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Management of nonmotor symptoms in Parkinson disease

Management of nonmotor symptoms in Parkinson disease
Authors:
Lana Chahine, MD
Daniel Tarsy, MD
Section Editor:
Howard I Hurtig, MD
Deputy Editor:
April F Eichler, MD, MPH
Literature review current through: Feb 2022. | This topic last updated: Sep 14, 2021.

INTRODUCTION — Parkinson disease (PD) is a chronic, progressive neurodegenerative disease characterized by bradykinesia (slowness of movement) and hypokinesia (reduced amplitude of movement) combined with rest tremor and/or rigidity. The clinical features most suggestive of idiopathic PD rather than an atypical or secondary parkinsonian syndrome include asymmetric or unilateral onset, the presence of resting tremor, and a clear-cut response to treatment with L-dopa.

In addition to these typical motor features, patients with PD may experience nonmotor symptoms related to the disease itself or to the medications used to treat it. These include various neuropsychiatric manifestations including cognitive dysfunction, hallucinations and other psychotic symptoms, anxiety, apathy, and mood disorders such as depression [1]. Disorders of sleep and wakefulness are common, including insomnia, parasomnias, restless legs syndrome (RLS), and daytime sleepiness. Autonomic problems are also prominent, including orthostatic hypotension, sexual dysfunction, and constipation.

Management of these nonmotor symptoms will be reviewed here. Dementia in PD and the clinical features of nonmotor symptoms in PD are discussed separately. (See "Cognitive impairment and dementia in Parkinson disease" and "Clinical manifestations of Parkinson disease", section on 'Nonmotor symptoms'.)

Other aspects of PD are reviewed elsewhere. (See "Etiology and pathogenesis of Parkinson disease" and "Diagnosis and differential diagnosis of Parkinson disease" and "Initial pharmacologic treatment of Parkinson disease" and "Nonpharmacologic management of Parkinson disease" and "Medical management of motor fluctuations and dyskinesia in Parkinson disease" and "Device-assisted and lesioning procedures for Parkinson disease".)

DEPRESSION — Depression is one of the most common psychiatric disturbances seen in PD. Depressive symptoms in PD are associated with increased motor disability and decreased quality of life. (See "Clinical manifestations of Parkinson disease", section on 'Mood disorders'.)

Treatment — Patients with depression should be offered antidepressant medication, cognitive behavioral therapy (CBT), or both.

Importantly, suicidal ideation and thoughts of death are common in PD. In surveys, such thoughts are present in 20 to 33 percent of patients [2], and depression is an important risk factor [3,4]. Though suicide attempts are fortunately uncommon, actively suicidal patients should be hospitalized [3].

In the absence of a clear first choice for treating depression associated with PD, drug selection should be based on potential advantages versus potential side effects [1,5]. It is reasonable to start with a selective serotonin-norepinephrine reuptake inhibitor (SNRI) or a selective serotonin reuptake inhibitor (SSRI) in most patients with PD, as the likelihood of adverse events is lower with these agents than with tricyclics such as amitriptyline (and nortriptyline, to a lesser extent) [1]. The anticholinergic side effects of tricyclic medications, which can include cognitive impairment and orthostatic hypotension with an increased risk of falls, may be particularly troublesome in the setting of PD [6]. However, for patients who do not improve with SNRI or SSRI treatment, a tricyclic antidepressant is a reasonable option, particularly when tremor is a dominant symptom and the potential benefit is thought to outweigh the risk of anticholinergic side effects.

A practice parameter from the American Academy of Neurology (AAN) reviewed six small, randomized controlled trials of pharmacologic treatment for depression in patients with PD [6]. In one of these trials, amitriptyline but not fluoxetine treatment was associated with significant improvement [7]. The AAN found insufficient evidence to support or refute the effectiveness of other antidepressant medications in this setting.

Since the AAN report, a number of randomized placebo-controlled trials have reported the following observations regarding the treatment of depression in patients with PD:

Desipramine and citalopram were equally effective [8]

Nortriptyline was efficacious while paroxetine controlled release was not [9]

Atomoxetine was not beneficial [10]

Paroxetine and venlafaxine improved depression and did not worsen motor function [11]

Evidence from other randomized controlled trials suggests that dopamine agonists may improve depressive symptoms in patients with PD [1,12-14].

Abundant data in the general population, as well as more limited data in patients with PD, indicate that CBT is also an effective treatment for depression in PD. In a pilot randomized trial of CBT versus observation in eight patients with PD, the CBT group had improved depression scores at 10 weeks [15]. A larger trial of telephone-based CBT in 72 patients with PD found improvements in depression scores over usual care, which were moderated primarily by a decrease in negative thoughts [16]. In the absence of additional evidence specifically in the PD population, data on the treatment of depression in older adults indicate that combining CBT with pharmacotherapy is superior to pharmacotherapy alone for the treatment of depression, and this should be considered in PD. There are limited and conflicting data on the efficacy of repetitive transcranial stimulation in patients with PD [1].

Overviews of depression in adults, including clinical manifestations and treatment, are found separately. (See "Unipolar depression in adults: Assessment and diagnosis" and "Unipolar major depression in adults: Choosing initial treatment".)

Safety considerations with SSRI use — SSRIs and SNRIs are generally safe in patients with PD. However, they can cause QT prolongation, and monitoring for this is essential where indicated, for example, when patients are known to be on other medications that cause QT prolongation and/or in patients with underlying heart disease.

Additional considerations include the following:

Exacerbation of motor symptoms – SSRIs carry a risk of exacerbating motor symptoms. SSRIs may induce or worsen dystonia, akathisia, tremor, and parkinsonism [17]. Patients with increased susceptibility to exacerbation of motor symptoms due to advanced age [18] or higher SSRI plasma levels because of drug-drug interactions [19] may be at greater risk for this complication. However, the risk of these motor complications is relatively low. Three prospective, open-label studies of several different SSRIs in patients with PD with [20,21] or without [22] depression have shown no worsening of quantitative motor scores following treatment lasting one to six months. Among the SSRIs, sertraline may be the least likely of SSRIs to worsen motor symptoms.

Exacerbation of comorbid sleep disorders – SSRIs and other antidepressants have the potential to worsen restless legs syndrome (RLS) and rapid eye movement sleep behavior disorder (RBD). Patients starting an SSRI, SNRI, or tricyclic antidepressant must be monitored for emergence or exacerbation of symptoms of RLS and RBD. Bupropion is commonly used for management of depression in PD, though little evidence supports its use. Of antidepressants, it is least likely to exacerbate RLS and RBD.

Serotonin syndrome – Serotonin syndrome is another uncommon but serious adverse event associated with SSRIs, especially when they are used in conjunction with other medications that can increase serotonin. Serotonin syndrome is a potentially severe condition associated with increased serotonergic activity in the central nervous system and severely disturbed mental, motor, and autonomic function. (See "Serotonin syndrome (serotonin toxicity)".)

The monoamine oxidase type B (MAO B) inhibitors selegiline and rasagiline should be used only at recommended doses and with caution when combined with other antidepressants, including tricyclics and SSRIs, because of the risk of causing the serotonin syndrome [23]. Despite this theoretical risk, movement disorder specialists often use an MAO B inhibitor and an antidepressant for patients with PD without causing serotonin syndrome. The risk of the serotonin syndrome is uncertain but is low. Two chart reviews have shown no serious side effects in a total of 48 patients receiving selegiline and an SSRI [24,25]. Another study surveyed 47 specialists who manage PD and reported that among 4568 patients treated with a combination of selegiline and an antidepressant, symptoms consistent with the serotonin syndrome were observed in only 11 (0.24 percent) [23]. The most reassuring data come from a post hoc analysis of a large randomized controlled trial of rasagiline in PD [26]. Among 1174 patients with early PD randomized to rasagiline or placebo, 191 patients were treated concurrently with antidepressants (76 percent with an SSRI, 21.4 percent with a tricyclic antidepressant). There were no serious adverse events suggestive of serotonin syndrome in the combined rasagiline-antidepressant group.

Published and US Food and Drug Administration-reported cases of adverse effects of selegiline-antidepressant combinations are also very few, and most do not fulfill criteria for the serotonin syndrome. At higher-than-recommended doses (10 mg daily for selegiline; 1 mg daily for rasagiline) the MAO B inhibitors may also inhibit MAO A and, when given with an antidepressant, carry the risk of the tyramine "cheese" reaction, characterized by a severe hypertensive crisis. However, this reaction is rare when the MAO B inhibitors are given at recommended doses.

APATHY — Apathy and abulia can be seen in patients with PD both in the context of depression and in the absence of other signs of clinical depression. Patients with PD who have apathy as a feature of depression should be treated with antidepressant medications and/or psychotherapy, as in other patients with depression. (See 'Treatment' above.)

There are no standardized treatments for apathy or abulia in the absence of depression or for persistent apathy despite treatment of depression. Based on results of a single small trial, the cholinesterase inhibitor rivastigmine may be considered [1], even in those without depression or cognitive dysfunction [27]. However, the clinical relevance and reproducibility of the changes observed in the trial are uncertain, and further studies are needed.

ANXIETY — Anxiety is common in patents with PD, occurring in over a third of patients. It may occur alone, or it may be comorbid with depression.

Importantly, anxiety may be a symptom of wearing off of dopaminergic medication in patients who experience motor and nonmotor fluctuations [28]. In such cases, management focuses primarily on levodopa dosing adjustments and other strategies to mitigate "wearing off" phenomena. Clinicians should also be aware that akathisia occurs in patients with PD and should be differentiated from anxiety, which may cause similar clinical manifestations. Like anxiety, akathisia may occur either spontaneously in patients with PD or due to end-of-dose levodopa withdrawal. (See "Medical management of motor fluctuations and dyskinesia in Parkinson disease", section on 'Approach to "wearing off"'.)

Evidence to guide the therapy of anxiety in the remaining patients with PD is limited and comes mainly from randomized trials for treatment of depression in PD, in which anxiety was a secondary outcome. A pooled analysis of these trials indicated some benefit from antidepressants on anxiety in PD [29].

Selective serotonin reuptake inhibitors (SSRIs) such as citalopram and sertraline, serotonin-norepinephrine reuptake inhibitors (SNRIs) such as venlafaxine and mirtazapine, and serotonin-selective agents such as buspirone may all be considered. Doses and safety considerations do not differ from use of these agents for treatment of depression. (See 'Safety considerations with SSRI use' above.)

Nonpharmacologic therapies such as mindfulness-based interventions have not been well studied, but preliminary data suggest they may be of utility [30].

Therapeutic use of cannabinoids is of interest in patients with PD and nonmotor symptoms, especially anxiety and sleep disturbances. A small pilot trial of synthetic nabilone (not available in the United States) found potential benefits on anxiety, sleep, and pain symptoms, with similar adverse effects compared with placebo [31]. In addition, a small randomized, placebo-controlled crossover study showed that a single dose of cannabidiol decreased anxiety symptoms including anxiety-related tremor in patients with PD [32]. Beneficial effects on anxiety have also been observed in adults without PD [33]. These preliminary findings are promising but require confirmation in larger studies before cannabinoids can be recommended for treatment of nonmotor symptoms in PD.

COGNITIVE IMPAIRMENT — While PD can coexist with other common causes of dementia, such as Alzheimer disease and vascular dementia, cognitive impairment and dementia are increasingly recognized as a common feature of PD itself. The diagnosis and management of dementia associated with PD are discussed separately. (See "Cognitive impairment and dementia in Parkinson disease".)

PSYCHOSIS

Clinical manifestations and causes — Psychosis is a frequent complication of PD. It is characterized mainly by visual hallucinations and delusions, which are often paranoid in content [34]. Hallucinations are the most common manifestation, and they affect up to 40 percent of patients with PD, particularly those at an advanced stage of illness.

The adverse effects of antiparkinson medications, the dopamine agonists in particular, are probably the most important cause of psychosis in patients with PD. Psychosis may also be triggered by infection, delirium, dementia, or medications. Underlying dementia predisposes to hallucinations and delusions, and psychosis is a risk factor for nursing home placement and mortality. (See "Clinical manifestations of Parkinson disease", section on 'Psychosis and hallucinations'.)

Evaluate and treat triggers — Management of psychosis in patients with PD (algorithm 1) involves identifying and treating the underlying causes and contributory factors [35], including general measures that are similar to the treatment of delirium. (See "Delirium and acute confusional states: Prevention, treatment, and prognosis".)

Psychosis can be triggered by systemic conditions such as symptomatic or occult infection (eg, pneumonia or urinary tract infection), so this possibility should be investigated and treated if present [35,36]. Anticholinergics can contribute to confusion and exacerbate psychosis in PD. Psychoactive medications, including sedatives, anxiolytics, and antidepressants, are potential culprits and should be reduced or stopped if possible.

Antiparkinson medication adjustments — Stopping all potentially offending antiparkinson drugs is usually not an option, although dose reduction can frequently be accomplished with amelioration of hallucinations and little loss of drug-related benefit.

Antiparkinsonian drugs may be reduced or stopped in an order that balances their potency as antiparkinson agents and their likelihood of exacerbating disabling hallucinations. Decisions regarding which drug to stop in this setting should also take into account which one drug might have triggered the psychosis. For example, if a patient's hallucinations began immediately after adding a catechol-O-methyl transferase (COMT) inhibitor to the combination of other drugs that had been previously well tolerated, then the COMT inhibitor should be stopped first.

If a temporal relationship is not clear, the suggested sequence of discontinuation begins with anticholinergic drugs, followed by amantadine, dopamine agonists, monoamine oxidase type B (MAO B) inhibitors, and COMT inhibitors (algorithm 1). Levodopa should be the last of a drug combination to be reduced, since it is the most effective antiparkinson agent and least likely to cause psychosis. However, if given in unusually high doses, it too might need to be reduced.

Role of cholinesterase inhibitors for dementia — Although the data are inconsistent, a potential benefit of cholinesterase inhibitors for improvement in neuropsychiatric symptoms in patients with PD dementia and dementia with Lewy bodies has been suggested by some studies [1]. However, these drugs do not appear to improve neuropsychiatric symptoms to a clinically significant extent. (See "Management of neuropsychiatric symptoms of dementia", section on 'Antidementia drugs'.)

Refractory psychotic symptoms — For patients with troublesome hallucinations or delusions despite antiparkinson medication adjustments, pharmacologic treatment directed at the psychotic symptoms may be necessary. If antipsychotic drugs are deemed necessary, preferred agents in patients with PD include quetiapine, pimavanserin, and clozapine [1].

All antipsychotic drugs carry risk, including an association with a small increase in all-cause mortality and cardiovascular events when used to treat behavioral disorders in older adults with dementia. In patients with PD specifically, data also suggest that antipsychotic use is associated with an increased risk of mortality [37] as well as morbidity and health care utilization [38]. However, these risks must be balanced with the high morbidity and mortality of untreated psychosis [6]. When the potential benefits are felt to outweigh the risks, antipsychotics should be prescribed cautiously, starting with low doses and using the lowest dose necessary to achieve clinical response. The need for ongoing dosing should be reviewed regularly. (See "Management of neuropsychiatric symptoms of dementia", section on 'Excess mortality'.)

Among antipsychotics, quetiapine is widely prescribed in patients with PD and clozapine may be the most effective, but the need for hematologic monitoring limited its use as a first-line option [35,36,39-44]. Pimavanserin is a newer alternative, and long-term safety and efficacy data are more limited. Due to limited head-to-head comparisons, treatment decisions should be individualized, taking into account these considerations as well as factors that are likely to vary by patient and region, such as drug costs. All three agents have a low likelihood of exacerbating parkinsonism, in contrast to the first-generation antipsychotics as well as other second-generation antipsychotics such as risperidone and olanzapine. (See "Drug-induced parkinsonism", section on 'Causative drugs'.)

Quetiapine – Evidence for the efficacy of quetiapine in patients with PD is mixed [14]. Supportive data include multiple observational studies, in which an improvement in psychosis was reported in approximately 80 percent of patients, and two partially blinded randomized trials comparing quetiapine and clozapine showing similar efficacy for PD-related psychosis [45]. However, only one of five small placebo-controlled trials has shown a benefit for quetiapine compared with placebo. Despite these inconsistent data, there seems to be some practical value of quetiapine in clinical practice, and it remains a widely used antipsychotic for dopaminergic-induced psychosis.

Quetiapine should be started at a low dose (eg, 12.5 mg at night) and may be titrated up to 100 mg at night according to response and tolerability. Quetiapine is sedating, and this property can be taken advantage of with evening/bedtime dosing to target exacerbation of confusion and psychosis with nightfall ("sundowning") and comorbid insomnia, when present. In some cases, evening/bedtime dosing is sufficient to control daytime psychotic symptoms, but in other cases, dosing during the day is required as well (usually in the morning, starting also at 12.5 mg and titrating upward as needed to a maximum of 100 mg). In such instances, daytime dosing can lead to or exacerbate daytime sleepiness, and the balance of risks and benefits must be continually reassessed.

Like other antipsychotic drugs, quetiapine is associated with QT prolongation. Additional side effects are reviewed in more detail separately. (See "Second-generation antipsychotic medications: Pharmacology, administration, and side effects", section on 'Adverse effects'.)

PimavanserinPimavanserin is a second-generation antipsychotic drug that acts as a selective serotonin 5-HT2A receptor inverse agonist. It was approved by the US Food and Drug Administration in 2016 for treatment of psychosis in patients with PD but has not been approved in Europe. It has also been studied in dementia-related psychosis in patients with Alzheimer dementia as well as PD-associated dementia [46]. (See "Management of neuropsychiatric symptoms of dementia", section on 'Clinical use'.)

Dosing – The usual dose of pimavanserin is 34 mg daily (two 17 mg tablets or one 34 mg capsule taken once, in the morning).

Adverse effects – The most common side effects are peripheral edema, nausea, and constipation. Rare but serious adverse effects include syncope, hypotension, and bradycardia. Like other antipsychotic drugs, pimavanserin is associated with QT prolongation. (See "Second-generation antipsychotic medications: Pharmacology, administration, and side effects", section on 'Adverse effects'.)

There are also concerns that pimavanserin, like antipsychotic drugs more generally, may increase the risk of mortality in patients with PD. In an administrative claims database cohort study of >20,000 adults ≥65 years of age with PD living in long-term care facilities in the United States, pimavanserin use, compared with nonuse, was associated with an increased risk of 30-day hospitalization (adjusted hazard ratio [aHR] 1.24, 95% CI 1.06-1.43) as well as mortality at multiple time points, including one year (aHR 1.56, 95% CI 1.42-1.72) [47]. The study used inverse probability of treatment weighting to adjust for potential confounding, and sensitivity analyses using several other methods showed generally similar results. However, residual confounding remains possible based on the retrospective nature of the study. As discussed above, the possibility of harm should be discussed with patients and families and weighed against the risks of alternative therapies for psychosis.

Efficacy – Supportive evidence consists of a six-week randomized placebo-controlled trial of pimavanserin in 199 patients with PD-related psychosis [48]. Compared with placebo, pimavanserin (40 mg daily) led to a 3-point greater reduction in scores on a 45-point PD-adapted scale for assessment of positive symptoms (PD-SAPS) from baseline to day 43. Treatment was not associated with worsening of motor symptoms. More patients discontinued therapy due to an adverse effect in the pimavanserin group (10 versus 2 patients), but the rate and type of individual adverse effects were otherwise balanced between treatment groups.

In an open-label follow-up study of patients enrolled in three randomized trials and a previous open-label study (n = 459, mean age 71 years, median follow-up 15 months), no new safety findings emerged, although a high rate of attrition over the course of the study limits confidence [49]. Only 15 patients (3.3 percent) had adverse effects reported as serious and drug related, including syncope, hypotension, and bradycardia. The rate of significant QT prolongation (QTc >500 milliseconds) over the course of the study was 2.6 percent. The overall rate of discontinuation at 48 months was 81 percent, most frequently voluntary (36 percent) or because of an adverse event (29 percent).

Additional supporting evidence in patients with Alzheimer dementia and PD-associated dementia is reviewed separately. (See "Management of neuropsychiatric symptoms of dementia", section on 'Efficacy'.)

Clozapine – Supportive evidence for clozapine in patients with PD-related psychosis includes two four-week placebo-controlled trials as well as two smaller trials comparing clozapine and quetiapine [44,50-52]. In the largest trial (n = 60), patients in the clozapine group had improved global impression scores, improved psychotic symptom assessment scores, and similar motor and cognitive function compared with patients in the placebo group [44]. At the end of a 12-week open-label extension, approximately 50 percent of patients had complete recovery from delusions and hallucinations on clozapine.

Clozapine is also started at 12.5 mg at night and can be titrated up to 50 mg or more as needed. As with quetiapine, a daytime dose can be added if needed to control daytime psychotic symptoms but may exacerbate daytime sleepiness.

Clozapine is underutilized because of the burdensome requirement of hematologic monitoring, but it is probably the most effective of the second-generation antipsychotics in this setting [6,14,53]. Clozapine can cause granulocytopenia in 1 to 2 percent of patients, and weekly to biweekly blood counts are required by law in order for patients to use it. The risk of clozapine-induced leukopenia or agranulocytosis decreases exponentially over time, and the likelihood of developing fatal granulocytopenia beyond six months of clozapine treatment is almost nil [54].

Side effects, monitoring, and guidelines for administration of clozapine are reviewed separately. (See "Guidelines for prescribing clozapine in schizophrenia".)

SLEEP DISORDERS — Disorders of sleep are common in PD, including sleep onset and maintenance insomnia, restless legs syndrome (RLS), and rapid eye movement sleep behavior disorder (RBD). They affect between 55 and 80 percent of patients with PD. Management is reviewed separately. (See "Clinical manifestations of Parkinson disease", section on 'Sleep disorders' and "Rapid eye movement sleep behavior disorder" and "Sleep-wake disturbances and sleep disorders in patients with dementia", section on 'Management'.)

DAYTIME SLEEPINESS — Excessive daytime sleepiness (EDS) is common in PD, and management requires a multipronged approach.

Optimize nocturnal sleep — Treatment of poor nocturnal sleep due to common factors such as poor sleep hygiene and nocturia can potentially improve EDS. (See "Sleep-wake disturbances and sleep disorders in patients with dementia" and "Nocturia: Clinical presentation, evaluation, and management in adults".)

Reduce or stop dopamine agonist — In some cases, EDS results from antiparkinson therapies. Dopamine agonists can cause EDS, sometimes significant enough to manifest with sudden narcolepsy-like sleep attacks. Reduction or cessation of the dopamine agonist is necessary in such cases.

Levodopa can also be sedating, but it can only be reduced to a degree, given its important role in controlling motor symptoms. Among treatments available for PD, anecdotal evidence indicates that the monoamine oxidase (MAO) inhibitor selegiline may help combat daytime sleepiness, as it is metabolized to a derivative of amphetamine, and it may thus be appropriate as an agent to treat motor symptoms in patients suffering from EDS.

Options for refractory sleepiness — In some instances, targeted treatment of EDS is necessary. Specifically, when nocturnal sleep has been optimized, when dopamine agonists are eliminated, and when levodopa and/or other PD medications cannot be reasonably adjusted further without exacerbating motor symptoms, nonpharmacologic and pharmacologic treatment of EDS may be required.

Patient education and safety — Regardless of cause, EDS raises important considerations related to driving safety and other activities. Driving cessation may be appropriate in certain patients. Prevention and countermeasures related to drowsy driving are reviewed separately. (See "Drowsy driving: Risks, evaluation, and management", section on 'Driver education'.)

Bright light and physical activity — There are limited data on the nonpharmacologic management of EDS in patients with PD. However, bright light therapy is emerging as one such promising treatment. In a randomized trial of 31 patients with PD and EDS, bright light administered twice daily in one-hour intervals for 14 days improved Epworth Sleepiness Scale (ESS) scores, multiple self-reported sleep quality measures, and physical activity levels compared with a dim red light control [55].

Structured physical activity and exercise also hold promise as a treatment for daytime sleepiness in PD, but evidence to guide specific exercise prescriptions is lacking [56]. In general, patients with PD should be encouraged to meet the recommendations of physical activity for adults. A useful online resource for patients is available from the National Institute on Aging [57]. Exercise likely has benefits similar to those seen in the general adult population and may benefit other aspects specific to PD, including EDS.

Pharmacotherapy — When nonpharmacologic measures are insufficient, pharmacotherapy options for EDS in patients with PD include modafinil and methylphenidate. Judicious use of caffeine during the day may also offer some benefit [58].

Data regarding the effectiveness of modafinil for treatment of EDS in PD are sparse and conflicting [59-61]. Some studies have suggested that modafinil may lead to subjective improvement in daytime sleepiness in some patients with PD [59,60], though efficacy on objective measures of sleep has not been demonstrated. In the largest of these small trials, 40 subjects with PD and EDS were randomly assigned to treatment with modafinil (200 to 400 mg/day) or placebo [61]. There was no benefit for modafinil treatment in the primary outcome measure, the ESS (calculator 1), or any of the secondary outcome measures. Modafinil is approved for treatment of narcolepsy in the general population but is not approved by the US Food and Drug Administration for the treatment of sleepiness in PD. A trial of modafinil for EDS in PD is reasonable, but it is important to set expectations for the patient; any benefit, when present, is usually mild and may not be sustained [1].

There are no clear data to support the use of methylphenidate for treatment of EDS in PD, but some data on its use in fatigue can be extrapolated. (See 'Fatigue' below.)

As for other potential treatments of EDS in PD, sodium oxybate, a controlled substance used to treat cataplexy in patients with narcolepsy, has been investigated as a potential treatment for EDS in PD on the basis that improving nighttime sleep could help daytime sleepiness. A small randomized trial showed improved ESS scores and sleep quality in 12 patients with PD compared with placebo [62]. However, obstructive sleep apnea or parasomnias developed in three patients, indicating the need for further study with close monitoring and longer-term follow-up. Until more information concerning efficacy and safety is available, sodium oxybate is not recommended for use in patients with PD and carries risk of significant adverse neuropsychiatric side effects such as depression, hallucinations, and rare thoughts of suicide.

FATIGUE — Fatigue is a common problem in patients with PD, and it appears to be an independent symptom of PD that overlaps with, but is not causally related to, depression and daytime sleepiness. (See "Clinical manifestations of Parkinson disease", section on 'Fatigue'.)

Treatment of fatigue in PD begins with an attempt to identify the cause. Excessive daytime sleepiness (EDS) and depression are both the most common and the most treatable identifiable causes (see 'Daytime sleepiness' above and 'Depression' above). Potentially reversible causes, such as hypothyroidism and medication side effects, should be investigated as well.

Differentiating between sleepiness and fatigue is also important. True fatigue unassociated with sleepiness or depression is more difficult to treat. Suboptimally treated bradykinesia sometimes presents as subjective fatigue and should be identified and treated by readjusting antiparkinson medications. However, in some cases fatigue appears in patients with mild bradykinesia and is poorly understood.

In the authors' clinical experience, no medications are reliably effective for fatigue in patients with PD, including methylphenidate or modafinil. However, it is not unreasonable to initiate a brief trial of these medications in selected patients, as a small subset may have a subjective response.

Medications used for empiric treatment of fatigue, including amantadine and stimulants such as methylphenidate and pemoline, are options. However, the response to these is often disappointing [63]. In one trial, 36 patients with PD were randomly assigned to treatment with either methylphenidate (10 mg three times daily) or placebo [64]. At six weeks, there was a significant reduction in two measures of self-reported fatigue for patients assigned to methylphenidate. Based upon the results of this trial, a practice parameter from the American Academy of Neurology (AAN) concluded that methylphenidate is "possibly useful" for treating fatigue in patients with PD [65]. However, it is unclear whether the benefit of methylphenidate for fatigue in this setting is clinically meaningful.

Of note, modafinil was not effective for improving either EDS (the primary outcome measure) or fatigue (a secondary outcome measure) in the randomized controlled trial cited above [61]. (See 'Daytime sleepiness' above.)

AUTONOMIC DYSFUNCTION

Constipation — Constipation is one of the most common nonmotor problems related to autonomic dysfunction and slowed colonic transit time in PD.

Treatment of constipation in PD does not generally differ from the treatment of constipation in other patient populations. The approach includes patient education, behavior modification and dietary changes (eg, increased fluid and fiber intake), and laxative therapy beginning with bulk-forming laxatives. (See "Management of chronic constipation in adults".)

Specifically in patients with PD, the following therapies have been studied and found to be more effective than placebo in small trials [1]:

Polyethylene glycol [66], an osmotic laxative. (See "Management of chronic constipation in adults", section on 'Osmotic agents'.)

Probiotics, including fermented milk containing probiotic strains and prebiotic fiber [67] and multistrain probiotic capsules [68]. Larger studies of various probiotics for constipation in the general population support a benefit in some but not all trials. (See "Probiotics for gastrointestinal diseases", section on 'Constipation'.)

Lubiprostone, a locally acting chloride channel activator [69]. Nausea is a common side effect of lubiprostone, and long-term safety has not been established. These factors limit use to patients with severe constipation in whom other approaches have been unsuccessful. (See "Management of chronic constipation in adults", section on 'Lubiprostone'.)

Sialorrhea — Sialorrhea or drooling are common symptoms of PD related to reduced oromotor control and autonomic dysfunction. For patients with mild symptoms, the use of chewing gum or hard candy to encourage swallowing may reduce drooling in social situations [70,71].

For patients with more severe symptoms, treatment with botulinum toxin injections into the salivary glands can be effective and is well tolerated, with dry mouth occurring in approximately five percent or less of patients [1,14,72-77]. Glycopyrrolate (1 mg three times daily) is also effective [14,78,79] and has only a limited ability to cross the blood-brain barrier, which may reduce the risk of central anticholinergic side effects. Other anticholinergic medications (eg, oral hyoscyamine and amitriptyline; sublingual ipratropium bromide and sublingual atropine [1 percent ophthalmic solution, one to two drops applied sublingually once or twice daily]) have also been used to control sialorrhea and drooling [80,81].

Rhinorrhea — Rhinorrhea is another nonmotor complication of PD that is commonly triggered by eating certain foods (gustatory rhinorrhea). Affected patients report a profuse runny nose that is unrelated to allergy, upper respiratory infection, or sinus disease [82-84].

There is no proven treatment for gustatory rhinorrhea in PD, but limited data and clinical experience suggest that ipratropium nasal spray, an anticholinergic agent, is effective [81]. Similar to the treatment of sialorrhea with anticholinergic agents, care should be exercised to watch for peripheral and central anticholinergic side effects.

Sexual dysfunction — Patients may not spontaneously discuss sexual dysfunction, making it important for the clinician to bring up this topic.

Sexual dysfunction can range from underactivity to hypersexuality and may affect up to 25 percent of patients with PD. Hypersexuality tends to occur more often in younger men and patients treated with dopamine agonist therapy or deep brain stimulation. (See "Initial pharmacologic treatment of Parkinson disease", section on 'Impulse control disorders' and "Device-assisted and lesioning procedures for Parkinson disease", section on 'Complications and adverse effects'.)

In some patients, improving motor function with dopaminergic treatment may lead to improved sexual function. Men with erectile dysfunction may benefit from treatment with sildenafil (25, 50, or 100 mg) taken one hour prior to sex [85]. Sildenafil should be used cautiously in patients with orthostatic hypotension [1]. Other medications such as tadalafil and vardenafil appear to be effective as well. Intrapenile injections of vasoactive drugs are effective in treatment-refractory cases (see "Treatment of male sexual dysfunction"). Women may benefit from vaginal lubricants and urinating prior to sexual activity. (See "Overview of sexual dysfunction in women: Management".)

Orthostatic hypotension — Orthostatic hypotension is common and disabling in PD. It may occur as a feature of the disease itself or the medications used to treat PD, including levodopa, dopamine agonists, and monoamine oxidase type B (MAO B) inhibitors. (See "Clinical manifestations of Parkinson disease", section on 'Autonomic dysfunction'.)

Treatment should be initiated in symptomatic cases, but no treatments are specific for PD. Nonpharmacologic should be tried first, including boluses of oral fluid intake, salt supplementation, physical counter-maneuvers, abdominal bands, stockings, and elevating the head of the bed [86]. Conditioning with exercise, such as resistance training, holds promise as a nonpharmacologic treatment option of orthostatic hypotension in PD [87].

Pharmacologic treatments are reserved for symptomatic patients who do not respond to these measures. Options include droxidopa, fludrocortisone, and midodrine, though these may lead to supine hypertension [1]. Pyridostigmine may also be useful and is less likely to cause supine hypertension. (See "Mechanisms, causes, and evaluation of orthostatic hypotension" and "Treatment of orthostatic and postprandial hypotension".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Parkinson disease".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topics (see "Patient education: Parkinson disease (The Basics)")

PATIENT PERSPECTIVE TOPIC — Patient perspectives are provided for selected disorders to help clinicians better understand the patient experience and patient concerns. These narratives may offer insights into patient values and preferences not included in other UpToDate topics. (See "Patient perspective: Parkinson disease".)

SUMMARY AND RECOMMENDATIONS

Depression is common in patients with Parkinson disease (PD) and associated with increased motor disability and decreased quality of life. In the absence of clear differences in efficacy in patients with PD, drug selection is based primarily on considerations of safety and tolerability.

In most patients with PD who desire drug therapy for depression, we suggest starting with a selective serotonin-norepinephrine reuptake inhibitor (SNRI) or a selective serotonin reuptake inhibitor (SSRI) rather than a tricyclic antidepressant (Grade 2C). Although comparative efficacy data are limited and mixed, the likelihood of adverse events is lower with SNRIs and SSRIs than with tricyclic antidepressants such as amitriptyline. (See 'Treatment' above.)

When prescribing antidepressants in patients with PD, clinicians should be aware of the potential for QT interval prolongation, drug-drug interactions, worsening motor symptoms, exacerbation of restless legs syndrome (RLS) and rapid eye movement sleep behavior disorder (RBD), and the low but important risk of serotonin syndrome. (See 'Safety considerations with SSRI use' above.)

Anxiety as a manifestation of wearing off of dopaminergic medication in patients who experience motor and nonmotor fluctuations should be managed with levodopa doing adjustments and other related strategies. In the remaining patients, pharmacologic options for anxiety include SSRIs, SNRIs, and buspirone, similar to the general population. (See 'Anxiety' above.)

Psychosis (mainly visual hallucinations and delusions) is a frequent complication of PD, especially in patients with cognitive dysfunction. Management involves identifying and treating the underlying causes and contributory factors, sequential decrease or elimination of potentially offending antiparkinson drugs as allowed by motor function, and symptomatic antipsychotic drug therapy for refractory symptoms (algorithm 1). (See 'Psychosis' above.)

Chronic use of antipsychotic drugs has been associated with increased all-cause mortality and cardiovascular events in older adults with dementia as well as in patients with PD. When the potential benefits are felt to outweigh the risks, antipsychotics should be prescribed cautiously, starting with low doses and using the lowest dose necessary to achieve clinical response. (See 'Refractory psychotic symptoms' above.)

When antipsychotic drugs are deemed necessary for PD-related psychosis, we suggest quetiapine, pimavanserin or clozapine rather than other antipsychotic drugs (Grade 2C). Second-generation antipsychotics are less likely to exacerbate parkinsonism than first-generation antipsychotics, and each of the drugs listed has at least some evidence of efficacy in patients with PD. The choice among them should be individualized. Clozapine may be the most effective antipsychotic of the three but requires hematologic monitoring. (See 'Refractory psychotic symptoms' above.)

First-generation antipsychotics, risperidone, and olanzapine should be avoided because they have a well-established, high risk of worsening motor symptoms in patients with PD. (See "Drug-induced parkinsonism", section on 'Causative drugs'.)

Management of excessive daytime sleepiness (EDS) in PD involves efforts to improve nocturnal sleep hygiene and to treat causes of poor nocturnal sleep. Pharmacologic treatment with modafinil, methylphenidate, or judicious use of caffeine during the day may offer some benefit. (See 'Daytime sleepiness' above.)

Treatment of fatigue in PD begins with an attempt to identify the cause. EDS and depression may be contributing treatable causes. Medications used for empiric treatment of fatigue, including amantadine and stimulants such as methylphenidate and pemoline, are options. However, the response to these is often disappointing. (See 'Fatigue' above.)

Sialorrhea or drooling are common in PD and can be treated with botulinum toxin injections into the salivary glands, oral glycopyrrolate, sublingual atropine in the form of a 1 percent ophthalmic solution, or sublingual ipratropium. (See 'Sialorrhea' above.)

Rhinorrhea can be treated with ipratropium nasal spray, with caution for the emergence of peripheral and central anticholinergic side effects. (See 'Rhinorrhea' above.)

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Topic 4900 Version 42.0

References

1 : Update on treatments for nonmotor symptoms of Parkinson's disease-an evidence-based medicine review.

2 : Suicidal and death ideation in Parkinson's disease.

3 : Suicidal ideation in Parkinson's disease.

4 : Risk of Suicide Among Patients With Parkinson Disease.

5 : Depression associated with Parkinson's disease: clinical features and treatment.

6 : Practice Parameter: evaluation and treatment of depression, psychosis, and dementia in Parkinson disease (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology.

7 : [A comparison between low doses of amitriptyline and low doses of fluoxetin used in the control of depression in patients suffering from Parkinson's disease].

8 : Comparison of desipramine and citalopram treatments for depression in Parkinson's disease: a double-blind, randomized, placebo-controlled study.

9 : A controlled trial of antidepressants in patients with Parkinson disease and depression.

10 : Atomoxetine for depression and other neuropsychiatric symptoms in Parkinson disease.

11 : A randomized, double-blind, placebo-controlled trial of antidepressants in Parkinson disease.

12 : Ropinirole 24-hour prolonged release: randomized, controlled study in advanced Parkinson disease.

13 : Pramipexole for the treatment of depressive symptoms in patients with Parkinson's disease: a randomised, double-blind, placebo-controlled trial.

14 : The Movement Disorder Society Evidence-Based Medicine Review Update: Treatments for the non-motor symptoms of Parkinson's disease.

15 : Cognitive-behavioral therapy for depression in Parkinson's disease: a randomized, controlled trial.

16 : Telephone-based cognitive behavioral therapy for depression in Parkinson disease: A randomized controlled trial.

17 : Complex movement disorders induced by fluoxetine.

18 : Extrapyramidal side-effects in elderly patients exposed to selective serotonin reuptake inhibitors

19 : Movement disorders associated with the serotonin selective reuptake inhibitors.

20 : Sertraline for the treatment of depression in Parkinson's disease.

21 : SSRIs do not worsen Parkinson's disease: evidence from an open-label, prospective study.

22 : Does fluoxetine aggravate Parkinson's disease? A pilot prospective study.

23 : Serotonin syndrome and the combined use of deprenyl and an antidepressant in Parkinson's disease. Parkinson Study Group.

24 : Fluoxetine and selegiline--lack of significant interaction.

25 : Is it safe to combine a selective serotonin reuptake inhibitor with selegiline?

26 : Combined rasagiline and antidepressant use in Parkinson disease in the ADAGIO study: effects on nonmotor symptoms and tolerability.

27 : Rivastigmine in apathetic but dementia and depression-free patients with Parkinson's disease: a double-blind, placebo-controlled, randomised clinical trial.

28 : Frequency of mood and anxiety fluctuations in Parkinson's disease patients with motor fluctuations: A systematic review.

29 : A meta-analysis of randomised placebo-controlled treatment trials for depression and anxiety in Parkinson's disease.

30 : Body awareness training in the treatment of wearing-off related anxiety in patients with Parkinson's disease: Results from a pilot randomized controlled trial.

31 : Non-Motor Symptoms in Parkinson's Disease are Reduced by Nabilone.

32 : Effects of acute cannabidiol administration on anxiety and tremors induced by a Simulated Public Speaking Test in patients with Parkinson's disease.

33 : Cannabinoids for the treatment of mental disorders and symptoms of mental disorders: a systematic review and meta-analysis.

34 : A 12-year population-based study of psychosis in Parkinson disease.

35 : Parkinson disease psychosis: Update.

36 : Treatment of cognitive, psychiatric, and affective disorders associated with Parkinson's disease.

37 : Association of Antipsychotic Use With Mortality Risk in Patients With Parkinson Disease.

38 : Antipsychotic Use and Physical Morbidity in Parkinson Disease.

39 : Low-dose clozapine in the treatment of levodopa-induced mental disturbances in Parkinson's disease.

40 : Quetiapine for the treatment of drug-induced psychosis in Parkinson's disease.

41 : Low-dose clozapine for the treatment of drug-induced psychosis in Parkinson's disease.

42 : Quetiapine versus clozapine: a preliminary report of comparative effects on dopaminergic psychosis in patients with Parkinson's disease.

43 : Quetiapine improves psychotic symptoms and cognition in Parkinson's disease.

44 : Clozapine in drug induced psychosis in Parkinson's disease: a randomised, placebo controlled study with open follow up.

45 : Quetiapine in the treatment of psychosis in Parkinson's disease.

46 : Trial of Pimavanserin in Dementia-Related Psychosis.

47 : Risk of Hospitalization and Death Associated With Pimavanserin Use in Older Adults With Parkinson Disease.

48 : Pimavanserin for patients with Parkinson's disease psychosis: a randomised, placebo-controlled phase 3 trial.

49 : Long-term evaluation of open-label pimavanserin safety and tolerability in Parkinson's disease psychosis.

50 : Clozapine for the treatment of drug-induced psychosis in Parkinson's disease: results of the 12 week open label extension in the PSYCLOPS trial.

51 : Rater-blinded, prospective comparison: quetiapine versus clozapine for Parkinson's disease psychosis.

52 : Quetiapine and clozapine in parkinsonian patients with dopaminergic psychosis.

53 : Pharmacological treatment of Parkinson disease: a review.

54 : Risk of clozapine-associated agranulocytosis and mandatory white blood cell monitoring.

55 : Timed Light Therapy for Sleep and Daytime Sleepiness Associated With Parkinson Disease: A Randomized Clinical Trial.

56 : The Therapeutic Potential of Exercise to Improve Mood, Cognition, and Sleep in Parkinson's Disease.

57 : The Therapeutic Potential of Exercise to Improve Mood, Cognition, and Sleep in Parkinson's Disease.

58 : Caffeine as symptomatic treatment for Parkinson disease (Café-PD): A randomized trial.

59 : Modafinil for the treatment of daytime sleepiness in Parkinson's disease: a double-blind, randomized, crossover, placebo-controlled polygraphic trial.

60 : Randomized trial of modafinil for treating subjective daytime sleepiness in patients with Parkinson's disease.

61 : Modafinil for daytime somnolence in Parkinson's disease: double blind, placebo controlled parallel trial.

62 : Sodium Oxybate for Excessive Daytime Sleepiness and Sleep Disturbance in Parkinson Disease: A Randomized Clinical Trial.

63 : Interventions for fatigue in Parkinson's disease.

64 : Methylphenidate improves fatigue scores in Parkinson disease: a randomized controlled trial.

65 : Practice Parameter: treatment of nonmotor symptoms of Parkinson disease: report of the Quality Standards Subcommittee of the American Academy of Neurology.

66 : Macrogol for the treatment of constipation in Parkinson's disease. A randomized placebo-controlled study.

67 : Probiotics and prebiotic fiber for constipation associated with Parkinson disease: An RCT.

68 : Probiotics for Constipation in Parkinson Disease: A Randomized Placebo-Controlled Study.

69 : Placebo-controlled trial of lubiprostone for constipation associated with Parkinson disease.

70 : Gastrointestinal dysfunction in Parkinson's disease.

71 : Gastrointestinal features of Parkinson's disease.

72 : Safety and efficacy of botulinum toxin type B for treatment of sialorrhea in Parkinson's disease: a prospective double-blind trial.

73 : A double-blind placebo-controlled trial of botulinum toxin B for sialorrhea in Parkinson's disease.

74 : Long-lasting benefits of botulinum toxin type B in Parkinson's disease-related drooling.

75 : Botulinum toxin type A for drooling in Parkinson's disease: a double-blind, randomized, placebo-controlled study.

76 : SIAXI: Placebo-controlled, randomized, double-blind study of incobotulinumtoxinA for sialorrhea.

77 : Safety and Efficacy of RimabotulinumtoxinB for Treatment of Sialorrhea in Adults: A Randomized Clinical Trial.

78 : Glycopyrrolate for sialorrhea in Parkinson disease: a randomized, double-blind, crossover trial.

79 : Glycopyrrolate Improves Disability From Sialorrhea in Parkinson's Disease: A 12-Week Controlled Trial.

80 : Sublingual atropine for sialorrhea secondary to parkinsonism: a pilot study.

81 : Ipratropium bromide spray as treatment for sialorrhea in Parkinson's disease.

82 : Rhinorrhea is increased in Parkinson's disease.

83 : Is rhinorrhea an under-recognized intrinsic symptom of Parkinson disease? A prospective pilot study.

84 : Rhinorrhea: a common nondopaminergic feature of Parkinson's disease.

85 : Efficacy and safety of fixed-dose oral sildenafil in the treatment of sexual dysfunction in depressed patients with idiopathic Parkinson's disease.

86 : The efficacy of nonpharmacologic intervention for orthostatic hypotension associated with aging.

87 : Effects of Progressive Resistance Training on Cardiovascular Autonomic Regulation in Patients With Parkinson Disease: A Randomized Controlled Trial.