MEDICINE AND MENTAL HEALTH : The Isotretinoin Issue

The possibility of introducing prescribing options for New Zealand psychologists is currently being considered. Clinicians have been invited to offer opinions on the advisability of such a move and to make suggestions on additional training requirements. Certainly, an extensive understanding of the possible side effects of such medications likely to be prescribed would be required.

 In fact, an understanding of the possible short- and long-term side effects of medications in general is already an area that warrants considerably more attention from all those working in mental health. The possible, very serious mental health consequences of ingesting certain prescription medicines are currently outlined in a number of medication inserts. In addition, agencies such as the US Food and Drug Administration (FDA) have published warnings cautioning against the use of some prescription medicines, which they state may cause serious psychiatric disturbance. There are also currently proposals in Britain to give every new drug licensed a ‘suicide rating’.

This reform, based on a system adopted recently in the United States, has been fuelled by a growing body of evidence that drugs that affect the brain can heavily influence behaviour through seemingly innocuous changes in body chemistry. Medicines to treat acne, swelling, heartburn, pain, obesity, high blood pressure and cholesterol, bacterial infections, smoking and insomnia have all been associated recently with psychiatric problems. (Mostrous, 2008).

 One such medication is isotretinoin (also known as Accutane or Roaccutane), prescribed for the treatment of acne. This vitamin A derivative, manufactured by Hoffman-La Roche, is one of that company’s most popular and controversial medications. In its most recent warnings the FDA (FDA, 2005), stated:

FDA ALERT [7/2005]: Suicidal Thoughts or Actions: In addition to the strengthened risk management program, FDA continues to assess reports of suicide or suicide attempts associated with the use of isotretinoin. All patients treated with isotretinoin should be observed closely for symptoms of depression or suicidal thoughts, such as sad mood, irritability, acting on dangerous impulses, anger, loss of pleasure or interest in social or sports activities, sleeping too much or too little, changes in weight or appetite, school or work performance going down, or trouble concentrating, or for mood disturbance, psychosis, or aggression. Patients should stop isotretinoin and they or their caregiver should contact their healthcare professional right away if the patient has any of the previously mentioned symptoms. Discontinuation of treatment may be insufficient and further evaluation may be necessary. 

The ‘Patient Information Sheet’ for this medication also reads:

Serious mental health problems: Isotretinoin may cause:

- Depression

- Psychosis (seeing or hearing things that are not real)

- Suicidal thoughts or actions

-Aggressive and violent behavior

 Although approved for the treatment of “the most severe form of acne (nodular acne) that cannot be cleared up by any other acne treatments” (FDA, 2005), isotretinoin has been used increasingly for the treatment of more mild and moderate forms of acne. “In 1995, doctors calculated that only sixteen percent of prescriptions were for severe disease” (Girling, 2002). As a consequence, it is now estimated that many millions have been treated with isotretinoin worldwide. Unfortunately, the numbers of those who have reported suffering serious mental health side effects has also continued to grow. A research documentary, which screened in November 2006, quoted over 6000 reported cases of psychiatric consequences of isotretinoin use, with “US Health Authorities” estimating this was around one percent of those actually affected (Tinari, 2006). Consistent with this claim, Carleton, Smith, Gelin, and Heathcote (2007) identified ADRs (adverse drug reactions) as an important cause of childhood morbidity and mortality and stated that as many as 95% of ADRs are not reported. In a New Zealand survey of secondary school students (Purvis, Robinson, & Watson, 2004), 14.1% reported having problem acne. It has been estimated that 5000 young New Zealanders take isotretinoin (Lawrence, 2006). By 2006, the Centre for Adverse Reactions Monitoring (CARM) had received 93 notifications of adverse reactions to this medication (MARC, 2006). If US Health Authority estimates are correct (Tinari & Häner, 2006), then around 930 New Zealanders have been significantly affected.

Isotretinoin was introduced on the market, as a treatment for acne, in 1982. By 1983 Hazen, Carney, and Walker had already published details of 24 cases of depression related to its use. These findings reinforced those reported earlier by Myskens (1982), who had been using isotretinoin as a treatment for patients with advanced cancer. Around 25 percent of those patients suffered “psychological changes”. These included 18 cases of depression. Four patients had attempted suicide. Subsequent years have witnessed much debate over the strength of the causal link between isotretinoin and mental health problems. The media have feasted on this debate and the medication “has made the kind of headlines normally reserved for mass murderers or airline disasters” (Girling, 2002). In 2007, Carleton et al. conducted a retrospective analysis of 1193 suspected ADRs in Canadian children (including 58.6% adolescents). The drug most cited was isotretinoin and the most frequent reaction descriptor was psychiatric disorders. In his overview of existing research linking isotretinoin to depression, psychosis, and suicide, O’Donnell (2003), having discussed the well-known birth defects caused by ingestion of isotretinoin during pregnancy, also concluded:

Less well known is the risk of this lipid-soluble chemical to affect the central nervous system. Reports of intracranial hypertension, depression and suicide ideation with accutane use, have prompted an examination of its serious life threatening potential…the public must be informed of the proper limited indication for its use, because depression and suicide can follow in patients with no prior history of psychiatric symptoms or suicide attempts.

Contrary to this conclusion, however, were the findings of Cohen, Adams, and Patten (2007), who used depression scales to assess signs of mental health disturbance at baseline and after two months of isotreinoin treatment. They found no correlation between isotretinoin use and the development of depression on their measures. This study has subsequently faced criticism since “most complaints about depression (following isotretinoin) come about four months after treatment begins” (“Study”, 2005). However, researcher Siegfried (who had made this comment) and her colleagues (Chia, Lane, Chibnall, Allen, & Siegfried, 2005) assessing levels of depression four months into isotretinoin treatment, also found that signs of this disorder were no more prevalent in these patients than in the conservative therapy group. Both studies measured depression using either the Centre for Epidemiological Studies Depression Scale (CES-D) or the Zung Self-Rating Depression Scale. Finally, consistent with both of these findings, Bremner et al. (2005) reported that, amongst their sample, there were no significant increases in depression scores (Hamilton Depression Scale) following four months of Isotretinoin treatment. However, the Bremner study is much better renowned for the other discoveries made during this research. In a world first, Bremner measured brain functioning in his subjects using [18F]fluorodeoxyglucose positron emission tomography, before and after four months of treatment with either isotretinoin or an antibiotic. Results showed clearly that the isotretinoin treatment, but not the antibiotic treatment, was associated with decreased brain metabolism in the orbitofrontal cortex (–21% change versus 2% change for antibiotic). This is a brain area known to mediate symptoms of depression. It seems that these observable brain function changes may produce symptoms (e.g. anger, aggression, paranoia) not well measured when depression screening tools are used in isolation. Depression scales “cannot take the place of a comprehensive clinical interview for confirming a diagnosis of depression” (WHO, 2008).

In recent research conducted at the Universities of Bath and Texas, researchers were able to monitor the effect of isotretinoin on the chemistry of the cells that produce serotonin. They found that the cultured cells significantly increased the production of proteins and cell metabolites that are known to reduce the availability of serotonin (O’Reilly, Trent, Bailey, & Lane, 2007). Researcher Sarah Bailey commented: “Serotonin is an important chemical that relays signals from nerve cells to other cells in the body…. In the brain it is thought to play an important role in the regulation of a range of behaviours, such as aggression, anger and sleep. Low levels of serotonin have been linked to depression as well as bipolar and anxiety disorders” (“Mechanism”, 2007). Previous research by some of the same scientists (O’Reilly, Shumake, Gonzalez-Lima, Lane, & Bailey, 2006) concluded that isotretinoin caused depressive behaviour in mice. These findings were supported by those of Crandall et al. (2004) who showed that a “clinical dose of 13-cis-RA (the active component of isotretinoin) in mice significantly reduced cell proliferation in the hippocampus and subventricular zone, suppressed hippocampal neurogenesis and severely disrupted capacity to learn a …maze task.” In a more recent review article, Strahan and Raimer (2006), taking such findings into account, have concluded: “It is clear that isotretinoin can stunt hormonal development and influence neurotransmitter receptors, including systems known to be involved in psychopathology”. This conclusion is similar to that of Bremner and McCaffery (2008) in their very recent review report, which describes several systems that may be targets of retinoic acid (isotretinoin component) and which contribute to the pathophysiology of depression.

Finally, numerous published case studies have documented the development of psychiatric symptoms following isotretinoin use. Barak et al. (2005) described a “series of cases of manic psychosis that developed in a one year period in association with isotretinoin treatment and resulted in suicidality and progression to long standing psychosis. Cases were drawn from 500 soldiers who had been evaluated in a military specialists’ dermatology clinic for severe acne.” Following on from this, Friedman et al. (2006) carried out a five year analysis and reported a significantly greater use of mental health services by those 1419 soldiers in the Israeli Defence Forces who had a history of isotretinoin use than by those in the control group. There are many singular case studies reporting symptom presentations similar to those described by Barak et al. (2005). Bachmann, Grabarkiewicz, Thiesen, and Remschmidt (2007), for example, presented the case of a 16-year-old boy who experienced two depressive episodes “strongly associated” with isotretinoin treatment and requiring “closed ward care”. They concluded, “The current case report strongly indicates that isotretinoin may induce depression in idiosyncratic patients. Hence prescribers of isotretinoin should be aware of the adverse drug reaction and, if necessary, refer patients to psychiatric institutions”.

Consistent with this recommendation for a referral to a “psychiatric institution”, the FDA (2005), having evaluated all available research findings on isotretinoin, followed their warning with the recommendation that: “A referral to a mental health professional may be necessary.” There is an assumption, then, that those mental health practitioners receiving such referrals will have the knowledge and skills to manage an individual suffering the psychiatric side effects of isotretinoin exposure.  Unfortunately, however, there has been a serious failure to educate practitioners in this regard. Many have little, if any, knowledge of the implications of the isotretinoin research and how these translate to effective client/patient management. Criticisms of the support offered to those who attribute their psychiatric symptoms to isotretinoin exposure abound. Numerous media and coroners’ reports of isotretinoin-related suicides make reference to slow or inadequate responses by mental health professionals and a lack of knowledge of the isotretinoin – mental illness link. (Acne Drug, 2004; Girling, 2002; Sims, 2005; Tinari & Häner, 2006). Without a thorough understanding of isotretinoin’s potential side effects, clinicians are failing to make an accurate assessment of the causal factors of presenting problems, failing to assist clients/patients in their understanding of these factors contributing to their disorders, failing to make notifications of adverse drug reactions and failing to refer clients/patients to those health professionals most likely to offer successful intervention.

It seems a significant communication gap exists between those approving the distribution of medications such as isotretinoin and the health practitioners who become responsible for the treatment of side effects. In 2006, the minutes of New Zealand’sMedicines Adverse Reactions Committee stated:

The Committee considered that dermatologists were well aware of the potential association between isotretinoin and depression or other mood changes, and they were well aware of the need to counsel patients on a possible effect on mood and when to discontinue treatment. The Committee discussed whether GPs who prescribed these products need to be reminded of the possible association between isotretinoin and effect on mood. (MARC, 2006)

So it seems that while dermatologists and (possibly) GPs have been made aware of the potential psychiatric side effects of isotretinoin, these warnings have not reached those responsible for the treatment of isotretinoin-activated disorders. To date, there are no specific treatment guidelines or published case studies outlining successful treatment strategies. Failure to recognise clients’ symptoms as isotretinoin-related has resulted in subsequent failure to share information on treatment successes and failures.

Whilst psychologists in New Zealand contemplate the pros and cons of adding prescribing rights to their professional responsibilities, it is timely to consider improving our knowledge base and assessment strategies relating to clients’ previous use of other medications, which may be causing or influencing their presenting problems, and should affect treatment choices. Good clinical practice should incorporate:

Specific questions on current and historic use of all medications;
Specific enquiries about the use of isotretinoin, by those working with acne-prone populations (e.g. adolescents);
A check of known side effects of all medications mentioned by clients.
Reporting any possible medication side effects to the Centre for Adverse Reactions Monitoring (CARM);
Educating clients on possible medication side-effect contributions to their presenting problems;
Taking recent research discoveries into consideration when contemplating treatment options (e.g. serotonin depletion in isotretinoin users);
Formal documentation and discussion of these cases with colleagues. A healthy exchange of information will facilitate growth in knowledge of the most successful treatment strategies.

References

Acne drug may have contributed to teens depression, (2004, October 28). ABC New South Wales. (Online). Retrieved February 8, 2008, from http://www.accutaneaction.com/press/28.10.04htm

Bachmann, C., Grabarkiewicz, J., Thiesen, F. M., & Remschmidt, H. (2007). Isotretinoin, depression and suicide in ideation in an adolescent boy. Pharmacopsychiatry, 40, 128-131.

Barak, Y., Wohl, Y., Greenberg, Y., Dayan, Y. B., Friedman, T., Shoval,.G., & Knobler, H. Y. (2005). Affective psychosis following accutane (isotretinoin) treatment. International Clinical Psychpharmacology, 20, 39-41.

Bremner, J. D., Fani, N., Ashraf, A., Votaw J. R., Brummer, M. E., Cummins,T., Vaccarino, V., Goodman, M. M., Reed, L., Siddiq, S., & Nemeroff, C. B. (2005). Functional brain imaging alterations in acne patients treated with isotretinoin. American Journal of Psychiatry, 162, 983-991.

Bremner, J. D., & McCaffery, P. (2008). The neurobiology of retinoic acid in affective disorders. Progress in Neoropsychopharmacology and Biological Psychiatry, 32, 315-331.

Carleton, B. C., Smith M. A., Gelin, M. N., & Heathcote, S. C. (2007). Paediatric adverse drug reaction reporting: understanding and future directions. Canadian Journal of Clinical Pharmacology, 14, 45-57.

Chanson, A, N., Cardinault, N., Rock, E., Martin, J. F., Souteyrand, P., D’Incan, M., & Brachet P. (2008). Decreased plasma folate concentration in young and elderly healthy subjects after a short-term supplementation with isotretinoin. Journal of the European Academy of Dermatology and Venereology, 22, 94–100.

Chia, C. Y., Lane, W., Chibnall, J., Allen, A., & Siegfried, E. (2005). Isotretinoin therapy and mood changes in adolescents with moderate to severe acne : A cohort study. Archives of Dermatology, 141. 557-560.

Cohen, J., Adams, S., & Patten, S. (2007). No association found between patients receiving isotretinoin for acne and the development of depression in a Canadian prospective cohort. Canadian Journal of Clinical Pharmacology, 14, 227-233.

Crandall, J., Sakai, Y., Zhang, J., Koul, O., Mineur, Y., Crusio, W. E., & McCaffery, P.(2004). 13-cis-retinoic acid suppresses hippocampal-dependent learning in mice. (Online).

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Girling, R. (2002). Scarred for life: Does the drug that cures acne have devastating side effects? (2002, June 30). Sunday Times (Online).

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O’Reilly, K. C., Shumake, J., Gonzalez-Lima, F., Lane, M. A. and Bailey, S. J. (2006). Chronic administration of 13-cis-retinoic acid increases depression-related behaviour in mice. Neuropsychopharmacology, 31, 1919-1927.

O’Reilly, K. C., Trent, S., Bailey, S. J., & Lane, M. A. (2007). 13-cis-retinoic acid alters intracellular serotonin, increases 5-HT1A receptor and serotonin reuptake transporter levels in vitro. Experimental Biology and Medicine, 232, 1195-1203.

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Sims, S. (2005, April) Wonder drug or deadly weapon? Real World. (Online).

Strahan, J. E., & Raimer, S. (2006). Isotretinoin and the controversy of psychiatric adverse effects. International Journal of Dermatology, 45, 789-799.

Study: No Link Between Accutane and Teen Depression (2005, May 17). Health News. (Online). Retrieved February 10, 2008, from http://health.dailynewscentral.com/content/view/780/63

Tinari, S., and Häner, H. (2006, November) To die for the skin.  Switzerland National TV. (Online). Retrieved January 10, 2008, from U.S. Food and Drug Administration (FDA; 2005, May) Isotretinoin (marketed as Accutane capsule information. Food and Drug Administration (FDA) Homepage.Retrieved February 10, 2008, from http://www.fda.gov/cder/drug/infopage/accutane/

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