Isotretinoin Innocent of All Charges: Case Closed?

T he recent article by Chia et al in Archives of Dermatology1 substantiated what most clinicians and researchers have known with certainty for many years — isotretinoin is innocent! Not only did the authors fail to find an association between isotretinoin and increased levels of depression, they actually found that there was an improvement in the emotional status in treated acne patients. Simply stated, for most people isotretinoin is a life enhancing, and for some, a potentially life saving medication. Why? Because untreated or under-treated acne is a known risk factor for depression, anger, anxiety and suicide. Isotretinoin is not a medication that causes depression or suicidal behavior in the vast majority of treated patients. However, acne is. By effectively removing the burden of acne before too much psychological damage has occurred, most patients experience an improvement in their mood. History Repeats Itself This is not new news. How many times must the benefits of this remarkable medication be observed, measured and documented? Previous studies have even substantiated that isotretinoin improved depressive symptoms in patients who were known to be suffering from clinical depression at the initiation of therapy. Other studies have examined the purported link between isotretinoin and depression and failed to show any causal association. Can We Close the Lid on This Case? So, now that we have more data showing the innocence and enormous benefits of isotretinoin, the case can finally be put to rest. Right? Unfortunately, I doubt that this will happen. Physicians appear to operate by one set of rules and assumptions while the lay public is often governed by a different set of rules and assumptions. As physicians, we are trained that evidence of causation must be proven according to the rules and rigors of the scientific method. These are the bases of science, research and rational thought. Therefore, when unforeseen or unfortunate events occur, any attributions regarding causation or culpability should be made by this scientific method. Sadly, many of the occurrences in life lack obvious and rational explanations. Physicians seek additional data; others seek explanation by other means. Playing the Blame Game Human nature has always sought explanations for those events that we cannot understand. Mythical figures such as the Greek gods were obvious attempts to explain many of the unpredictable and frightening mysteries of life and the universe. Devastating life events elicit greater human needs for explanation and or blame. The search for an explanation can be long and painful. Often, the lack of an obvious answer leads to feelings of anguish, confusion and personal blame. What most people seek if a rational and palatable explanation cannot be found is a perpetrator. You see, a perpetrator can be blamed and punished. Once this occurs, some degree of emotional closure can take place to restore some degree of psychological equilibrium. By externalizing blame, feelings of personal responsibility and guilt can be assuaged. The emotionally wounded individual can now focus his or her energies on seeking revenge and restitution for this “obviously avoidable” life event. They think, If only the physician, pharmaceutical company, or pharmacist had done their jobs correctly, this could have been avoided. We have evolved into a society in which all unfortunate events in life are viewed as unfair and avoidable. It is no longer the responsibility of the individual to avoid or accept what life brings. Rather, it is the responsibility of others and the greater society to protect us from harm and demise. Thus, within this cognitive framework, random, unfair, and painful occurrences are by definition the fault of others and therefore compensation for the “injured” is deserved. It seems as if even dying has become optional. After all, if someone dies, it must be because somebody screwed up! Not So Fast With this latest study, it appears rather clear that the data are becoming quite consistent. Not so fast. In a very recent article by Bremner in the American Journal of Psychiatry,2 MRI and PET scan data showed that isotretinoin caused decreased metabolism in the orbitofrontal region of the brain. Patients who reported headaches during treatment had the greatest decreases. What are the implications if any? We really don’t know. Maybe this will be beneficial in helping us to identify patients at risk for idiosyncratic effects. Where Are We and What to Do? Certain realities and data points remain constant: • Acne is ubiquitous. • Acne has the proven potential to cause devastating short- and long-term emotional and functional damage. • Depression and suicide are common in the population that is often most in need of isotretinoin. • Suicide is the second leading cause of death in teenagers, and acne, especially on the face, increases the risk of suicide. • Idiosyncratic medication reactions, including depression, are always possible Controversies will continue. There will inevitably be future suicide attempts and other negative occurrences in adolescents and other high-risk populations. We will continue our clinical vigilance for any new data about isotretinoin that will necessitate changes in our prescribing habits. In the interim, we must continue to use this life saving and life enhancing medication to the benefit of our patients. A Look at the Latest Research Study #1: Isotretinoin Isn’t Linked to Depression In the May issue of Archives of Dermatology,1 researchers reported on mood changes in adolescents who had moderate to severe acne and were undergoing therapy with isotretinoin. In a non-randomized study of 132 teenagers between the ages of 12 and 19 years, researchers tested whether treatment with isotretinoin could be associated with an increase in depressive symptoms. Participants in the study were screened to make sure they weren’t pregnant, hadn’t used isotretinoin in the past or had any history of a psychiatric disease. Patients were assessed for depressive symptoms at baseline using a highly sensitive screening test and then again 3 to 4 months after undergoing therapy with either 1 mg/kg per day of isotretinoin or maximum conservative therapy (an oral antibiotic b.i.d. combined with a topical retinoid and topical antibiotic). Both groups of patients who underwent therapy realized an improvement in their scores on the scale used to score depressive symptoms. When all participants’ scores were adjusted for baseline scoring and sex of the patient, it was found that isotretinoin did not increase the prevalence of depressive symptoms. In the group treated with isotretinoin, the incidence of suicidal ideation was gauged to be 0, while it was 1 in the group treated with conservative therapy. Study #2: Altered Brain Images with Isotretinoin Therapy The American Journal of Psychiatry recently published an interesting study that compared the brain functioning scans of patients with acne who were undergoing treatment with isotretinoin vs. an antibiotic.2 In an open-label, non-randomized study, researchers performed both positron emission tomography (PET) scans and functional magnetic resonance imaging (fMRI) scans in 28 patients (mean age 29). None of the patients had previously undergone isotretinoin therapy and all had treatment-resistant acne. In this study, 15 patients were switched to therapy with isotretinoin and 13 had their therapy switched to one of four antibiotics. None of the patients undergoing treatment with isotretinoin had a history of psychiatric disorders. Two of the participants undergoing antibiotic treatment had no previous history of psychiatric disorders. Patients were assessed with standardized tests for acne severity and depression at baseline and following 4 months of designated therapy in additional to the brain scans. Several areas of the brain were scanned, including the orbitofrontal cortex, which is an area of the brain that can be affected in depressed people. At the 4-month assessment, researchers found that the depression scores for each treatment group were similar at baseline and follow-up. However, they also discovered that patients who underwent therapy with isotretinoin experienced significantly decreased brain activity in the orbitofrontal cortex compared with the patients who underwent therapy with an antibiotic — 21% vs. 2%. Patients who experienced headaches while on isotretinoin treatment had the greatest decrease in glucose uptake. Despite all these observed changes, researchers determined that the scan outcomes did not correlate with depression or acne-severity scores. Researchers concluded that the study findings support anecdotal evidence that isotretinoin may activate depression-specific areas of the brain and might potentially cause problems for adolescents with mood disorders. However, it’s important to underscore the fact that researchers also found no differences in the severity of depressive symptoms between the patients who underwent treatment with isotretinoin and those who received antibiotic therapy.