Note: The testimony presented here consists of witnesses' prepared statements and are not official transcripts of the proceedings.
Statement By Douglas G. Jacobs, M.d. Associate Clinical Professor Of Psychiatry Harvard Medical School Before The Committee On Government Reform U.S. House Of Representatives
"Accutane: Is This Acne Drug
Treatment Linked To Depression And Suicide?"
December 5, 2000
Mr. Chairman and Members of the Committee, thank you for the opportunity to testify before the Committee on Government Reform on issues related to Accutane (isotretinoin), depression and suicide. I am an Associate Clinical Professor of Psychiatry at Harvard Medical School, where my major research interests have been the study of the phenomenon of suicide and the evaluation and treatment of suicidal patients. My work has included using principles of a psychological autopsy in reviewing over 300 suicides on an intensive basis. I have served as a consultant to Hoffmann-La Roche in the clinical review and evaluation of reports of suicide in the isotretinoin-treated patient population, and I recently presented that clinical review to the Food and Drug Administration's Dermatologic and Ophthalmic Drugs Advisory Committee.
Over the past decade and a half, reports have emerged proposing a possible link between isotretinoin and depression, suicidal ideation, and suicide. In my statement today, I would like to review the clinical features of depression and suicide, and then provide an overview of my clinical analysis of suicide reports in the Accutane patient population. As I will explain, based on a careful review of the variety of factors relevant to suicide and the relevant suicide reports, it is my conclusion that Accutane use is not causally linked to suicide.
Suicide: An Overview
Although the base rate of suicide in the United State has remained unchanged since 1979, averaging between 11.9 and 12.1 per 100,000 people, with an annual incidence rate of suicide of less than 0.01%, the demographics of suicide have changed substantially over the last quarter century. Currently, 50% of all suicides are under the age of 40. The suicide rate for those age 15-19 has increased over the past 25 years and suicide is the third leading cause of death for this age group, the population most likely to be treated with Accutane.
Suicide is a complex and multi-causal event (see Table 1). There are typically many factors and circumstances involved in the suicide of a particular individual, and there is no single variable that allows us to predict who will and who will not suicide. While there have been studies on the putative biological substrates associated with suicide, we can not determine precisely one neurologic or biologic pathway to the act of suicide.
Suicide risk factors include the presence of psychiatric illness, life stressors, family history of suicide, the presence of hopelessness, access to weapons, and the presence of a comorbid medical condition. No one factor, however, even psychiatric illness, can predict or determine suicide. Although 90-95% of people who commit suicide have some form of psychiatric illness, generally depression, alcoholism or schizophrenia, the majority of people with these disorders do not kill themselves. Therefore, while we consider psychiatric illness a necessary but not sufficient condition for suicide, it is a distal risk factor and not the sole factor related to suicide.
Suicide is generally associated with clinical depression, although the majority of people who commit suicide are not in mental health treatment at the time of death. Despite the fact that most people who commit suicide are not receiving mental health treatment, 75% have seen a physician in the previous six months. The majority of these individuals have seen a physician for a physical complaint, rather than a mental health complaint.
To date, no drug product has been found to cause suicide. Although certain drugs have been accused of such an association, there is no evidence to support these claims.
Suicidal Ideation and Suicide Attempts; Definitional Issues
Studies indicate that approximately 5 million adults in the U.S. experience suicidal ideation each year, a prevalence of 2.6%. Suicidal ideation is specifically defined as not only a fleeting thought of suicide, but an active wish to die and an active thought of one's own self-annihilation. A non-specific version, which is less clinically significant, refers to just thoughts of death and has a prevalence of 28%. It is this version that appears in most of the spontaneous reports.
It is estimated that for each completed suicide there are approximately 18 to 23 suicide attempts, resulting in a 0.3% annual prevalence of suicide attempts, or 600,000 suicide attempts annually. Although a previous suicide attempt is a risk factor for suicide, 90% of those who attempt suicide do not go on to complete suicide. Definitional issues are again important in understanding the Medwatch reports. The basic distinction is self-destructive behavior that is accompanied by suicidal intent versus self-destructive behavior that is reported regardless of intent to die. This has particular relevance in the youth population. The suicide attempts or self-destructive behaviors that are described in the reports generally do not refer to the presence or absence of the intent to die.
Depression and Suicide
In examining depression in relation to isotretinoin, it is important to distinguish between depression and "the blues." Whereas depression is a whole body illness that includes both physical complaints and mood disturbances, the blues refers simply to changes in mood and affect. In addition, while depression can result in suicide and may include suicidal ideation as a symptom, the blues rarely produce suicidal thoughts. While approximately 6-8% of the U.S. population currently has depression, mood symptoms consistent with the blues are experienced by 25% of the population at any given time.
Biologically, it is hypothesized that depression is associated with altered functioning of neurotransmitters. Psychologically, negative life experiences can exacerbate or precipitate depressive episodes. The etiology of depression is complex, however, and it must be kept in mind that personality, developmental, genetic, and environmental factors all play a role in the onset of depression. There is a strong genetic component to depression and a family history of major depression is a risk factor.
Depression is characterized by nine criteria, five of which must be met for a diagnosis of depression (see Table 2). The first two symptoms, depressed mood and loss of interest in life and activities, are key, and one must be present for a diagnosis of depression. In addition, four of the additional seven criteria must also be present. All criteria must be present for a two-week period. One of the major difficulties in recognizing and diagnosing depression is that many of the symptoms, such as appetite and sleep changes, are non-specific and are present in a number of emotional and physical disorders. In addition, the somatic complaints that accompany depression are often mistaken for signs of physical illness and a diagnosis of depression is overlooked.
Isotretinoin: Examining the Data
In looking at the signal of psychiatric events in the isotretinoin patient population, it is important to note that the reports of depression in the Medwatch reports and in the literature on isotretinoin are below the background incidence of depression for the general population. The depressions that are reported are typically not severe and do not meet the full criteria for clinical depression. Because the patients were not evaluated psychiatrically prior to the onset of their mood disturbances, it is difficult to evaluate how drastic the mood changes truly were and whether or not they were pre-existing. Many of the patients were not treated for depression, even though depressive symptoms were reported. Had these patients been suffering from clinical depression, treatment would have been required to alleviate the symptoms. In fact, many of the patients remained on isotretinoin without exacerbation of their depressive symptoms.
In the original controlled clinical trials of isotretinoin there were no diagnoses of depression. In the subsequent studies, up to 5.5% of the patients reported major depressive symptoms, some of which were confirmed by a psychiatrist. None of these patients required antidepressants according to the physician's reports. In another study, only 1% reported depressive symptoms but, again, none required antidepressant treatment, indicating a low level of severity of depressive symptoms. Therefore, while these patients may have had depressive symptoms, there is not conclusive evidence that they had a major depressive disorder.
In addition, as previously mentioned, confounding factors may result in depressive symptoms without the presence of clinical depression. Although in the dechallenge and rechallenge reports in the Medwatch reports, the changes in mood and the temporal relationship to isotretinoin may have met some of the criteria for a Substance-Induced Mood Disorder (drug-induced depression), serious questions still remain. The clinical significance of this observation is uncertain in light of the often cyclic nature of these symptoms or diseases. For example, there are no reported studies or observations which suggest an association between Substance Induced Mood Disorder and suicide. Furthermore, this diagnostic category fails to account for potentially confounding variables and risk factors and is generally attributed to substances used in abuse. In particular, in the majority of Medwatch reports, we do not have the patients' complete histories and, therefore, do not know if they had any pre-existing depression, other psychopathology or genetic predisposition and thus cannot use them to assign a diagnosis such as Substance-Induced Mood Disorder (drug-induced depression).
Based upon my review, the suicides in the Accutane-treated population, as recorded in the Medwatch reports, are consistent with what we know about suicide. There were multiple scenarios, generally involving a psychiatric illness, family history of depression or suicide, family problems, concurrent medication, and other confounding factors. The average age and gender -- young and male -- of the victims were consistent with the typical profile.
Although many of the Medwatch reports from families indicated that the suicide appeared to come "out of the blue," this is not atypical of suicide cases in general. Despite the fact that 70% of people who commit suicide communicate their suicidal intent, young people in particular often discuss it with friends rather than family, or keep it suppressed. This means that many families are not aware of their child's suicidal thoughts and do not recognize the warning signs of the impending suicide. In fact, many of the cases reported in the Medwatch reports appear to have exhibited other, preexisting risk factors for suicide that remained unrecognized or undiagnosed. If a full psychological autopsy, which examines multiple factors, were to be performed, the cause of suicide in these patients would not be viewed as associated with isotretinoin, but rather to the myriad of other factors that indicated suicide risk.
Finally, there is no evidence that there is a biochemical basis for Accutane to be associated with depression, suicide, or suicide attempts. While there is evidence that suggests that clinical depression is associated with an alteration in the neurotransmitter system, there are no current data to conclude that isotretinoin causes such alterations. Although the retinoids may have some postulated relationship to CNS functions, and it remains a rare possibility that isotretinoin may be associated with some mood symptoms in certain individuals, the evidence does not suggest a causal link between isotretinoin and major depression or suicide. In addition, there is no evidence that the reported mood symptoms are of clinical significance.
In summarizing my findings on the Medwatch reports, I examined various categories in terms of their relationship to isotretinoin use; demographics, confounding factors, pre-existing psychiatric history, concealment of symptoms and no apparentpsychopathology. There was no alteration in the gender distribution in the suicide cases. There was no significant impact in terms of the suicides occurring on or off Accutane. There was no exacerbation of underlying psychiatric disorders. The lack of warning signs seen in many of the cases is consistent with what we know about youth suicide.
You have asked for my thoughts on the adequacy of a passive adverse event reporting system in this context. Although I am not an expert in adverse event reporting mechanisms generally, I believe that in this matter the adverse event reporting system has performed its function of providing a signal of a potential issue. In light of the overall incidence of these conditions, the appropriate focus at this point is on education of prescribers and patients as well as further scientific study and analysis.
In conclusion, although the current scientific evidence does not support a link between isotretinoin and depression, suicidal ideation, or suicide, given the clinical population in dermatology, it is still important for health care professionals to be aware of psychiatric risk factors. Monitoring patients for depression, depressive symptoms, and suicidal ideation can help identify any patients who may be at risk and improve patient care by facilitating appropriate diagnosis and treatment of patients experiencing clinical depression. It is my understanding that enhancements are being implemented in the communication of psychiatric information to isotretinoin prescribers and patients. I welcome these efforts, and I believe they will have a beneficial impact on the dermatological patient population as a whole.
Thank you for the opportunity to provide this statement. I will be happy to take questions.
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