Pramipexole Successfully Treats Depressive and Motor Symptoms

Pauline Anderson

May 11, 2010

May 11, 2010 — The dopamine agonist pramipexole improves depressive symptoms in patients with Parkinson's disease (PD), according to results of a new double-blind, placebo-controlled trial.

The study, published online May 10 in The Lancet, determined that improvement in depressive symptoms was mainly through a direct antidepressant effect rather than through improved motor symptoms.

The advantage of using a dopamine agent instead of an antidepressant to treat depression in PD patients is that it could mean taking fewer drugs, said lead author Paolo Barone, MD, PhD, from the Department of Neurological Sciences at the University of Naples, Italy.

"Parkinson's disease patients are already on polytherapy, and if we can treat depressive symptoms with an agent that is also able to treat dopaminergic symptoms, we can get 2 effects from 1 pill," said Dr. Barone. "The message for doctors is that before treating your patients with antidepressants, try to optimize antiparkinsonian treatment, including pramipexole."

The study was funded by Boehringer Ingelheim.

Clinically Relevant Depression

The trial included 287 patients at least 30 years of age from 76 centers in 12 European countries and South Africa. Most patients had early or mild to moderate PD. They did not have motor fluctuations and were undergoing stable antiparkinsonian treatment.

Patients also had clinically relevant depressive symptoms as documented by baseline scores of at least 5 on the 15-item Geriatric Depression Scale (GDS-15) and at least 2 on part 1, item 3 (depression) of the Unified Parkinson's Disease Rating Scale (UPDRS).

During the study, subjects were allowed to take antidepressant drugs, such as selective serotonin reuptake inhibitors (SSRIs), if the dose was stable for at least 6 weeks before baseline and remained unchanged.

The patients were randomly assigned to receive pramipexole (0.125, 0.25, 0.5, or 1.0 mg) or placebo. Patients visited study centers for assessment at screening and baseline and then at weeks 1, 2, 3, 5, and 12. Local investigators carried out assessments by telephone at weeks 4, 6, 8, and 10.

The primary endpoint was the change from baseline to 12 weeks in the score on the Beck Depression Inventory (BDI). Secondary outcomes included the proportion of patients with at least a 50% reduction in BDI scores and changes on the motor section (part 3) of the UPDRS, the GDS-15, and other tests.

The researchers also performed a secondary analysis designed to separate direct effects of the treatment from indirect effects

Significant Improvement

Results showed that both the BDI and the UPDRS motor scores improved significantly among patients taking pramipexole compared with those taking placebo. The adjusted mean change in the BDI was −5.9 in the pramipexole group compared with −4.0 in the placebo group (a difference of −1.9; 95% confidence interval [CI], −3.4 to −0.5).

The number of BDI clinical responders was 38 of 139 in the pramipexole group and 27 of 147 in the placebo group.

The UPDRS motor scores decreased by an adjusted mean of 4.4 points in the treatment group and 2.2 points in the placebo group (a difference of 2.2; 95% CI, 0.7 to 3.7; P = .003).

As for GDI-15 scores, the adjusted mean change was −2.5 in the pramipexole group and −1.7 in the placebo group (a difference of −0.8; 95% CI, −1.5 to −0.1).

The adverse events, which included nausea, somnolence, and dyskinesia, were consistent with the known safety profile of pramipexole.

Mostly Direct Effect

The separate analysis determined that 80% of the effect of pramipexole was mediated by a direct effect on depressive symptoms, with the remaining 20% mediated through alleviation of motor symptoms.

"It's difficult to show whether improvement of depressive symptoms with a dopaminergic agent is secondary to improvement of motor symptoms" because improving motor fluctuations tends to also alleviate depressive symptoms, said Dr. Barone. "The tricky point in this study was to disentangle motor from depressive improvement."

In this case, it is not surprising that improvement of depressive symptom was not due to improved motor function because motor fluctuations of the study population were stable to begin with, said Dr. Barone.

Impulsivity Avoided

Impulse control disorder (for example, pathological gambling) occurs in about 5% of people who take a dopamine agonist like pramipexole, although none of the patients in this study developed this adverse effect. Dr. Barone attributes this to the low dose of the drug used in the study, the short treatment duration, and the exclusion of patients with cognitive problems.

This is the largest double-blind, placebo-controlled study of depression treatment in PD to date, according to Dr. Barone. There have been only 2 other recent double-blind, controlled studies — one using the SSRI citalopram and the other the tricyclic antidepressant, desipramine. Both were relatively small.

Results of this research indicate that "there is very little evidence of the efficacy of classic antidepressants in PD," said Dr. Barone. He added that although tricyclic agents may be superior to SSRIs, "we try to avoid tricyclic agents in older people with Parkinson's disease because of the side effects."

Depression is common in patients with PD. In this population, it has a prevalence of 17%, although 35% have clinically significant depressive symptoms, according to background information included in the paper.

Depression in patients with PD might be caused by dysfunction in brain serotoninergic, noradrenergic, and dopaminergic pathways and in particular by dopamine depletion in subcortical-cortical circuits that regulate mood, motivation, and reward, said the study authors.

Two Birds, One Stone

An accompanying editorial by Hubert H. Fernandez, MD, associate professor in the Department of Neurology at the University of Florida, Gainesville, and Marcelo Merello, MD, PhD, from the Movement Disorders Section, Neuroscience Department, Fundcion para la Lucha contra las Enfermedades, Neurologicas de la Infancia, Buenos Aires, Argentina, addresses the question of whether pramipexole can "kill two birds with one stone."

The commentators said the design of the study, for which a diagnosis of depression was not based on strict Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) criteria, "is likely to provide a good representation of clinical practice."

The strategy of considering pramipexole in PD patients with depression "could offer a combined, yet independent, benefit on motor disability and depressive symptoms," they write.

Whether pramipexole is effective for more severe depressive symptoms or for those with more advanced disease remains to be determined, and future studies are needed to determine whether dopamine agonists are as effective as other therapies for depression in PD patients, they conclude.

"For now, however, evidence of a positive effect of one drug on both motor and nonmotor domains is an important addition to the treatment armamentarium against Parkinson's disease."

The study was funded by Boehringer Ingelheim. Dr. Barone has received compensation for consulting services and research support from Boehringer Ingelheim and payment for consulting services and symposia from Novartis, Schwarz Pharma/UCB, Merck-Serono, Eisai, Solvay, General Electric, and Lundbeck. For conflict of interest information on the remaining study authors, please see the original article. Dr. Fernandez and Dr. Merello have disclosed no relevant financial relationship.

Lancet. Published online May 10, 2010.

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