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Original Investigation |

Combined Rasagiline and Antidepressant Use in Parkinson Disease in the ADAGIO Study Effects on Nonmotor Symptoms and Tolerability FREE

Kara M. Smith, MD1; Eli Eyal, MSc2; Daniel Weintraub, MD1,3,4 ; for the ADAGIO Investigators
[+] Author Affiliations
1Department of Neurology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia
2Teva Pharmaceutical Industries, Petach Tikva, Israel
3Department of Psychiatry, Perelman School of Medicine at the University of Pennsylvania, Philadelphia
4Department of Veterans Affairs, Philadelphia VA Medical Center, Philadelphia, Pennsylvania
JAMA Neurol. 2015;72(1):88-95. doi:10.1001/jamaneurol.2014.2472.
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Published online

Importance  Depression, cognitive impairment, and other nonmotor symptoms (NMSs) are common early in Parkinson disease (PD) and may be in part due to disease-related dopamine deficiency. Many patients with PD are treated with antidepressants for NMSs, and the effect of the combination of PD medications that enhance dopamine neurotransmission and antidepressants on NMSs has not been studied. We report the effects of the addition of a monoamine oxidase B inhibitor, rasagiline, to antidepressant treatment in PD.

Objective  To evaluate the effect of rasagiline on depression, cognition, and other PD NMSs in patients taking an antidepressant in the Attenuation of Disease Progression With Azilect Given Once Daily (ADAGIO) study.

Design, Setting, and Participants  The ADAGIO study was a double-blind, placebo-controlled, delayed-start trial of rasagiline in de novo PD. In this exploratory post hoc analysis, we analyzed patients taking an antidepressant during the 36-week phase 1 period, in which patients were randomized to rasagiline (1 or 2 mg/d) or placebo.

Main Outcomes and Measures  We evaluated the change in NMSs in patients taking an antidepressant and rasagiline compared with those taking placebo. The NMSs were assessed by Movement Disorder Society–sponsored revision of the Unified Parkinson's Disease Rating Scale Nonmotor Experiences of Daily Living, the original Unified Parkinson's Disease Rating Scale, and the Parkinson Fatigue Scale.

Results  A total of 191 of the 1174 patients (16.3%) were treated with antidepressants during phase 1 and provided efficacy data. Depression and cognition scores revealed significantly less worsening in the rasagiline group compared with the placebo group (differences in Movement Disorder Society–sponsored revision of the Unified Parkinson's Disease Rating Scale item-adjusted means [SEs], −0.19 [0.10], P = .048, and −0.20 [0.05], P < .001, respectively). Parkinson Fatigue Scale (mean [SE] difference, −0.42 [0.09], P < .001) and daytime sleepiness (mean [SE] difference, −0.24 [0.09], P = .006) scores also revealed significantly less worsening in the rasagiline group compared with placebo. There was a nonsignificant trend toward less worsening in apathy and no significant between-group differences in anxiety or sleep. The effect on depression remained significant after controlling for improvement in motor symptoms (mean [SE] difference, −0.23 [0.09], P = .009). There were no serious adverse events in the combined rasagiline-antidepressant group suggestive of serotonin syndrome.

Conclusions and Relevance  The combination of rasagiline and antidepressants in patients with de novo PD is associated with reduced worsening of a range of NMSs in preliminary analyses. Adverse effects appear uncommon with this combination. These findings suggest a role for dopamine-enhancing therapies in NMSs in early PD and encourage further study and confirmation.

Trial Registration  clinicaltrials.gov Identifier: NCT00256204

Figures in this Article

Depression is an important nonmotor symptom (NMS) in Parkinson disease (PD), with approximately 35% of patients having clinically significant depressive symptoms and a higher prevalence of major depression in patients with PD compared with age-matched controls.1 Patients with PD and depression have a higher co-occurrence of cognitive impairment, worse motor outcomes, and poorer quality of life.24

Antidepressant use is common in patients with PD, with one study5 reporting that 23% of patients with mild PD were taking an antidepressant and 78% had received an antidepressant since their PD diagnosis. Antidepressants were efficacious for PD depression in the largest controlled trial to date,6 but a meta-analysis7 reported mixed results.

Monoamine oxidase B (MAO-B) inhibitors are used to treat the motor symptoms of PD but also have been used in the treatment of depression. In the general population, selegiline hydrochloride is effective in treating depression at higher doses that are nonselective for MAO-B,8 including in refractory geriatric depression.9

Depression in PD may be partially related to dopamine deficiency in limbic system pathways,10 and enhancement of dopaminergic neurotransmission via a selective MAO-B inhibitor could therefore improve depression in PD. There is evidence that frontostriatal dopaminergic deficiency underlies cognitive impairment in early PD,11 and apathy also appears to be mediated by dopaminergic deficiency and improves with dopamine replacement therapy.12

Concerns exist about the safety of combining an MAO-B inhibitor with antidepressants, particularly selective serotonin reuptake inhibitors, because of the risk of potentially fatal serotonin syndrome. However, the frequency of this adverse event has not been evaluated in a controlled clinical trial.

Antidepressant augmentation strategies are common in treating depression in general.13 We hypothesized that enhancing the dopamine system would improve depression and other NMSs in patients with PD already taking an antidepressant. We evaluated the effects of combined rasagiline and antidepressant use on a range of NMSs in patients with early de novo PD. In addition, we report on the tolerability and safety of this combination.

Study Design

Written consent was obtained from all participants. The study was approved by participating sites’ institutional review boards for human research. The Attenuation of Disease Progression With Azilect Given Once Daily (ADAGIO) study was a 72-week, double-blind, placebo-controlled, multicenter trial in patients with untreated early PD that used a delayed-start design.14 There were 2 phases of 36 weeks each. Phase 1, the focus of this article, assigned patients to receive rasagiline (1 or 2 mg/d) or corresponding placebo. No concomitant antiparkinsonian medication was permitted.

Participants

Patients 30 to 80 years of age with idiopathic PD were enrolled. Patients with major psychiatric illness, including major depression based on the impression of site investigators, were excluded. At baseline the following antidepressants (daily dose) were allowed: amitriptyline, 50 mg or less; trazodone hydrochloride, 100 mg or less; citalopram hydrobromide, 20 mg or less; sertraline hydrochloride, 100 mg or less; paroxetine hydrochloride, 30 mg or less; and escitalopram oxalate, 10 mg or less. There was no restriction in tyramine dietary intake. Patients were included in the ADAGIO study antidepressant subpopulation if they were taking an antidepressant at any time during phase 1. One patient of the 192 randomized and taking an antidepressant at some point did not provide postbaseline efficacy data, so the efficacy population presented here includes 191 patients, all of whom were assessed at week 36 or at an early termination visit.

Assessments

Both the original Unified Parkinson's Disease Rating Scale (UPDRS)15 and Movement Disorder Society (MDS)–sponsored revision of the UPDRS16 were used. Both versions have cognition and depression rater-scored items in the Nonmotor Experiences of Daily Living (nmEDL). The MDS-UPDRS nmEDL at baseline and week 36 or early termination was used to assess severity of depressed mood, cognitive impairment, apathy, anxious mood, sleep problems, and daytime sleepiness (scores of 0-4 for each item, with higher scores indicating greater impairment). The Parkinson Fatigue Scale (PFS) was used to assess fatigue.17 Adverse events were recorded at each visit.

Statistical Analysis

To increase sensitivity, rasagiline-treated patients were first analyzed as a pooled group; if there was a significant difference between the pooled rasagiline and placebo groups for a given measure, then the 2 dose groups were analyzed separately. The change from baseline to week 36 or early termination in the original UPDRS and MDS-UPDRS item scores for depression, cognition, apathy, fatigue, anxiety, and sleep was calculated. The last observation carried forward was applied for patients who terminated the study early for the MDS-UPDRS because it was measured at baseline and week 36 or termination only. The adjusted mean changes from baseline were estimated using an analysis of covariance model, adjusting for baseline score of the analyzed outcome and site. For the original UPDRS motor and depression scores, a mixed model for repeated measure was applied, adjusting for the respective baseline scores and site. The differences of the adjusted means were calculated comparing the rasagiline and placebo groups. P < .05 was considered significant. Effect sizes for depression and cognition were calculated using the Cohen conventions.18 To assess the association between changes in motor symptoms and NMSs, Pearson correlation coefficients were calculated for changes over time in depression, cognition, apathy, sleep, and motor scores. We then also controlled for change in UPDRS motor score in the analysis of covariance model comparing the effect of rasagiline and placebo on depression.

Comparison of Study Participants by Antidepressant Treatment Status

In phase 1 of the study, 191 of the 1174 patients (16.3%) were treated with an antidepressant at baseline (144 patients [12.3%]) or after baseline (47 patients [4.0%]) and provided postbaseline efficacy data. These patients likely had clinically significant depression, as evidenced by their significantly higher baseline MDS-UPDRS depression item scores compared with patients not treated with an antidepressant (Table 1). The baseline MDS-UPDRS cognition item score was also higher (ie, worse) in patients taking an antidepressant (mean [SE] between-group difference, 0.15 [0.04] points; P < .001). There were no significant group differences in age, sex, baseline UPDRS motor score, or Hoehn and Yahr stage. Patients taking an antidepressant had significantly worse UPDRS activities of daily living scores.

Table Graphic Jump LocationTable 1.  Descriptive Statistics of Baseline Variables by Antidepressant Use During the Controlled Phasea

Of antidepressant-treated patients in the phase 1 period, 93 were randomized to rasagiline (1 or 2 mg/d) and 98 to placebo, and 137 (71.4%) completed phase 1 of the study medication (Figure). Twenty-nine patients (29.6%) in the placebo group and 18 (19.4%) in the pooled rasagiline group were not taking antidepressants at baseline but were prescribed an antidepressant during phase 1 (P = .10). Baseline variables were similar for participants taking an antidepressant at baseline and those who began during the study (eTable 1 in the Supplement).

Place holder to copy figure label and caption
Figure.
Randomization and Treatment of Study Participants

The Attenuation of Disease Progression With Azilect Given Once Daily study participants taking an antidepressant at any time during the 36-week, placebo-controlled phase 1 period were included. The efficacy population of 191 participants was assessed at week 36 or at an early termination visit. PD indicates Parkinson disease.

Graphic Jump Location
Characteristics of Antidepressant-Treated Participants by Randomization Status

There were no significant differences in baseline variables for antidepressant-treated patients randomized to rasagiline vs placebo (Table 2) or for those randomized to 1 or 2 mg/d (eTable 2 in the Supplement). The antidepressant classes taken by participants were as follows: serotonin reuptake inhibitors, 76.0%; tricyclic antidepressants, 21.4%; serotonin-norepinephrine reuptake inhibitors, 0.5%; and other, 8.3% (eTable 3 in the Supplement).

Table Graphic Jump LocationTable 2.  Descriptive Statistics of Baseline Variables for Patients Taking Antidepressants During the Controlled Phase by Treatment Assignment
Outcomes for NMSs
Depression

Both the UPDRS and MDS-UPDRS depression item scores worsened between baseline and 36 weeks but significantly less so in the pooled rasagiline group compared with the placebo group. The mean (SE) combined rasagiline-placebo difference was −0.24 (0.11) points (P = .03) for the UPDRS and −0.19 (0.10) points (P = .048) for the MDS-UPDRS depression items (Table 3). There was evidence of a dose-response effect (eTable 4 in the Supplement). The difference between rasagiline and placebo on the MDS-UPDRS depression item score represented a small to medium effect size (Cohen d = 0.36) (eTable 5 in the Supplement).

Table Graphic Jump LocationTable 3.  Changes in Nonmotor Symptoms Over Time in the Pooled Rasagiline and Placebo Groups
Cognition

The MDS-UPDRS cognition item revealed significantly less worsening in the pooled rasagiline group compared with placebo. The treatment mean (SE) difference was −0.20 (0.05) points (P < .001) (Table 3 and by dose differences in eTable 4 in the Supplement). The difference in the pooled rasagiline group compared with placebo suggested a moderate to large treatment effect on cognition (Cohen d = 0.68) (eTable 5 in the Supplement).

Apathy

The pooled rasagiline group revealed a nonsignificant trend toward reduced worsening in apathy compared with placebo, with a mean (SE) treatment difference of −0.17 (0.09) points (P = .07) (by dose differences in eTable 4 in the Supplement). There was a moderate correlation between the changes in depression and apathy scores over time (eTable 6 in the Supplement).

Fatigue

On the PFS, the pooled rasagiline group had significantly less worsening compared with the placebo group (mean [SE] difference, −0.42 [0.09]; P < .001). The 1- and 2-mg/d groups responded similarly (eTable 4 in the Supplement). This likely represents a clinically significant improvement based on the PFS validation study.17

Sleep and Wakefulness

On the daytime sleepiness item, there was significantly less worsening in the pooled rasagiline group, with a mean (SE) difference of −0.24 (0.09) points (P = .006). For the MDS-UPDRS sleep problems item, there was no significant difference between treatment groups (mean [SE] difference, 0.10 [0.09]; P = .30). There was a low but statistically significant correlation between changes in depression and sleep items over time (eTable 6 in the Supplement).

Anxiety

There was no significant difference between treatment groups in the change in the MDS-UPDRS anxiety item (mean [SE] difference, −0.12 [0.10]; P = .23).

Association Between Motor and Depression Outcomes

At week 36 there was a significant improvement in the UPDRS motor score in the pooled rasagiline group compared with the placebo group (mean [SE] difference, −2.22 [0.80]; P = .006), consistent with the motor treatment effect observed in the entire cohort. To determine whether the rasagiline effect on NMSs was explained simply by its effect on motor symptoms, we determined the association between change in motor symptoms and NMSs in rasagiline-treated patients. No significant correlation was found between the changes in depression (Pearson r = 0.16, P = .12) or cognition (Pearson r = 0.03, P = .80) scores and the change in the UPDRS motor score over time (eTable 7 in the Supplement). In addition, when controlling for change in the UPDRS motor score over time, the UPDRS depression score at baseline, and site, rasagiline-treated patients had an even greater reduction in worsening of depression symptoms over time compared with the placebo group (eTable 8 in the Supplement). This finding indicates that the effect on depression scores with rasagiline was independent of motor improvement.

Tolerability

During phase 1 there was no difference in the number of serious adverse events in the pooled rasagiline group (n = 7) compared with the placebo group (n = 9). There was no clear pattern of any adverse events that were more common and not previously described in the rasagiline groups compared with the placebo group (eTable 9 in the Supplement). There were no serious or nonserious adverse events that could be interpreted as possible serotonin syndrome (Table 4 and eTable 9 in the Supplement).

Table Graphic Jump LocationTable 4.  Frequency of Serious Adverse Events for Antidepressant-Treated Patients

In this post hoc exploratory analysis of the ADAGIO study, participants taking an antidepressant in combination with rasagiline had less worsening of depression, cognition, fatigue, and daytime sleepiness compared with placebo, suggesting a positive effect for rasagiline on NMSs. The aim of the ADAGIO study was to examine a possible disease-modifying effect of rasagiline using a delayed-start design. The large cohort of participants (>1000 participants) had recently diagnosed conditions and were untreated. The placebo-controlled phase 1 period revealed that rasagiline was safe and well tolerated and exerted a symptomatic motor benefit. Primary end points were met for the 1-mg/d but not the 2-mg/d rasagiline group; thus, no clear conclusions could be drawn about a disease-modifying effect.14

In this post hoc analysis of those ADAGIO study participants taking an antidepressant during the phase 1 period, we confirmed that rasagiline was safe and well tolerated and improved PD motor symptoms similarly to the overall group. On the basis of the combined patient-rater assessment (MDS-UPDRS) and the PFS, NMSs worsened overall between baseline and 36 weeks but less so in the rasagiline group compared with the placebo group, suggesting a possible treatment effect for rasagiline on NMSs in general. Also similar to the primary ADAGIO study, a consistent dose-response effect was not noted on the NMSs.

Because rasagiline inhibits metabolism of dopamine and increases synaptic availability,19 the effects we observed may be due to enhanced dopaminergic neurotransmission. Dopaminergic neurotransmission is affected in non-PD depression, and antidepressants act in part by increasing nucleus accumbens dopamine receptor sensitivity.20 Dopamine enhancement therapies, including the MAO-B inhibitor selegiline8,21 and the D2/3 agonist pramipexole, are effective in treating major depressive disorder in the general population.22,23

Striatal and extrastriatal dopaminergic pathways have been implicated in the pathogenesis of depression and other NMSs in PD.20 Our results are consistent with previous work reporting that dopaminergic medications can improve depression and other NMSs in PD. Levodopa may improve depression in PD, although the literature is limited and focused on patients with motor fluctuations.24,25 Pramipexole improved depressive symptoms in patients with PD in a placebo-controlled study.26 Examination of MAO-B inhibitors for the treatment of depression in PD is limited. In the Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism study, selegiline improved depression compared with placebo on secondary analysis.27 Rasagiline improved depressive symptoms in patients with de novo PD in a small masked study.28 Because MAO-B inhibitors also affect other monoamines (eg, phenethylamine), further research is needed to determine the relative roles of dopamine vs other neurotransmitters and their projections in the antidepressant effect of this medication class.

Cognitive impairment is common even in early PD,29 and executive dysfunction is frequently predominant.30 Executive dysfunction may involve parallel dopaminergic pathways that connect the cortex and basal ganglia because levodopa can help normalize these deficits.11 Rasagiline may improve attention and verbal fluency in patients with PD and mild cognitive impairment.31 In addition, catechol-O-methyltransferase polymorphisms that increase dopamine levels in the prefrontal cortex correlate with better executive abilities,11 and neuroimaging studies3234 have reported a correlation between nigrocaudate dopamine impairment and executive dysfunction and future cognitive decline. Our results therefore add to the literature that suggests that dopamine-enhancing therapies may improve cognitive symptoms in PD and warrant further study.

We also found that rasagiline in combination with antidepressant treatment reduced worsening of fatigue and daytime sleepiness scores. Sleepiness has been correlated with striatal dopamine loss in early PD,35 but further research is needed to determine the role of dopamine in PD fatigue.

A significant concern when combining MAO-B inhibitors and antidepressants with serotonergic properties is serotonin syndrome, an acute medical-neurologic condition that can be life-threatening. Previous literature is limited to uncontrolled data and focuses on selegiline rather than rasagiline. Richard et al36 reported an incidence of 0.04% of possible serotonin syndrome in this population. The package insert for rasagiline reports postmarketing nonfatal cases of serotonin syndrome in patients coprescribed antidepressants. We report on the tolerability and safety of the combination of rasagiline and antidepressants for the first time, to our knowledge, in a controlled trial, and our analysis of serious adverse events did not reveal any events suggestive of serotonin syndrome in almost 100 participants treated for 9 months with this combination. Additional controlled studies with larger sample sizes and longer durations are needed to provide more conclusive data about this risk, and health care professionals should remain vigilant regarding this potential complication.

Selectively analyzing ADAGIO study participants taking antidepressants, who had more NMSs at baseline than those not taking antidepressants, likely increased our ability to detect significant improvement in numerous NMSs in those randomized to receive rasagiline vs placebo. A post hoc analysis that included all ADAGIO study participants found that the total MDS-UPDRS nmEDL scores improved modestly but significantly in the 1-mg/d rasagiline group compared with the placebo group but not in the 2-mg/d rasagiline group.37 Similarly, the lack of a consistent dosage effect for 1 vs 2 mg/d for NMSs in our study remains a limiting factor in interpretation. In our analysis, this may possibly be due to the relatively small sample size in each active treatment subgroup. There were significant correlations between depression and other NMSs (eg, apathy and sleep), which could explain some of the effects across symptoms that we observed. Future studies would benefit from larger sample size and more detailed instruments to disentangle the “neuropsychiatric” effect that we report here.

Our analysis was additionally limited by several factors. The first limitation was the post hoc (not prespecified) exploratory nature. Second, we were limited to the use of the MDS-UPDRS rather than validated individual NMS assessment instruments for the assessment of NMSs, except for fatigue, for which a dedicated instrument was used. The MDS-UPDRS nmEDL correlates with other validated assessments of NMSs over time, such as the Parkinson’s Disease Questionnaire 39 and the Geriatric Depression Scale,38 and one benefit of using the MDS-UPDRS nmEDL is its clinical relevance because it is used on routine clinic visits to gauge NMSs. Future studies are needed to determine whether the MDS-UPDRS nmEDL is sensitive to possible nonmotor effects for other PD medication classes. Third, the exclusion of patients with major or severe depression limits the generalizability of our findings, as does the de novo population. However, an advantage of the de novo population is that the confounding effects of concomitant PD medication and fluctuations were excluded.

As outlined above, other dopaminergic therapies may improve NMSs, due to specific antidepressant or more global effects, and it is not clear to what extent the results reported here, if confirmed, are specific to rasagiline. Further research is also required to elucidate the mechanism of action of MAO-B inhibitors and antidepressants on PD NMSs because there is emerging evidence that these compounds may have neuromodulatory or neuroprotective effects in addition to their symptomatic effects.39,40

Rasagiline was well tolerated in patients with de novo PD who were taking antidepressants, and this combination reduced worsening of a range of NMSs. These preliminary findings suggest that augmentation with dopamine-enhancing therapies may have a role in the treatment of early PD NMSs, at least in those patients already taking an antidepressant. Given the limitations of the analyses, these findings require confirmation. Additional prospective, controlled studies are warranted to further evaluate the specific nonmotor effects of rasagiline, including larger sample sizes and use of standardized NMS scales, before this strategy can be recommended for clinical practice.

Accepted for Publication: July 14, 2014.

Corresponding Author: Kara M. Smith, MD, Department of Neurology, Perelman School of Medicine at the University of Pennsylvania, 330 S Ninth St, Philadelphia, PA 19107 (kara.smith@uphs.upenn.edu).

Published Online: November 24, 2014. doi:10.1001/jamaneurol.2014.2472.

Author Contributions: Mr Eyal had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Weintraub.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Smith.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Eyal.

Conflict of Interest Disclosures: Dr Weintraub reported receiving research funding from the Michael J. Fox Foundation for Parkinson’s Research, National Institutes of Health, Novartis Pharmaceuticals, Department of Veterans Affairs, and Alzheimer’s Disease Cooperative Study; honoraria from Teva Pharmaceuticals, Lundbeck Inc, Pfizer, Avanir Pharmaceuticals, Merck & Co, UCB, Bristol-Myers Squibb Company, Novartis Pharmaceuticals, Eli Lilly and Company, Clintrex LLC, Theravance, Medivation, CHDI Foundation, and Alzheimer’s Disease Cooperative Study; license fee payments from the University of Pennsylvania for the Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease and Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease–Rating Scale; and fees for testifying in a court case related to impulse control disorders in PD (March 2013). Dr Smith reported receiving an unrestricted educational grant from Medtronic. Mr Eyal reported being an employee of Teva Pharmaceuticals. No other disclosures were reported.

Funding/Support: The ADAGIO study was funded by Teva Pharmaceuticals.

Role of the Funder/Sponsor: Teva Pharmaceuticals funded and conducted the ADAGIO study and offered statistical support for this secondary analysis of the data set and proofread the manuscript.

Group Members: The ADAGIO investigators are as follows. Argentina:Jose Bueri (Hospital Universitario Austral); Nelida Garretto (Hospital Ramos Mejia); Oscar Gershanik (Hospital Frances); Rolando Giannaula (Hospital Espanol); Federico Micheli (Instituto Frenopatico SA). Austria: Elisabeth Wolf (Medizinische Universität Innsbruck). Canada:Mark Guttman (Center for Movement Disorders, Markham); Douglas Hobson (Dr. Douglas Everett Hobson Medical Corporation); Mandar Jog (London Health Sciences Centre); David King (private clinic, Halifax); Tilak Mendis (Parkinson's & Neurodegenerative Disorders Clinic, Ottawa); Janis Miyasaki (Toronto Western Hospital); Michel Panisset (CHUM Hôtel-Dieu); Emmanuelle Pourcher (Memory and Motor Skills Disorders); Ali Rajput (Royal University Hospital, Saskatoon); Ranjit Ranawaya (University of Calgary);Joseph Tsui (Pacific Parkinson's Research Centre). France:Pierre Cesaro (Hôpital Henri Mondor); Philippe Damier (C.H.U. de Nantes); Alain Destee (C.H.R.U. de Lille); Franck Durif (C.H.U. de Clermont-Ferrand); Tarik Slaoui (C.H.U. de Toulouse); François Tison (C.H.U. de Bordeaux); François Viallet (C.H. du Pays d'Aix). Germany:Günther Deuschl (Universitätsklinikum Schleswig-Holstein); Thomas Gasser (Universitaettsklinikum Tübingen); Albert Ludolph (Universitaet Ulm); Christian Oehlwein (private practice, Gera); Horst Przuntek (Ruhr-Universitaet im St. Josef-Hospital); Gerd Reifschneider (private practice, Erbach); Alfons Schnitzler (Universitaetsklinikum Düsseldorf); Claudia Trenkwalder (Paracelsus-Elena Klinik). Hungary:Magdolna Bokor (Nyiro Gyla Hospital); Agnes Katona (Javorszky Odon Hospital); Julia Lajtos (Kenezy Gyula County Hospital); Janos Nikl (Zala County Hospital); Annamaria Takats (Semmelweis University); Attila Valikovics (BAZ County Hospital and University Teaching Hospital). Israel:Samih Badarny (Carmel Medical Center); Ruth Djaldetti (Rabin Medical Center); Nir Giladi (Sourasky Medical Center); Sharon Hassin (Sheba Medical Center); Jose Martin Rabey (Asaf Harofe Medical Center); Avinoam Reches (Hadassah Medical Center); Miguel Schwartz (Bnei Zion Medical Center); Itzhak Wirguin (Soroka Medical Center). Italy:Alberto Albanese (Fondazione IRCCS Istituto Neurologico C. Besta); Annarita Bentivoglio (Università Cattolica del Sacro Cuore); Ubaldo Bonuccelli (Ospedale Unico "Versilia"); Stefano Calzetti (A.O. Universitaria di Parma); Giancarlo Comi (Fondazione Centro S. Raffaele del Monte Tabor); Luigi Curatola (Ospedale di Zona Territoriale N.12); Carlo Ferrarese (Ospedale San Gerardo Nuovo); Paolo Lamberti (Università degli Studi di Bari); Roberto Marconi (Ospedal Misericordia); Emilia Martignoni (Fondazione "Salvatore Maugeri"); Giuseppe Meco (Università degli Studi di Roma "La Sapienza"); Stefano Ruggieri (Istituto Neurologico Mediterraneo Neuromed [IRCCS]); Fabrizio Stocchi (IRCCS San Raffaele Pisana). Netherlands: M.A.M. Bomhof (Amphia Hospital); Ad Hovestadt (Meander Medical Center); Jean Michel Krul (Tergooi Hospitals); K.L. Leenders (University Medical Center Groningen). Portugal:Luis Cunha (Hospitais da Universidade de Coimbra); Joaquim Ferreira (Hospital de Santa Maria). Romania:Ovidiu Alexandru Bajenaru (University Emergency Hospital Bucharest); Nicolae Carciumaru (CFR University Hospital Constanta); Angelo Corneliu Bulboaca (Clinical Rehabilitation Hospital Cluj); Ioan Pascu (County Clinical Hospital Targu Mures); Mihaela Simu (County Clinical Hospital Timisoara). Spain:Matilde Calopa (Ciutat Sanitaria de Bellvitge-Neurologia); Jose Manuel Fernández García (Hospital De Basurto-Neurologia); Jaime Kulisevsky (Fundació de l'Hospital de la Santa Creu i Sant Pau); Cristobal Linazasoro (Policlínica Gipúzkoa); Francesco Miquel (Hospital General Universitari Vall d'Hebrón); Ignacio Javier Posada (Hospital Universitario 12 de Octubre); Maria Jose Martí (Hospital Clínic I Provincial de Barcelona). United Kingdom:David Burn (Newcastle General Hospital); Doug MacMahon (Cambourne- Redruth Hospital); Roger Barker (Addenbrooke's Hospital). United States:Neil Allen (Consultants in Neurology, Ltd); Peter Barbour (Lehigh Valley Hospital); John Bertoni (Creighton University); Kersi Bharucha (University of Oklahoma Health Sciences Center); Sudeshna Bose (University of Arizona); Edward Drasby (Port City Neurology); Rodger Elble (Southern Illinois University School of Medicine); Lawrence Elmer (Medical University of Ohio); Bradley Evans (Northern Michigan Neurology); Stewart Factor (Emory University School of Medicine); Hubert Fernandez (University of Florida); Joseph Friedman (NeuroHealth); Keith Hull (Raleigh Neurology Associates); Lawrence Golbe (UMDNJ-RWJMS); John Goudreau (Michigan State University); Thomas Guttuso (University of Buffalo); Mohamed Hassan (Hartford Hospital); Robert Hauser (University of South Florida); Neal Hermanowicz (University of California); Melissa Houser (Scripps Clinic); Howard Hurtig (University of Pennsylvania); Stuart Isaacson (Parkinson's Disease and Movement Disorders Center, Boca Raton); Danna Jennings (The Institute for Neurodegenerative Disorders); Aikaterini Kompoliti (Rush University Medical Center); John Morgan (Medical College of Georgia); John Murphy (Associated Neurologists); Paul Nausieda (Wisconsin Institute for Neurologic and Sleep Disorders); Rajesh Pahwa (University of Kansas); Sotirios Parashos (Struthers Parkinson's Center); Padraig O'Suilleabhain (University of Texas); Brad Racette (Washington University School of Medicine); Stephen Reich (University of Maryland); John Roberts (Benaroya Research Institute); Ted Rothstein (George Washington University); Alok Sahay (University Neurology Inc); Marie Saint-Hilaire (Boston University Medical Center); Mya Schiess (University of Texas HSC); Burton Scott (Duke Health Center); Joohi Shahed (Baylor College of Medicine); Tanya Simuni (Northwestern University); Carlos Singer (University of Miami); Robert Smith (University of Texas); Lynn Struck (Iowa Health Physicians); James Sutton (Pacific Neuroscience Medical Group); David Swope (Loma Linda University School of Medicine); Michele Tagliati (Mount Sinai Medical Center); James Tetrud (The Parkinson's Institute); Daniel Togasaki (KECK/USC School of Medicine); Ray Watts (University of Alabama).

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PubMed   |  Link to Article
Starkstein  SE, Preziosi  TJ, Bolduc  PL, Robinson  RG.  Depression in Parkinson’s disease. J Nerv Ment Dis. 1990;178(1):27-31.
PubMed   |  Link to Article
Weintraub  D, Moberg  PJ, Duda  JE, Katz  IR, Stern  MB.  Recognition and treatment of depression in Parkinson’s disease. J Geriatr Psychiatry Neurol. 2003;16(3):178-183.
PubMed   |  Link to Article
Richard  IH, McDermott  MP, Kurlan  R,  et al; SAD-PD Study Group.  A randomized, double-blind, placebo-controlled trial of antidepressants in Parkinson disease. Neurology. 2012;78(16):1229-1236.
PubMed   |  Link to Article
Rocha  FL, Murad  MG, Stumpf  BP, Hara  C, Fuzikawa  C.  Antidepressants for depression in Parkinson’s disease: systematic review and meta-analysis. J Psychopharmacol. 2013;27(5):417-423.
PubMed   |  Link to Article
Mann  JJ, Aarons  SF, Wilner  PJ,  et al.  A controlled study of the antidepressant efficacy and side effects of (-)-deprenyl: a selective monoamine oxidase inhibitor. Arch Gen Psychiatry. 1989;46(1):45-50.
PubMed   |  Link to Article
Sunderland  T, Cohen  RM, Molchan  S,  et al.  High-dose selegiline in treatment-resistant older depressive patients. Arch Gen Psychiatry. 1994;51(8):607-615.
PubMed   |  Link to Article
Chaudhuri  KR, Schapira  AH.  Non-motor symptoms of Parkinson’s disease: dopaminergic pathophysiology and treatment. Lancet Neurol. 2009;8(5):464-474.
PubMed   |  Link to Article
Kehagia  AA, Barker  RA, Robbins  TW.  Cognitive impairment in Parkinson’s disease: the dual syndrome hypothesis. Neurodegener Dis. 2013;11(2):79-92.
PubMed   |  Link to Article
Thobois  S, Lhommée  E, Klinger  H,  et al.  Parkinsonian apathy responds to dopaminergic stimulation of D2/D3 receptors with piribedil. Brain. 2013;136(pt 5):1568-1577.
PubMed   |  Link to Article
Connolly  KR, Thase  ME.  If at first you don’t succeed: a review of the evidence for antidepressant augmentation, combination and switching strategies. Drugs. 2011;71(1):43-64.
PubMed   |  Link to Article
Olanow  CW, Rascol  O, Hauser  R,  et al; ADAGIO Study Investigators.  A double-blind, delayed-start trial of rasagiline in Parkinson’s disease. N Engl J Med. 2009;361(13):1268-1278.
PubMed   |  Link to Article
Fahn  S, Elton  RL; Members of the UPDRS Development Committee. Unified Parkinson's Disease Rating Scale. In: Fahn  S, Marsden  CD, Calne  DB,  et al, eds. Recent Developments in Parkinson's Disease. Florham Park, NJ: Macmillan Health Care Information; 1987:153-163.
Goetz  CG, Tilley  BC, Shaftman  SR,  et al; Movement Disorder Society UPDRS Revision Task Force.  Movement Disorder Society–sponsored revision of the Unified Parkinson’s Disease Rating Scale (MDS-UPDRS): scale presentation and clinimetric testing results. Mov Disord. 2008;23(15):2129-2170.
PubMed   |  Link to Article
Brown  RG, Dittner  A, Findley  L, Wessely  SC.  The Parkinson fatigue scale. Parkinsonism Relat Disord. 2005;11(1):49-55.
PubMed   |  Link to Article
Cohen  J. Statistical Power Analysis for the Behavioral Sciences. New York, NY: Academic Press; 1977.
Thébault  JJ, Guillaume  M, Levy  R.  Tolerability, safety, pharmacodynamics, and pharmacokinetics of rasagiline: a potent, selective, and irreversible monoamine oxidase type B inhibitor. Pharmacotherapy. 2004;24(10):1295-1305.
PubMed   |  Link to Article
Picillo  M, Rocco  M, Barone  P.  Dopamine receptor agonists and depression in Parkinson’s disease. Parkinsonism Relat Disord. 2009;15(suppl 4):S81-S84.
PubMed   |  Link to Article
Robinson  DS, Gilmor  ML, Yang  Y,  et al.  Treatment effects of selegiline transdermal system on symptoms of major depressive disorder: a meta-analysis of short-term, placebo-controlled, efficacy trials. Psychopharmacol Bull. 2007;40(3):15-28.
PubMed
Corrigan  MH, Denahan  AQ, Wright  CE, Ragual  RJ, Evans  DL.  Comparison of pramipexole, fluoxetine, and placebo in patients with major depression. Depress Anxiety. 2000;11(2):58-65.
PubMed   |  Link to Article
Cusin  C, Iovieno  N, Iosifescu  DV,  et al.  A randomized, double-blind, placebo-controlled trial of pramipexole augmentation in treatment-resistant major depressive disorder. J Clin Psychiatry. 2013;74(7):e636-e641.
PubMed   |  Link to Article
Maricle  RA, Nutt  JG, Carter  JH.  Mood and anxiety fluctuation in Parkinson’s disease associated with levodopa infusion: preliminary findings. Mov Disord. 1995;10(3):329-332.
PubMed   |  Link to Article
Maricle  RA, Nutt  JG, Valentine  RJ, Carter  JH.  Dose-response relationship of levodopa with mood and anxiety in fluctuating Parkinson’s disease: a double-blind, placebo-controlled study. Neurology. 1995;45(9):1757-1760.
PubMed   |  Link to Article
Barone  P, Poewe  W, Albrecht  S,  et al.  Pramipexole for the treatment of depressive symptoms in patients with Parkinson’s disease: a randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2010;9(6):573-580.
PubMed   |  Link to Article
Parkinson Study Group.  Effects of tocopherol and deprenyl on the progression of disability in early Parkinson’s disease. N Engl J Med. 1993;328(3):176-183.
PubMed   |  Link to Article
Korchounov  A, Winter  Y, Rössy  W.  Combined beneficial effect of rasagiline on motor function and depression in de novo PD. Clin Neuropharmacol. 2012;35(3):121-124.
PubMed   |  Link to Article
Aarsland  D, Brønnick  K, Alves  G,  et al.  The spectrum of neuropsychiatric symptoms in patients with early untreated Parkinson’s disease. J Neurol Neurosurg Psychiatry. 2009;80(8):928-930.
PubMed   |  Link to Article
Kehagia  AA, Barker  RA, Robbins  TW.  Neuropsychological and clinical heterogeneity of cognitive impairment and dementia in patients with Parkinson’s disease. Lancet Neurol. 2010;9(12):1200-1213.
PubMed   |  Link to Article
Hanagasi  HA, Gurvit  H, Unsalan  P,  et al.  The effects of rasagiline on cognitive deficits in Parkinson’s disease patients without dementia: a randomized, double-blind, placebo-controlled, multicenter study. Mov Disord. 2011;26(10):1851-1858.
PubMed   |  Link to Article
Jokinen  P, Brück  A, Aalto  S, Forsback  S, Parkkola  R, Rinne  JO.  Impaired cognitive performance in Parkinson’s disease is related to caudate dopaminergic hypofunction and hippocampal atrophy. Parkinsonism Relat Disord. 2009;15(2):88-93.
PubMed   |  Link to Article
Sawamoto  N, Piccini  P, Hotton  G, Pavese  N, Thielemans  K, Brooks  DJ.  Cognitive deficits and striato-frontal dopamine release in Parkinson’s disease. Brain. 2008;131(pt 5):1294-1302.
PubMed
Arnaldi  D, Campus  C, Ferrara  M,  et al.  What predicts cognitive decline in de novo Parkinson’s disease? Neurobiol Aging. 2012;33(6):1127e11-e20.
PubMed   |  Link to Article
Happe  S, Baier  PC, Helmschmied  K, Meller  J, Tatsch  K, Paulus  W.  Association of daytime sleepiness with nigrostriatal dopaminergic degeneration in early Parkinson’s disease. J Neurol. 2007;254(8):1037-1043.
PubMed   |  Link to Article
Richard  IH, Kurlan  R, Tanner  C,  et al; Parkinson Study Group.  Serotonin syndrome and the combined use of deprenyl and an antidepressant in Parkinson’s disease. Neurology. 1997;48(4):1070-1077.
PubMed   |  Link to Article
Rascol  O, Fitzer-Attas  CJ, Hauser  R,  et al.  A double-blind, delayed-start trial of rasagiline in Parkinson’s disease (the ADAGIO study): prespecified and post-hoc analyses of the need for additional therapies, changes in UPDRS scores, and non-motor outcomes. Lancet Neurol. 2011;10(5):415-423.
PubMed   |  Link to Article
Lang  AE, Eberly  S, Goetz  CG,  et al; LABS-PD Investigators.  Movement disorder society unified Parkinson disease rating scale experiences in daily living: longitudinal changes and correlation with other assessments. Mov Disord. 2013;28(14):1980-1986.
PubMed   |  Link to Article
Valera  E, Ubhi  K, Mante  M, Rockenstein  E, Masliah  E.  Antidepressants reduce neuroinflammatory responses and astroglial alpha-synuclein accumulation in a transgenic mouse model of multiple system atrophy. Glia. 2014;62(2):317-337.
PubMed   |  Link to Article
Schapira  AH.  Monoamine oxidase B inhibitors for the treatment of Parkinson’s disease: a review of symptomatic and potential disease-modifying effects. CNS Drugs. 2011;25(12):1061-1071.
PubMed   |  Link to Article

Figures

Place holder to copy figure label and caption
Figure.
Randomization and Treatment of Study Participants

The Attenuation of Disease Progression With Azilect Given Once Daily study participants taking an antidepressant at any time during the 36-week, placebo-controlled phase 1 period were included. The efficacy population of 191 participants was assessed at week 36 or at an early termination visit. PD indicates Parkinson disease.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 1.  Descriptive Statistics of Baseline Variables by Antidepressant Use During the Controlled Phasea
Table Graphic Jump LocationTable 2.  Descriptive Statistics of Baseline Variables for Patients Taking Antidepressants During the Controlled Phase by Treatment Assignment
Table Graphic Jump LocationTable 3.  Changes in Nonmotor Symptoms Over Time in the Pooled Rasagiline and Placebo Groups
Table Graphic Jump LocationTable 4.  Frequency of Serious Adverse Events for Antidepressant-Treated Patients

References

Reijnders  JS, Ehrt  U, Weber  WE, Aarsland  D, Leentjens  AF.  A systematic review of prevalence studies of depression in Parkinson’s disease. Mov Disord. 2008;23(2):183-189
PubMed   |  Link to Article
Santangelo  G, Vitale  C, Trojano  L,  et al.  Relationship between depression and cognitive dysfunctions in Parkinson’s disease without dementia. J Neurol. 2009;256(4):632-638.
PubMed   |  Link to Article
Starkstein  SE, Rabins  PV, Berthier  ML, Cohen  BJ, Folstein  MF, Robinson  RG.  Dementia of depression among patients with neurological disorders and functional depression. J Neuropsychiatry Clin Neurosci. 1989;1(3):263-268.
PubMed   |  Link to Article
Starkstein  SE, Preziosi  TJ, Bolduc  PL, Robinson  RG.  Depression in Parkinson’s disease. J Nerv Ment Dis. 1990;178(1):27-31.
PubMed   |  Link to Article
Weintraub  D, Moberg  PJ, Duda  JE, Katz  IR, Stern  MB.  Recognition and treatment of depression in Parkinson’s disease. J Geriatr Psychiatry Neurol. 2003;16(3):178-183.
PubMed   |  Link to Article
Richard  IH, McDermott  MP, Kurlan  R,  et al; SAD-PD Study Group.  A randomized, double-blind, placebo-controlled trial of antidepressants in Parkinson disease. Neurology. 2012;78(16):1229-1236.
PubMed   |  Link to Article
Rocha  FL, Murad  MG, Stumpf  BP, Hara  C, Fuzikawa  C.  Antidepressants for depression in Parkinson’s disease: systematic review and meta-analysis. J Psychopharmacol. 2013;27(5):417-423.
PubMed   |  Link to Article
Mann  JJ, Aarons  SF, Wilner  PJ,  et al.  A controlled study of the antidepressant efficacy and side effects of (-)-deprenyl: a selective monoamine oxidase inhibitor. Arch Gen Psychiatry. 1989;46(1):45-50.
PubMed   |  Link to Article
Sunderland  T, Cohen  RM, Molchan  S,  et al.  High-dose selegiline in treatment-resistant older depressive patients. Arch Gen Psychiatry. 1994;51(8):607-615.
PubMed   |  Link to Article
Chaudhuri  KR, Schapira  AH.  Non-motor symptoms of Parkinson’s disease: dopaminergic pathophysiology and treatment. Lancet Neurol. 2009;8(5):464-474.
PubMed   |  Link to Article
Kehagia  AA, Barker  RA, Robbins  TW.  Cognitive impairment in Parkinson’s disease: the dual syndrome hypothesis. Neurodegener Dis. 2013;11(2):79-92.
PubMed   |  Link to Article
Thobois  S, Lhommée  E, Klinger  H,  et al.  Parkinsonian apathy responds to dopaminergic stimulation of D2/D3 receptors with piribedil. Brain. 2013;136(pt 5):1568-1577.
PubMed   |  Link to Article
Connolly  KR, Thase  ME.  If at first you don’t succeed: a review of the evidence for antidepressant augmentation, combination and switching strategies. Drugs. 2011;71(1):43-64.
PubMed   |  Link to Article
Olanow  CW, Rascol  O, Hauser  R,  et al; ADAGIO Study Investigators.  A double-blind, delayed-start trial of rasagiline in Parkinson’s disease. N Engl J Med. 2009;361(13):1268-1278.
PubMed   |  Link to Article
Fahn  S, Elton  RL; Members of the UPDRS Development Committee. Unified Parkinson's Disease Rating Scale. In: Fahn  S, Marsden  CD, Calne  DB,  et al, eds. Recent Developments in Parkinson's Disease. Florham Park, NJ: Macmillan Health Care Information; 1987:153-163.
Goetz  CG, Tilley  BC, Shaftman  SR,  et al; Movement Disorder Society UPDRS Revision Task Force.  Movement Disorder Society–sponsored revision of the Unified Parkinson’s Disease Rating Scale (MDS-UPDRS): scale presentation and clinimetric testing results. Mov Disord. 2008;23(15):2129-2170.
PubMed   |  Link to Article
Brown  RG, Dittner  A, Findley  L, Wessely  SC.  The Parkinson fatigue scale. Parkinsonism Relat Disord. 2005;11(1):49-55.
PubMed   |  Link to Article
Cohen  J. Statistical Power Analysis for the Behavioral Sciences. New York, NY: Academic Press; 1977.
Thébault  JJ, Guillaume  M, Levy  R.  Tolerability, safety, pharmacodynamics, and pharmacokinetics of rasagiline: a potent, selective, and irreversible monoamine oxidase type B inhibitor. Pharmacotherapy. 2004;24(10):1295-1305.
PubMed   |  Link to Article
Picillo  M, Rocco  M, Barone  P.  Dopamine receptor agonists and depression in Parkinson’s disease. Parkinsonism Relat Disord. 2009;15(suppl 4):S81-S84.
PubMed   |  Link to Article
Robinson  DS, Gilmor  ML, Yang  Y,  et al.  Treatment effects of selegiline transdermal system on symptoms of major depressive disorder: a meta-analysis of short-term, placebo-controlled, efficacy trials. Psychopharmacol Bull. 2007;40(3):15-28.
PubMed
Corrigan  MH, Denahan  AQ, Wright  CE, Ragual  RJ, Evans  DL.  Comparison of pramipexole, fluoxetine, and placebo in patients with major depression. Depress Anxiety. 2000;11(2):58-65.
PubMed   |  Link to Article
Cusin  C, Iovieno  N, Iosifescu  DV,  et al.  A randomized, double-blind, placebo-controlled trial of pramipexole augmentation in treatment-resistant major depressive disorder. J Clin Psychiatry. 2013;74(7):e636-e641.
PubMed   |  Link to Article
Maricle  RA, Nutt  JG, Carter  JH.  Mood and anxiety fluctuation in Parkinson’s disease associated with levodopa infusion: preliminary findings. Mov Disord. 1995;10(3):329-332.
PubMed   |  Link to Article
Maricle  RA, Nutt  JG, Valentine  RJ, Carter  JH.  Dose-response relationship of levodopa with mood and anxiety in fluctuating Parkinson’s disease: a double-blind, placebo-controlled study. Neurology. 1995;45(9):1757-1760.
PubMed   |  Link to Article
Barone  P, Poewe  W, Albrecht  S,  et al.  Pramipexole for the treatment of depressive symptoms in patients with Parkinson’s disease: a randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2010;9(6):573-580.
PubMed   |  Link to Article
Parkinson Study Group.  Effects of tocopherol and deprenyl on the progression of disability in early Parkinson’s disease. N Engl J Med. 1993;328(3):176-183.
PubMed   |  Link to Article
Korchounov  A, Winter  Y, Rössy  W.  Combined beneficial effect of rasagiline on motor function and depression in de novo PD. Clin Neuropharmacol. 2012;35(3):121-124.
PubMed   |  Link to Article
Aarsland  D, Brønnick  K, Alves  G,  et al.  The spectrum of neuropsychiatric symptoms in patients with early untreated Parkinson’s disease. J Neurol Neurosurg Psychiatry. 2009;80(8):928-930.
PubMed   |  Link to Article
Kehagia  AA, Barker  RA, Robbins  TW.  Neuropsychological and clinical heterogeneity of cognitive impairment and dementia in patients with Parkinson’s disease. Lancet Neurol. 2010;9(12):1200-1213.
PubMed   |  Link to Article
Hanagasi  HA, Gurvit  H, Unsalan  P,  et al.  The effects of rasagiline on cognitive deficits in Parkinson’s disease patients without dementia: a randomized, double-blind, placebo-controlled, multicenter study. Mov Disord. 2011;26(10):1851-1858.
PubMed   |  Link to Article
Jokinen  P, Brück  A, Aalto  S, Forsback  S, Parkkola  R, Rinne  JO.  Impaired cognitive performance in Parkinson’s disease is related to caudate dopaminergic hypofunction and hippocampal atrophy. Parkinsonism Relat Disord. 2009;15(2):88-93.
PubMed   |  Link to Article
Sawamoto  N, Piccini  P, Hotton  G, Pavese  N, Thielemans  K, Brooks  DJ.  Cognitive deficits and striato-frontal dopamine release in Parkinson’s disease. Brain. 2008;131(pt 5):1294-1302.
PubMed
Arnaldi  D, Campus  C, Ferrara  M,  et al.  What predicts cognitive decline in de novo Parkinson’s disease? Neurobiol Aging. 2012;33(6):1127e11-e20.
PubMed   |  Link to Article
Happe  S, Baier  PC, Helmschmied  K, Meller  J, Tatsch  K, Paulus  W.  Association of daytime sleepiness with nigrostriatal dopaminergic degeneration in early Parkinson’s disease. J Neurol. 2007;254(8):1037-1043.
PubMed   |  Link to Article
Richard  IH, Kurlan  R, Tanner  C,  et al; Parkinson Study Group.  Serotonin syndrome and the combined use of deprenyl and an antidepressant in Parkinson’s disease. Neurology. 1997;48(4):1070-1077.
PubMed   |  Link to Article
Rascol  O, Fitzer-Attas  CJ, Hauser  R,  et al.  A double-blind, delayed-start trial of rasagiline in Parkinson’s disease (the ADAGIO study): prespecified and post-hoc analyses of the need for additional therapies, changes in UPDRS scores, and non-motor outcomes. Lancet Neurol. 2011;10(5):415-423.
PubMed   |  Link to Article
Lang  AE, Eberly  S, Goetz  CG,  et al; LABS-PD Investigators.  Movement disorder society unified Parkinson disease rating scale experiences in daily living: longitudinal changes and correlation with other assessments. Mov Disord. 2013;28(14):1980-1986.
PubMed   |  Link to Article
Valera  E, Ubhi  K, Mante  M, Rockenstein  E, Masliah  E.  Antidepressants reduce neuroinflammatory responses and astroglial alpha-synuclein accumulation in a transgenic mouse model of multiple system atrophy. Glia. 2014;62(2):317-337.
PubMed   |  Link to Article
Schapira  AH.  Monoamine oxidase B inhibitors for the treatment of Parkinson’s disease: a review of symptomatic and potential disease-modifying effects. CNS Drugs. 2011;25(12):1061-1071.
PubMed   |  Link to Article

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Multimedia

Supplement.

eTable 1. Descriptive Statistics of Baseline Variables by Antidepressant Use at Baseline and Initiation During Phase 1 of the Study

eTable 2. Descriptive Statistics of Baseline Variables for Patients Taking Antidepressant During the Controlled Phase by Rasagiline Dose Assignment

eTable 3. Distribution of Antidepressant Classes at Any Time During the Placebo-Controlled Phase of the Study

eTable 4. Changes in Nonmotor Symptoms Over Time in the Rasagiline Group Separated by Dose

eTable 5. Effect Size for Rasagiline on Depression and Cognition Symptoms

eTable 6. Correlation Between Changes in UPDRS Cognition, Apathy, and Sleep Scores at Week 36 in the Pooled Rasagiline Group

eTable 7. Correlation Between Changes in the UPDRS Motor Score, Cognition Score, and Depression Scores at Week 36 in the Pooled Rasagiline Group

eTable 8. Change in UPDRS Depression Item in the Pooled Rasagiline and Placebo Groups Controlling for Change in the UPDRS Motor Score and Site

eTable 9. Frequency of All Adverse Events for Antidepressant-Treated Patients

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