Treatment-Resistant Depression Linked to Parkinson's

Pauline Anderson

October 02, 2013

Not only is depression a risk factor for Parkinson's disease (PD), but older age and treatment-resistant depression also increase the chances of developing PD in depressed patients, results of a new population-based study suggest.

Researchers found that patients diagnosed with depression are more than 3 times more likely to develop PD than those without depression.

However, study author Albert C. Yang, MD, PhD, Department of Psychiatry, National Chung-Cheng University, and attending psychiatrist, Taipei Veterans General Hospital School of Medicine, Taiwan, doesn't want patients with depression to worry that they will inevitably develop PD.

"I want to be cautious," said Dr. Yang, who is also visiting assistant professor, medicine, Harvard University, Boston, Massachusetts. "I don't want patients with depression to panic. What is important is that we found 2 specific factors that could increase the risk of PD: one is age and the other is difficult-to-treat depression, so not all people with depression have a risk of PD."

The study is published online October 2 in Neurology.

Newly Diagnosed

Using data from the National Health Insurance Research Database in Taiwan, investigators conducted a retrospective cohort study of patients aged 20 years and older who were newly diagnosed with depressive disorder between January 1, 2000, and December 31, 2001. For each patient with depression, they randomly selected from the database 4 age- and sex-matched control patients without psychiatric disease.

The study included 4636 patients with depression and 18,544 patients without depression.

Between 2002 and 2009, 66 patients with depression (1.42%) and 97 controls (0.52%) were diagnosed with PD. After adjustment for age and sex, the hazard ratio (HR) for developing PD during follow-up was 3.24 times (95% confidence interval [CI], 2.36 - 4.44; P < .001) greater for patients with depression than for controls.

The risk of developing PD continued long term. After exclusion of patients diagnosed with PD within the first 2 years of follow-up, the HR for developing PD in the remaining patients with depression was still higher than in controls (HR, 3.10). It was also higher after exclusion of those with PD diagnosed within the first 5 years of enrollment (HR, 2.84).

According to Dr. Yang, this new information points to depression being an independent risk factor for PD rather than an early symptom.

Analysis also revealed that older age (odds ratio, 1.09; 95% CI, 1.07 - 1.11; P < .001) was a risk factor for PD in those with depression. When the researchers divided the cohort into those under 65 years and those 65 years and older, the HR for developing PD was 10.39 times greater for the older patients than for the younger ones.

"New-onset depression in the elderly could be risk factor for PD," said Dr. Yang.

Difficult-to-treat depression, for which antidepressant treatment regimens, each lasting more than 60 consecutive days, were altered 2 or more times in the first 2 years after diagnosis, was another risk factor for PD in those with depression (odds ratio, 2.18; 95% CI, 1.18 - 4.02; P = .013) This finding, according to the authors, may imply that neurotoxicity of depression is related to depression resistance, and the more resistant the depression, the higher the risk for PD in these patients.

Patients with depression that is difficult to treat often use medications besides antidepressants, such as antipsychotics. Dr. Yang speculates that this may indicate more complicated cases, which may contribute to the increased risk for PD.

Nonspecialist Diagnoses

The risk for PD was not confined to patients whose depression was diagnosed by a specialist. A sensitivity analysis found that the HR for developing PD was 2.52 times greater in patients with depressive illness newly diagnosed by psychiatrists or nonpsychiatrists, such as general practitioners, than in the control patients. It's not uncommon in Taiwan for family doctors to diagnose depression and prescribe antidepressants, said Dr. Yang.

Could antidepressants themselves increase the risk for PD? "In our study, there was no difference in antidepressant use between those with depression with PD and those with depression without PD, suggesting that antidepressant use is not really a factor," said Dr. Yang. "We argue that there are other factors, probably depression itself, that cause PD."

Interestingly, sex was not a risk factor for developing PD. This could be because, unlike in North America, prevalence of PD among men in Taiwan is similar to that among women.

Impaired monoamine neurotransmission and chronic inflammation may explain part of the relationship between depression and PD. Dr. Yang surmised that dopamine and serotonin may play a role in both disorders. He noted that some depressive patients have dopamine-related symptoms, such as lack of energy.

The study did not consider information on family history of PD; lifestyle factors, such as tobacco and coffee use; or environmental factors, such as exposure to pesticides. Another possible limitation was that the Taiwanese database didn't carry depression ratings, but it did provide information on medication history; this, said Dr. Yang, indicated difficult-to-treat cases and provided "the only feasible measure" of depression severity.

Dr. Yang and his research associates are now carrying out imaging studies of patients with PD both with and without depression. Using functional MRI, they aim to determine whether there are any differences in brain circuitry.

PD is the second most common neurodegenerative disease after Alzheimer disease. Its worldwide prevalence is estimated to be 1% to 2% for people older than 65 years.


Invited to comment on this new study, Rajesh Pahwa, MD, director, Parkinson's Disease and Movement Disorder Center, University of Kansas Medical Center, said that including difficult-to-treat or resistant depression as a possible risk factor for PD has several limitations.

"This is a retrospective study using an insurance database, so although it's interesting, I would like to see this confirmed with other studies." he said "As well, diagnosis of PD and depression was by independent clinicians using their own diagnostic criteria."

Dr. Pahwa stressed that depression has already been shown to be a "premotor symptom" of PD, occurring before the actual diagnosis of PD, and a possible risk factor for PD.

The study was supported by Taipei Veterans General Hospital and Taiwan National Science Council. The authors have disclosed no relevant financial relationships.

Neurology. Published online October 2, 2013. Abstract


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