Website Edition: October/November 2012

Editor's Choice Article and Review

Movement Disorders
DOI: 10.1002/mds.24978

Tricyclic antidepressants delay the need for dopaminergic therapy in early Parkinson's disease
Katrina L. Paumier PhD, Andrew D. Siderowf MD, MSCE, Peggy Auinger MS, David Oakes PhD, Lalitha Madhavan MD, PhD, Alberto J. Espay MD, MSc, Fredy J. Revilla MD, Timothy J. Collier PhD, for the Parkinson Study Group Genetics Epidemiology Working Group

Article first published online: 3 MAY 2012

Abstract

This study examined whether antidepressants delay the need for dopaminergic therapy or change the degree of motor impairment and disability in a population of early Parkinson's disease (PD) patients. Preclinical studies have indicated that antidepressants modulate signaling pathways involved in cell survival and plasticity, suggesting they may serve to both treat PD-associated depression and slow disease progression. A patient-level meta-analysis included 2064 patients from the treatment and placebo arms of the following trials: FS1, FS-TOO, ELLDOPA, QE2, TEMPO, and PRECEPT. Depression severity was determined at baseline, and antidepressant use was reported in a medication log each visit. Kaplan-Meier curves and time-dependent Cox proportional hazards models determined associations between depression severity and antidepressant use with the primary outcome, time to initiation of dopaminergic therapy. ANCOVAs determined associations with the secondary outcome, degree of motor impairment and disability, reported as annualized change in UPDRS scores from baseline to final visit. When controlling for baseline depression, the initiation of dopaminergic therapy was delayed for subjects taking tricyclic antidepressants compared with those not taking antidepressants. No significant differences were found in UPDRS scores for subjects taking antidepressants compared with those not taking antidepressants. Tricyclic antidepressants are associated with a delay in reaching the end point of need to start dopaminergic therapy. The lack of change in overall UPDRS scores suggests the delay was not attributable to symptomatic effects.

© 2012 Movement Disorder Society

Volume 27, Issue 7, June 2012, pages 880-887

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Summary and review by Dr. Kelvin Chou, Associate Prof. of Neurology and Neurosurgery, University of Michigan Medical School, Ann Arbor, Michigan, USA

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The Editor's Choice article for October/November 2012 is "Tricyclic Antidepressants Delay the Need for Dopaminergic Therapy in Early Parkinson's Disease" by Katrina Paumier for the Parkinson Study Group Genetics Epidemiology Working Group. This study looked at the effect of antidepressant therapy on time to initiation of dopaminergic therapy in a population of early, mild PD patients.

This study utilized a retrospective cohort design, consisting of data from six different clinical trials: ELLDOPA, QE2, TEMPO, PRECEPT, FS1 and FS-TOO. These trials were all conducted by either the Parkinson Study Group or the NET-PD consortium in the United States and included newly diagnosed PD patients who were not exposed to dopaminergic therapy, and did not have any antidepressant exclusions except for MAOIs. The one exception was the TEMPO study, a double-blind, placebo-controlled trial of the efficacy of the MAO-B inhibitor rasagiline in early PD. In the TEMPO study, the only antidepressants that were permitted were amitriptyline, paroxetine, sertraline, fluvoxamine, and trazodone. A total of 2064 subjects were included in this analysis, and those who were on antidepressants at the start of their trials had to have been on stable doses for at least 60 days prior to baseline.

The primary endpoint for the analysis was the time needed to start dopaminergic therapy. The authors also looked at the percentage of subjects who had not reached the end point at 1 year. Secondary outcomes included the annualized change in the total UPDRS score, as well as the subscores of the UPDRS and a tremor subscore (tremor items in UPDRS parts 2 and 3). These endpoints were analyzed based on whether subjects were taking an antidepressant, on which type of antidepressant they were taking (SSRI, SNRI, tricyclic, amitriptyline specifically, atypical, and >1 antidepressant), and baseline depression severity. Because 3 different depression scales (Geriatric Depression Scale, Hamilton Depression Rating Scale, and the Beck Depression Inventory) were used among the 6 different studies, baseline depression severity (none, mild, and moderate/severe) was classified based on reported cutoffs for the scales.

Kaplan-Meier curves were generated for the primary endpoint as well as the percentage of subjects who had not reached the end point at 1 year. Time-dependent Cox regression models were used to evaluate the role of antidepressants on the need for therapy and this model included antidepressant use as a cumulative proportion of study time the subject was taking medication. The analysis looking at the annual rate of change of the UPDRS used ANCOVAs with the UPDRS scores as dependent variables and baseline exposure to antidepressants ,depression severity and potential confounders as predictors. Confounding variables used in adjusted analyses included age, sex, race, treatment group, study, site, baseline UPDRS score and pre-study antidepressant use.

Of the 2064 patients, 451 were on an antidepressant at some time during the study. Approximately 15% of patients presented with some form of depression at study entry, and 71% of those patients were not on antidepressant treatment, suggesting that depression in PD remains underrecognized and undertreated. The unadjusted median time to dopaminergic therapy was shorter for those with baseline depression compared to those without depression, as well as for those taking an antidepressant compared to those not taking an antidepressant. However, when stratified by antidepressant class, the unadjusted median time to endpoint was longer and the percentage of subjects who had not reached the endpoint at 1 year was larger for those on amitriptyline or atypical antidepressants than those not taking antidepressants. When adjusting the analyses for depression and other confounders, those taking tricyclics and amitriptyline in particular, had a lower probability of initiating dopaminergic therapy. The annualized rate of change of the total UPDRS and its subscores were no different in those taking an antidepressant compared to those not taking an antidepressant. However, the presence of mild depression at baseline was associated with a higher probability of starting dopaminergic therapy in adjusted analyses.

The main message of this featured article is that early PD patients treated with tricyclic antidepressants, and with amitriptyline in particular, have a delay in the need for dopaminergic therapy. Unfortunately, this study cannot tell us why. While it certainly may represent a disease-modifying effect as the authors mention, the results could just as easily be explained by antidepressant efficacy not captured by the UPDRS. It has been shown in a previous study that depressed PD patients are more likely to complain of symptoms and have a shorter time to needing dopaminergic therapy than non-depressed PD patients. There was no change in the annualized UPDRS scores in those patients on antidepressants in this study compared to those not on antidepressants, so there is no symptomatic motor effect with antidepressants. Unfortunately, antidepressant efficacy could not be adjusted for in the analysis because most of the studies included only baseline depression severity. Nevertheless, the findings here are interesting and suggest that the presence of mild depression in early PD is associated with needing dopaminergic therapy earlier, and treatment with tricyclic antidepressants, and specifically amitriptyline, delay that need. Whether it is because tricyclics such as amitriptyline alter disease progression or improve depression by decreasing non-motor disability remains to be seen.

About Kelvin Chou
Kelvin L. ChouKelvin L. Chou, MD is the Thomas H. and Susan C. Brown Professor and Clinical Associate Professor of Neurology and Neurosurgery at the University of Michigan Medical School, where he serves as Co-Director of the STIM (Surgical Therapies Improving Movement) Program. Board-certified in Neurology, Dr. Chou's main research interests are the non-motor features of Parkinson's disease (PD) and how to improve deep brain stimulation for Parkinson's disease.