Pseudotumor cerebri

Abstract

Oral retinoids are among the first line agents for treatment of pustular and erythrodermic psoriasis, and they are effective in combination with phototherapy and other topical and systemic agents for the treatment of plaque psoriasis. Acitretin is the leading oral retinoid used today for the treatment of psoriasis. Recently, possible side effects such as pseudotumor cerebri and depression have gained a warning and precaution respectively on the acitretin package insert. This paper presents a review of the scientific literature and attempts to clarify whether warnings of these side effects have arisen from a scientific evidence base or from theoretical concern/class labeling. A paucity of scientific evidence was found in this review for acitretin-associated pseudotumor cerebri and depression. The authors conclude that these 2 acitretin side effects must be further investigated to assess whether these associations are scientifically certain or if class labeling has led to inclusion in the package insert.

Introduction

Oral retinoids are among the first line agents for treatment of pustular and erythrodermic psoriasis, and they are effective in combination with phototherapy and other topical and systemic agents for the treatment of plaque psoriasis. Acitretin is a synthetic oral vitamin A derivative that was approved by the Food and Drug Administration (FDA) in 1997 for treatment of psoriasis. (1) As it is the free aromatic acid metabolite of etretinate, acitretin is 50 times less lipophilic than etretinate. As a result it is cleared from the body more quickly with a 2- to 4-day half-life compared with the 120-day half-life of etretinate. This more favorable pharmacokinetic profile has allowed acitretin to become the leading oral retinoid for the treatment of psoriasis, causing the removal of etretinate from the US market in March 1998. (1)

Since the advent of oral retinoids, such as acitretin, there has been concern about their multiple side effects. The mucocutaneous side effects (ie, cheilitis, skin peeling, dry skin), alopecia, and the known teratogenicity of acitretin are well established and will not be discussed here. However, the side effects of pseudotumor cerebri and depression have gained significant notoriety by gaining a warning and precaution respectively on the acitretin package insert. (2)

Such warnings/precautions of pseudotumor cerebri and depression that possibly may occur during acitretin therapy necessitate a careful review of the science and literature surrounding the side effects of this medication. This report will examine the literature base of these 2 side effects in order to more accurately assess whether the warnings have arisen from a scientific evidence base or from theoretical concern and class labeling. Class labeling is the practice of labeling a drug class with a certain side effect because one member of the class is associated or suspected to carry a certain side effect. It is of interest that such class labeling may occur without a scientific evidence base.

Methods

A review of the literature was conducted by searching the National Library of Medicine's PubMed database coverage of MEDLINE (1965-2005), OLDMEDLINE (1950-1965), in-process citations, and publisher-supplied citations. The generic retinoid name with either "pseudotumor cerebri," "intracranial hypertension," or "benign intracranial hypertension" were used as keywords to search this database for reports of acitretin-associated pseudotumor cerebri. These terms were also combined with the keywords "minocy-cline," "doxycycline," and "tetracycline" to retrieve reports of pseudotumor cerebri induced by administration of tetra-cycline-class drugs in conjunction with acitretin therapy.

The FDA MedWatch (3) database records of Safety-Related Drug Labeling Changes and Safety Alerts for Drugs, Biologics. Medical Devices, and Dietary Supplements were examined from January 1997 to January 2005 for citations regarding acitretin-associated pseudotumor cerebri. Polls of the Medical Information Departments of F. Hoffman-La Roche, Ltd., and the Connetics Corporation were made to obtain any phase IV postmarketing reports of acitretin-induced pseudotumor cerebri.

A review was conducted in a similar manner for acitretin-induced depression/suicidal ideation. Keywords used to search MEDLINE were the generic name of the retinoid with either "depression," "suicide," or "suicidal ideation." The FDA MedWatch database records were searched in an identical manner as above for reports of acitretin-associated depression/suicidal ideation. Polls to both manufacturers were made to examine Phase IV postmarketing reports of this association. In addition, the PsycINFO database was searched using the Ovid Web Gateway with keywords of "acitretin" combined with either "depression," "suicide," or "suicidal ideation."

Pseudotumor Cerebri/Intracranial Hypertension

Pseudotumor cerebri, also known as idiopathic intracranial hypertension, has been a possible rare but serious side effect of acitretin since the pivotal clinical trial that was a step in gaining FDA approval for the drug in June 1997 for the treatment of psoriasis. (1) This study mentions that pseudotumor cerebri during therapy with other oral retinoids has occurred during concurrent administration of tetracycline-class antibiotics. Case reports and reviews of tetracycline, (4,8) minocycline, (4,5,9-17) and doxycycline (4,18,19) monotherapy exist with regard to an association with pseudotumor cerebri. The literature as shown by the numerous citations above reveals that minocycline monotherapy has been especially associated with pseudotumor cerebri since 1978. (9)

Tetracycline antibiotics such as minocycline have been shown to decrease cerebrospinal fluid absorption, (20) possibly by an effect on cyclic adenosine monophosphate at the arachnoid villi. (8) In addition, minocycline is capable of crossing the blood-brain barrier more effectively than tetracycline (21) because it has greater lipid solubility (22)--possibly contributing to a greater effect on decreasing cerebrospinal fluid absorption. (9)

The association between doxycycline and pseudotumor cerebri is the least well established of all the tetracyclines. A recent query to the membership of the North American Neuro-Ophthalmology Society by Friedman et al (23) revealed 7 new cases of doxycycline-associated pseudotumor cerebri. Three of the 7 developed symptoms of increased intracranial pressure within weeks of starting doxycycline, and 5 patients experienced permanent visual deficits.

There are case reports of other systemically administered synthetic retinoids such as isotretinoin producing pseudotumor cerebri as monotherapy (24-26) and when taken concurrently with the tetracycline family of antibiotics. (5) Etretinate as monotherapy has been reported to cause pseudotumor cerebri. (27,28) However, these cases are not proven since these examples of etretinate-associated pseudotumor cerebri do not have available a documented lumbar puncture, opening pressure recordings, or test results of CSF for cell count, differential, glucose, and protein. According to Friedman, (4) headaches are a known adverse effect of retinoid therapy and, therefore, the diagnosis of intracranial hypertension in these 2 patients is unsubstantiated. In the pivotal 525 person study in 1997 specific to acitretin monotherapy, pseudotumor cerebri occurred in less than 1% of the study population, and that one case of pseudotumor cerebri was not associated with use of the tetracycline class of antibiotics. (2) Such statements in the acitretin package insert make the precise incidence of pseudotumor cerebri occurring in the clinical trial unclear. There has nevertheless been anecdotal evidence of physicians having an acitretin prescription fill request denied because the patient was also taking a tetracycline antibiotic.

A comprehensive literature review yielded a paucity of case reports with an association between acitretin monotherapy and pseudotumor cerebri. There was one study found that suggests a probable causal relationship between oral retinoids and intracranial hypertension. This study by Fraunfelder and Fraunfelder (29) reviewed 331 case reports of ocular side effects associated with tretinoin, acitretin, and etretinate. Of these 331 case reports, 21 were found with specifically retinoid-associated intracranial hypertension. Three of these 21 case reports showed instances of acitretin-associated intracranial hypertension. The authors concluded that these 3 cases allowed an inference of a "probable" causal relationship by WHO criteria of intracranial hypertension from acitretin. A "certain" causal relationship by WHO criteria could not be inferred from their results because of a paucity of rechallenge data.

The same literature search yielded no published citations of pseudotumor cerebri occurring with concurrent administration of acitretin with tetracycline, minocycline, or doxycycline. A thorough search of the FDA MedWatch (3) database records from January 1997 to January 2005 of Safety-Related Drug Labeling Changes and Safety Alerts for Drugs, Biologics, Medical Devices, and Dietary Supplements revealed no specific citations regarding acitretin-associated pseudotumor cerebri. In the April 2003 edition of the FDA MedWatch (3) Safety-Related Drug Labeling Changes, acitretin is listed as having numerous changes to the package insert including the Warnings, Precautions, and Adverse Reactions sections. The package insert does not specify which changes in the above sections occurred in April 2003. However, the Doctor's Guide DGNews (30) online resource detailed such changes in May 2003, and does not report increased intracranial hypertension as a new warning. Moreover, a query to F. Hoffman-La Roche, Ltd., and Connetics Corporation medical information departments yielded no phase IV postmarketing events of acitretin-associated pseudotumor cerebri.

Depression/Suicidal Ideation

As mentioned above, in the April 2003 edition of the FDA MedWatch (3) Safety-Related Drug Labeling Changes, acitretin is listed as having numerous changes to the package insert including the Warnings, Precautions, and Adverse Reactions sections. The Doctor's Guide DGNews (30) online resource detailed such changes in May 2003, and reports that the revised label included a new precaution on the side effect of depression. The precaution reads that "depression and/or other psychiatric symptoms such as aggressive feelings or thoughts of self-harm have been reported ... in patients taking other systemically administered retinoids, as well in patients taking Soriatane." (2) The precaution then states that confounding factors may have contributed to such events, and thus it is not known if these events are related to Soriatane administration.

This precaution was added to the package insert because such adverse events listed above were identified during post approval use of Soriatane. However, the cases were reported voluntarily from a population of uncertain size, and so it is not always possible to establish a causal relationship between Soriatane exposure and possible psychiatric side effects. Reliably estimating frequency of the possible psychiatric side effects is also not always possible given these circumstances. (2) The Soriatane package insert illustrates this by saying:

Given that the label changes occurred in April of 2003, the data for the new precaution above were accumulated during for approximately 6 years after acitretin was approved for treatment of psoriasis. The pivotal 525 patient study of 1997 that was a step in gaining acitretin FDA approval for the treatment of psoriasis mentioned originally that acitretin therapy was related to "depression" with a frequency of "1% to 10%" of the trial population. (2)

This study has never been published in the world literature other than in the acitretin package insert. A query to the Connetics medical information department revealed no additional information on these findings other than the briefly quoted percentage. The authors have searched for any data used to generate these percentages, but have been unable to find any records from the Connetics Corporation regarding a specific set of parameters used to define "depression" in this study. The authors were unable to gain any information from F. Hoffman La Roche, Ltd., as their dermatology division has recently discontinued its research and development efforts. Also, the authors were unable to uncover whether or not this body of subjects who "developed depression" during the study were compared to any other group--either placebo or another active comparator. The authors find 2 issues that are somewhat problematic with the quoted 1% to 10% of patients "developing depression" during the acitretin clinical trial discussed in the package insert. The first is how there would be a tenfold difference in the incidence of depression in this study. Second, if the upper end of the incidence was in fact 10% in this study, then it is interesting that there has there been no convincing scientific evidence published elsewhere in the public arena concerning such an association.

As shown above, the acitretin package insert noted that such psychiatric conditions have also been noted in "other systemically administered retinoids." (2) The most well known oral retinoid whose therapy is debated to be associated with depression is isotretinoin. Brecher and Orlow (31) reviewed the evidence for the psychological side effect warning that accompanies isotretinoin. They relate that the only evidence concerning the association between isotretinoin and depression involves anecdotal reports, and on the basis of postmarketing anecdotal reports, F. Hoffman-La Roche, Ltd., at that time added neuropsychiatric events to the black box warning. Their final conclusion was that on the basis of such reports, aside from a temporal relationship, there was no clear understanding if any of the population is at increased risk for developing depression while on isotretinoin.

Brecher and Orlow (31) also quote Jick et al (32) who used a large-scale epidemiological study to investigate if there was any relationship between isotretinoin and the risk for depression psychosis, attempted suicide, and suicide. They investigated the Canadian Saskatchewan Health Database and the United Kingdom General Practice Research Database. These sources included 7,195 patients with acne who had used isotretinoin and 13,700 who were on oral antibiotics. The researchers found no increase in relative risk for any of the mental parameters studied in these 2 populations, and concluded that there was no evidence that use of isotretinoin is associated with any increased risk for depression or suicide.

Sekula-Gibbs et al (33) in their 2004 periodic synopsis reviewed studies systematically and found that no evidence for a causal connection could be determined between isotretinoin and either depression or suicidal ideation.

Bremner et al (34) in their May 2005 study investigated a possible relationship between isotretinoin treatment and depression by examining functional brain imaging alterations in acne patients treated with isotretinoin. The authors performed [18F] fluorodeoxyglucose positron emission tomography (PET) on patients before and after 4 months of treatment with either isotretinoin or an antibiotic. A 4-month treatment trial of isotretinoin was associated with a significant decrease in brain metabolism in the orbitofrontal cortex relative to treatment with an antibiotic. The orbitofrontal cortex is a brain region shown by Bremner et al (35,36) to have an analogous specific decrease in metabolism with experimental induction of depression.

There are limitations to this study as it is a pilot study with a small study group of 28 patients who completed it. The investigators were unable to randomly assign subjects to treatment with isotretinoin or antibiotics, and were unable to control which antibiotic the subjects were taking. The authors therefore have called for further randomized, placebo-controlled studies to further evaluate the effects of isotretinoin effects on brain functioning.

Chia et al (37) recently conducted a cohort study comparing depressive symptoms in adolescents with moderate to severe acne receiving isotretinoin therapy and those receiving maximal conservative therapy. Maximal conservative therapy was defined as a topical antibiotic, topical retinoid, and twice-daily administration of an oral antibiotic. The Center for Epidemiologic Studies Depression Scale (CES-D) was used in order to screen for the presence of depressive symptoms in the study participants at baseline and 3 to 4 months after the initiation of acne treatment. The CES-D is a highly sensitive and simple screening tool that cannot diagnose major depressive disorders but can facilitate detection of patients at risk. All subjects who scored 17 or higher on this screening tool either at baseline or 3 to 4 months after initiating treatment were further evaluated for suicidal ideation and interviewed using the mood disorders portion of the Structured Clinical Interview for DSM-IV Axis I Disorders.

This cohort study showed no increase in the prevalence of depressive symptoms in the isotretinoin treatment group compared with the group treated with maximal conservative therapy. The incidence of suicidal ideation in the isotretinoin group was zero, and the incidence of suicidal ideation in the control group was 1.4% (one subject at baseline). The use of isotretinoin in the treatment of moderate to severe acne in adolescents did not increase depressive symptoms, and this study also demonstrated that the treatment of acne improves depressive symptoms.

This study was limited by a small sample size of 101 patients who completed it. Selection into the 2 treatment groups was non-randomized, and many potential confounding variables such as age, family history of depression, suicide, suicide attempt, alcoholism, illegal drug use, concomitant illness, and socioeconomic status were not addressed by the study. Also, the CES-D used to screen for depressive symptoms in the patients has an inherent bias. This highly sensitive screening tool would overestimate rather than underestimate the degree of mood disorder and therefore could exaggerate the incidence and any associations between depressive mood changes and treatments in the study.

In a comprehensive literature review along with a query to the medical information departments at F. Hoffman-La Roche, Ltd., and the Connetics Corporation, only one case report of depression associated with acitretin was found in the world literature. Bleiker et al (38) relate this case in their 1997 paper:

In this case report, the patient reportedly developed depression when his therapy was switched from etretinate to acitretin monotherapy, and his depression resolved when the patient was switched back to etretinate. However, this is problematic to explain biologically because acitretin is not only the free acid metabolite of etretinate but also the main biologically active form of the compound. Therefore, one cannot infer from this reported case whether such an association truly exists as the patient technically was receiving acitretin directly or indirectly throughout the entire course of treatment.

Conclusion

Acitretin is the leading oral retinoid used today in the treatment of psoriasis, and possible side effects of pseudotumor cerebri and depression have gained a warning and precaution respectively on the acitretin package insert. (2) A review of the literature has revealed that there is a paucity of documented cases not only in the published literature but also in the phase IV postmarketing reports regarding an association between pseudotumor cerebri and acitretin therapy. There is an absence of any reported case that reports an association of pseudotumor cerebri with concurrent administration of acitretin and tetracycline-class antibiotics. Therefore, at this time there is a lack of a scientific evidence base for any clear association between acitretin and pseudotumor cerebri either in monotherapy or in combination with tetracycline class antibiotics. The authors agree with Fraunfelder and Fraunfelder (29) that, "postmarketing surveillance systems suffer from underreporting, incomplete information, and lack of follow-up." It is also agreed that. "These systems, however, provide information as to a temporal relationship, a pattern of presentation, and dechallenge and rechallenge data may suggest possible probable, or certain causation of an adverse drug event." (29) Therefore, the phenomenon of acitretin-associated intracranial hypertension needs to be further investigated via phase IV trials, vigilant physician monitoring, and reporting of cases with complete information and follow-up before this association can be determined to be scientifically certain or a theoretical concern arising from class labeling.

The acitretin package insert has contained a precaution for depression/self-injurious behavior since April 2003 based on collected postmarketing reports of such an association. Also, the package insert reads that such symptoms have been experienced in patients taking other systemically administered retinoids. (2) It appears from a review of the literature that depression occurring even with isotretinoin therapy is still a controversial topic, and the evidence concerning an association involves case reports and anecdotal sources. Systematic studies, a cohort study, and large scale epidemiological studies have revealed no association for depression occurring secondary to isotretinoin therapy. A recent pilot study has shown preliminary evidence that isotretinoin may be associated with changes in brain functioning that are analogous to experimentally induced depression, but the authors have determined that larger scale, randomized placebo-controlled trials are needed to further solidify such an association. (34)

The review has shown one example of an acitretin-depression association, but this report has a confounding factor as there is no clear biologic explanation as to how this patient could become depressed on acitretin instead of etretinate as acitretin is the biologically active metabolite of etretinate. Accounts of depression occurring secondary to acitretin therapy have been quoted as occurring in 1% to 10% of the patients in the pivotal study of acitretin. (2) However, the authors were unable to obtain any details concerning this percentage either from F. Hoffman-La Roche, Ltd., that developed acitretin or the Connetics Corporation that currently markets acitretin. Such a percentage seems unlikely given the paucity of published scientific literature concerning an association of depression with acitretin therapy despite years of worldwide use. There are no phase IV postmarketing reports of such an association to this date. Therefore, the review and polls conducted reveal that there is a lack of a convincing scientific evidence base for this phenomenon of acitretin-associated depression/self-injurious behavior. As with the above conclusion of acitretin-associated pseudotumor cerebri, this phenomenon of acitretin-associated depression/self-injurious behavior too must be investigated via phase IV trials, vigilant physician monitoring, and reporting of cases with complete information and follow-up before this association can be determined to be scientifically certain or a theoretical concern arising from class labeling.

Disclosure: John Koo MD is an investigator, speaker, and consultant to the Connetics Corporation--the current manufacturer of Soriatan[R] (acitretin).

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Address for Correspondence

John Starling, III, MD

283 South Ann Arbor Street

Saline, MI 48176

Phone: 734-429-9715

Email: johnthree@gmail.com

John Starling, III, MD, (a) John Koo MD (b)

a. Resident Physician, University of Michigan Health System, Department of Internal Medicine, Ann Arbor, MI

b. Professor and Vice Chairman, University of California, San Francisco, Department of Dermatology Director, UCSF Psoriasis and Skin Treatment Center and Phototherapy Unit, San Francisco, CA

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