Animals with lesions of the medial prefrontal cortex have an impaired ability to regulate emotional responding. Patients with depression were found to have a loss of glia and/or neurons in the orbitofrontal cortex and other related parts of the medial prefrontal cortex, including subgenual cortex. MRI brain imaging studies showed smaller volume of the orbitofrontal cortex in patients with depression, in addition to decreased orbitofrontal function with depressive relapse. It is probable that the orbitofrontal cortex, which has both input and output connections to the hippocampus, plays a critical role in the effects of RA on the brain. This cortical region is another area in which dopamine has been tied to depression (specifically mesolimbic pathways) and D2 dopamine receptor expression in the prefrontal cortex may be a target for RA. The hippocampus modulates dopaminergic function in the medial prefrontal cortex and deficits in hippocampal function lead to a downstream effect on orbitofrontal function. Based on these findings alterations in hippocampal-medial prefrontal function have been hypothesized to play a role in neuropsychiatric symptoms. Retinoids may lead to a decrease in orbitofrontal function via their effect on the hippocampus. Clinically, many patients on isotretinoin exhibit signs of behavioral dysinhibition and affective lability that suggest orbitofrontal dysfunction. Brain imaging studies described below are in fact consistent with decreased orbitofrontal function with isotretinoin administration. Therefore retinoids may mediate dysregulation in hippocampal-orbitofrontal function that contributes to symptoms of depression. The effect of isotretinoin on brain function was assessed in acne patients. Twenty-eight subjects completed four months of treatment with 13-cis RA or antibiotic with PET FDG imaging of brain metabolism and assessment of depression with the Hamilton Depression Scale (Ham-D) before and after treatment. Thirteen subjects were treated with 13-_cis_ RA and 15 with antibiotics. All subjects suffered from acne. Administration of isotretinoin (but not antibiotic) was associated with a 16% decrease in brain metabolism in the orbitofrontal cortex after four months of treatment. Five patients treated with isotretinoin had symptoms of headache. These patients also had subtle changes in irritability and/or mood as assessed by self, family, or the research staff. These subjects all had decreases in orbitofrontal brain metabolism with isotretinoin administration. A representative subject is shown in this figure:
There is significant change in rate in metabolism in a brain region (orbitofrontal cortex) that is a component in the neural circuitry that contributes to depression. It may be conjectured that isotretinoin may interfere with function in this and perhaps other regions leading to increased susceptibility to depression in some individuals.
(”The Neurobiology of Retinoic Acid in Affective Disorders. 2008”)
These results strongly suggest a link between 13-cis RA and depression; however the association is likely to be highly complex and the results are not yet sufficiently detailed to provide a precise model of how 13-cis RA may engender depression. Nevertheless, they provide an initial guide to the systems that may be affected. 13-cis RA may not act on a single system but have multiple depressogenic actions, including a dysregulation of neurotransmitters in striatum and hippocampus (in particular the dopaminergic system), suppression of hippocampal neurogenesis and interference with prefrontal cortex function. The exact action of RA in these systems will require further research and it is probable that there will be an interrelationship between several of these actions.
An interesting finding from the brain imaging studies in isotretinoin treated subjects was that the patients with headache were more likely to have decreased orbitofrontal function with isotretinoin. This finding parallels the findings that headache is associated with depression in isotretinoin-treated patients. It raises the possibility that subjects who are sensitive to isotretinoin induced effects on the CNS, such as headache, may also be susceptible to other neural side-effects of this drug such as depression.
Drug regulatory agencies world-wide are now warning patients about the risk of depression and suicide with isotretinoin, which has had an impact on prescribing behavior. Additionally, there is a growing consensus in the medical and mental health community that this is a real problem that can affect a minority of treated individuals, and that patients treated with isotretinoin need to be monitored closely for psychiatric side effects, and that patients and families should be fully informed of the risks and benefits of this medication.
(”Retinoic Acid and Affective Disorders: The Evidence for an Association. 2012”)