Newer Agents Effective in Parkinson's Disease Depression

Pauline Anderson

April 11, 2012

April 11, 2012 — For the first time, research has demonstrated the efficacy of a serotonin and norepinephrine reuptake inhibitor (SNRI) in treating depression in patients with Parkinson's disease (PD).

Results of a randomized trial show that both venlafaxine extended-release (XR), an SNRI, and paroxetine, a selective serotonin reuptake inhibitor (SSRI), are superior to placebo in treating depressive symptoms in patients with PD.

The study, the largest of its kind, also demonstrated the safety of these antidepressant drugs. Importantly, the agents did not significantly worsen PD motor function.

"The study demonstrated that both of these agents were effective and that neither one worsens Parkinson's motor function or the physical symptoms of PD," said the study's lead author, Irene H. Richard, MD, associate professor, neurology and psychiatry, University of Rochester, New York. "These agents should be the first line treatment for depression in PD patients."

The results should change the view that tricyclic antidepressants are the preferred treatment for depression in PD, the researchers suggest.

"I don't think this proves that these other drugs are more effective than tricyclics because we haven't actually compared that, but it shows that they are effective and we know that they are better tolerated and have less associated potential for toxicity like cardiac toxicity," said Dr. Richard.

The results are published online April 11 and will appear in the April 17 issue of Neurology.

Study of Antidepressants in PD

The Study of Antidepressants in PD (SAD-PD) included 115 patients from 20 centers in the United States, Canada, and Puerto Rico. Patients were 30 years of age or older and had a diagnosis of idiopathic PD, without dementia. They also met criteria for depressive disorder (Hamilton Rating Scale for Depression [HAM-D] score > 12), with more than half having major depressive disorder.

The patients were randomly assigned in a double-blind fashion to 12 weeks of treatment with paroxetine (n = 42), venlafaxine XR (n = 34), or placebo (n = 39). Eighteen patients withdrew from the study — 10 of these (6, 2, and 2 patients in the paroxetine, venlafaxine XR, and placebo groups, respectively) because of adverse events.

Researchers used 4 different depression rating scales: the HAM-D (change on this 17-item scale was the primary outcome measure), the Montgomery-Asberg Depression Rating Scale, the Beck Depression Inventory, and the Geriatric Depression Scale. Investigators also measured PD motor function and quality of life using the Unified Parkinson's Disease Rating Scale (UPDRS).

All 3 treatment groups improved on the HAM-D scale, but the effects of paroxetine and venlafaxine XR relative to those of placebo were both statistically significant.

Table. Mean Change in HAM-D Score by Treatment

Treatment Mean Change in Active Treatment Group Mean Change in Placebo Group Change vs Placebo (97.5% Confidence Interval) P Value
Paroxetine −13.0 −6.8 −6.2 (−10.3 to −2.2) .0007
Venlafaxine XR −11.0 −6.8 −4.2 (−8.4 to −0.1) .02


For the secondary depression outcomes, beneficial effects of the medications relative to placebo were also seen.

"Despite the fact that there was a significant placebo response, the patients in the treatment groups did even better," said Dr. Richard. "I'd say that either an SSRI or an SNRI should be our first line of treatment because we now have data to support their use."

Significantly, the active treatments were well tolerated. UPDRS total and motor scores improved in all 3 groups. There was no evidence of worsening of motor function associated with the treatments.

"Depression is incredibly common in PD and I think to date we've not been very good at recognizing that," commented Dr. Richard. "It's now more important than ever to make sure that we recognize it because now we know that we have safe and effective treatments."

Some Caveats

In an accompanying editorial, Joseph H. Friedman, MD, Department of Neurology, Butler Hospital, Providence, Rhode Island, and Daniel Weintraub, MD, Department of Neurology, University of Pennsylvania, Philadelphia, said the study authors should be congratulated for "an important and well done job."

The study "gives clinicians and patients with PD scientific evidence to support the use of newer antidepressants, specifically SSRIs and SNRIs, for the treatment of depression in patients with PD without dementia," they write.

However, they added that there are some caveats. For one thing, no data indicate whether the results generalize to more severely affected patients with PD. They also found it surprising that there was no effect on anxiety or cognition because these are so closely associated with depression.

In their editorial, Dr. Friedman and Dr. Weintraub also noted that the sample was only half the projected enrollment. "With depression affecting somewhere between 30% and 50% of patients with PD, it is startling to note that 20 sites, with experienced investigators and large populations, recruited an average of 1 subject/site every 8 months," they write.

In response, Dr. Richards commented how "incredibly difficult" it is to involve patients in clinical trials, especially those that include medications that are already available by prescription.

"It's not as if we're offering them the potential for something they couldn't otherwise get," said Dr. Richard, adding that prospective study participants were already depressed and so had decreased motivation and also probably weren't keen to be receive a placebo.

Supported by National Institutes of Health (NIH)/National Institute of Neurological Disorders and Stroke (NINDS) and the General Clinical Research Center at Johns Hopkins University School of Medicine (National Center for Research Resources/NIH). Wyeth Pharmaceuticals provided venlafaxine XR and matching placebo. Glaxo-Smith Kline provided paroxetine. 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 National Institutes of Health/National Institute of Neurological Disorders and Stroke, Cornell University, and the Michael J. Fox Foundation. For conflict of interest information on other authors, see original paper. Dr. Friedman serves on scientific advisory boards of and as a consultant for Teva Pharmaceutical Industries Ltd., EMD Serono Inc, ACADIA Pharmaceuticals, Genzyme Corporation, and Addex; has received funding for travel or speaker honoraria from Teva Pharmaceutical Industries Ltd., Boehringer Ingelheim, GlaxoSmithKline, United BioSource Corporation, and SCHWARZ PHARMA. Dr. Weintraub serves on scientific advisory boards for Pfizer Inc, CHDI, Teva Pharmaceutical Industries Ltd, Avanir Pharmaceuticals, and Merck Serono; has received funding for travel or speaker honoraria from Novartis and Teva Pharmaceutical Industries Ltd. For additional conflict of interest information, see original editorial.

Neurology. Published online April 11, 2012. Abstract Editorial Extract