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Neurology. 2012 April 17; 78(16): 1229–1236.
PMCID: PMC3324323

A randomized, double-blind, placebo-controlled trial of antidepressants in Parkinson disease

I.H. Richard, MD,corresponding author M.P. McDermott, PhD, R. Kurlan, MD, J.M. Lyness, MD, P.G. Como, PhD, N. Pearson, RN, MS, S.A. Factor, DO, J. Juncos, MD, C. Serrano Ramos, MD, M. Brodsky, MD, C. Manning, PhD, L. Marsh, MD, L. Shulman, MD, H.H. Fernandez, MD, K.J. Black, MD, M. Panisset, MD, C.W. Christine, MD, W. Jiang, MD, C. Singer, MD, S. Horn, DO, R. Pfeiffer, MD, D. Rottenberg, MD, J. Slevin, MD, L. Elmer, MD, PhD, D. Press, MD, H.C. Hyson, MD, and W. McDonald, MD, For the SAD-PD Study Group
From the University of Rochester (I.H.R., M.P.M., R.K., J.M.L., P.G.C., N.P.), Rochester, NY; Atlantic Neuroscience Institute (R.K.), Summit, NJ; Emory University (S.A.F., J.J., W.M.), Atlanta, GA; University of Puerto Rico (C.S.R.), San Juan; Oregon Health Sciences University (M.B.), Portland; University of Virginia (C.M.), Charlottesville; Johns Hopkins University (L.M.), Baltimore, MD; University of Maryland (L.S.), College Park; University of Florida (H.H.F.), Gainesville; Washington University (K.J.B.), St. Louis, MO; Hotel-Dieu Hospital-CHUM, Notre Dame (M.P.), Montreal, Canada; University of California San Francisco (C.W.C.), San Francisco; Duke University (W.J.), Durham, NC; University of Miami (C.S.), Miami, FL; University of Pennsylvania (S.H.), Philadelphia; University of Tennessee (R.P.), Knoxville; University of Minnesota (D.R.), Minneapolis; University of Kentucky (J.S.), Lexington; Medical University of Ohio (L.E.), Toledo; Beth Israel Deaconess (D.P.), Boston, MA; London Health Sciences Centre (H.C.H.), London, Canada.
Irene Richard, PI, William McDonald, Co-PI, Michael McDermott, Chief Biostatistician, Peter G. Como, Neuropsychologist, Roger Kurlan, Investigator Representative, Jeffrey M. Lyness, Geriatric Psychiatry Consultant, Nancy Pearson, Project Manager, Barbara Sommerfeld, MSN, RN, Coordinator, Cheryl Deeley, MS RNc, Coordinator, and Tania de la Torre, MD, Coordinator
Irene Richard, University of Rochester;
Michele Barnard, Coordinator and April Wilson, Coordinator
Oregon Health and Sciences University
Maryann Lincoln, Coordinator and Paula Damgaard, RN, CCRC, Coordinator
University of Virginia
Melissa Gerstenhaber, RNC MSN, Coordinator
Johns Hopkins University
Kelly Dustin, RN, MS, CCRC, Coordinator and Nancy Zappala, RN, Coordinator
University of Maryland
Camille Swartz, Coordinator
University of Florida
Mary Creech, Coordinator, Elda Shipley, Coordinator, and Samantha Blankenship, MSW, Coordinator
Washington University
Monica Beland, Coordinator and Jessie Roth, RN, Coordinator
Monica Beland, Hotel-Dieu Hospital-CHUM, Notre Dame;
Heather Burnette, Coordinator and Tamara Foxworth, Coordinator
Duke University
Monica Quesada, MA, Coordinator, Mary Lloyd, RN, PhD, Coordinator, and Brenda Pfeiffer, RN, BSN, Coordinator
Monica Quesada, University of Miami;
Joy Hansen, MSN, RN, Coordinator and Joy Folie, Coordinator
University of Minnesota
Renee Wagner, RN CCRC, Coordinator
University of Kentucky
Julia Spears, Coordinator and Colleen Taylor, Coordinator
Medical University of Ohio
Rachel Brown, Coordinator, Lisa Iguchi, Coordinator, and Chen Lim, Coordinator
Beth Israel Deaconess
Kori LaDonna, Coordinator and Julie Megens, RN, Coordinator
London Health Sciences Centre
Matthew Menza, DSMB Members, Jeffrey Cummings, DSMB Members, Robert Hamer, DSMB Members, Kathleen Shannon, DSMB Members, Joanne Odenkirchen, NINDS Staff, Robin Conwit, NINDS Staff, Christopher Beck, Additional SAD-PD Personnel, Donna LaDonna, Additional SAD-PD Personnel, Jan Bausch, Additional SAD-PD Personnel, and Scott Kim, Additional SAD-PD Personnel
Matthew Menza, Chair, Robert Wood Johnson;
Ron Chismar, RN, Additional SAD-PD Personnel and Sinead Quinn, Additional SAD-PD Personnel
Rating Scale Evaluators, Emory University
Steve Bean, Additional SAD-PD Personnel
Pharmacist, University of Rochester
Susan Daigneault, Additional SAD-PD Personnel, Patricia Lindsay, Additional SAD-PD Personnel, and Tori Ross, Additional SAD-PD Personnel
CTCC Staff, University of Rochester
Katie Kompoliti, Medical Monitor

Abstract

Objective:

To evaluate the efficacy and safety of a selective serotonin reuptake inhibitor (SSRI) and a serotonin and norepinephrine reuptake inhibitor (SNRI) in the treatment of depression in Parkinson disease (PD).

Methods:

A total of 115 subjects with PD were enrolled at 20 sites. Subjects were randomized to receive an SSRI (paroxetine; n = 42), an SNRI (venlafaxine extended release [XR]; n = 34), or placebo (n = 39). Subjects met DSM-IV criteria for a depressive disorder, or operationally defined subsyndromal depression, and scored >12 on the first 17 items of the Hamilton Rating Scale for Depression (HAM-D). Subjects were followed for 12 weeks (6-week dosage adjustment, 6-week maintenance). Maximum daily dosages were 40 mg for paroxetine and 225 mg for venlafaxine XR. The primary outcome measure was change in the HAM-D score from baseline to week 12.

Results:

Treatment effects (relative to placebo), expressed as mean 12-week reductions in HAM-D score, were 6.2 points (97.5% confidence interval [CI] 2.2 to 10.3, p = 0.0007) in the paroxetine group and 4.2 points (97.5% CI 0.1 to 8.4, p = 0.02) in the venlafaxine XR group. No treatment effects were seen on motor function.

Conclusions:

Both paroxetine and venlafaxine XR significantly improved depression in subjects with PD. Both medications were generally safe and well tolerated and did not worsen motor function.

Classification of Evidence:

This study provides Class I evidence that paroxetine and venlafaxine XR are effective in treating depression in patients with PD.

Depression in Parkinson disease (PD) (dPD) is associated with functional impairment1 and reduced quality of life24 but the optimal approach to treatment remains uncertain.

Tricyclic antidepressants (TCAs), which inhibit the reuptake of norepinephrine and serotonin, are efficacious in the treatment of dPD5,6 but are associated with cardiac, autonomic, and anticholinergic side effects.79

Selective serotonin reuptake inhibitors (SSRIs) have demonstrated similar efficacy and better tolerability when compared to traditional TCAs in depressed patients without PD1015 but have been reported to worsen parkinsonian motor features.1619 There have been 2 modestly sized, single site, placebo-controlled clinical trials of SSRIs in dPD. A study by Menza et al.5 suggested that nortriptyline, but not paroxetine, was significantly more effective than placebo. Devos et al.6 concluded that desipramine and citalopram were more effective than placebo; however, desipramine was not as well tolerated. PD motor function did not appear to be affected in either study.

Serotonin and norepinephrine reuptake inhibitors (SNRIs), like TCAs, act on both neurotransmitter systems but are generally better tolerated. In broader patient populations SNRIs have been shown to be at least as efficacious as SSRIs2022 but there have been no controlled trials of SNRIs in dPD.

We present the results of a multicenter randomized, double-blind, placebo-controlled clinical trial of an SSRI, paroxetine, and an SNRI, venlafaxine extended release (XR), in dPD. We hypothesized that both medications would reduce depressive symptoms. We also hypothesized that these medications would be safe and well-tolerated and, in particular, would not worsen PD motor function.

METHODS

Standard protocol approvals, registrations, and patient consents.

The study was approved by the institutional review board at each participating institution. Participants provided written informed consent for all procedures after demonstrating capacity to do so.23 The study is registered with clinicaltrials.gov (trial registration: http://clinicaltrials.gov/ct2/show/NCT00086190).

Participants.

The Study of Antidepressants in PD (SAD-PD) enrolled 115 participants from 20 centers in the United States, Canada, and Puerto Rico from June 2005 through March 2009. Subjects were recruited from movement disorder clinics. Eligible subjects included men and women ≥30 years of age diagnosed with idiopathic PD, without dementia. Subjects had to meet diagnostic (DSM-IV24) criteria for a depressive disorder (i.e., major depressive disorder, dysthymic disorder, minor depressive disorder) or operationally defined subsyndromal depression (see online supplemental material on the Neurology® Web site at www.neurology.org for details regarding definitions of PD, dementia, and depression). Antidepressant medications other than study drug, antipsychotics, and MAO (including selective B) inhibitors were not permitted. Subjects were excluded if they had had an adequate trial of paroxetine or venlafaxine (see online supplemental material for details and other exclusion criteria).

Assessment, randomization, and follow-up.

Research participants were initially evaluated during a screening visit at which informed consent was obtained and eligibility criteria and demographic information were verified. The baseline visit occurred within 4 weeks of the screening visit. At this visit, the site coordinator or investigator called the University of Rochester Clinical Trials Coordination Center (CTCC, Rochester, NY) to enroll the participant (see online supplemental material for details of the randomization process and preparation of study medication).

Double-blind treatment lasted 12 weeks and consisted of a 6-week dosage titration period and a 6-week maintenance period. During the dosage titration period (weeks 0–6), participants received 10 mg of paroxetine or 37.5 mg of venlafaxine XR (or matching placebos) each day for the first 2 weeks. The investigator then adjusted the dosage of the experimental medications as necessary and tolerated (up to a maximum daily dosage of 40 mg for paroxetine and 225 mg for venlafaxine XR) to achieve the “optimal dosage” based on a suggested dosage escalation schedule. The investigator was encouraged to increase the dosage until the participant's depression was effectively treated (a suggested criterion was HAM-D score ≤7). The investigator was allowed to decrease or to not escalate the dosage if the participant was experiencing significant adverse events. PD medications were optimized prior to enrollment and every effort was made to maintain stable dosages for the duration of the study.

Participants were evaluated at visits at screening, baseline/randomization, and 2, 4, 6, 8, and 12 weeks after randomization. There was a telephone visit to assess efficacy and tolerability at week 10. Participants who withdrew from the trial were assessed at a final visit.

Outcome measures.

The primary outcome measure was the change from baseline to week 12 in the 17-item HAM-D,25 which was administered by the site investigator. The protocol specified that all evaluations should be conducted in the “on” state for patients who experienced motor fluctuations. Details regarding training and reliability assessment for the HAM-D can be found in the online supplemental material.

Secondary outcome measures for antidepressant efficacy included the Montgomery-Åsberg Depression Rating Scale (MADRS),26 the Beck Depression Inventory II (BDI-II),27 and the Geriatric Depression Scale (GDS),28 each administered at all in-person visits. The NIMH Clinical Global Impression Scale (CGI)29 was also obtained from site investigators and participants at weeks 4, 8, and 12. Prespecified dichotomous HAM-D outcomes were also assessed, including HAM-D ≤7 at week 12 (“remission”) and a ≥50% reduction in HAM-D score from baseline to week 12 (“response”).

Other outcome measures included the Unified Parkinson's Disease Rating Scale (UPDRS)30 total and subscale scores31 to assess PD motor function as well as measures of quality of life, anxiety, psychotic symptoms (a potential side effect of antidepressant medications), sleep, and cognition. A detailed description of these outcome measures is presented in the online supplemental material.

Safety and tolerability outcomes included ability to complete the trial, adverse events, and vital signs. Compliance with study medication was assessed using pill counts at each visit. Participants and investigators were asked to guess the identity of the assigned treatment at week 12 to assess possible compromise of the blind.

Statistical methods.

Analysis of the primary outcome variable was performed using a repeated-measures analysis of covariance model that included treatment group as the factor of interest with adjustment for site, type of depression (major, nonmajor), and baseline HAM-D score. Week (2, 4, 6, 8, 12, treated as a categorical variable) and the interaction between treatment group and week were also included in the model. Treatment effects (paroxetine vs placebo, venlafaxine XR vs placebo) were estimated using the adjusted group means obtained from this model, along with corresponding 97.5% confidence intervals (CIs) (Bonferroni-adjusted). Tests of the null hypotheses of zero treatment effects were performed using a 2.5% significance level. The parameters of interest in the repeated-measures analysis of covariance model (treatment effects) were estimated using restricted maximum likelihood, a valid approach for dealing with missing data under the missing at random assumption.32 All available data from all randomized participants were included in the analysis, in accordance with the intention-to-treat principle. The results using alternative approaches for dealing with missing data (e.g., multiple imputation and last observation carried forward) did not differ substantially from those of the primary analysis and are not reported here. Exploratory analyses of treatment effects in prespecified subgroups of participants were also performed. The methods used for these analyses and the results are presented in the online supplemental material.

Similar analyses were performed for the continuous secondary outcome variables for efficacy as well as vital signs. For categorical outcome variables at week 12 (HAM-D ≤7 and ≥50% reduction in HAM-D score from baseline), a logistic regression model that included treatment group, type of depression, and baseline HAM-D score as independent variables was used to estimate odds ratios comparing each active treatment group with the placebo group. The logistic regression analyses were performed in 2 ways: 1) using only observed responses and 2) imputing a poor response for those with missing outcomes at week 12. Safety outcomes, medication dosage, compliance, and results of treatment guesses were analyzed descriptively.

A description of the sample size determination and data and safety monitoring for the trial can be found in the online supplemental material.

RESULTS

Participants.

The flow of participants through the trial is described in figure 1. A total of 115 subjects were randomized to receive paroxetine (n = 42), venlafaxine XR (n = 34), or placebo (n = 39). Eighteen subjects (16%) withdrew participation, 8 (19%) in the paroxetine group, 4 (12%) in the venlafaxine XR group, and 6 (15%) in the placebo group (figure 1). Adverse events led to withdrawal of 6 subjects in the paroxetine group (cardiac arrhythmia; dizziness, nausea, and balance problems; restless legs symptoms; panic attack; sexual dysfunction and lethargy; and insomnia, heartburn, and anxiety), 2 subjects in the venlafaxine group (increased tremor; loss of concentration), and 2 subjects in the placebo group (nausea, palpitations, and stiffness; dizziness and fatigue).

Figure 1
Participant flow

Baseline characteristics of the participants are outlined in table e-1. Participants in the paroxetine group were slightly older on average, more likely to be male, and more likely to be taking levodopa. Participants in the placebo group were less likely to have had education beyond high school and to have major depression. Mean scores on rating scales for depression and PD were comparable among the groups, as were other participant characteristics.

Efficacy.

All 3 treatment groups demonstrated improvement on the HAM-D at week 12, with mean changes of −13.0 in the paroxetine group, −11.0 in the venlafaxine XR group, and −6.8 in the placebo group (table e-2, figure 2). The effects of paroxetine (−6.2; 97.5% CI −10.3 to −2.2; p = 0.0007) and venlafaxine XR (−4.2; 97.5% CI −8.4 to −0.1, p = 0.02), relative to placebo, were statistically significant (table e-2). The mean response did not differ significantly between the 2 active treatment groups (p = 0.28).

Figure 2
Adjusted mean change in Hamilton Rating Scale for Depression (HAM-D) score over time by treatment group

There were no statistically significant differences between medication and placebo groups for dichotomized HAM-D outcomes (table e-3). The percentages of participants who met remission criteria (HAM-D ≤7 at week 12) were 44% (15/34) in the paroxetine group, 37% (11/30) in the venlafaxine XR group, and 32% (11/34) in the placebo group. These percentages decreased to 36% (paroxetine), 32% (venlafaxine XR), and 28% (placebo) when poor responses were imputed for participants with missing HAM-D scores at week 12. The percentages of participants who met response criteria (≥50% reduction in HAM-D score from baseline to week 12) were 68% (23/34) in the paroxetine group, 53% (16/30) in the venlafaxine XR group, and 44% (15/34) in the placebo group. These percentages decreased to 55% (paroxetine), 47% (venlafaxine XR), and 38% (placebo) when poor responses were imputed for participants with missing HAM-D scores at week 12.

Significant beneficial effects of paroxetine and venlafaxine XR relative to placebo were also apparent for the secondary depression outcome variables (MADRS, BDI-II, and GDS; p ≤ 0.01 for all comparisons; table e-2). Neither treatment had a significant impact on the CAS, but BPRS scores were significantly improved with both paroxetine (p = 0.01) and venlafaxine XR (p = 0.004) (table e-2) relative to placebo. There were no significant treatment effects on any of the neuropsychological outcome variables. Venlafaxine XR appeared to have a beneficial impact on sleep, as measured by the PSQI (p = 0.02, table e-2).

UPDRS total and motor scores improved in all 3 treatment groups, but there were no significant group differences in mean response (table e-2). In particular, there was no evidence of treatment-associated worsening of motor function. Both treatments appeared to favorably impact responses on the bulbar subscale (table e-2), which consists of UPDRS items that evaluate speech, swallowing, salivation, and facial expression.31

There was no significant effect of either medication on the PDQ-39 overall score (p > 0.30; table e-2). On both the PDQ-39 and the Short Form (SF)–36, however, both medications were associated with improvements on some emotional/mental components of the scales (PDQ-39 Emotional Well-Being subscale; SF-36 Mental Component Summary and Mental Health subscale; table e-2). Paroxetine was also associated with improvements on the Vitality and Role-Emotional subscales of the SF-36 (table e-2). Neither medication was associated with a significant effect on any other PDQ-39 or SF-36 subscale, or on the Schwab and England Activities of Daily Living Scale. Results for the CGI outcomes are presented in the online supplemental material.

Safety.

One hundred participants (87%) reported at least one adverse event during the trial: 86% in the paroxetine group, 85% in the venlafaxine XR group, and 90% in the placebo group. The most commonly reported AEs (those reported in at least 10% of subjects in at least one treatment group) are listed in table 1. Insomnia was reported significantly less frequently in the paroxetine group than in the venlafaxine XR and placebo groups (table 1).

Table 1
Adverse events by treatment groupa

There were 3 serious adverse events. One subject in the placebo group was hospitalized after 4 days of intermittent chest pressure; however, this subject completed the study. Another subject in the placebo group was hospitalized for a bowel obstruction; this subject also completed the study. One subject in the paroxetine group had frequent, significant ventricular ectopy with >13,000 premature ventricular contractions detected during 24-hour Holter monitoring; the subject withdrew from the trial and treatment assignment was disclosed.

Venlafaxine XR was associated with an increase in sitting blood pressure at the final visit (systolic: 8.5 mm Hg, 97.5% CI 1.2 to 15.9, p = 0.009; diastolic: 4.1 mm Hg, 97.5% CI −0.01 to 8.3, p = 0.03). Hypertension was reported as an AE in 4 subjects on venlafaxine, 1 subject on paroxetine, and no subjects on placebo (table 1). Paroxetine was associated with an increase in weight (1.3 kg, 97.5% CI −0.1 to 2.7, p = 0.03); however, no subjects on paroxetine reported weight gain as an AE, whereas 2 subjects in each of the other 2 groups did. No other significant effects of treatment (relative to placebo) on vital signs were noted.

Additional outcomes.

For participants assigned to paroxetine, the mean dosage at week 12 was 24 ± 11 mg/day, with 50% of participants taking 30 or 40 mg/day. For the venlafaxine XR group, the mean dosage at week 12 was 121 ± 75 mg/day, with 47% of participants taking 150 or 225 mg/day. For placebo-treated participants, the mean dosage of (placebo) paroxetine at week 12 was 26 ± 12 mg/day and the mean dosage of (placebo) venlafaxine XR at week 12 was 135 ± 76 mg/day. Compliance with study medication, as measured by the percentage of pills apparently taken out of those expected to be taken, averaged 94%–97% for paroxetine/placebo and 94%–96% for venlafaxine XR/placebo. Finally, guesses of treatment assignments did not suggest any significant compromise of the blind (details available in the online supplemental material).

DISCUSSION

This is the largest randomized, placebo-controlled clinical trial of commonly used antidepressant medications for the treatment of dPD, had the longest observation period, and was the first to evaluate an SNRI. The study demonstrated that both paroxetine (an SSRI) and venlafaxine XR (an SNRI) are more effective than placebo for the treatment of depressive symptoms. This finding was consistent across all measures of dPD that were used.

Our findings differ somewhat from those of the trial by Menza et al.5 In that single-site trial, 52 patients with dPD were randomized to receive paroxetine (n = 18), nortriptyline (a TCA, n = 17), or placebo (n = 17) for 8 weeks. Nortriptyline, but not paroxetine, was found to be significantly better than placebo in decreasing the mean score on the HAM-D. This finding led some to question the use of SSRIs in dPD and whether TCAs should be the preferred treatment of dPD.33 There are several possible explanations for the different results, including shorter duration of treatment, higher dropout rate, and strategy used for missing data in the study by Menza et al. (see online supplemental material for further discussion).

In our study we observed a fairly prominent improvement in mean HAM-D score in the placebo group (figure 2), which was consistent across all of our measures of depression and has been demonstrated in other antidepressant treatment studies.34 Despite this response, and a sample size smaller than anticipated, we were still able to detect significant beneficial effects of paroxetine and venlafaxine XR using 4 different depression rating scales. Although the observed percentages of participants in each treatment group who achieved a ≥50% reduction in HAM-D score supported the results of the primary analysis, these treatment group comparisons were not statistically significant. It is well known that there can be a substantial loss of information when continuous outcome variables are dichotomized35; this, coupled with our substantially reduced sample size, is a possible explanation for the lack of statistical significance of treatment effects on this outcome. Although the effects of paroxetine and venlafaxine XR appeared to be quite comparable, our sample size was not large enough to make any conclusions concerning the equivalence of these effects.

Other approaches toward the treatment of depression in PD have been to consider the effects of antiparkinsonian medications on mood. A recent study reported results from a randomized, double-blind, placebo-controlled trial of the dopamine agonist pramipexole, which was thought to have antidepressant effects, involving 296 participants with dPD who were followed for 12 weeks.36 The effect of pramipexole, while statistically significant, was considerably smaller (1.9 points on the BDI, version 1A) than the effects of paroxetine and venlafaxine XR observed in our trial (4.4–4.5 points in the BDI-II).

This study demonstrates the efficacy and safety of antidepressants in patients with dPD without dementia. Both study medications were significantly more effective than placebo on a number of depression scales and did not show any significant side effects or worsening of PD motor function. Emotional subscale scores, but not overall QOL, improved with both medications.

As with other depression treatment studies, we found that some subjects failed to respond to the study medications while others improved but did not achieve full remission. Our sample size was not large enough to identify subject characteristics that predict response to study medications. Further research aimed at understanding predictors of response, including identification of patients who may respond preferentially to one class of medication vs another, is warranted.

Supplementary Material

Data Supplement:
Coinvestigators:
Accompanying Editorial:

GLOSSARY

BDI-II
Beck Depression Inventory II
CGI
Clinical Global Impression Scale
CI
confidence interval
CTCC
Clinical Trials Coordination Center
dPD
depression in Parkinson disease
DSM-IV
Diagnostic and Statistical Manual of Mental Disorders, 4th edition
GDS
Geriatric Depression Scale
HAM-D
Hamilton Rating Scale for Depression
MADRS
Montgomery-Åsberg Depression Rating Scale
PD
Parkinson disease
SAD-PD
Study of Antidepressants in Parkinson Disease
SF
Short Form
SNRI
serotonin and norepinephrine reuptake inhibitor
SSRI
selective serotonin reuptake inhibitor
TCA
tricyclic antidepressant
UPDRS
Unified Parkinson's Disease Rating Scale
XR
extended release.

Footnotes

Editorial, page 1198

Supplemental data at www.neurology.org

Coinvestigators are listed on the Neurology® Web site at www.neurology.org.

Contributor Information

Irene Richard, University of Rochester.

William McDonald, Emory University.

Michael McDermott, University of Rochester.

Peter G. Como, University of Rochester.

Roger Kurlan, University of Rochester.

Jeffrey M. Lyness, University of Rochester.

Nancy Pearson, University of Rochester.

Barbara Sommerfeld, Emory University.

Cheryl Deeley, University of Rochester.

Tania de la Torre, University of Puerto Rico.

Monica Beland, Hotel-Dieu Hospital-CHUM, Notre Dame.

Jessie Roth, University of California San Francisco.

Monica Quesada, University of Miami.

Mary Lloyd, University of Pennsylvania.

Brenda Pfeiffer, University of Tennessee.

Matthew Menza, Chair, Robert Wood Johnson.

Jeffrey Cummings, UCLA.

Robert Hamer, UNC.

Kathleen Shannon, RushUniversity.

Joanne Odenkirchen, DSMB.

Robin Conwit, Program Officer.

Christopher Beck, Statistician, University of Rochester.

Donna LaDonna, Administrator, University of Rochester.

Jan Bausch, Biostatistics Programmer, University of Rochester.

Scott Kim, MaCAT Consultant, University of Michigan.

AUTHOR CONTRIBUTIONS

Dr. Richard: drafting/revising the manuscript, study concept or design, analysis or interpretation of data, study supervision, obtaining funding. Dr. McDermott: drafting/revising the manuscript, study concept or design, analysis or interpretation of data, statistical analysis. Dr. Kurlan: drafting/revising the manuscript, study concept or design, analysis or interpretation of data, acquisition of data, study supervision. Dr. Lyness: drafting/revising the manuscript, study concept or design, analysis or interpretation of data. Dr. Como: drafting/revising the manuscript, study concept or design, study supervision. N. Pearson: analysis or interpretation of data, acquisition of data, study supervision. S.A. Factor: drafting/revising the manuscript, acquisition of data, study supervision. Dr. Juncos: drafting/revising the manuscript, study concept or design, analysis or interpretation of data, acquisition of data, study supervision. Dr. Serrano Ramos: drafting/revising the manuscript, acquisition of data. Dr. Brodsky: drafting/revising the manuscript, acquisition of data. Dr. Manning: drafting/revising the manuscript, study concept or design, acquisition of data. Dr. Marsh: drafting/revising the manuscript, study concept or design, analysis or interpretation of data, acquisition of data, study supervision. Dr. Shulman: drafting/revising the manuscript, acquisition of data. Dr. Fernandez: drafting/revising the manuscript, analysis or interpretation of data, acquisition of data, study supervision. Dr. Black: drafting/revising the manuscript, analysis or interpretation of data, acquisition of data. Dr. Panisset: drafting/revising the manuscript, acquisition of data. Dr. Christine: drafting/revising the manuscript, acquisition of data. Dr. Jiang: drafting/revising the manuscript, analysis or interpretation of data, acquisition of data, study supervision. Dr. Singer: drafting/revising the manuscript, analysis or interpretation of data, acquisition of data. Dr. Horn: drafting/revising the manuscript, acquisition of data, study supervision. Dr. Pfeiffer: drafting/revising the manuscript, acquisition of data. Dr. Rottenberg: drafting/revising the manuscript, acquisition of data. Dr. Slevin: drafting/revising the manuscript, acquisition of data. Dr. Elmer: drafting/revising the manuscript, acquisition of data. Dr. Press: drafting/revising the manuscript, analysis or interpretation of data, acquisition of data. Dr. Hyson: drafting/revising the manuscript, analysis or interpretation of data, acquisition of data. Dr. McDonald: drafting/revising the manuscript, study concept or design, analysis or interpretation of data, study supervision, obtaining funding.

DISCLOSURE

Dr. Richard serves on a scientific advisory board for the Michael J. Fox Foundation; has received a speaker honorarium from Teva Pharmaceutical Industries Ltd.; and receives/has received research support from Neurologix, Inc., Eli Lilly and Company, the NIH/NINDS, Cornell University, and the Michael J. Fox Foundation. Dr. McDermott serves on data safety monitoring boards for Isis Pharmaceuticals, Inc., Biogen Idec, the ALS Association/FDA, and the Muscular Dystrophy Association; serves on the editorial board of Movement Disorders; has served as a consultant for the New York State Department of Health, Teva Pharmaceutical Industries, Ltd., Synosia, Inc., Smith and Nephew, Inc., and IMPAX Laboratories, Inc.; and receives/has received research support from Forest Laboratories, Inc., Medivation, Inc., NeuroSearch, Boehringer Ingelheim, Pfizer Inc, Endo Pharmaceuticals, the NIH, the CDC, the FDA, the Michael J. Fox Foundation, Spinal Muscular Atrophy Foundation, Muscular Dystrophy Association, and American Dental Association. Dr. Kurlan serves as Supplement Editor for Neurology® and receives research support from Boehringer Ingelheim, Kyowa Hakko Kirin Pharma, Inc., Neurologix, Inc., and the NIH. Dr. Lyness serves on data safety monitoring board for the NIH/NIA; serves as Consulting Editor for Psychology and Aging; and receives/has received research support from the NIH (NIMH, NIA, NINDS). Dr. Como and N. Pearson report no disclosures. Dr. Factor serves as a Section Editor for Current Treatment Options in Neurology and Clinical Neurology and Neuroscience; receives publishing royalties for Parkinson's Disease Diagnosis and Clinical Management (Demos, 2008) and Drug Induced Movement Disorders (Blackwell Futura, 2005); receives research support from Teva Pharmaceutical Industries Ltd., Ipsen, Merck Serono, Ceregene, the NIH (NHLBI, NINDS), and the Michael J. Fox Foundation; and has served as an expert witness in a medico-legal proceeding. Dr. Juncos has served on the speakers' bureaus of UCB and Novartis and receives research support from the NIH (NINDS, NICHD). Dr. Serrano Ramos has received research support from the NIH. Dr. Brodsky has served on scientific advisory boards for Ipsen, Merz Pharmaceuticals, LLC, and Teva Pharmaceutical Industries Ltd.; has received speaker honoraria from Teva Pharmaceutical Industries Ltd. and Medtronic, Inc.; and serves on speakers' bureaus for Teva Pharmaceutical Industries Ltd., Allergan, Inc., Merz Pharmaceuticals, LLC, and Ipsen. Dr. Manning reports no disclosures. Dr. Marsh serves on scientific advisory boards for Merck Serono, Ovation Pharmaceuticals (Lundbeck Inc.), ACADIA Pharmaceuticals, Boehringer Ingelheim, National Parkinson Foundation, American Parkinson's Disease Association, and Parkinson Study Group; serves on the editorial board of the Journal of Parkinson's Disease; receives publishing royalties for Psychiatric Issues in Parkinson's Disease: A Practical Guide (Taylor & Francis/ Informa, 2005); serves as a consultant for Merck Serono, Ovation Pharmaceutical (Lundbeck Inc.), ACADIA Pharmaceuticals, and Boehringer Ingelheim; and receives/has received research support from Forest Laboratories, Inc., Eli Lilly and Company, Boehringer Ingelheim, the NIH, the American Psychiatric Association, Baylor College of Medicine, and the Michael J. Fox Foundation. Dr. Shulman serves as Editor-in-Chief of the Neurology Now Patient Book Series and on the editorial advisory board of Neurology Now; receives publishing royalties for Parkinson's Disease: A Complete Guide for Patients and Families (Johns Hopkins University Press, 2000, 2007); receives research support from Teva Pharmaceutical Industries Ltd., the NIH, and the Michael J. Fox Foundation; and has served as a consultant in medico-legal proceedings. Dr. Fernandez serves on scientific advisory boards for Solvay Pharmaceuticals, Inc. and EMD Serono, Inc.; has received funding for travel or speaker honoraria from Medical Communications Media, Health Professions Conferencing, Ipsen, Merz Pharmaceuticals, LLC, and US World Meds; serves as Medical Editor of the Movement Disorders Society's Web site; is patent co-owner of COMPRESS, a neurosurgical candidate selection tool; receives publishing royalties from Demos, Manson, and Springer; and receives/has received research support from Abbott, ACADIA Pharmaceuticals, Biotie Therapeutics, EMD Serono, Inc., Novartis, Teva Pharmaceutical Industries Ltd., the NIH/NINDS, Huntington Study Group, Movement Disorders Society, Parkinson Study Group, the Michael J. Fox Foundation, National Parkinson Foundation, and Society of Progressive Supranuclear Palsy. Dr. Black serves on a scientific advisory board for the Tourette Syndrome Association; serves on the editorial advisory board of The Open Neuroimaging Journal; is listed as author on patents re: Novel methods for medicinal dosage determination and diagnosis and A2A antagonists as cognition and motor function enhancers; has served as a consultant for Synosia Therapeutics, Merck Serono, and Gerson Lehman Group; and receives/has received research support from Synosia Therapeutics, ACADIA Pharmaceuticals, the NIH (NIDDK, NIMH, NCRR), the Tourette Syndrome Association, and the McDonnell Center for Systems Neuroscience at Washington University. Dr. Panisset serves on scientific advisory boards for Teva Pharmaceutical Industries Ltd., Novartis, Allergan, Inc., and Merz Pharmaceuticals, LLC; has received funding for travel or speaker honoraria from Merz Pharmaceuticals, LLC, Medtronic, Inc., and Teva Pharmaceutical Industries Ltd.; and receives research support from Allon Therapeutics, Inc. and Teva Pharmaceutical Industries Ltd. Dr. Christine receives research/salary support from Genzyme Corporation, Kyowa Hakko Kirin Pharma, Inc., Eisai Inc., and the NIH/NINDS. Dr. Jiang reports no disclosures. Dr. Singer serves on scientific advisory boards for Lundbeck Inc., Merz Pharmaceuticals, LLC, and Ipsen; has received funding for travel from Ipsen; and receives/has received research support from Schwartz Biomedical, LLC, Merz Pharmaceuticals, LLC, Teva Pharmaceutical Industries Ltd., the NIH, Parkinson Study Group, Huntington Study Group, and National Parkinson Foundation. Dr. Horn reports no disclosures. Dr. Pfeiffer serves on the scientific advisory board for the National Parkinson Foundation; serves as Co-Editor in Chief of Parkinsonism and Related Disorders and on the editorial board of the Journal of Parkinson's Disease; receives publishing royalties for Parkinson's Disease (Taylor & Francis, 2008-present), Parkinson's Disease and Nonmotor Dysfunction (Humana, 2008–present), and Neuro-Gastroenterology (Butterworth-Heinemann, 2008); serves as a consultant for Solvay Pharmaceuticals, Inc., Theravance Inc., Genactis, Schlesinger Associates, and UCB; serves on speakers' bureaus for Boehringer Ingelheim, Novartis, and Teva Pharmaceutical Industries Ltd.; receives research support from Novartis, Boehringer Ingelheim, UCB/SCHWARZ PHARMA, Santhera Pharmaceuticals, Molecular Biometrics, Columbia University, Weill Cornell Medical College, Northwestern University, Indiana University, Parkinson Study Group, and the Michael J. Fox Foundation; and has served as a consultant in medico-legal proceedings. Dr. Rottenberg reports no disclosures. Dr. Slevin serves/has served on speakers' bureau for Boehringer Ingelheim, Novartis, and Teva Pharmaceutical Industries Ltd.; and receives/has received research support from Solvay Pharmaceuticals, Inc. and the NIH. Dr. Elmer has received research support from Teva Pharmaceutical Industries Ltd. and serves on speakers' bureaus for Teva Pharmaceutical Industries Ltd., GlaxoSmithKline, Novartis, and UCB. Dr. Press receives/has received research support from the NIH (NIMH, NIA), the Milton Fund, and the Harvard Center for Neurodegeneration and Repair. Dr. Hyson has served on scientific advisory boards for Biogen Idec; and has received speaker honoraria from Merz Pharmaceuticals, LLC and Biogen Idec. Dr. McDonald serves as Triage Editor for American Journal of Geriatric Psychiatry and on the editorial board of the Journal of ECT; serves as a consultant for Cervel Neurotech; and receives/has received research support from the NIH/NIMH, GlaxoSmithKline, Wyeth, Boehringer Ingelheim, and Janssen.

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