Association of Dopamine Agonist Use with Impulse Control Disorders in Parkinson Disease

ORIGINAL CONTRIBUTION Association of Dopamine Agonist Use With Impulse Control Disorders in Parkinson Disease

Daniel Weintraub, MD; Andrew D. Siderowf, MD, MSCE; Marc N. Potenza, MD, PhD; Joseph Goveas, MD; Knashawn H. Morales, ScD; John E. Duda, MD; Paul J. Moberg, PhD; Matthew B. Stern, MD

Objective: To determine the frequency and correlates of cluding 11 (4.0%) with an active ICD. Compulsive gam- impulse control disorders (ICDs) in Parkinson disease (PD). bling and compulsive sexual behavior were equally common. In a multivariate model, treatment with a dopamine Design: An unstructured screening interview for ICDs agonist (P=.01) and a history of ICD symptoms prior to (compulsive gambling, buying, and sexual behavior) fol- PD onset (P=.02) predicted current ICD. There were no lowed by a telephone-administered structured inter- differences between the dopamine agonists in their as- view for screen-positive patients. sociation with ICDs (P=.21), and daily doses of dopa- Setting: Two university-affiliated movement disorders mine agonists were higher in patients with an ICD than centers. in dopamine agonist–treated patients without an ICD (PϽ.001). Participants: A convenience sample of 272 patients with idiopathic PD who were screened for psychiatric com- Conclusions: Patients with PD treated with a dopa- plications. mine agonist should be made aware of the risk of devel- oping an ICD and monitored clinically. Because dopa- Main Outcome Measures: Presence of compulsive mine agonists are increasingly being used for other gambling, buying, or sexual behavior as assessed by the indications, future research should assess the dopamine Minnesota Impulsive Disorders Interview. agonist–associated risk for ICDs in other populations. Results: Eighteen patients (6.6%) with PD met criteria for an ICD at some point during the course of PD, in- Arch Neurol. 2006;63:969-973

ECENT OBSERVATIONAL case series, all 11 patients with PD identi- studies suggest that im- fied as meeting DSM-IV criteria for patho- pulse control disorders logical gambling were taking a dopamine (ICDs), particularly patho- agonist, 9 of whom were taking pramipex- logical gambling, may have ole and 2, ropinirole hydrochloride.3 increased frequency in Parkinson disease Regarding other ICDs in PD, in a series R1-3 (PD). Impulse control disorders consti- of 15 patients with either PD or multiple sys- Author Affiliations: tute a group of psychiatric disorders in tem atrophy and compulsive hypersexual- Departments of Psychiatry DSM-IV-TR,4 their essential feature being ity, dopamine agonist treatment was impli- (Drs Weintraub, Goveas, and a failure to resist an impulse, drive, or cated as the cause of the behavior in 14 Moberg), Neurology 7 (Drs Weintraub, Siderowf, temptation to perform an act that is harm- cases. There have also been anecdotal re- Duda, Moberg, and Stern), and ful to the person or to others. Other ICDs ports of compulsive buying in association 8 Biostatistics and Epidemiology without formal diagnostic criteria in DSM- with dopamine replacement therapies. (Dr Morales), University of IV-TR include compulsive sexual behav- We report the results of a screening and Pennsylvania, and Parkinson’s ior and compulsive buying.5 assessment study of ICDs in PD investi- Disease Research, Education, Although there are case reports of le- gating the: (1) frequencies of compulsive and Clinical Center vodopa-induced ICDs in PD,6 recent case buying, gambling, and sexual behaviors; (Drs Weintraub, Duda, Moberg, series have implicated treatment with (2) demographic and clinical correlates of and Stern) and Mental Illness dopamine agonists as a more frequent the aforementioned ICDs; and (3) asso- Research, Education, and cause of pathological gambling. Driver- ciation between ICDs and dopamine ago- Clinical Center (Dr Weintraub), 2 Philadelphia Veterans Affairs Dunckley et al identified 9 patients (0.5% nist use. We hypothesized that ICDs in PD Medical Center, Philadelphia; of clinic sample) with a documentation of are associated with dopamine agonist treat- Department of Psychiatry, pathological gambling, 8 of whom were ment and that this association is dose de- Yale University, New Haven, treated with pramipexole dihydrochloride pendent and similar across the entire class Conn (Dr Potenza). and 1 with pergolide mesylate. In another of dopamine agonists.

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©2006 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/01/2021 METHODS culated both for dopamine agonists only (dopamine agonist LEDD) and for dopamine agonistsϩlevodopa (total LEDD). To probe for possible risk factors for the development of ICDs PARTICIPANTS in PD, data were obtained for factors that have been reported to be associated with ICDs in PD (type and dose of dopamine The study population was outpatients diagnosed with idio- replacement therapy, disease duration, age, and sex)1-3 or that pathic PD, predominantly of mild to moderate severity, con- were factors of interest (history of ICD behavior, global cog- firmed by a movement disorders specialist. Subjects were es- nition, educational level, and marital status). For the pur- tablished patients at 1 of 2 movement disorders centers (either poses of this study, dopamine agonists were considered to be the University of Pennsylvania or the Philadelphia Veterans Af- pramipexole, ropinirole, and pergolide. Amantadine hydro- fairs Medical Center) and were thought to represent a cross- chloride, which has an unclear mechanism of action but has section of the clinics’ populations, save the exclusion of pa- some dopamine agonist properties,15 was considered sepa- tients unable to provide informed consent because of cognitive rately, and no patient was prescribed bromocriptine mesylate impairment. Participants completed a psychiatric screening in- or apomorphine hydrochloride. Reliable data were not avail- terview as part of a study of the frequency and correlates of de- able for the duration of treatment with dopamine replacement pression in PD. The institutional review boards at the 2 insti- therapies. All clinical and demographic data were obtained di- tutions approved the study, and written informed consent was rectly from the patient during the screening interview and, when obtained from all subjects. possible, verified by medical record review.

DATA COLLECTION AND MEASURES ANALYSIS Patients were screened between July 2004 and June 2005. Movement disorders professionals were instructed to refer Demographic and clinical characteristics of ICD and non-ICD any willing patient with PD, without regard for their psychi- subjects were compared using a Fisher exact test for categori- atric status (eg, no patient was referred for having an ICD), cal variables and the Wilcoxon 2-sample test for continuous for the screening interview at the conclusion of his or her variables. A comparison of the frequency of ICDs on different clinic appointment. dopamine agonists was made using a Fisher exact test. The as- Two trained research assistants administered the screen- sociation between dopamine agonist dosage and ICDs was de- ing battery, which included open-ended questions about the termined using the Wilcoxon 2-sample test. Variables signifi- existence (lifetime, anytime during PD, and currently) of re- cant at the 0.1 significance level (uncorrected for multiple current compulsive buying, gambling, or sexual behaviors. Sub- comparisons) in the univariate analysis were entered as inde- jects were also administered the 15-item Geriatric Depression pendent variables in an exact logistic regression model, with Scale9 and the Mini-Mental State Examination10 as part of the presence of an active ICD as the dependent variable. For the screening process. logistic regression model, all continuous measures were di- Those who screened positive for an ICD during the chotomized at the median. Results of the exact logistic regres- course of PD were contacted by telephone in August or Sep- sion model are presented in terms of odds ratios, 95% confi- tember 2005 by 1 of us (D.W. or J.G.) and administered a dence intervals, and P values. Analyses were performed with modified Minnesota Impulsive Disorders Interview (MIDI),11 SPSS version 13.0 (SPSS Inc, Chicago, Ill) and SAS version 9.1 which includes queries for the presence of clinically signifi- (SAS Institute, Inc, Cary, NC). cant compulsive gambling, sexual, and buying behaviors. Patients were instructed to answer the questions based on RESULTS their state at the time they were symptomatic. Impulse control disorders were defined as answering in the affirmative to 1 (compulsive sexual behavior and compulsive shopping) or PATIENT CHARACTERISTICS 2 (compulsive gambling) gateway questions plus an affirmative answer to 1 or more of the remaining questions of the Two hundred seventy-two patients, ranging in age from relevant ICD module of the MIDI. The same threshold has 35 to 91 years, completed the screening process. The use been used to define problem gambling in other studies.12 of the Philadelphia Veterans Affairs Medical Center as a The MIDI was administered to confirm the presence of ICDs site led to a preponderance of men in the study popula- during the course of PD only (ie, not applied to pre-PD– tion. One half of subjects (137 [50.4%] of 272) were tak- onset ICD symptoms). ing a dopamine agonist at screening. For patients taking To verify data accuracy, the study primary investigator (D.W.) reviewed the medical records of all patients identified as hav- a dopamine agonist, there were no between-group dif- ing an ICD some time during the course of PD. For patients ferences in mean dopamine agonist LEDD (F2,134=2.6; with an ICD at some time during the course of PD but who were P=.08), but pergolide-treated patients were more likely no longer symptomatic, medical records were reviewed and to be taking a dopamine agonist LEDD of 500 mg/d or medications recorded for the period when they were most symp- higher (Fisher exact test, P=.002). tomatic. For analytic purposes, a levodopa-equivalent daily dose FREQUENCY OF ICDs (LEDD) was calculated on the basis of the following formula, 13,14 similar to that previously reported : Twenty-one patients screened positive for an ICD dur- 100 mg of levodopa=130 mg of controlled-release le- ing PD, but 2 patients did not meet MIDI criteria for an vodopa=70 mg of levodopaϩcatechol-O-methyl-transferase inhibitor=1 mg of pergolide=1 mg of pramipexole=5 mg of ICD and 1 other could not be reached for follow-up. The ropinirole. frequencies of 1 or more ICDs were 4.0% (n=11) for an Other PD medications (eg, anticholinergics and mono- active ICD and 6.6% (n=18) for anytime during PD. Of amine oxidase inhibitors) that have not been associated with patients with an active ICD, the problem was docu- ICDs were not included in the analyses. The LEDDs were cal- mented in their clinical record in 3 cases (27.3%).

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©2006 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/01/2021 Table 1. Demographic and Clinical Correlates of ICDs* Table 2. Exact Logistic Regression Model*

No Active ICD Active ICD P Exact OR (95% CI) Variable (n = 261)† (n = 11) Value Variable Crude Adjusted Age, y 68.6 (10.2) 59.5 (9.4) .006‡§ Male, No. (%) 182 (69.7) 10 (90.9) .18࿣ Age 0.21 (0.02-1.04) 0.44 (0.04-2.87) Married, No. (%) 206 (79.2) 9 (81.8) Ͼ.99࿣ PD duration 3.03 (0.71-18.10) 2.10 (0.27-20.79) Education, y 14.7 (3.0) 14.7 (3.1) .98‡ Total LEDD† 1.84 (0.46-8.79) 0.55 (0.08-4.12) ࿣ PD duration, y 6.9 (5.8) 11.2 (7.5) .04‡§ Dopamine agonist 16.27 (2.61‡) § 10.47 (1.54‡)¶ Levodopa dosage, 448.1 (335.2) 543.6 (453.5) .49‡ use mg/d Amantadine use# 5.15 (1.25-22.26)¶ 3.16 (0.55-20.52) Total LEDD, mg/d ¶ 569.3 (369.1) 925.5 (534.9) .04‡§ ICD behavior prior 15.54 (2.83-76.16)§ 10.73 (1.48-83.78)¶ Dopamine agonist 126 (48.3) 11 (100.0) Ͻ.001࿣§ to PD use, No. (%) Amantadine use, 49 (18.8) 6 (54.5) .01࿣§ Abbreviations: CI, confidence interval; LEDD, levodopa-equivalent daily No. (%)# dose; OR, odds ratio; PD, Parkinson disease. MMSE10 score 28.3 (2.0) 28.6 (1.4) .96‡ *Adjusted values are adjusted for other 5 variables. ϩ GDS9 score 4.0 (3.8) 6.0 (5.5) .26‡ †LEDD for dopamine agonists levodopa from other medications. ‡Upper boundary approaches infinity. ICD behavior prior 9 (3.5) 4 (36.4) Ͻ.001࿣§ §P Ͼ.01. to PD, No. (%) ࿣Median unbiased estimate owing to boundary. ¶PϽ.03. Abbreviations: GDS, Geriatric Depression Scale; ICD, impulse control #Amantadine hydrochloride. disorder; LEDD, levodopa-equivalent daily dose; MMSE, Mini-Mental State Examination; PD, Parkinson disease. *Values are expressed as mean (SD) unless otherwise indicated. EXACT LOGISTIC REGRESSION MODEL †Includes patients who once had an ICD either prior to onset or some time during the course of PD. Based on the univariate results, age, PD duration, his- ‡Wilcoxon 2-sample test. §P Յ .05. tory of ICD symptoms prior to development of PD, do- ࿣Fisher exact test. pamine agonist or amantadine use, and total LEDD met ¶LEDD for dopamine agonists ϩ levodopa from other medications. criteria to enter the multivariate model. In this model, #Amantadine hydrochloride. dopamine agonist use and history of ICD symptoms prior to PD were the only significant predictors of an active ICD (Table 2). Compulsive sexual behavior was as common as com- SPECIFIC DOPAMINE AGONISTS pulsive gambling among both active cases (2.6% [n=7] vs 2.2% [n=6], respectively) and those with an ICD At screening, approximately half of patients with PD were anytime during PD (2.6% [n=7] vs 2.6% [n=7], respec- taking a dopamine agonist (Table 3). Pramipexole was tively). The frequency of compulsive buying was 0.4% most frequently prescribed (53.3% of dopamine agonist (n=1) for active cases and 1.5% (n=4) for anytime use), followed by ropinirole (35.8%) and pergolide during PD. (10.9%). There were no differences between the 3 do- Thirteen subjects reported a history of ICD symp- pamine agonists in their association with ICDs (Fisher toms prior to PD onset, including 5 of the 18 subjects exact test, P=.21). Examining the larger group of pa- with an ICD some time during the course of PD. For these tients who had experienced an ICD some time during the 5 subjects, their ICD behavior during the course of PD course of PD, 8 were taking ropinirole; 7, pramipexole; was the same as the behavior exhibited prior to PD on- and 3, pergolide, while symptomatic. set (3 cases of compulsive sexual behavior and 1 case each of compulsive gambling and buying). DOPAMINE AGONIST DOSE DEMOGRAPHIC AND CLINICAL CORRELATES Examining only patients currently taking a dopamine agonist, ICDs were associated with exposure to higher daily On univariate analysis, younger age, longer PD dura- doses of pergolide (t =−3.38; P=.05) but not pramipex- tion, history of ICD symptoms prior to PD, and use of a 13 ole (t =−2.14; P=.06) or ropinirole (t =−0.81; P=.40). dopamine agonist or amantadine were associated with 71 47 Using LEDDs and examining the 3 dopamine agonists the presence of an active ICD, with a suggestion for higher as a class, treatment with higher doses was associated with total LEDD (Table 1). All 11 active ICD cases were cur- the presence of an ICD (t =−4.06; P=.001). rently taking a dopamine agonist. 135 Examining the larger group of 18 patients who had experienced an ICD some time during the course of PD, COMMENT all were taking a dopamine agonist while symptomatic. Based on the follow-up interview and review of medical Estimated frequencies of compulsive gambling in PD range records, 7 of them became asymptomatic either with dis- from 0.5%1 to 4.9%.2 Our frequency estimate for com- continuation of dopamine agonist treatment (n=4), a re- pulsive gambling (2.2% for active cases and 2.6% for any- duction in the dopamine agonist dosage (n=2), or coun- time during PD) fell in the intermediate range of those seling (n=1). previously reported. We may have underestimated the

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Dopamine Agonist No Dopamine Agonist Use† Pramipexole Ropinirole Pergolide Treated, No. 135 73 49 15 ICD cases, No. 0 5 3 3 ICD frequency, % 0 6.8 5.8 20.0

Abbreviations: ICD, impulse control disorder; PD, Parkinson disease. *Pramipexole given as pramipexole dihydrochloride; ropinirole, as ropinirole hydrochloride; and pergolide, as pergolide mesylate. †One hundred fourteen (84.4%) of 135 patients not taking a dopamine agonist were taking levodopa. The rest were taking other nondopamine agonist medications or no PD medications at all.

frequency of ICDs in our population, because patients was in pergolide-treated patients, because this group may have been either hesitant to acknowledge symp- was more likely to receive doses at the upper end of toms or less likely to be present in the clinic and there- the therapeutic range. fore unavailable for screening. Limitations of our study include the following: (1) Our To our knowledge, there is no published literature on study population was not randomly chosen; (2) subjects the estimated prevalence of other ICDs in PD. We found came from 2 centers (including 1 veterans’ hospital) in 1 that compulsive sexual behavior was as common as com- region of the country, limiting the generalizability of our pulsive gambling, though that may have been due to the findings; (3) the follow-up telephone interview to verify predominance of men in our sample. Regardless, our find- the history of ICD behaviors was conducted up to 15 ings are consistent with recent reports7 suggesting an as- months after the screening process, which may have af- sociation between dopamine agonist treatment and com- fected the validity of the data; (4) no measures of PD se- pulsive sexual behavior in PD. verity, other than duration of illness, were available for Of the 6 potential risk factors for ICDs identified in analysis; (5) ICD status was determined through the use preliminary analyses, only dopamine agonist treatment of the MIDI rather than formal diagnostic interviews, and and a history of ICD symptoms prior to PD predicted pres- determination of ICD symptoms prior to PD onset was ence of an active ICD in the multivariate model. Previ- based on the unstructured screening interview only; and ous reporting of younger patients with PD being dispro- (6) only 11 ICD cases were identified, limiting the con- portionately affected with ICDs may reflect prescribing clusions that can be reached about the nature of the as- patterns (eg, older patients are less likely to be treated sociations between dopamine agonist treatment and ICDs with a dopamine agonist). Our data suggest that a his- in PD. Multisite studies involving larger random samples tory of ICD symptoms prior to PD is the main demo- of patients are needed to definitively determine the preva- graphic or clinical variable that predicts an increased risk lence and clinical correlates of ICDs in PD. for the development of an ICD in the setting of dopa- Our findings highlight the importance of screening for mine agonist treatment. a variety of ICDs in patients with PD treated with a do- The risk associated with ICDs was specific to the dopamine agonist, particularly since only one quarter of ac- pamine agonist medication class. Although there was a tive ICD cases in this study had been identified clini- suggestion on univariate analysis of an association be- cally. It is not known whether the risk for ICDs with tween the total LEDD and ICDs, this relationship was no exposure to this medication class is specific to patients longer observed after controlling for dopamine agonist with PD. As dopamine agonists are increasingly pre- use. These results suggest a distinct mechanism of ac- scribed for other indications (eg, recent Food and Drug tion, as opposed to an additive effect, for dopamine ago- Administration approval of ropinirole for the treatment nists in the development of ICDs. of restless legs syndrome), it will be important to assess Our findings did not support a differential association the prevalence and risk for ICDs in other dopamine ago- between specific dopamine agonists and ICDs, suggesting nist–treated populations. a class effect. Two case series2,3 implicated pramipexole as the agent most likely to cause an ICD, but neither ac- Accepted for Publication: February 16, 2006. counted for the relative frequency of pramipexole use in Correspondence: Daniel Weintraub, MD; 3535 Market comparison with other dopamine agonists. St, Room 3003, Philadelphia, PA 19104 (weintrau@mail There is great variability in the dosing of dopamine .med.upenn.edu). agonists in PD. Using LEDDs to examine the 3 dopa- Financial Disclosure: Drs Weintraub, Siderowf, Potenza, mine agonists as a class, ICD cases were treated with Duda, and Stern have served as consultants to Boe- higher dopamine agonist doses. These findings are hringer Ingelheim Pharmaceuticals, Inc. Dr Siderowf has consistent with 2 case series2,3 suggesting that the received grant support from Boehringer Ingelheim Phar- greatest risk for ICDs may involve dopamine agonist maceuticals, Inc. doses at the high end of the therapeutic range. If true, Funding/Support: This study was supported by grant that may help explain why the highest frequency of K23MH067894 from the National Institute of Mental ICD cases, even though not statistically significant, Health and by the Mental Illness Research, Education,

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©2006 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/01/2021 and Clinical Centers at the Philadelphia and West Ha- 4. American Psychiatric Association. Diagnostic and Statistical Manual of Mental ven Veterans Affairs Medical Centers. Disorders, Fourth Edition, Text Revision. Washington, DC: American Psychiat- ric Association; 2000. Author Contributions: Dr Weintraub had full access to 5. Grant JE, Levine L, Kim D, Potenza MN. Impulse control disorders in adult psy- all of the data in the study and takes responsibility for chiatric inpatients. Am J Psychiatry. 2005;162:2184-2188. the integrity of the data and the accuracy of the data analy- 6. Tyne HL, Medley G, Ghadiali E, Steigner MJ. Gambling in Parkinson’s disease sis. Study concept and design: Weintraub and Stern. Ac- [abstract]. Mov Disord. 2004;19(suppl 9):S195. quisition of data: Weintraub, Goveas, Duda, and Stern. 7. Klos KJ, Bower JH, Josephs KA, Matsumoto JY, Ahlskog JE. Pathological hyper- Analysis and interpretation of data: Weintraub, Siderowf, sexuality predominantly linked to adjuvant dopamine agonist therapy in Parkin- son’s disease and multiple system atrophy. Parkinsonism Relat Disord. 2005; Potenza, Morales, Duda, Moberg, and Stern. Drafting of 11:381-386. the manuscript: Weintraub, Potenza, and Duda. Critical 8. Giovannoni G, O’Sullivan JD, Turner K, et al. Hedonistic homeostatic dysregu- revision of the manuscript for important intellectual con- lation in patients with Parkinson’s disease on dopamine replacement therapies. tent: Weintraub, Siderowf, Potenza, Goveas, Morales, J Neurol Neurosurg Psychiatry. 2000;68:423-428. Duda, Moberg, and Stern. Statistical analysis: Weintraub 9. Sheikh JI, Yesavage JA. Geriatric Depression Scale (GDS): recent evidence and and Morales. Administrative, technical, and material sup- development of a shorter version. Clin Gerontol. 1986;(5):165-173. 10. Folstein MF, Folstein SE, McHugh PR. “Mini-Mental State”: a practical method port: Weintraub, Siderowf, Duda, Moberg, and Stern. Study for grading the cognitive state of patients for the clinician. J Psychiatr Res. 1975; supervision: Weintraub and Stern. 12:189-198. Acknowledgment: We acknowledge Donna Taraborelli, 11. Christenson GA, Faber RJ, deZwaan M. Compulsive buying: descriptive charac- BA, Katherine Oehlberg, BA, and Kirsten Saboe, BA, for teristics and psychiatric comorbidity. J Clin Psychiatry. 1994;55:5-11. the collection of the data. 12. Cunningham-Williams RM, Cottler LB, Comptom WM, Spitznagel EL. Taking chances: problem gamblers and mental health disorders—results from the St Louis Epidemiologic Catchment Area Study. Am J Public Health. 1998;88: REFERENCES 1093-1096. 13. Hobson DE, Lang AE, Martin WR, Razmy A, Rivest J, Fleming J. Excessive day- 1. Molina JA, Sa´inz-Artiga MJ, Fraile A, et al. Pathologic gambling in Parkinson’s time sleepiness and sudden-onset sleep in Parkinson disease: a survey by the disease: a behavioral manifestation of pharmacologic treatment? Mov Disord. Canadian Movement Disorders Group. JAMA. 2002;287:455-463. 2000;15:869-872. 14. Herzog J, Volkmann J, Krack P, et al. Two-year follow-up of subthalamic deep 2. Driver-Dunckley E, Samanta J, Stacy M. Pathological gambling associated with do- brain stimulation in Parkinson’s disease. Mov Disord. 2003;18:1332-1337. pamine agonist therapy in Parkinson’s disease. Neurology. 2003;61:422-423. 15. Olanow CW, Watts RL, Koller WC. An algorithm (decision tree) for the manage- 3. Dodd ML, Klos KJ, Bower JH, et al. Pathological gambling caused by drugs used ment of Parkinson’s disease (2001): treatment guidelines. Neurology. 2001; to treat Parkinson disease. Arch Neurol. 2005;62:1377-1381. 56(suppl 5):S1-S88.

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