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Abstract

Although levodopa is an effective medication for the treatment of Parkinson disease, physicians and patients face significant management challenges related to disease progression. Patients typically develop fluctuations in motor symptoms and dyskinesias. Novel treatment options may help clinicians more effectively manage patients’ symptoms by extending the duration of response to medication, with improved tolerance. For many patients, nonmotor symptoms impact daily activities more than motor symptoms do. Many pharmacotherapeutic strategies are approved to address motor and nonmotor symptoms and fluctuations. A clear understanding of the advantages and potential adverse effects of each therapy can help clinicians individualize the choice and timing of medications to optimize patient response and hopefully improve quality of life.

J Clin Psychiatry 2020;81(1):MS18003BR2C

From the Parkinson’s Disease and Movement Disorders Center of Boca Raton, Florida.See the entire activity

Abstract

Although levodopa is an effective medication for the treatment of Parkinson disease, physicians and patients face significant management challenges related to disease progression. Patients typically develop fluctuations in motor symptoms and dyskinesias. Novel treatment options may help clinicians more effectively manage patients’ symptoms by extending the duration of response to medication, with improved tolerance. For many patients, nonmotor symptoms impact daily activities more than motor symptoms do. Many pharmacotherapeutic strategies are approved to address motor and nonmotor symptoms and fluctuations. A clear understanding of the advantages and potential adverse effects of each therapy can help clinicians individualize the choice and timing of medications to optimize patient response and hopefully improve quality of life.

J Clin Psychiatry 2020;81(1):MS18003BR2C

From the Parkinson’s Disease and Movement Disorders Center of Boca Raton, Florida.

Target Audience

  • Neurologists

Learning Objectives

After completing this educational activity, you should be able to:

  • Provide evolving treatment for the motor symptoms of PD as the patient’s disease progresses
  • Address nonmotor symptoms of PD in the treatment plan

Support Statement

Supported by educational grants from Biogen MA, Inc.; Lundbeck LLC; and Sunovion Pharmaceuticals, Inc.

Release, Review, and Expiration Dates

This brief report activity was published in December 2019 and is eligible for AMA PRA Category 1 Credit™ through December 31, 2021. The latest review of this material was November 2019.

Statement of Need and Purpose

Because clinicians have incorrectly diagnosed patients with PD who did not have the disease and have not diagnosed those who do have PD, they need information on diagnostic criteria for PD and strategies to improve clinical observations. In addition, when motor symptoms present or worsen, treatment change is often needed. However, there are discrepancies among physicians regarding what treatment changes to make. Patients also say they have heard of advanced treatment options that their clinicians have not discussed with them. Clinicians, then, need education about recently updated guidelines for treating the motor symptoms of PD and how to adjust treatment as the disease progresses and the patient’s response to medication changes. They need to be familiar with the latest treatment advances to best manage OFF episodes and have an appreciation for emerging agents that are moving beyond dopamine and into the realm of disease modification and neuroprotection. Even when clinicians show familiarity with motor symptoms, they must also be aware of nonmotor symptoms and therapeutic strategies. To aid in recognition of nonmotor symptoms, clinicians need education about talking with patients and the use of patient questionnaires, as well as on the importance of addressing nonmotor symptoms and on options for treating these symptoms. This activity was designed to meet the needs of participants in CME activities provided by the CME Institute of Physicians Postgraduate Press, Inc., who have requested information on PD.

Disclosure of Off-Label Usage

The author has determined that, to the best of his knowledge, levodopa and apomorphine administered by a continuous pump; sublingual apomorphine; opicapone; and domperidone are not approved by the US Food and Drug Administration for the treatment of Parkinson disease.

Review Process

The faculty member(s) agreed to provide a balanced and evidence-based presentation and discussed the topic(s) and CME objective(s) during the planning sessions. The faculty’s submitted content was validated by CME Institute staff, and the activity was evaluated for accuracy, use of evidence, and fair balance by a peer reviewer who is without conflict of interest.

Acknowledgment

This brief report is derived from the teleconference series “Earlier Diagnosis and Expanded Treatment Options for Parkinson Disease,” which was held in July 2019 and supported by educational grants from Biogen MA, Inc.; Lundbeck LLC; and Sunovion Pharmaceuticals, Inc. The opinions expressed herein are those of the faculty and do not necessarily reflect the opinions of the CME provider and publisher or the commercial supporters.

Faculty Affiliation


Stuart H. Isaacson, MD
Boca Raton Regional Hospital, Florida

Financial Disclosure

The faculty for this CME activity and the CME Institute staff were asked to complete a statement regarding all relevant personal and financial relationships between themselves or their spouse/partner and any commercial interest. The Accreditation Council for Continuing Medical Education (ACCME) defines a commercial interest as any entity producing, marketing, re-selling, or distributing health care goods or services consumed by, or used on, patients. The ACCME defines relevant financial relationships as financial relationships in any amount occurring within the past 12 months that create a conflict of interest. The CME Institute has resolved any conflicts of interest that were identified. No member of the CME Institute staff reported any relevant personal financial relationships. Faculty financial disclosure is as follows:

Dr Isaacson has received grant/research support and honoraria from and is a member of the speakers bureaus for Abbvie, Acadia, Acorda, Adamas, Addex, Allergan, Amarantus, Axovant, Benevolent, Biogen, Britannia, Cerecor, Eli Lilly, Enterin, GE Healthcare, Global Kinetics, Impax, Intec Pharma, Ipsen, Jazz, Kyowa, Lundbeck, Michael J. Fox Foundation, Neurocrine, Neuroderm, Parkinson Study Group, Pharma2B, Roche, Sanofi, Sunovion, Teva, Theravance, UCB, US World Meds, and Zambon.

Accreditation Statement

The CME Institute of Physicians Postgraduate Press, Inc., is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

Credit Designation

The CME Institute of Physicians Postgraduate Press, Inc., designates this enduring material for a maximum of 1.0 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Note: The American Nurses Credentialing Center (ANCC) and the American Academy of Physician Assistants (AAPA) accept certificates of participation for educational activities certified for AMA PRA Category 1 Credit™ from organizations accredited by the ACCME.

To obtain credit for this activity, study the material and complete the CME Posttest and Evaluation.

MOC Approval Statement

Through the American Board of Medical Specialties (“ABMS”) ongoing commitment to increase access to practice relevant Continuing Certification Activities through the ABMS Continuing Certification Directory, Effective Treatment Strategies for Motor and Nonmotor Symptoms of Parkinson Disease has met the requirements as a MOC Part II CME Activity (apply toward general CME requirement) for the following ABMS Member Boards:

MOC Part II CME Activity

Psychiatry and Neurology

Available Credit

  • 0.50 AMA PRA Category 1 Credit™
  • 0.50 Participation

This CME activity is expired. For more CME activities, visit cme.psychiatrist.com.

Find more articles on this and other psychiatry and CNS topics:
The Journal of Clinical Psychiatry
The Primary Care Companion for CNS Disorders

This activity is based on: Ramirez-Zamora A. Parkinson disease: current and emerging treatment strategies. J Clin Psychiatry. 2018 May/Jun;79(3). doi:10.4088/JCP.PP17030TX1C. Updated in November 2019.

 

Parkinson disease (PD) is a progressive, neurodegenerative disorder characterized by cardinal  motor symptoms that include bradykinesia, cogwheel rigidity, resting tremor, and, later, impaired postural reflexes.1,2 Motor symptoms primarily reflect nigral-striatal dopaminergic degeneration, but recent studies reveal more widespread neurodegeneration in PD resulting in a range of nonmotor symptoms, including a variety of neuropsychiatric symptoms, autonomic and enteric dysfunction, and sleep disorders.3 For many patients, nonmotor symptoms contribute to disability4 and often impact daily activities more than motor symptoms do.

Although there are no approved therapies to slow disease progression, a variety of clinical trials are underway. Many pharmacotherapeutic strategies to address motor and nonmotor symptoms, as well as to improve motor fluctuations and dyskinesia, are approved. A clearer understanding of the advantages and potential adverse effects of each therapy can help clinicians individualize the choice and timing of medications to optimize patient response and hopefully improve quality of life.

Symptom Fluctuations and Dyskinesia Often Occur as the Disease Progresses

The pathophysiology of PD is complex. Degeneration of dopaminergic neurons in the substantia nigral leads to hallmark motor symptoms of bradykinesia, rigidity, and tremor.5,6 Treatments for motor symptoms address striatal dopamine depletion; the cornerstone of treatment remains levodopa, the metabolic precursor of dopamine.7 Degeneration in other pathways involving multiple neurochemicals also occurs and leads to a variety of nonmotor symptoms.

Motor fluctuations. One of the most challenging aspects of managing PD is the emergence of motor fluctuations. Initially, levodopa has a long duration of response, despite its short pharmacokinetic plasma half-life. However, as the disease progresses, motor fluctuations emerge. Periods when the benefit of a levodopa dose has waned are termed “OFF episodes,” during which PD motor6 and nonmotor symptoms occur.8  Common types of OFF episodes include “wearing off,” “delayed on,” and “dose failure.”5 The majority of patients with PD will eventually exhibit motor fluctuations, with 14% by 5 years, 39% by 9 years, and 67% by 10 or more years among those taking levodopa (AV 1).9

AV 1. Rate of Motor Fluctuations, by Disease Duration (N=124) (00:44)

Data from Schrag and Quinn9

  Patient Perspectives
 
I started having levodopa-induced dyskinesias last year. My right arm and leg have a mind of their own when I’ve had too much levodopa. Unfortunately, ‘too much levodopa’ is now not enough to keep my symptoms at bay.”10

“Timing of medications requires planning at all times.”11

“I was diagnosed 8 years ago, but this is the first year that the PD has really become annoying. I was just thinking the other day that I just wish this would go away. Even my highly educated and well-trained MDS cannot understand what’s it like to constantly be searching for that medication “sweet-spot”—where you have enough levodopa to control the symptoms within reason, but not so much that you are walking around with brain fog and feeling constant fatigue. I get so tired of just being tired all of the time. And then there is the sciatica, carpal tunnel, back spasms, foot and leg dystonia, constipation, hemorrhoids, and all of the other symptoms that the doctors want to ignore because they are more worried about your tremor. It can be absolutely maddening.”12

The causes of motor fluctuations include both central and peripheral factors. Levodopa when given with carbidopa has a short half-life of approximately 90 minutes.13 Gastrointestinal dysmotility and transporter competition with protein in the intestine can result in variable and unpredictable absorption of oral levodopa doses.6 Problems include delayed gastric emptying, interference with enteric absorption by dietary amino acids, and competition between amino acids and levodopa for transport across the blood-brain barrier.14 With disease progression, striatal denervation leads to loss of buffering capacity and dopamine reuptake and storage. Derangement of other neurochemical systems (ie, glutamatergic, adenosine) may also contribute.

Wearing off. End-of-dose wearing off refers to the re-emergence of motor and nonmotor symptoms when the benefit of a medication dose begins to wane.15 Wearing off can occur at certain times of the day, including in the early morning and overnight. It is important to recognize that OFF symptoms can vary among patients and can occur in multiple domains ranging from tremor, slowness, stiffness, low voice, and gait difficulties to anxiety, fatigue, bloating, mental cloudiness, depressed mood, or cognitive slowing.16,17

Delayed on. Patients may discover that the therapeutic onset of a dose of levodopa is delayed.18 This delay can be due to gastroparesis and/or protein effect, and it may be especially common in the morning and around meals.

Dose failure. A patient may have a failed medication dose when it is not absorbed sufficiently.18 The patient will not show any relief from symptoms during the dosage duration. Meals that are high in protein can affect levodopa absorption, as can gastroparesis with delayed gastric emptying.14

Dyskinesia

In addition to motor fluctuations, loss of striatal buffering capacity coupled with increasing levodopa dose can result in peak dose dyskinesia. Glutamatergic overactivity has also been implicated in the emergence of dyskinesia, as have postsynaptic changes.

Patients who have had years of treatment for PD may develop involuntary abnormal movements, or dyskinesias. Dyskinesias are typically dystonic or choreiform, and various areas of the patient’s body can be affected.19 Half or more of patients experience dyskinesia after 10 years (AV 2).9 Dyskinesias can affect balance and interfere with activities of daily living.19

AV 2. Rate of Dyskinesias, by Disease Duration (n=87) (00:29)

Data from Schrag and Quinn9

Current Treatment Options for Motor Fluctuations and Dyskinesia

Clinicians may try a variety of strategies as their patients’ PD progresses and motor fluctuations and dyskinesias emerge.

Increase IR carbidopa-levodopa dose or dosing frequency. Increasing the dose of IR carbidopa-levodopa may improve motor response but may not prolong the duration of response.13 The interval between doses can be shortened, increasing the number of times that a patient takes medication each day.6 Alternatively, fractionating doses can be tried by lowering each dose but reducing the interval between doses, such that the overall daily dosage does not change.20 With increased frequency of doses, compliance decreases, so patients need to be advised to be careful about taking medications on time.

Switch to extended-release carbidopa-levodopa. CR carbidopa/levodopa was erratic in its absorption and often increased motor complications. The older, sustained-release carbidopa-levodopa has a durational effect similar to that of the immediate-release version,21 and guidelines22 recommended disregarding its use for reducing wearing off.

A novel extended-release formulation of carbidopa-levodopa, which was approved by the FDA, maintains medication concentrations longer than both the immediate-release and controlled-release formulations.21 This new extended-release formulation combines immediate-release and extended-release microbeads so that plasma levels are sustained for 4–5 hours in patients with PD.23 The ADVANCE-PD trial24 showed that this extended-release formulation, in patients with daily OFF time of more than 2 hours,  had a reduction in OFF time of 1.17 hours with extended-release carbidopa-levodopa compared with the immediate-release carbidopa-levodopa, with fewer doses per day. Adverse events include insomnia, dizziness, falls, nausea, and headache.24,25 The incidence of dyskinesia as an adverse effect increased with higher dosing.25 Conversion from immediate-release to extended-release formulations should be conducted carefully, and dosing should be tailored to specific patients’ needs and response.23 Clinicians may prescribe extended-release carbidopa-levodopa because it provides a longer therapeutic plasma concentration than the immediate-release version.

Add adjunctive therapy for OFF episodes. Another strategy to minimize motor complications is adjunctive therapy.7,26 Three dopamine agonists have been approved by the FDA for the treatment of OFF time in PD: oral pramipexole, oral ropinirole, and transdermal rotigotine. Adding a long-acting dopamine agonist to levodopa reduces OFF time by 1–2 hours.27 Potential side effects include pedal edema, nausea, hallucinations, somnolence, and impulse control disorders.28

Adding a monoamine oxidase B (MAO-B) inhibitor can reduce catabolism of striatal dopamine and has been shown to reduce OFF time.29 The MAO-B inhibitors include selegiline, rasagiline, and safinamide.30 Side effects are uncommon and include nausea and orthostatic hypotension.

Another adjunctive therapy option for OFF time is catechol-O-methyltransferase (COMT) inhibitors,7 which can extend the plasma half-life of levodopa. Two have been approved by the FDA, entacapone and tolcapone. Tolcapone is uncommonly used because tolcapone may increase the risk of liver toxicity,31 and monitoring of liver enzymes is recommended. Side effects of entacapone include discolored urine, nausea, and diarrhea.32

Initiate on-demand therapies. Due to the variability in onset of oral levodopa, several non-oral medications are available. Subcutaneous apomorphine injection was approved in 2004 for treatment of an OFF episode. It can improve OFF episodes rapidly and reliably, and its effect is as robust as that of levodopa.33 Onset occurs within 20 minutes, and side effects include nausea, orthostatic hypotension, and somnolence.34 More recently, inhaled levodopa was approved as on-demand treatment of OFF episodes. Treatment effect was evident at 10 minutes and remained significantly improved through the 60-minute assessment.35 After 4 weeks, 58% of participants taking levodopa had UPDRS motor score reductions of 11 points or more, compared with 28% of those taking placebo.35 Dizziness, cough, and nausea are the most common adverse effects.35,36

Treat dyskinesia. Peak-dose dyskinesia (or “ON dyskinesia”) can sometimes be managed using a smaller dose of levodopa administered more frequently during the day (ie, fractionating), but may result in increased bradykinesia in patients with moderate to severe disability related to the excessive movements.37 If patients are receiving adjunctive medications such as dopamine agonists, MAO-B inhibitors, or COMT inhibitors, reducing polypharmacy  may reduce dyskinesia.38 An extended-release, high-dose, bedtime preparation of amantadine has been approved for the treatment of levodopa-induced dyskinesia in patients with PD. In trials, OFF time was also improved; the most common adverse events were hallucination, dizziness, dry mouth, peripheral edema, constipation, falls, and orthostatic hypotension.39

Use advanced therapies. Advanced therapies that can provide marked benefit in motor fluctuations and dyskinesias include deep brain stimulation (DBS) and infusion therapies.7,20 DBS40 and continuous jejunal infusion of levodopa-carbidopa intestinal gel41 have been proven to be safe and effective, although infection and device failures can occur. DBS has demonstrated marked benefit in treatment of motor fluctuations when compared with best medical therapy, but surgical and programming adverse events can occur.42 Continuous subcutaneous apomorphine infusion is another (less invasive) option available in Europe and under investigation in the US.43

  Care Partner Perspectives
“I strongly urged my wife to have the DBS surgery. I had been hesitant, but her dystonia was getting so bad that her feet would curl up for an hour to an hour and a half. It was painful and she couldn’t move. The side effects of her meds for the dystonia affected her personality and she was miserable to live with, and I was ready to move out for a while to take a break from her. It has been very good for her, and she had the optimum response. Now, as the disease progresses and the DBS is turned up, there are side effects and it has about maxed out what it can do for her.”44

Emerging Treatment Options for Motor Fluctuations and Dyskinesia

Disability is progressive in PD. As the disease continues to transform over time—despite multiple medication adjustments or more advanced interventions—patients develop more debilitating and progressive symptoms. Clinicians need better treatment options (ie, with increased efficacy and minimal adverse effects) and also better medication delivery methods.45 Some emerging therapies are described below.

On-demand therapies. Apomorphine is being studied in a sublingual formulation. In a study by Hauser et al,46 76 patients were given sublingual apomorphine (APL-130277) during an OFF period. Onset of action began in 5 to 12 minutes; 38% of patients had full clinical benefit by 15 minutes, and 78% by 30 minutes.46

Extended-release preparations. IPX203 is an oral extended-release capsule of carbidopa-levodopa. In an open-label study,47 IPX203 had a significantly longer duration of effect based on UPDRS motor scores compared with immediate-release carbidopa-levodopa (P < .0001) and another extended-release carbidopa-levodopa capsule (P ≤ .0290).

COMT inhibitor. Opicapone is a novel, once-daily, peripherally acting, highly selective COMT inhibitor proposed for use as adjunctive therapy to levodopa/carbidopa in patients with PD. Treatment with 50 mg/d of opicapone has demonstrated reduction in OFF time compared to placebo and was noninferior to entacapone.48,49 The most common adverse events reported with the drug are dyskinesia, constipation, and dry mouth.

Subcutaneous infusion of liquid levodopa. Liquid levodopa-carbidopa subcutaneous infusion pumps are under investigation for motor fluctuations.50  In early studies,51,52 ND0612 showed reduction in OFF time by a mean of 2.4 hours and 2.1 hours from baseline according to in-clinic and subjective home diaries, respectively.

Current Treatment Options for Nonmotor Symptoms

Patients with PD experience a number of nonmotor features that include sleep disorders and autonomic and neuropsychiatric symptoms. Sensory dysfunction also occurs, including pain and impaired smell.53 These symptoms can contribute greatly to disability and must be addressed in treatment.

Sleep disorders. Sleep disorders are commonly experienced by patients with PD, including insomnia, excessive daytime sleepiness, narcolepsy-like episodes, sleep-disordered breathing, circadian rhythm disorders, rapid eye movement sleep behavior disorder, vivid dreams, and restless legs syndrome.54,55 The origins of these sleep issues are likely multifactorial and include age, disease, comorbidities such as depression, and medication adverse effects.55 Sleep difficulties become more common as patients age, and PD symptoms such as stiffness, nocturia, pain, and dystonic movements can make sleep difficult to initiate and maintain.55 Furthermore, the neurodegenerative processes that occur as a result of the progression of PD may affect brain circuits responsible for regulating sleep, and some of the medications used to treat PD have been found to have effects on sleep processes.54 Sleep hygiene education and bright light therapy have shown benefit for PD-related sleep dysfunction, as well as the careful use of sleep aids such as melatonin or a hypnosedative, depending on the type of sleep problem that the patient is experiencing.55,56 The dosage of the patient’s dopaminergic drug should be increased only if nighttime motor manifestations (nocturnal bradykinesias) are the primary cause of sleep difficulties.56

Autonomic symptoms. During the course of PD, the autonomic nervous system will be affected, resulting in gastrointestinal, urogenital, cardiovascular, and thermoregulatory problems.57

  • Gastrointestinal dysfunction. Gastrointestinal disturbances include constipation, swallowing difficulties, and gastric emptying disorders.57 Constipation can be managed with exercise, a high-fiber diet, proper fluid intake, and preventive use of laxatives and stimulants.58 Gastroparesis or delayed gastric evacuation can affect the dispersion and absorption of PD drugs, but treatment options require more research. Domperidone7 and nizatidine may be helpful.58 Smaller, more frequent meals and exercise may also be helpful. Sialorrhea, or drooling, is particularly bothersome to patients. Anticholinergic medications, glycopyrrolate, and botulinum toxin injections are treatment options.58
  • Urogenital symptoms. Urogenital symptoms can involve the bladder, such as increased frequency and urgency of urination, and sexual dysfunction, such as erectile dysfunction.57 Overactive bladder symptoms can be managed with antimuscarinics, although these drugs may exacerbate constipation.59 Excluding other causes of urinary dysfunction is critical.7 Avoiding alcohol and caffeine may aid urinary problems, and nocturia may be improved by avoiding fluids at least 4 hours before bedtime and the use of diuretics in late afternoon.59 Management of sexual dysfunction can include behavioral and pharmacologic options (eg, sildenafil).7,59
  • Cardiovascular symptoms. Orthostatic hypotension is the most common cardiovascular symptom associated with PD and can cause marked disability and lead to falls and injury.57 Symptoms, which can be exacerbated by dehydration, poor muscle tone, and a sedentary lifestyle, include lightheadedness, orthostatic dizziness, weakness, headache, dimmed vision, aching of shoulders, and fainting. Initially, management should consist of adequate hydration and salt intake, use of abdominal binders or support stockings, and elevating the head of the bed during sleep.60 If further steps are needed, medications include approved droxidopa.61 Also, fludrocortisone and midodrine have been used.7,60

Neuropsychiatric symptoms. Many patients with PD will experience neuropsychiatric symptoms such as depression, apathy, anxiety, psychosis, cognitive impairment, or dementia.62 These symptoms can fluctuate in the same manner as motor symptoms, greatly diminishing patient independence and quality of life.8 Depression, apathy, and anxiety are common in PD and may precede the motor symptoms in some patients.62

  • Depression. Clinical features of depression in PD are similar to those of patients with primary depression, but patients with PD generally experience less suicidal behavior.63 Evidence to support antidepressant treatment selection is scarce, but antidepressants such as selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, and tricyclic antidepressants can be used.62 Dopamine agonists that are used to treat the motor symptoms of PD may also help improve mood. Psychotherapy has not been well studied, but some evidence shows efficacy of cognitive-behavioral therapy for depression in PD.64
  • Apathy. Apathy is common in PD and reduces a patient’s desire to engage in treatment, thereby increasing caregiver stress and straining the patient-physician relationship. Apathy can occur alone but frequently overlaps with depression or dementia in patients with PD. Treatment options are limited, and more evidence is needed.65 Available research has suggested reduced apathy with improved control of fluctuations via infusion therapies (subcutaneous apomorphine infusion and levodopa-carbidopa intestinal gel).65 The rotigotine patch and ropinerole also have suggested efficacy in apathy, along with the potential use of rivastigmine.62,66
  • Anxiety. Various anxiety disorders manifest in the PD population; generalized anxiety disorder, panic disorder, and social phobia are most common.62 For many patients, anxiety may accompany medication wearing-off periods, and aggressive treatment of fluctuations may lessen anxiety. Similar to treatments for depression in PD, evidence for anxiety treatments specifically in PD is scarce, but antidepressants may be used; benzodiazepines are usually not routinely recommended due to side effects.62 Nonpharmacologic treatments including counseling, relaxation, or psychotherapy may also be helpful.62
  • Psychosis. More than half of individuals with PD will experience hallucinations.62 Delusions are less common but very bothersome to patients and caregivers.62 These symptoms are associated with increased institutionalization.67 The pathophysiology of psychosis in PD is not fully understood, but intrinsic and extrinsic factors appear to be involved. Degeneration of serotonin neurons with serotonin 2A receptor overactivity has been implicated. The dopaminergic medications used to treat PD may contribute to the pathogenesis of psychotic symptoms; disease-related processes, genetics, and structural and neurochemical abnormalities in the brain are also likely involved.68 Treatment should begin with a thorough evaluation to rule out medication errors and other medical or neurologic disorders (AV 3).69,70 All antipsychotic drugs block postsynaptic D2 receptors and can worsen motor symptoms and should be avoided, but low-dose quetiapine and clozapine may be considered.71 Pimavanserin, a novel antipsychotic that is a highly selective serotonin 2A inverse agonist, has shown efficacy without worsened motor function68 and has been approved for treatment of PD psychosis.72,73 Cholinesterase inhibitors may be used in patients with dementia,74 but a recent trial75 found no preventive effect of donepezil against psychosis.

AV 3. Recommendations for Managing Parkinson Disease Psychosis (00:35)

Based on Martinez-Ramirez et al69 and Wilby et al70

  Patient Perspectives
“My husband was diagnosed with PD almost 5 years ago. . . . He has accused me for over 5 years of having multiple boyfriends, lying, cheating, and stealing money from him. We have been meeting with a Neuropsychiatrist and just recently learned about ‘Psychosis.’”76

Dementia. Cognitive function may decline throughout the course of PD, and many patients with PD eventually develop dementia.62 Because dementia impairs overall functioning, it increases caregiver burden and often leads to nursing home placement. Cholinesterase inhibitors such as rivastigmine can improve cognitive function and behavioral disturbance.74

Conclusion

Many drugs are available for the management of PD, and treatment decisions should be individualized for each patient. Factors that should be weighed in treatment decisions include medical comorbidities, polypharmacy, potential side effects, and patient access to medications.

Clinical Points

  • Monitor patients to determine if they are experiencing problems with motor fluctuations and/or dyskinesia.
  • Determine whether on demand therapy is needed for patients with delayed onset of levodopa.
  • Consider new, novel formulations of levodopa when appropriate.
  • Address nonmotor symptoms as part of the overall treatment plan.

Abbreviations

COMT = catechol-O-methyltransferase
CR = controlled release
CT = computed tomography
DBS = deep brain stimulation
FDA = US Food and Drug Administration
MAO-B = monoamine oxidase B
PD = Parkinson disease
UPDRS = Unified Parkinson’s Disease Rating Scale

© Copyright 2019 Physicians Postgraduate Press, Inc.

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