The Nonmotor Symptoms of Parkinson’s Disease: Update on Diagnosis and Treatment

Though the mechanisms are not fully understood, it is suspected that psychosocial as well as neuropathological changes contribute to the pathogenesis of depression in PD. In a study comparing 104 PD patients and 61 patients with equivalent disability scores, functional disability was found to be responsible for only 9% of the variation of depression scores [22]. The increased prevalence of depression in PD patients can in part be explained by the neuropathological changes seen in post-mortem studies. Two neurotransmitters that are fundamental in the pathogenesis of depression are serotonin, from the raphe nuclei, and norepinepherine, from the locus ceruleus [20]. Both of these brainstem structures demonstrate alpha-synucleinopathy-associated degeneration and these changes can precede the development of motor dysfunction [3].

Diagnosing depression in PD is complicated by the fact that there is overlap between other PD symptoms and clinical features of depression (ie, amotivation, bradykinesia, fatigue, and sleep disturbances). However, many depressed PD patients are less likely to report feelings of guilt or failure and tend to have higher rates of anxiety [9,20,25]. Typically, PD patients are more likely to be diagnosed with minor depression or dysthymia rather than a major depressive disorder [19,20]. Formal testing through systematic questionnaires are diagnostically useful in the clinic, and serial testing can reveal changes over time to guide more effective treatment. Validated tools to evaluate depression in PD include the Beck Depression Inventory, Hamilton Depression Rating Scale, Montgomery-Asberg Depression Rating Scale, Geriatric DRS, and Hospital Anxiety and Depression scale [20].

Treatment Options

Treatment of depression in PD demonstrates generally poorer responses to typical antidepressants and side effects that may worsen other PD symptoms. Selective serotonin reuptake inhibitors (SSRIs) have been widely used as there are generally few drug-drug interactions and minimal effect on motor symptoms; however, several studies have demonstrated little benefit on depression in PD [26]. In a randomized, double-blind, placebo-controlled trial of the antidepressants paroxetine and venlafaxine, both were found to be effective and well tolerated [27]. Tricyclic anti-depressants (TCAs) have also demonstrated efficacy. In randomized controlled trials comparing TCAs to SSRIs, a greater benefit on depression symptoms has been found with TCAs [28–30]. The use of TCAs, however, is limited by anticholinergic side effects that occasionally worsen orthostatic hypotension or cognitive impairment [15,31]. Dopamine agonists have also been studied in depressed PD patients. In a randomized, double-blind, placebo-controlled trial [32] and a prospective observational study [33], pramipexole demonstrated significant improvements in depression symptoms. Ropinirole also demonstrated significant symptomatic improvement [34]. These studies suggest that while SSRIs are commonly used, evidence is accumulating to support the role of TCAs, SNRIs, and dopamine agonists in the treatment of depression in PD.

Other therapies have also been tried in pharmacologic-resistant patients. Electroconvulsive therapy has been reported to improve both depression and motor symptoms [35,36]; however, this is a treatment reserved for patients with severe and drug-refractory depression. A randomized controlled trial investigating cognitive behavioral therapy has also demonstrated improvement of depression scores [37]. The role of physical activity as treatment for depression in PD patients is unclear. As described in a recent review by Loprinzi et al [38], the literature is contradictory, with one group experiencing reduced depression but with no signficant effect in several other studies.