What research has been conducted to examine the effects of Accutane/Roaccutane on the adult brain?
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Animal Studies Other work funded by Mr Grant focused on the the effects of a therapeutic dose of Accutane on the adult brains of mice. It was suggested that if Accutane caused depression then Accutane would influence the "embryonic-like" regions of the adult brain. "Embryonic-like" regions of the adult brain refer to regions where the birth of new neurons continues throughout life. Accutane was found to inhibit the growth of neurons in a brain area called the hippocampus that is involved in memory and emotion. This brain area was previously found to be smaller in patients with depression. The report by Crandal et al, published in 2004 concluded that "This report demonstrates that a clinical dose (1 mg/kg/day) 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." This article can be downloaded from http://www.pnas.org/cgi/content/full/101/14/5111. |
Although the effects of Accutane/Roaccutane on the devoloping brain of the fetus has been known since the drug was introduced in 1982, there was no research conducted to examine the effects of Accutane/Roaccutane on the adolescent or adult brain. The emergence of cases of depression and suicide along with spontanous reports which were consistently submitted to health authorties (see ADR) did not prompt the FDA, NIH or Roche to conduct any meaningful studies. At the FDA hearings in 2000, Roche representatives presented a review of the literature and concluded that "although the role of retinoic acid in the devoloping CNS is well characterized, extrapolation to effects on the mature brain seem unwarranted" and were also quoted in a newspaper article in 2003 saying "We've spent the better part of 2 1/2 years trying to figure out how to conduct such a study, and it has baffled the best scientific minds at both the FDA and Roche -We are committed to finding out if there is any possible link, but we haven't figured out how to do that" [Source, Did A Powerful Acne Drug Play A Role In A Palo Alto 14-Year-Old's Killing Himself? San Francisco Chronicle, April 2003] Human Studies |
| For full list of articles on retinoids and the central nervous system click here |
Why do scientific studies refer to Accutane/Roaccutane as Isotretinoin and/or 13-cis-retinoic acid?
Many scientific studies refer to Accutane or Roaccutane as Isotretinoin or 13-cis-retinoic acid. The reason for this is that the active ingredient of Accutane/Roaccutane is Isotretinoin (which is the generic name for the drug) and Isotretinoin is chemically known as 13-cis-retinoic acid.Isotretinoin is sold under many brand names, including Accutane inside the USA and as Roaccutane outside of the USA, both of these brands being produced by Hoffmann-La Roche. It is also marketed as Accure (Alphapharm), Oratane (Douglas Pharmaceuticals), Isohexal (Hexal Australia), Amnesteem (Bertek) and Claravis (Barr).
What is Accutane/Roaccutane? How is it related to Vitamin A?
Accutane/Roaccutane is in the class of compounds called retinoids that includes
the active form of Vitamin A.
The active ingredient of Accutane/Roaccutane is Isotretinoin, chemically
known as 13-cis-retinoic acid which is related to both retinoic acid
(cis-13-retinoic acid is an isomer of all-trans-retinoic acid) and retinol
(Vitamin A).
Retinoids are a family of natural and synthetic compounds related to
Vitamin A.
The majority of the functions of Vitamin A (growth, vision, reproduction,
immune response, nervous system devolopment and maturation) are carried
out by its metabolite, retinoic acid -.i.e. Vitamin A does not act function
directly rather it acts as a precusor for biologically active retinoids.
Retinoids are powerful regulators of epithelial,
differentiation
and are essential for its maintance.
Click here for more detailed definitions and descriptons of Vitamin
A, retinoids, retinal, retinoic acid etc: Retinoids
and Vitamin
A
Discovery
of Accutane, Clinical Trials and Approval of Accutane/Roaccutane
For decades high doses of Vitmain A were found to have a positive
effect on keratinising disorders (psorasis, acne etc) but the side effects could not be tolerated. Scientists synthesised
other vitamin A derivatives (retinoids) in an effort to find a drug with
similar or greater therapeutic activity with less toxic side effects.
In 1969, Dr William Bollag of F.Hoffman La Roche, synthesised Accutane
(cis-13-retinoic acid/Isotretinoin) and found a definate clinical response.
According to Orfanos [Br J Dermatol 1980 103 473-81] the risk of side
effects, in particular the teratogenic side effect, were considered too
high to be used to treat such a common compaint as acne.
However the drug subsequently used in clinical trials in USA in the
1970's and approved by the FDA in May 1982 for use in the treatment
of severe recalcitrant cystic acne. The approval came only nine months
after the NDA submission on 523 patients, 160 of which had acne. [See
Dr. Cunnignham presentation (on behalf of Roche) at FDA meetingin 1983]
A review of the NDA submission (obtained via FOI Act) found that patients
were excluded from three of the protocols (including those where the
effect of the drug was examined on patients with keratinisation disorders)
if they had "Neurological function which might be exacerbated by
vitamin-A type toxicity".
Dr Del Vecchio [at the FDA meeting in 1983] described the side effects
of Accutane and said that "just about everything that happens with
Accutane may happen with Vitamin A overdosage". They said that the
only clinical side effects that were known initially were the musocutaneous
and muscoloskeletal side effects.
What is the mechanism of action of Accutane/Roaccutane?
Accutane/Roaccutane acts to inhibit sebaceous
gland secretions. The current label warnings for Accutane/Roaccutane state
that "the exact mechanism of action of isotretinoin is unknown".
"Retinoic acid (active form of Accutane/Roaccutane) induces differentiation
and reduces proliferation of stem and progenitor cells. It works on
acne by inducing similar events in basel sebocytes. These same actions
also lead to 13-cis-retinoic's side effects, and these are directed
towards proliferating cells in the adult such as in the skin, gut and
bone." Crandall
2004
"A wide ranging effect of retinoic acid is to inhibit proliferation in dividing cells, and this accounts for its frequent consideration as an anti-cancer agent."Crandall 2004.
Are there published cases of psychiatric adverse events occuring in association with Accutane/Roaccutane?
Below is a table of published case reports linking ingestion of Accutane/Roaccutane to psychiatric adverse events, including depression and suicide, from 1982 onwards.
| See also prospective and retrospective studies discussed
for reports of depression and other psychiatric disorders - Click
here. See also ADR's for adverse reaction reports reported to the manufacturer, Roche, and Licensing Authorties - Click here. |
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| Year | Author | Psychiatric Adverse Event | Reference | Brief Description |
| 2007 | Sarah J Bailey & Simon Trent, Dept of Pharmacy & Pharmacology, University of Bath, UK. Kally C. O'Reilly & Michelle A Lane from The University of Texas at Austin, TX, USA | Aggression and Clinical Depression | "13-Cis-Retinoic Acid Alters Intracellular Serotonin, Increases 5-HT Receptor, and Serotonin Reuptake Transporter Levels In Vitro" Published by Experimental Biology and Medicine | Using cells cultured in a laboratory, scientists from the University of Bath (UK) and University of Texas at Austin (USA) were able to monitor the effect of the drug (Roaccutane) on the chemistry of the cells that produce serotonin. They found that the cells significantly increased production of proteins and cell metabolites that are known to reduce the availability of serotonin. .....“Low levels of serotonin have been linked to depression, as well as bipolar and anxiety disorders. |
| 2006 | Sarah J Bailey, Dept of Pharmacy & Pharmacology, University of Bath, UK. Kally C O Reilly, Jason Shumake, Gonzalez-Lima & Michelle A Lane from The University of Texas at Austin, TX, USA | Depression Related behaviour | A team at Bath University and the University of Texas at Austin investigated the effect of Roaccutane on mice using two tests. Both tests involve putting the mice under stress. In one, they are put in water and forced to swim; in the other, suspended by their tails. Under these circumstances mice will normally swim, climb, or make running movements and thrash around in a bid to escape. But these bouts of activity will be interspersed with periods of immobility, during which the mice appear passive and resigned. A mouse that is depressed spends longer in the immobile state than one that is healthy. So the team gave adolescent mice Roaccutance in doses that are equivalent to those given to human adolescents, and found that the periods of immobility were significantly increased. The same tests have been used in the past to test anti-depressants, so are well validated. The conclusion, Dr Bailey said, was that Roaccutane does tend to increase depression-related behaviour in adolescent mice, at levels proportionate to those given to human patients. | |
| 2005 | La Placa M et al | Acute depression | La Placa M. J Eur Acad Dermatol Venereol. 2005 May;19(3):387. Acute depression from isotretinoin. Another case. | A 16-year old male teenager, a high school student and
basketball player, was prescribed Isotretinoin. Five weeks later,
the patient appeared to be fretful and began to complain about his
acne, where he had previously showed no embarrassment. His mother
reported an increase in irritability and a loss of concentation at
school. Two weeks later the mother returned to the dermatologist and
said that her son was terribly depressed, often crying and frequently
arguing with his parents.The dermatologist noted that typical features
of major depression were clearly detectable including mood disturbances
and behaviour changes. The treatment was discontinued and mother and
son were advised that psychotic symptoms quickly disappear after discontinuing
the isotretinoin. Unfortunately contact was lost after this episode. The author noted that "I believe that the number of reports of acute depression due to isotretinoin therapy are widely underestimated" and concluded that "it is quite likely that he was probably susceptible to developing depression, and that his mother;s anxiety had increased the depressive symptoms". |
| 2005 | Barak Y et al | Psychosis on Roaccutane therapy | Barak Y, Wohl Y, Greenberg Y, Bar Dayan Y, Friedman T, Shoval G, Knobler HY.Affective psychosis following Accutane (isotretinoin) treatment.Int Clin Psychopharmacol. 2005 Jan;20(1):39-41. | Barak reported 10% of soldiers who developed psychosis while on Roaccutane therapy |
| 2003 | Van Broekhaven et al | Completed suicide | Psychiatric symptoms during Isotretinoin therapy | A 22-year old patient with known bipolar disorder was admitted to psychiatric department for depression and suicide ideation. He had been given Isotretinoin for ance. During admission, he committed suicide. The author states that "methodologically well-performed research is lacking". |
| 2002 | Robusto et al | Depression | Robusto et al. Acta Med Port. 2002; 15(4):325-6. Depression caused by an anti-acne agent | The present clinical case reports an adolescent with depression, strongly correlated with the adverse reactions of isotretinoin. |
| 2001 | Ng et al | Suicide attempt | Ng CH, Tam MM, Hook SJ. Acne, Isotretinoin treatment and acute depression. World J Biol Psychiatry. 2001 Jul;2(3):159-61 | A 17-year old man with acne vulgaris developed symptoms of acute depression two weeks after beginning isotretinoin therapy. The depressive symptoms improved with reduction of dose and treatment with antidepressants. Dr. Ng however noticed that when isotretinoin treatment was increased, the depressive symptoms recurred despite clearing of the skin, leading to an unsuccessful suicide attempt. Isotretinoin was finally discontinued and the depressive symptoms resolved |
| 1999 | Middelkoop et al | Completed suicide | Adverse Medication Events: Roaccutane (Isotretinoin) and the Risk of Suicide: Case Report and a Review of The Literature and Pharmacovigilance Reports (click here to download article) | The article outlines the close relationship between vitamin A and Roaccutane/Accutane and accordingly similar unwanted effects to be expected. A review of the literature is documented from 1856 to the present date illustrating these side effects experienced with Vitamin A intoxication, which include vertigo, headache, irritability, depression, lethargy, fatigue and Pseudotumor cerebri. It describes a patient who was treated with Roaccutane and committed suicide. The author produces evidence to over 1000 reports of psychiatric ADRs including 47 suicides, 67 suicide attempts and 56 patients with suicide ideation. This is contrasted with very low numbers for various antibiotics also used in the treatment of acne. The events surrounding the increased warnings on Roaccutane in France, the United States, the United Kingdom and Ireland are documented. Finally caution is recommended for practitioners to be aware of this life threatening adverse event and that patients should be thoroughly screened and evaluated for signs of depression on a frequent and regular basis during therapy. |
| 1998 | Byrne et al | Depression (3 patients) | Byrne A, Costello
M, Greene E, Zibin T. Isotretinoin therapy and depression - evidence
for an association. Ir J Psych Med.1998;15(2)58-60 *Note this publication was submitted for publication on 7 Nov 1996 and accepted on 27 March 1998 |
Three case reports of depression associated with Accutane therpay are described by psychiatrist, Dr. Alan Byrne. All three cases had no previous history of depression and no family history of depression or affective disorders. A gradual improvement of mood was noted in all patients upon cessation of accutane treatment. Dr Byrne states " We believe, however, that an association does exist between depression and the use of isotretinoin for the treatment of acne and the cases reported here add weight to this belief". |
| 1995 | Aubin et al | Suicide attempt | Aubin S, Lorette G, Muller C, et al Massive isotretinoin intoxicationClin Exp Dermatol;20(4):348-50 | Describes massive isotretinoin intoxication in a patient who took 900 mg (30 times the prescribed dose) in a suicide attempt. |
| 1995 | Byrne et al | Depression (3 patients) | Byrne A. Hnatko G. Depression associated with isotretinoin therapy [letter]. Canadian Journal of Psychiatry -Revue Canadienne de Psychiatrie. 40(9):567, 1995 | A letter descrbing three cases characterized by depression, anergia, headache, irritability and agitation; two were actively suicidal. None had previous psychiatric history. |
| 1993 | Bravard et al | Suicide attempt, completed suicide and depression (3 patients) | Isotrétinoíne et dépression: syons vigilants (Isotretinoin and Depression: Care is needed) | This article describes three cases of which depression is attributed to the ingestion of Roaccutane. It also analyses the literature on the appearance of depression during treatment with Roaccutane. |
| 1992 | Duke et al | Depression | Duke EE, Guenther L: Psychiatric reactions to the retinoids. Can J Dermatology 1993; 5:467. | This article was based on observations of psychiatrists at Edmonton, Canada who treated two patients for psychiatric disorders while the patient was taking Roaccutane. The article noted that the patients had no previous history of depression and also indicated that the depressive symptoms disappeared when Roaccutane was discontinued. 12. 1993 Nouv Dermatol; 12:215. Bravard P, Krug M, Rzeznick JC: Isotrétinoíne et dépression: syons vigilants (Isotretinoin and Depression: Care is needed) This article describes three cases of which depression is attributed to the ingestion of Roaccutane. It also analyses the literature on the appearance of depression during treatment with Roaccutane. |
| 1991 | Gatti et al | Completed suicide | Gatti S, Serri F: Acute depression from isotretinoin. J Am Acad Dermatology 1991; 25:132. | This article reports the case of a 17-year-old boy who developed psychiatric problems one month after completing a four-month course of Isotretinoin. He received psychiatric care but three weeks later committed suicide.[Also includes Peck answer to letter] |
| 1990 | Hepburn et al | Suicide attempt | Hepburn et al. Deliberate self-poisoning with isotretinoin. Br J Dermatol; 122, 840-1 | |
| 1990 | Scheinman et al | Depression (7 patients) | Scheinman PL et al. Acute Depression from Isotretinoin. JAAD 1990; 22:1112-1114 | Scheinman et al reported depression in 7 of 700 patients with cystic acne, psoriasis, cutaneous disorders of keratinization, or basal cell carcinoma on isotretinoin therapy. The symptoms of depression resolved within 1 week of stopping therapy. One patient was rechallenged and symptoms recurred. Two of the seven patients had had previous Accutane® treatment without episodes of depression. |
| 1989 | Villalobos et al | Psychosis | Duke EE, Guenther L: Psychiatric reactions to the retinoids. Can J Dermatology 1993; 5:467. | This is a report on a 16 year old male with acne who on day 11 of therapy the patient had the onset of hallucinations, paranoia and impaired speech. This behaviour subsided when drug intake was stopped, but recurred shortly after resumption of Roaccutane. 8. 1988 Cutis, 42, 399-400 Roytman, M et al Pseudotumor cerebri caused by isotretinoin Case report of 16-year old girl treated with isotretinoin at a dosage of 0.7 mg per Kg each day. Side effects included depression, sever headaches, neurological disorders and impaired night vision. |
| 1986 | Lindermayr et al | Suicide attempt | Lindermayr et al. Isotretinoin intoxication in attempted suicide Acta Derm Venereol; 66; 452-3 | |
| 1982 | Hazen et al | Depression (6 patients) | Hazen PG et al. Depression-a side effect of 13-cis-retinoic acid therapy. JAAD1983; 9:278-279. | Hazen et al reported that 6 of 110 patients with acne or keratinizing disorders experienced depressive symptoms while being treated with isotretinoin. One of these patients had a previous history of depression. Five patients continued on the drug despite the symptoms, which rapidly resolved upon discontinuation of the isotretinoin. |
| 1982 | Meyskens et al | Depression/psychological changes | Meyskens, F. L., Jr., Gilmartin, E., Chase, E., Alberts, D., Surwit, E., Jones, S. E. & Salmon, S. E. (1981). A broad phase II trial of 13-cis-retinoic acid in advanced cancer. Paper presented at the Proceedings of the American Association for Cancer Research, 72nd Annual Meeting, Washington D.C. | Dr Meyskens observed that in his treatment of cancer patients with Roacuutan doses of 3 mg/kg/day about 20% developed psychological changes. He found this observation unusual and did not attribute the psychological changes to the inability of his patients to tolerate the side-effects of isotretinoin because these responses were not seen for other drugs including cytotoxic drugs, which are ten times worse in terms of toxicity. |
What about biologic plausibility - Are any other retinoids associated with psychiatric disturbance?
Symptoms
similar to those seen in Accutane® reports (depression, mood swings,
insomnia, fatigue, headache, aggressive behavior, irritability,
and/or uncontrollable crying) have been published for other retinoids
including high dose-vitamin A. Vitamin
A deficiency has also been shown to produce spatial learning and
memory impairment in rats [Neuroscience. 2002;115(2):475-82] and
excess of retinoic acid can cause learning difficulties [Proc
Natl Acad Sci U S A. 2004 6;101(14):5111-6] |
Can 13-cis-retinoic acid be found naturally
in the body?
| 13-cis-retinoic
acid is a naturally occuring form of retinoic acid that is normally
present in blood and tissues of humans. 13-cis-retinoic acid is found
in the body upon consumption of Vitamin A, such as liver [Blanar,
2001]. It is understood that the activity of retinoic acid in
specific tissues is controlled by the regulation or its availability,
balancing the rate of retinoic acid synthesis with that of destruction.
The consequences of retinoc acid excess or deficiency can be severe
[Petkovich,
2001]. A study to measure the concentration of retinoids
in the tissues of mice published in 1980 found concentrations of retinoic
acid in the brain of mice [Wang, 1980, Yang, 2005]. |
Do retinoids (Vitamin A, retinoic acid etc) have a role in the adult human brain?
| Several reviews have been published
which discuss retinoid signalling in the adult brain. One of the first
publications suggesting a role of retinoids in the central nervous
system was published in 1994 The function of retinoids (growth, vision, reproduction immune function etc) are mediated via a retinoid signalling system which include enzymes, RA receptors and RA binding proteins. In order for retinoic acid to be present and to have a function in the brain, this sophisticated molecular machinery must be present. The presence of these retinoid receptors and proteins have been found in the hippocampus, an area of the brain associated with memory, learning and emotion. Retinoic acid exerts its influences at the DNA level where it plays an important role in regulating transcription of a number of genes. |
Are meetings being held to discuss the link between Accutane/Roaccutane and psychiatric adverse effects?
| FDA
Meeting, 2000 entitled - "Accutane
Associated Psychiatric Events": Congressional Hearings- 2000 - 'Accutane - Is this Acne Drug Treatment Linked to Depression and Suicide?' Congressional Hearing - 2002 "Issues Relating to the Safety of Accutane" National Institure of Mental Health (NIMH) - 2002 - 'Functional Effects of Retinoids in the Adolescent and Adult Central Nervous System': Workshop participants reached consensus that available genetic, behavioral, and neurochemical data are consistent with the idea that retinoids do exert effects in the adult brain. American Academy of Dermatology - 2001 -American Academy of Dermatology Consensus Conference on the safe and optimal use of isotretinoin: summary and recommendations. British Academy of Dermatology - Advice on the safe introduction and continued use of isotretinoin in acne prepared by the Retinoid Working Party |
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