Recognizing and Treating Neuropsychiatric Symptoms in Parkinson's Disease

Suicide is not common in PD, however suicidal ideation is estimated at about 11% in PD patients [90], and while there was concern initially after deep brain stimulation procedures began that suicide incidence was increased, evidence does not support this [91].

Pathophysiology

The pathophysiology of depression in PD is largely unknown however is thought to be less causally due to psychosocial factors and more etiologically driven by brainstem monoamine and serotonergic dysfunction [92]. Nonetheless, similar to other chronic conditions, PD patients can certainly develop fear of disability, guilt about impact on others, or other reactive mood changes. Overall, rates of depression are higher in PD compared with patients with similar conditions matched for disability [93].

Treatment

First, the clinician must determine if depression is a result of short-term fluctuations, chronic undertreatment of motor disease, or longer-term mood phenomenon. One important pattern to recognize are mood fluctuations, which can parallel motor OFF-ON cycling. It can be valuable to distinguish this as “subsyndromic” depression or anxiety (sometimes referred to as “OFF dysphoria”), as it can respond to improvement in antiparkinsonian medication dosing patterns that reduce fluctuations[94–96]. Similarly, elevating chronic motor undertreatment to goal therapy can result in mood normalization.

If symptoms persist despite optimization of motor/nonmotor fluctuations or chronic undertreatment and are severe enough to warrant treatment, then therapies used can range from nonpharmacologic education, support, and mental health referrals, as well as pharmacologic support in the form of medications.

A frequent but uncontrolled observation was that when undertreatment of motor disease was finally redressed, mood often improved. A multicenter randomized controlled trial of pramipexole in PD patients without motor fluctuations but with mild to moderate depressive symptoms showed the drug improved scores on the Beck Depression Inventory over a 12-week period. The improvement in mood was 6 points overall, but by 2 points over placebo, illustrating the importance of the size of the placebo effect [97]. Given the potential side effect profile of dopamine agonists, it may be useful to weigh the antidepressant effects only when their motor benefits are already being employed.

Controlled trials have demonstrated efficacy of both selective serotonin reuptake inhibitors (SSRI) and selective norepinephrine reuptake inhibitors (SNRI) antidepressants in PD. Clinical trials have demonstrated efficacy against placebo or with other antidepressant comparators. Examples of drugs with demonstrated efficacy include citalopram, paroxetine, venlafaxine, and nortriptyline. Results have attempted to illuminate the small unique differences between classes of antidepressants or dynamic properties between drugs within a class. For example, desipramine may nudge scores on a mood scale a few weeks sooner than a purer SSRI. Paroxetine (SSRI) versus venlafaxine (SNRI) improved mood scores comparably in a multicenter trial with a placebo comparator. In general, all have all been demonstrated to be effective and with a relatively low side-effect profile, comparable to the general population[98–102]. While case reports exist in the literature, the interaction of monoamine oxidase B inhibitors and SSRIs has not caused significant hypertensive crises or risk of serotonin syndrome [103,104]. Electroconvulsive therapy (ECT) can be used for severe refractory depression in PD as for non-PD patients, with case reports of very effective results. Due to the rarity of use, systematic evidence for its use is lacking [105,106].