Note: The testimony presented here consists of witnesses' prepared statements and are not official transcripts of the proceedings.
Accutane - Is this Acne Drug Treatment Linked to Depression and Suicide?
Tuesday, December 5, 2000 1 p.m. Room 2154 Rayburn House Office Building
Presentation by:James O'Donnell PharmD MS ABCP FACN CNS, Assistant Professor of Pharmacology Rush Medical College, Chicago
I, James O'Donnell, earned Bachelor's and Doctorate degrees in Pharmacy from the Universities of Illinois and Michigan respectively, and earned a Master's degree in Clinical Nutrition from the Rush University. I completed a residency in Clinical Pharmacy at the University of Illinois Research Hospitals. I am an Assistant Professor of Pharmacology at the Rush Medical College and a Lecturer in the Department of Medicine at the University of Illinois College of Medicine. I have served as a consultant to the Drug Enforcement Administration, Illinois Department of Public Health, Illinois Department of Mental Health, and several Public Defender=s and State=s Attorneys offices, all in the areas of pharmacology, drug effects and drug use. I am the Founding Editor of the Journal of Pharmacy Practice. I am a Diplomate of the American Board of Clinical Pharmacology, a Diplomate of the Board of Nutritional Specialties, and a Fellow in the American College of Nutrition, and member of several professional societies. I have consulted to government agencies and pharmaceutical companies in matters related to research, evaluation of adverse event reports, and preparation of technical material supporting marketing and sales. I am a co-editor of Pharmacy Law: Litigating Pharmacy Cases (L&J, 1995) and the editor of Drug Injury: Liability, Analysis, and Prevention (L&J, 2000). A copy of my Curriculum Vitae is attached. I have not received any Federal Government grants and contracts.
I have testified as a witness for plaintiffs in product liability suits against Roche; however, I am not here in the capacity of an expert witness, and am not being compensated for my time associated with this Committee presentation.
My objective today is to provide information describing the association of Accutane to depression, psychosis, and suicide to the Committee. That information comes from a variety of sources, including my experience and training as a pharmacist, pharmacologist, and nutritionist:
Basic pharmacology and toxicology of Vitamin A and Retinoids
Accutane clinical research
Published literature describing Hypervitaminosis A as well as Accutane
Adverse reaction Reports (US and Europe)
Expert Analysis of Causation
My own personal assessment and recommendations.
Introduction : Vitamin A and Retinoids
Since early this century animal research revealed modifications of epithelial structure such as increased epidermal keratinization and squamous metaplasia of the mucous membrane, under conditions of vitamin A deficiency. The finding that these defects could be corrected by administering vitamin A lead to the emergence of vitamin A as an anti-keratinizing factor. The first synthesis of vitamin A fifty years ago opened a new era into the chemical synthesis of vitamin A derivatives, collectively known as retinoids.
First synthesized in 1955 Accutane (Ro 4-3780, isotretinoin), a first generation retinoid, was shown to be highly efficacious in the therapy of disorders of keratinization (e.g., Dariers disease, ichthyosis). Peck et al. (1978) were the first investigators to demonstrate this drugs value in the treatment of severe acne and in September 1982 it was approved for use in the USA by the Food and Drug Administration (FDA). From 1993 to 1997, prescriptions in the US jumped 52% (to 1.5 million).
Mechanism Of Action
Acne is due to an interaction of the normal skin bacteria with the patients abnormal type of sebaceous lipids (Cunliffe, 1998) and is associated with anincreased sebum production and ductal cornification. The acne bacteria, Propionibacterium acnes, reside on the surface of the skin in quite high numbers, especially in oil-rich areas. If they colonize the pilosebaceous duct in the presence of comedones (blackheads and whiteheads), then inflammation is likely to be triggered resulting in papules, pustules and if inflammation is more expansive, nodules. Although the exact mechanism of the anti-acne action of isotretinoin is unknown it is unique in its ability to affect, albeit not to the same degree, all the known etiological factors of acne; reduction of sebum production, lessening of comedogenesis, decreases surface and ductal colonization by Propionibacterium acnes (Cunliffe, 1997).
Chemistry, Terminology and Metabolism
Although the term vitamin A has been used to denote specific chemical compounds, such as retinol or its esters, this term now is used more as a generic descriptor for compounds that exhibit the biological properties of retinol. Retinoid refers to the chemical entity retinol or other closely related naturally occurring derivatives. Retinoids also include structurally related synthetic analogs, which need not have retinol-like (vitamin A) activity. (Marcus, 1996)
Isotretinoin is a metabolic product of the dietary vitamin A and provitamin A carotenoids. Retinol (vitamin A) is absorbed from the gastrointestinal tract and metabolized in the liver, into retinal. Retinal is then irreversibly oxidized into retinoic acids, which reversibly interconvert into each other. The 2 isomers (retinoic acid and 13-retinoic-acid) have an identical chemical structure. Isotretinoin and retinoic acid are further metabolized into oxo-isotretinoin and oxo-retinoic acid, respectively, where interconversion again takes place between both metabolites (Wiegand, 1998). The elimination half-life of isotretinoin and it=s 4-oxo metabolite are 29 and 22 hours, respectively (Nulman, 1998).
Adverse Effects Of Accutane
Over the years Accutane has proven its excellence in the treatment of severe recalcitrant acne. However it is associated with a long list of side-effects which are frequent, varied and at times severe. The most commonly occurring adverse reactions are those involving the skin and mucous membranes, which occur in all patients treated with Accutane. Other side effects reported include skin fragility, pyogenic granuloma-like lesions and epidermal blistering, paronychia and alopecia (Bigby, 1988). Gastrointestinal intolerance occurs in 20% of patients treated (Bigby, 1988). Muscular or joint pain, are quite common with Accutane use. Myalgia and arthralgias occur in 16% of patients treated, which usually abate when the medication is discontinued (Orfanos, 1997).
Blepharitis and conjunctivitis associated with Accutane use were recognized well before it=s marketing. Corneal opacities and acute myopia have been reported in government publications and in the ophthalmologic literature. Other ocular reactions include optic neuritis, cataracts, decreased night vision, blurred vision and photosensitivity. Pseudotumor cerebri (PTC) and headaches are also associated with the drug. In common with other retinoids at pharmacological doses, Accutane causes elevation of serum lipids particularly triglycerides.
Hypervitaminosis A is the condition resulting from an excess of retinol in the body.
Vitamin A is an essential factor in physiological growth, visual function, epithelial cell differentiation and reproduction and is believed to exert its influences at the DNA level where it plays an important role in regulating transcription of a number of genes.
An intake of retinoids greatly in excess of requirement results in a toxic syndrome know as hypervitaminosis A. Some or all of the symptoms of hypervitaminosis A also are the major toxic effects that are manifest during the therapeutic use of natural and synthetic retinoids in the treatment of skin disorders. Accutane(Isotretinoin), being an analog of vitamin A, shares many of the side effects experienced with vitamin A. Vitamin A (retinol) is ingested in the diet as retinyl esters, which are transported to the liver and hydrolyzed in hepatic parenchymal cells. Excess retinol is converted to retinyl esters again and stored in the liver. Retinol binds to Retinol Binding Protein (RBP). When the amount of vitamin A present exceeds the capacity of RBP to bind to it the excess retinol binds to lipoproteins, and in this form it has toxic effects (Bendich, 1989).
There are two types of Hypervitaminosis A, acute and chronic. Acute hypervitaminosis A results from ingestion of a very high dose of vitamin A over a short period of time. Typical symptoms include bulging fontanels in infants and headache in adults, nausea, vomiting, fever, vertigo and visual disorientation. Peeling of the skin may also occur. Chronic hypervitaminosis A is more common than the acute form and results from continued ingestion of high doses for months or even years. Symptoms include anorexia, dry itchy skin, alopecia, increased intracranial pressure, fatigue, irritability, somnolence pronounced craniotabes and occipital edema, skin desquamation, fissuring of the lips, pain in the legs and forearms, neurologic disturbances and lethargy. Elevated blood lipids are also common.(Wilson, 1996 ) This reads just like the Accutane package insert.
Most frequently, high intakes in children are the result of overzealous prophylactic vitamin therapy on the part of parents. Toxicity in adults has resulted from extended self-medication or food fads, as well as from the use of retinoids for the therapy of acne or other skin lesions. The toxicity of retinol depends on the age of the patient, the dose, and the duration of administration. Although vitamin A toxicity is uncommon in adults who consume less than 30 mg of retinol per day, mild symptoms of chronic retinoid intoxication have been detected in individuals whose intake was about 10 mg per day for 6 months (see Bendich and Langseth, 1989). In infants, the daily consumption of as little as 7.5 to 15 mg of retinol for 30 days has induced toxicity. The acute consumption of more than 500 mg of retinol in an adult, 100 mg in a young child, or 30 mg in an infant frequently results in poisoning. Acute and sometimes fatal poisoning in human beings also is known to follow the ingestion of polar bear liver, which contains up to 12 mg of retinol per gram. The Food and Nutrition Board of the National Research Council (1980) has warned that the ingestion of more than 7.5 mg of retinol daily is ill advised. Nevertheless, almost 5% of users of vitamin A in the United States exceed that amount.
Signs and symptoms of acute poisoning include drowsiness, irritability or irresistible desire to sleep, severe headache due to increased intracranial pressure, dizziness, hepatomegaly, vomiting, papilledema, and, after 24 hours, generalized peeling of the skin. (Guzzo, 1996)
Psychiatric Adverse Events
Vitamin A intoxication resulting in generalized as well as Central Nervous System (CNS) symptoms, was first alluded to in 1856 by Elisha Kane (Kane, 1856), the arctic explorer. He recorded symptoms of vertigo, headache, drowsiness and irritability following ingestion of polar bear liver, which was later found to contain a high concentration of vitamin A. Over the succeeding 140 years, case reports of the occurrence of acute schizophrenia or remitting psychosis associated with either hypervitaminosis A (Halter, 1991; Haupt, 1977; Landy, 1985) or vitamin A deficiency (Oliver, 1986) have appeared in the literature. These provide literature precedent and biologic plausibility to the causation analysis.
In 1972, Restak reported a case of toxic psychosis in a patient following vitamin A treatment (50,000 IU 2/3 times daily) for acne, which required hospitalization. About six months after initiating vitamin A therapy, the patient experienced the onset of prolonged depression, bouts of elation alternated with despondency, disturbed sleep, insomnia and loss of appetite. Twelve months later, while on holidays, she became more agitated and depressed, and lost weight. She also developed blurred vision, hyperacusis, vertigo, strong feelings of ego alienation, and lethargy. Following psychiatric referral, total remission occurred over 6 months of close observation and anti-depressant therapy. The authors cautioned the Ause of the vitamins as preventatives for such benign entities as acne." (Middelkoop, 2000)
In 1992, a case report described a patient, with no previous psychiatric history, who presented with a 1 year history of depressed mood and poor concentration (McCance-Katz, 1992). Medication included only a multivitamin preparation of 25,000 IU of vitamin A per day, for 2 years. Hamilton Depression Ratings confirmed full cessation of depressive symptoms after stopping treatment. Other reports of lethargy, loss of interest in surroundings, insomnia, listlessness, profound daily fatigue, anorexia and irritability, in association with vitamin A, have been documented (Stimson, 1961; Shaw, 1953; Oliver, 1958; Bifulco, 1957; Elliot, 1965).
Pseudotumor Cerebri (PTC)
First described by Gerber et al., in 1954, PTC (benign intracranial hypertension) has long been associated with Vitamin A administration (Lombaert, 1976; Siegel, 1972). PTC is accompanied by symptoms such as papilledema, vision problems, nausea and severe headaches. PTC occurs in 30% to 50% of patients with hypervitaminosis A (Selhorst, 1984) and is characterized clinically by 3 criteria (Spector, 1984; Marcus, ; DiGiovanna et al, 1986):
Neurologic and ocular symptoms and signs of increased intracranial pressure, which may include headache, nausea, transient visual obscurations, sixth-nerve palsies and papilledema.
Radiologically demonstrable normal or small-sized cerebral ventricles
Elevated Cerebrospinal fluid.
PTC has been associated with isotretinoin therapy (Lee, 1995; Roytman, 1988) and the retinoid, etretinate (Bonnetblanc, 1983) and combination therapy with tetracyclines may increase the risk for it occurring.
I testified In the case of Wagner v. Roche Laboratories (decided Nov. 13th 1996), a consumer brought a products liability action against Roche, allegingthat the defendant failed to adequately warn of the association of Accutane with PTC and of the dangers of concomitant use of Accutane and certain antibiotics such as Minocin (minocycline), a tetracycline derivative. Ms. Wagner was prescribed Accutane on Nov 8th 1982 for acne in addition to Minocin which the patient had previously been on. Six weeks later the a neurologist diagnosed papilledema and PTC. Steroids were prescribed to treat the PTC and as a result, the appellant experienced avascular necrosis. Appellant underwent several surgeries to replace both hip joints and a shoulder joint. The appellants theory of recovery at trial was premised on her presentation of expert testimony by myself that (a) "Accutane is so similar chemically to Vitamin A that appellees either were aware, or should have been aware, that Accutane also had the potential to cause PTC", and (b) "that because the two antibiotics the appellant was receiving were both associated with PTC, the combination of the two increased that risk." Dr. Elias, one of the physician investigators who participated in the clinical trials of Accutane, testified that the testing done by the appellees prior to FDA approval, was deficiently designed because it failed to monitor for neurological toxicity, and that because of the similarity with vitamin A, Roche should have predicted the same association of Accutane with PTC. In addition, I testified that even in the absence of specific instances of PTC in clinical trials, Roche should have predicted an association and should have warned of this possible effect. In fact, the Investigational Drug Brochure", dated March 20th 1978, which contains an extensive listing of abnormalities in it's "Precautions and Warnings" section, reported in patients with "chronic vitamin A intoxication. "Papilledema with increased intracranial hypertension" was one of the reported associated abnormalities listed. The same document also stated "A review of the clinical studies discussed in this brochure indicates that the adverse reactions seen with the use of orally administered Accutane are essentially those of hypervitaminosis A".
Retinoids Implicated in Schizophrenia
Goodman has recently proposed retinoid dysregulation as a possible cause of schizophrenia (Goodman, 1995). Schizophrenia is now considered to be a neurodevelopmental disorder with first evidence of the disorder occurring in the midgestational period, the time when fetal brain is actively developing. Vitamin A which is essential in gene regulation and expression, is particularly active in brain neurodevelopment at this time. Goodman has put forward three lines of evidence for an association. The first is the resemblance of symptom presentations of retinoid toxicity to the stigmata of schizophrenia e.g., thought disorder, mental deficit, enlarged ventricles, microcephaly and congenital malformations. The second line of evidence comesfrom the finding that specific gene loci which have been suggestively linked to schizophrenia, are known loci of genes within the retinoid signaling system. Retinoids are handled in the body by a complex genetic cascade necessary for the metabolism of retinol to retinoic acids. The major genes in the retinoid cascade are the nuclear retinoid receptors RAR and RXR. The loci of two of the genes involved in the regulation of this cascade, RXR_ and RAR_, have been suggestively linked to schizophrenia. It has recently been found that RXR is necessary for the expression of dopaminergic neurons in the midbrain region in mice, which have been implicated by numerous studies as abnormal in schizophrenia (Kapur, 1996). The third line of evidence shows schizophrenia genes as targets of retinoid regulation. Retinoic acid binds to RARs and RXRs and this complex then binds specific regions of target genes and in this way regulate the expression of multiple target genes. Among the many genes shown to be targets of retinoic acid are dopamine and serotonin, both of which have been proposed as candidate schizophrenia genes. (Middelkoop, 2000)
Alteration of neurotransmitters is a classic hallmark of the psychoses. Recent work has shown that retinoic acid is a major regulator of several of the genes involved in neurotransmission (Berrard, 1993).
Accutane and Depression Literature Reports
Depression associated with Accutane therapy has, in the past, been described as idiosyncratic. Increasing reports of depression associated with it's use show it is not the rarity it was once considered to be. Between 1982 and 1998 24 cases of psychological distress associated with the use of this drug were reported in the literature. Most of these cases reported the subsequent emergence of depression with features similar to that of hypervitaminosis A. (Middelkoop, 2000) Other authors have published case reports of Vitamin A poisoning. (Nagai, 1999; Aggarwal, 1996; Grisson, 1996; Alemayehu, 1995; Fishbane, 1995; Lewin, 1994; Drouet, 1998; Sharieff, 1996; Gerber 1954; Pasquariello, 1977; Rose, 1967; Braun, 1962)
Systemic side effects are generally less significant if therapy is short-term. Transitory abnormal elevations in serum transaminases occur rarely. Acute idiosyncratic hepatitis has not been seen with isotretinoin as it has with etretinate. Hyperlipidemia is frequent, with 25% of patients developing increased triglyceride levels and, less frequently, increased cholesterol and low-density lipoproteins and decreased high-density lipoproteins (Bershad et al., 1985). Myalgia and arthralgia are common complaints. Headaches occur and rarely are a symptom of pseudotumor cerebri. Occasionally, patients have drug-associated depressive episodes. Long-term therapy may produce skeletal side effects, including diffuse idiopathic skeletal hyperostoses, extraskeletal ossification, particularly at tendinous insertions, and, in children, premature epiphyseal closure (DiGiovanna et al., 1986; Marcus, 1996).
In 1983, one year after market release, Hazen et al. (1983) reported 5.5% (6/110) of patients with acne experienced depressive symptoms, manifested by malaise, crying spells and forgetfulness, within 2 weeks of commencing isotretinoin therapy. Meyskens also noted similar psychological changes in patients with cancer treated with 3mg/kg/d isotretinoin. The ADRRS of the American Academy of Dermatology, received reports of 104 suspected adverse reactions to isotretinoin, between October 1982 and June 1985, of which CNS Disorders represented 22.1% (23/104), second to Skin and Mucous membrane reactions (27.9%) (29/104) (Bigby, 1988). These CNS reactions included headache, depression, dizziness and personality disorder. Scheinman (1990) reported 1% of patients treated developed depressive symptoms with oral isotretinoin, which were diagnosed by a psychiatrist and which the severity of symptoms interfered with their normal functioning. In this particular report, the relationship of depression to isotretinoin therapy was confirmed by rechallenge. This was also confirmed by Villalobos= (1989) patient, who reported the onset of hallucinations and paranoia on day 11 of isotretinoin therapy, which subsided when drug intake was stopped and recurred shortly after resumption of isotretinoin. Gatti in Italy (1991), reported a case of suicide which happened 2 months after stopping isotretinoin therapy. Bravard et al. (1993) described 3 case reports of depression where none had a prior history. One of these patients attempted suicide during the 4th month of isotretinoin therapy, and one committed suicide 3 months after cessation of therapy. (Middelkoop, 2000)
Cessation of depressive symptoms does not always occur upon withdrawal of the drug. Byrne et al. (1995) described three patients who presented with severe depression, which required active treatment. In all three cases, the patients moods improved with anti-depressant therapy. Despite the recurrence of one of the patients acne, follow-up showed no depressive symptoms, confirmed by a score of 5 on the Hamilton Depression Rating Scale.
Adverse Drug Reaction Reports
Middelkoop conducted a pharmacoepidemiologic analysis of Accutane and other drugs used to treat acne and reports of suicide, depression, and other psychiatric adverse drug effects.
Among the many products available, Diannette, doxycycline, minocycline, oxytetracycline and tetracycline are five most commonly prescribed anti-acne treatments. Based on available information, there are more reports of psychiatric adverse events and suicide worldwide from isotretinoin than from the use of the other 5 acne therapies combined (Table 1, World Health Organization). Worldwide 1830 reports of psychiatric events attributable to the 6 medications, are identified, of which isotretinoin was implicated in 59.8% (1095/1830). Second to this was minocycline, implicated in 14.2% (261/1830). 47 and 56 cases of suicide and suicidal ideation were reported in association with the use of Accutane, respectively, with none being reported for the other medications. Of 75 cases of attempted suicide reported, 89.3% (67/75) were associated with the use of isotretinoin, with 4% (3/75) associated with the use of both Dianette and tetracycline, and 2.6% (2/75) for minocycline. ADR data for the UK (Table 2, Medicines Control Agency (MCA)) reflect a similar pattern, with 51.9% (135/262) of psychiatric ADRs attributed to isotretinoin. In addition, all cases of suicide/suicide attempt/suicide ideation were associated with the use of this medication. The source for this data relies on voluntary reporting and probably represents significant underreporting as not all serious ADR's are reported. (Middelkoop, 1999; 2000)
Isotretinoin, an acne drug used by more than 8 million people, has been associated with severe depression and even suicidal behavior that may remit when the drug is withheld. A definite cause and effect relationship between isotretinoin use and depression has not been established, and it is not surprising that the presence of severe acne itself may predispose teenagers and young adults to depression. Nonetheless, this possible side effect of isotretinoin should be kept in mind whenever the drug is prescribed. (Hauser, 1998)
Minocycline is used extensively in the treatment of acne vulgaris (8,802,000 prescriptions issued between 1982-97. Between 1970-97, 6.5 million patients (Shapiro et al., 1997) were treated with minocycline in the UK. A total of 45 psychiatric adverse events were received by the MCA between 1973 and 1997. Accutane has a UK patient exposure of 50,000 (8 million worldwide, PharmFocus data) and has received reports of 135 psychiatric adverse events. Based on these figures, the incidence rates of psychiatric adverse reactions for Accutane and Minocycline are 270 and 0.692 per 100,000 people treated, respectively. These medications, (with the exception of Accutane) are used to treat conditions other than acne. As patient exposure data for these medications, where the indication was acne, was unobtainable the frequency of psychiatric reactions attributable to these medications, in the population of acne patients, remains unknown. Middelkoop concluded that Accutane is several hundred times more likely to cause depression than the five other acne.
A major component of the evaluation of reports of suspected adverse drug reactions, or events in a clinical trial, can be a judgment about the degree to which any reported event is, in fact, causally associated with the suspected, or investigational drug. In reality, a particular event is associated or is not associated with a particular drug, but the current state of information almost never allows a definitive determination of this dichotomy. (Jones 1994)
The analysis of causality and association in adverse drug events has not changed in the last 20 years. Riddell (1983) describes the Aways and means@ of confirming or denying the possibility of an ADR which constitute a validation process that removes suspected cases from the merely anecdotal category. They are:
1. Temporal eligibility - drug must be administered at some interval of time before the reaction occurs.
2. Latent period - There is an interval from the time at which a drug is first administered to the beginning of the ADR.
3. Exclusion - are any other drugs or existing conditions responsible. This method is not applicable in all cases of possible ADR, either because of insufficient data or because of simultaneous eligibility of more than one drug.
4. De-challenge - condition improves on discontinuation of the drug, and
5. Re-challenge - condition reoccurs upon re-exposure to the drug (usually not deliberately, since a suspicion of an association with an adverse event would preclude intentional re-exposure of a patient to the same adverse event.
6. Singularity of the drug - Is there something unique about the adverse reaction experience that is not consistent with any other drug taken or any existing disease condition.
7. Pattern - ADR been described in the literature with this drug or another in the same pharmacologic class, or it may refer to a morphologic pattern in a target organ that suggests an association with a particular drug or group of drugs. (Prior history with Hypervitaminosis A provides a literature precedent, a biological plausibility).
8. Drug Identification (qualitative or quantitative) - a major utility in overdose cases.
Causality assessments were usually expressed in terms of a qualitative probability scale, for example Adefinite vs. Aprobably vs. Apossible vs. Adoubtful vs. Unrelated. (Hutchnson1989)
FDA Meeting of the Dermatologic and Ophthalmic Drugs Advisory Committee Accutane Associated Psychiatric Events September 19, 2000
Several experts from Roche as well as FDA addressed the issue of Accutane and depression and suicide.
Dr. Russell Ellison (Roche) stated:
AWe had a signal (psychiatric events) which had yet to be confirmed , and stated that Roche has been very diligent in trying to evaluate and trying to confirm this signal.@ He and his consultants (Drs. Nelson and Jacobs) opined that there was insufficient evidence to attribute causality to the Accutane psychiatric toxicity reports. AWe believe that the evidence from these investigations does not support a causal association between Accutane and psychiatric events, including suicide. That is, the signal has not been confirmed by these investigations.@
Dr. Robert Nelson (Roche, Pharmacoepidemiological Analysis) provided his analysis and opinions.
Suicide attempts and completed suicides. Suicidal ideation is under DSM-IV as a depressive case. There were a total -- and this is worldwide total -- of 168 reports before the data lock point. 104 were attempts; 64 were completed suicides. My overall conclusions. Given no clear biological plausibility, no consistent pattern in the data that I reviewed, complex environment of background symptoms, very high background rates of disease, very high background rates of alternative risk factors, I conclude that there is no evidence in these data to support a causal relationship between Accutane administration and psychiatric disorders.
Dr. Mills, and epidemiologist, commented and criticized Middelkoop=s data (slide presented by Liam Grant):
If I remember the slide correctly, 1,400,400 prescriptions for one of the antibiotics with no suicides, no suicidal ideation. Now, you tell me that there's a population of a million and a half people anywhere in this country where nobody has any of those problems. It's a classic case of poor reporting. I personally would make absolutely nothing out of the data there for that simple reason, that you're just not getting accurate reporting at all.@
Lawyer Richard Josephson who has represented Roche on Regulatory and other matters, pleaded the Advisory Committee for a scientific review.
AIn law and in science we have adopted your methodologies. After years of not considering the scientific method in courts, we now have adopted from science the scientific method. If you look just briefly at the scientific method, they ask on the question of the contention of whether Accutane causes psychiatric reactions, the extent to which the theory has been assessed based on scientific valid reasoning and methodology, whether the theory has been subjected to peer review, case reports versus peer-reviewed studies, whether the theory is only based on subjective belief or speculation, whether there is a potential rate of error in this case in the adverse drug reports, and whether the underlying theory or technique has been generally accepted as valid by the scientific community.
I merely ask you to consider the fact that you now have a label, which under the scientific method, no one here can conclude that Accutane causes those effects. As you consider what remedial action, if any, is needed or additional action is needed, I only ask that you keep that in mind.@
Dr. Alan Byrne (FDA), stated:
ATherefore, in relation to isotretinoin, my clinical observations have been that this agent can influence mood in certain individuals. My feeling is that the effects on mood may be very persistent, and obviously anything that can precipitate a depressive illness may be life-threatening because there is a significant risk of suicide with depressive illness.
Dr. Marilyn Pitts (FDA, Case Review) offered the following comments:
AThe top 10 adverse events for Accutane include depression, ranked number 6. By contrast, we looked at tetracycline, which is another agent used for less severe acne. We have 8 cases of depression and 2 deaths, and we looked at Claritin in the AERS database where we have 10 cases of depression and 2 deaths.
In 1998, OPDRA analyzed spontaneous adverse drug event reports of positive dechallenge/rechallenge cases of depression, mania, psychosis, and suicide attempt. The 2998 case series supported the Accutane labeling change, which included a warning concerning psychiatric disorders. The warning stated that Accutane may cause depression, psychosis, and rarely, suicidal ideation, suicide attempts, and suicide.
In summary, we have 41 Accutane associated dechallenge/rechallenge cases. 76 percent were without a reported psychiatric history. The median time to onset of symptoms during the first course of Accutane was 30 days, and a median recovery time of 4.5 days. During the second course, or the rechallenge course, the time to onset of symptoms was shorter in the cases that provided the information. Also, after the second course of Accutane, depression persisted in some patients after discontinuation of Accutane and/or medical intervention. There was a possible dose-response to Accutane observed in 6 patients.
In conclusion, dechallenge/rechallenge cases provide strong evidence to support a link between a drug and an observed adverse event. We have presented 41 cases of positive dechallenge/rechallenge which provide further evidence to support a relationship between Accutane and depressive symptoms.
Dr. Wysowski (FDA, Postmarketing Experience Suicide and Depression), provided the following analysis:
Over the 18-year period of marketing, the FDA received reports of 37 U.S. patients who committed suicide, 24 on Accutane and 13 after stopping the drug. Twenty two (22) percent of suicide cases were reported to have a psychiatric history. About 57 percent had other possible contributing factors for depression. n addition to the suicides, the FDA received reports of 110 U.S. Accutane users hospitalized for depression, suicidal ideation, and suicide attempt, 85 on Accutane and 25 after stopping the drug.
About a third of patients had positive dechallenges with psychiatric treatment, and nearly a third experienced persistent depression after drug discontinuation. one person had a positive rechallenge, while three others were rechallenged and were able to continue on Accutane with alcohol abstinence, dose lowering, and continued use of an antidepressant.
As of May 2000, the FDA received reports of 284 U.S. Accutane users with non-hospitalized depression. 45 percent were received in 1998 after depression and suicide were added as a warning to the labeling. About half of the non-hospitalized patients reported accompanying side effects such as dry mucous membranes, headaches, hair loss, and joint and muscle pain. About 50 percent of reports were from consumers and relatives, a higher proportion compared with most reports for most drugs.
The top 10 adverse events reported for Accutane include depression that ranks number 6. Of course, the degree of under-reporting is unknown and may be quite substantial.
There are several pieces of evidence supportive of a possible association between Accutane and depression and suicide. These include the relatively large number of reports of serious depression, more than for most drugs in the FDA's database, the temporal association between use of Accutane and onset of depression, positive dechallenges in individuals who felt better once Accutane was discontinued and psychiatric care was obtained, and positive rechallenges in individuals who experienced symptoms again after restarting the drug.
So, in summary, the FDA has received reports of suicide and serious depression in U.S. Accutane-treated patients. The case reports are suggestive of an association with Accutane, but do not allow definitive determination as to whether Accutane causes depression and suicide in treated patients.
Dr. Kathryn O'Connell (FDA, Biological Plausibility and Risk Management):
The first item that I mentioned was we ask ourselves, do we see psychiatric adverse events? Have they been reported with distinct substances that bind to the same physiologic receptor? Dr. Byrne and several other people have already referred to the fact that it is known that high dose vitamin A, hypervitaminosis A, has been associated with psychiatric adverse events. If you look in the published cases about time to offset, the most useful data -actually the paper has already been referred to I think by Dr. Byrne and perhaps by the sponsor as well that was published by Scheinman, et al. in 1990. I want to emphasize that this was not a trial done to examine the psychiatric adverse events of Accutane. This was just 700 patients -- I believe it was an NIH trial that had received Accutane for various indications. It wasn't even all acne. 7 patients in that group had enough psychiatric problems to come to attention. Let's put it that way. But of those 7 patients that they reported in this paper, it's notable that the symptoms in all 7 of them resolved within 1 week of stopping Accutane, and 1 of the patients was rechallenged and did have a positive rechallenge.
For Accutane, the central nervous system, interestingly, ranks second only to psychiatric in the highest percentage of serious adverse events -- serious adverse events -- in the Hoffmann-LaRoche postmarketing database for Accutane. So, I think it's clear that Accutane affects the central nervous system.
We don't know a mechanism for the psychiatric adverse events observed with any of the retinoids...
Dr. Miller recommended improvements in asking Accutane patients appropriate question to evaluate them from a psychiatric point of view.
What would help me and make my practice much easier would be to have a specific form that would be dealt with with each patient that would include the pregnancy contraceptive issues, that would include the appropriate questions that I would ask from a psychiatric standpoint because I don't know what those questions are, but those questions that the psychiatrists feel are appropriate. And upon completion of that form, I would then be able to write a prescription for a patient. But the fulfillment of the recommendations would be the sine qua non fox my writing the prescription for Accutane. I think this would help.
On the second question before the committee regarding what kinds of future studies are both desirable and feasible:
Would further studies help clarify the relationship between Accutane use and psychiatric events? Yes: Intervention; Basic science studies; retrospective epidemiological studies.
Submission Of ADR Reports
ADR reports often paint an incomplete picture as the cases which are filed each year represent only a fraction of actual cases. According to the UK MCA only 10-15% of serious ADRs are ever reported. A FDA MedWatch Continuing Education article (Goldman et al 1996)describes significant underreporting in the United States. He cited estimates that rarely more than 10% of serious ADRs, and 204% of non-serious reactions are reported to the British spontaneous reporting program. A similar estimate is that FDA receives direct reports of less than 10% of suspected serious ADRs This means that cases spontaneously reported to any surveillance program, which comprise the numerator, generally represent only a small portion of the number that have actually occurred. The effect of underreporting can be somewhat lessened if submitted reports, irrespective of number, are of high quality.
Under regulations a pharmaceutical company must submit all ADR reports to the FDA periodically (at least annually) or on an expedited basis within 15 days of receipt. The FDA, on January 5th 1998, sent a warning letter to Hoffman-LaRoche (New Jersey) for failing to submit a number of adverse drug experience reports that were both serious and unexpected, within 15 working days as required by regulations (21 CFR 314.80 (c)(1)) as recently as October 1997 (with some dating back to 1989)(Scrip 1998). The letter documented, among others, two ADR reports for Accutane which were received by the manufacturers on 9/04/91 and 7/24/91. Both reports were not received by the FDA until 10/8/97 (FDA/Middelkoop personal communication). In one case, for Tigason, the company reported the adverse drug event almost 11 years after receiving the information. Thus, although regulations require it, sometimes even the companies do not report in a timely basis, if at all. (Middelkoop, 2000)
Revised Label Warning
On February 25th 1998, the FDA issued a Talk Paper declaring new safety information regarding isotretinoin, as a result of adverse event reports the agency received. The revised information leaflet, now reads "Psychiatric disorders: Accutane may cause depression, psychosis and, rarely, suicide ideation, suicide attempt and suicide. Discontinuation of Accutane therapy may be insufficient; further evaluation may be necessary. ...Of the patients reporting depression, some reported that the depression subsided with discontinuation of therapy and recurred with reinstitution of therapy". Earlier information leaflets read "depression has been reported in some patients on Accutane therapy. In some of these patients, this has subsided with discontinuation of therapy and recurred with reinstitution of therapy". Thus, FDA has spoken: Accutane is linked to depression, psychosis, and suicide.
Almost one year prior to this revision, the French product label was altered on March 3rd 1997, to include >suicide attempt= as a side effect of isotretinoin therapy, and reads "In rare occasions, neuropsychological problems have been recorded (behavioral difficulties, depression, convulsions and suicide attempts)" (French Product License, 1997). This revision was introduced in France following a prospective national inquiry (1993-94) in which Roche and more than 2000 state dermatologists participated. This inquiry followed a paper presentation, which reported on a suicide associated with isotretinoin therapy (Bravard, 1993). The results of this inquiry were presented at the 3rd Forum of the National and Provincial Journal of Dermatology at Mont Pellier (March 14-17 1996) but were never published. It was almost one year later, before this warning was introduced in any other country. According to The Star-Ledger (11/16/98) "Roche never informed the FDA of this new label change, who did not learn of the French label warning until this summer ". Revised warnings have now been introduced in Ireland (May 1998) and UK (April 1998). Many have asked why French physicians and their parents were given a stronger and more explicit warning than their counterparts in the U.S., UK, and Ireland.
FDA's Battle With Accutane
During the 1980s and early 1990s FDA officials debated options to control and prevent the occurrence of Accutane-exposed pregnancies, including its removal from the market. The Columbus Dispatch (07/14/1996) documented David Graham=s (section chief of the FDAs epidemiology branch) investigation of the situation and detailed several documents and memos which showed the FDA battling itself and Hoffman-LaRoche. Such documents revealed that between 1982 and 1987 approximately 1.2 million people were treated with Accutane. 560,000 were women of which 427,000 were between the ages of 12 and 44, and more than 90% of females treated did not have severe cystic acne. In a 1990 memo Graham wrote "The magnitude of injury and death has been great and permanent with 11,000 to 13,000 Accutane-related abortions and 900-1,100 Accutane-related birth defects. There is no alternative to immediate withdrawal". This analysis by Graham provides strong evidence that the overwhelming use of Accutane is not for severe acne.
INDICATIONS FOR USE - OVERPRESCRIBING
The package insert approved indication for Accutane states that "Accutane is indicated for the treatment of severe recalcitrant nodular acne... Because of significant adverse effects associated with its use, Accutane should be reserved for patients with severe nodular acne who are unresponsive to conventional therapy including systemic antibiotics."
Despite the plethora of serious side-effects associated with Accutane therapy and the high number of exposed pregnancies which occur every year due to poor compliance with prescription guidelines, there is evidence of prescription outside of the specified indication. Published accounts document high rates of use in non-severe acne patients, and many authors endorse its use in mild and moderate acne, claiming and excellent safety profile. Clearly, teenagers with acne benefit from improvement of their disease. However, to ignore the serous reports of depression and other psychiatric toxicities is to continue to place this population at risk.
SUMMARY AND RECOMMENDATIONS
While the future may hold interesting possibilities for the therapeutic uses of the retinoids, the present ambiguity about therapeutic versus potential hazardous side-effects of these retinoids, shows that a greater level of scrutiny needs to be given to adverse reactions. Given the increasing reports of depression and suicide associated with Accutane, special care must be exercised in prescription and in monitoring.
An FDA memo of February 1998 stated that for a majority of the evaluable cases of suicide, suicide attempt or suicide ideation associated with Accutane, for the majority, there was no antecedent history of depression, and the patients were not noted or known to be depressed in the time period prior to their suicide. As a result of underreporting, the actual number of suicides could be 10 times greater than the number of reports.
Clearly, Roche's and FDA=s and Middelkoop=s number differ and vary greatly. Any study, any case evaluation, any reporting system can be faulted, criticized, subject to bias and misinterpretation.
The numbers are alarming. The price is death and destruction of our children and young adults.
We don't need absolute scientific proof in order to recognize a signal and act on it. Indeed, the mechanism of action of Accutane in treating acne is unknown! In fact, the FDA rarely has more than signal before significant warning changes and sometimes drug withdrawal occurs.
In my opinion, we have sufficient evidence to be very concerned and take some corrective steps. The link between Vitamin A toxicity, including CNS toxicity, and Accutane is indisputable. This gives us literature precedent and biologic plausibility. Opponents claim that the teenage population is at high risk for suicide. All the more reason to be cautious when prescribing Accutane, a drug which is suspected of causing psychiatric toxicity even though causality has not been proven. The link between retinoids and schizophrenia is biologically plausible.
I'm not suggesting that Accutane be withdrawn from the market. Clearly, for patients with severe acne, it has an important place in therapy. However, the drug is overwhelmingly prescribed for minor and moderate conditions, despite existing warnings to the contrary in the package insert.
Patient registries, independent epidemiologic studies, and scientific research documenting the pathophysiological basis of Accutane psychiatric toxicity are needed. A consumer education campaign via FDA consumer alerts, encouraging prescribers to limit prescriptions in non-severe patients and use whatever consent forms are developed can help inform the public and prescribers, and thus limit the toxicity. Clear patient package information, describing and informing of the psychiatric risks is important so that the patient and their family make a decision to accept the risk, and if so, to be vigilant for signs of toxicity, so that the drug can be stopped and the patient monitored. Since an informed consent is already designed to warn of pregnancy risks, the psychiatric toxicities could easily be added.
Free Legal Consultation | Accutane Facts | Depression and Suicide
New FDA Warnings | Congressional Hearing | Submit a Case | Home
Aggarwal A: Acute toxicity of vitamin A administered with measles immunization [letter; comment]. Comments Comment on: Indian Pediatr 1996 Dec;33(12):1053-5 Indian Pediatrics. 34(5):456-7, 1997 May
Alemayehu W: Pseudotumor cerebri (toxic effect of the "magic bullet"). Source Ethiopian Medical Journal. 33(4):265-70, 1995 Oct.
Bendich A, Langseth L: Safety of vitamin A. Am J Clin Nutr 1989;49:358-371.
Berrard S, Faucon BN, Houhou L, Lamouroux A, Mallet J. Retinoic acid induces cholinergic differentiation of cultured newborn rat sympathetic neurons. J Neurosci Res 1993;35:382-89.
Bifulco MH: The relation of vitamin A intake to cerebrospinal fluid pressure. J Mount Sinai Hosp NY 1957;24:713-719.
Bigby M, Stern RS: Adverse reactions to isotretinoin. J Am Acad Derm 1988;18:543-552.
Bonnetblanc JM, Hugon J, Dumas M: Intracranial hypertension with etretinate. Lancet 1983;22:974.
Braun I: Vitamin A excess, deficiency, requirements, metabolism, and misuse. Pediatr Clin North Am 1962;9:935.
Bravard P, Krug M, Rzeznick JC: Isotretinoin et depression: soyons vigilants. Nouv Dermatol 1993;12:215.
Byrne A, Costello M, Greene E et al: Isotretinoin therapy and depression - Evidence for an association. Ir J Psych Med 1998;15(2):58-60.
Comments Comment in: Rev Neurol (Paris) 1998 Nov;154(11):784-5
Cunliffe WJ: Optimum treatment of acne: a mechanistic approach to a good clinical outcome. Mod Med Ireland 1998;28(7/8):31-34.
Cunliffe WJ, van de Kerkhof PCM, Caputo R: Roaccutane treatment guidelines: Results of an international survey. Dermatology 1997;194:351-357.
Drouet A and Valance J:[Benign intracranial hypertension and chronic hypervitaminosis A (see comments)]. [French]
Elliot RA, Dryer CG: Hypervitaminosis A: Report of a case in an adult. JAMA 1965;161:1157-1159.
Fishbane S, Frei GL, Finger M, et al: Hypervitaminosis A in two hemodialysis patients. American Journal of Kidney Diseases. 25(2):346-9, 1995 Feb.
Gatti S, Serri F: Acute depression from isotretinoin (letter). J Am Acad Derm 1991;25:132.
Gerber A, Raab AP, Sobel AE: Vitamin A poisoning in adults: With description of a case. Am J Med 1954;16:729-745.
Goldman SA, Kennedy DL, Graham DJ, Gross TP, Kapit RM, Love LA, and White GG. The Clnical Impact of Adverse Event Reporting, Staff College, Center for Drug Evaluation and Research, Food and Drug Administration, October, 1996.
Goodman AB: Chromosomal locations and modes of action of genes of the retinoid (Vitamin A) system support their involvement in the etiology of schizophrenia. Am J Med Gen 1995;60:335-348.
Goulden V, Layton AM, Cunliffe WJ: Current indications for isotretinoin as a treatment for Acne vulgaris. Dermatology 1995;190:284-287.
Grissom LE, Griffin GC and Mandell GA: Hypervitaminosis A as a complication of treatment for neuroblastoma. Pediatric Radiology. 26(3):200-2, 1996.
Guzzo CA, Lazarus GS, and Werth VP: Chapter 64 Dermatological Pharmacology in Goodman & Gillman=s The Pharmacological Basis of Therapeutics, 9th Edition, 1996.
Halter U: Der fall aus der Praxis (224). Akuter exogener reaktionstypus (Delirium) nach einnahme von Tigason. Schweizerische Rundschau fur Medizin Praxis 1991;80:883-884.
Haupt R: Acute symptomatic psychosis in vitamin A intoxication (authors translation) [German]. Nervenartz 1977;48:91-95.
Hauser SL: Isotretinoin May Be Implicated in Severe Depression. Update to Chapter 385: Mental Disorders and to Chapter 55: Eczema, Psoriasis, Cutaneous Infections, Acne, and Other Common Skin Disorders in Harrison=s Principles of Internal Medicine, 14th Edition, 1998
Hazen PG, Carney JF, Walker AE et al: Depression - a side-effect of 13-cis retinoic acid therapy. J Am Acad Derm 1983;9(2):278-279.
Hutchinson TA, Lane DA. Assessing methods for causality assessment. J Clin Epidemiol 1989, 42: 5-16.
Jones JK. Determining Causation from Case Reports, in Strom BL, Pharmacoepidemiology, Second Edition, Wiley, New York, 1994, at page 365.
Kane EK: Arctic explorations in the years 1853, 1854, 1855. Philadelphia. Childs and Peterson Pub 1856;1:392.
Kapur S: High levels of dopamine D2 receptor occupancy with low-dose haloperidol treatment: A PET study. Am J Psychiatry 1996;153(7):948-950.
Landy D: Pibloktoq (hysteria) and inuit nutrition: Possible implication of hypervitaminosis A. Soc Sci Med 1985;21:173-185.
Layton AM: Long-tern safety and efficacy of oral isotretinoin in less severe acne. Retinoids Today and Tomorrow 1996;43:6-7
Lee AG: Pseudotumor cerebri after treatment with tetracycline and isotretinoin. Cutis 1995;55:165-168.
Lewin AH, Bos ME, Zusi, et al: Evaluation of retinoids as therapeutic agents in dermatology. Pharmaceutical Research. 11(2):192-200, 1994 Feb.
Lombaert A, Carton H: Benign intracranial hypertension due to hypervitaminosis A in adults and adolescents. Eur Neurol 1976;14:340-350.
Marcus R and Coulston AM: Chapter 63, Fat-Soluble Vitamins, Vitamin A, K, and E; Vitamin A, in Goodman & Gillman=s The Pharmacological Basis of Therapeutics, 9th Edition, 1996.
McCance-Katz EF, Price LH: Depression associated with vitamin A intoxication. Psychosomatics 1992;33(1);117-118.
Meyskens, F.L. Jr. Short clinical reports. J Am Acad Derm, 6:732, 1982.
Middelkoop T: Accutane: Focus on Psychiatric Toxicity and Suicide, Chapter in O=Donnell JT: Drug Injury, Liability, Analysis and Prevention, Lawyers & Judges Publishers, Tucson, AZ, 2000
Nagai K, Hosaka H, Kubo et al: Vitamin A toxicity secondary to excessive intake of yellow-green vegetables, liver and laver. Journal of Hepatology. 31(1):142-8, 1999 Jul.
Nulman I, Berkovitch M, Klein J: Steady-state pharmacokinetics of isotretinoin and it's 4-oxo metabolite: Implications for fetal safety. Pediatrics 1998;38:926-930.
Oliver TK and Havener WH: Eye manifestations of chronic vitamin A intoxication. Arch Ophthal 1953;60:19-22.
Oliver J: Keratomalacia on a "healthy diet". Br J Ophthalmol 1986;70:357-360.
Orfanos CE, Zouboulis CC, Almond-Roesler B, Geilen CC: Current use and future potential role of retinoids in dermatology. Drugs 1997;53(3):358-388.
Ortonne JP: Oral isotretinoin treatment policy. Do we all agree? Dermatology 1997;195(suppl 1):34-37.
Pasquariello PS, Schut L, Borns P: Benign increased intracranial hypertension due to chronic vitamin A overdosage in a 26-month-old child. Clin Pediatr 1977;16:379-382.
Peck GL, et al: Treatment of Darier's disease, lamellar ichthyosis, pityriasis rubra pilaris, cystic acne and basal cell carcinoma with oral 13-cis-retinoic acid. Dermatologica 1978;157 (Suppl.):11.
Revue Neurologique. 154(3):253-6, 1998 Apr.
Riddell RH.,ed. Pathology of Drug-Induced and Toxic Diseases. Churchill Livingstone, New York, 1982 (3-9).
Rose A, Matson D: Benign intracranial hypertension in children. Pediatrics 1967;39:227
Roytman M, Frumkin A, Bohn TG: Pseudotumor cerebri caused by isotretinoin. Cutis 1988;42:399-400.
Scheinman PL, Peck GL, Rubinow DR et al: Acute depression from isotretinoin. J Am Acad Derm 1990;22(6):1112-1114.
Scrip Magazine: French tighten rules on Roaccutane. Scrip 1996;2159:21.
Selhorst JB, Jennings S, et al: Liver lover's headache: Pseudotumor cerebri and vitamin A intoxication. JAMA 1984;252(24):3365.
Shapiro LE, Knowles SR, Shear NH: Comparative safety of tetracycline, minocycline and doxycycline. Arch Dermatol1997;133:1224-30.
Sharieff GQ: Pseudotumor Cerebri and Hypercalcemia Resulting From Vitamin A Toxicity [Case Report]. Volume 27(4) April 1996 pp 518-521
Shaw EW, Niccoli JZ: Hypervitaminosis A: Report of a case in an adult male. Ann Intern Med 1953;39:131-134.
Siegel NJ, Spackman TJ: Chronic hypervitaminosis A with intracranial hypertension and low cerebrospinal fluid concentration of protein. Clin Pediatr (Phila) 1972;11:580-584.
Spector RH, Carlisle J: Pseudotumor cerebri caused by a synthetic vitamin A preparation. Neurology 1984;34:1509-1511.
Stimson WH: Vitamin A intoxication in adults: Report of a case with a summary of the literature. New Eng J Med 1961;265:369-373.
Villalobos D, Ellis M and Snodgrass WR: Isotretinoin (Accutane)-associated psychosis. Vet Human Toxicol 1989;31(4):231.
Wiegand UW, Chou RC: Pharmacokinetics of oral isotretinoin. J Am Acad Derm 1998;39(suppl. pt 3):S8-S12
Use of this site is dictated by our terns and conditions