Tricyclic Superior to SSRI in Treatment of Depression in Parkinson's Disease

Susan Jeffrey

December 19, 2008

December 19, 2008 — Results of a randomized trial show that the tricyclic antidepressant (TCA) nortriptyline was efficacious in treating depression in Parkinson's disease (PD) patients vs placebo, while paroxetine controlled release (CR), a selective serotonin-reuptake inhibitor (SSRI), was not.

Conclusions from the study are 2-fold, lead author Matthew Menza, MD, professor of psychiatry and neurology at Robert Wood Johnson Medical School, in Piscataway, New Jersey, told Medscape Neurology & Neurosurgery. "One is that depression in Parkinson's disease can respond to antidepressants," he said. "That's something that I think we expected, but no one had shown in a convincing way previously."

But in addition, Dr. Menza added, "We found that the drug that affects both norepinephrine and serotonin, a dual reuptake inhibitor, seemed to be superior to the newer drug that affects only serotonin. That was a little surprising and suggests there's something about depression in Parkinson's disease that involves more than just serotonin. You may have to use a dual reuptake inhibitor to get the best response rates."

The trial results were published online December 17 in Neurology. The study was funded by the National Institute of Neurological Disorders and Stroke.

Compound the Problem

Parkinson's disease affects up to 1 million people in the United States, and of these, about 50% have depression, a comorbidity that is associated with a variety of poorer outcomes, the authors write. Among these are faster progression of physical symptoms, greater decline in cognitive skills and the capacity for self-care, poorer treatment compliance and quality of life, and greater caregiver distress, as well as the personal suffering it causes.

A recent Cochrane review concluded there are insufficient data on effectiveness and safety of antidepressants in PD to guide recommendations (Ghaxi-Noori S et al. Cochrane Database Syst Rev. 2003;3:CD003465). A Veterans Affairs database study in 2007 found that 63% of patients with PD and depression were on SSRIs and only 7% were taking older tricyclic antidepressants (Chen P et al. J Geriatr Psychiatry Neurol. 2007;20:161-165).

Recently, Dr. Menza said, PD advocacy groups have lobbied for more funding to study depression in the setting of Parkinson's disease, a problem that has been largely unaddressed. "So the [National Institute of Health] NIH has been more willing to fund some studies looking at the treatment of depression in PD, and ours was the first one of those to get finished and into press," he said.

In this randomized, controlled trial, the researchers compared nortriptyline, a tricyclic antidepressant, paroxetine CR, an SSRI, and placebo, among 52 patients with PD and depression. The primary outcomes were the change in the Hamilton Depression Rating Scale (HAM-D) and the percentage of depression responders at 8 weeks.

Dosing was flexible, and decisions on dosing made at each visit or between visits if the patients had problems. Paroxetine CR was started at 12.5 mg and could be increased up to 37.5 mg; nortriptyline was started at 25 mg and could be increased to 75 mg, and placebo could be increased from 1 to 3 pills.

"What we found, somewhat surprisingly, is that the older antidepressant, nortriptyline, outperformed both placebo and the newer antidepressant, paroxetine," Dr. Menza said. Nortriptyline was superior to placebo for the change in HAM-D (P < .002), while paroxetine CR was not. There was a trend toward superiority of nortriptyline over paroxetine CR at 8 weeks, they note, but this did not reach statistical significance.

Response rates, defined as a 50% change in the HAM-D score, also significantly favored nortriptyline (P = .024), they note.

Response Rates for Nortriptyline, Paroxetine CR, and Placebo

End Point Nortriptyline Paroxetine CR Placebo
50% Change in HAM-D Score (%) 53 11 24

In planned contrasts of response rates, the authors write, nortriptyline was superior to paroxetine CR (P = .034).

Finally, nortriptyline was superior to placebo on a variety of secondary end points, including sleep, anxiety, and social functioning, while paroxetine CR was not, they conclude. "This really speaks to the point that the advocacy groups have been making, that while everybody's waiting for a better treatment for Parkinson's disease, what difficulties do the patients face day to day?" Dr. Menza. "I think the study showed fairly convincingly that treatment of depression is something that is worthwhile not only for depression itself, but for these other outcomes, such as quality of life, sleep, anxiety, and cognition."

Both active drugs were well tolerated in this study, the authors note. "One of the reasons tricyclics are not used very much anymore is that they're not quite as well tolerated [as SSRIs]," Dr. Menza said. Overall, the drugs were similarly well tolerated, with equal numbers of dropouts in all 3 groups, although there were higher rates of mild constipation, dry mouth, and dizziness with nortriptyline, he added. "So it may well be that in clinical practice, nortriptyline is not going to be as well tolerated as paroxetine, but at least in this trial, we didn’t see any indication of that."

In the paper, the researchers speculate on what the findings may mean for the mechanism of depression in PD. "You certainly can't prove it from a study like this, but it may indicate there are slightly different mechanisms at work in Parkinson's disease relative to those without PD, because in the general population, depression responds quite well to a selective serotonin-reuptake inhibitor."

Their findings also echo those from the basic-science arena, some of which suggest that in PD, which is characterized by degeneration of dopamine in the brain, there may also be issues relating to processing of norepinephrine, he said.

Nortriptyline has the potential to cause cardiac-conduction delay, although this was not seen in this trial, the authors note. Two nontricyclic dual reuptake inhibitors, venlafaxine and duloxetine, have not been evaluated in depression in PD, they add.

"There are ongoing trials evaluating some of these compounds in PD, so we await, with interest, the results of these trials," they conclude. "Further studies, with larger numbers of patients, broader entrance criteria, and antidepressants that affect neurotransmitters other than serotonin, are needed."

Larger, Longer Trials Needed

In an editorial accompanying the paper, Michael S. Okun, MD, and Hubert H. Fernandez, MD, both from the McKnight Brain Institute, in Gainesville, Florida, call the report by Dr. Menza and colleagues an important study, but it yielded conflicting results with those comparing desipramine, a tricyclic antidepressant, with citalopram, an SSRI, in 48 patients with PD and depression.

They suggest, for example, that extending the trial by 4 weeks might have yielded a different outcome, given that paroxetine CR is slower acting and the sample size was small. In addition, tricyclics have an inherent advantage over SSRIs in that they address sleep and anxiety, making up 5 of 17 items on the HAM-D, which "may have had little to do with improving depression," they write.

"What we can conclude from this study is that cumulative data on PD depression are limited and conflicting," Drs. Okun and Fernandez write. "This study reminds us that TCAs are not necessarilyless tolerated and SSRIs may not be as efficacious as currently perceived by practice patterns."

A larger and longer study taking into account the lessons from this study will be important, they add. "Such trials may demonstrate that, for a subpopulation of patients with nonmotor PD symptoms, a TCA may be the right choice."

Dr. Menza acknowledged that more study is needed and called the editorial "appropriately cautious."

"In clinical medicine, 1 study never answers any question in a final way," he said.


The study was funded by a grant from the National Institute of Neurologic Disorders and Stroke. GlaxoSmithKline provided free paroxetine CR and matching placebo. Dr. Menza reports that he has received research support from the National Institutes of Health, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, and Forest Laboratories.

Neurology. Published online December 16, 2008.


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