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INTRODUCTION

Parkinson disease (PD) remains second only to Alzheimer disease in terms of neurodegenerative disease prevalence.¹ In the United States alone, there are approximately 1 million people living with the disease.² There is no routine laboratory testing used to diagnose PD. Rather, having ruled out other etiologies, clinicians rely on the identification of signs and symptoms suggestive of PD pathology.³ While traditionally thought of as a movement disorder characterized by the primary motor symptoms associated with the diagnosis (e.g., tremor, rigidity, bradykinesia/akinesia, and postural instability), more and more the approach to treatment is shifting to routinely include non-motor symptoms. It is becoming widely accepted that PD is best described as a syndrome encompassing not only motor symptoms, but also symptoms that stem from autonomic nervous system dysfunction (eg, orthostatic hypotension, urinary frequency, and slowed gastrointestinal transit time), as well as psychiatric and psychosocial symptoms (e.g., depression, anxiety, impulse control disorder, psychosis, apathy, and punding).⁴ In one study, patients with drug-naive PD who were matched with 50 healthy controls were given the 12-item General Health Questionnaire to determine whether there was a difference in diagnosable psychiatric disorders between the groups. Those with PD met criteria for a diagnosable psychiatric disorder at a rate of 92% vs 16% of the control group.⁵ Some have suggested that the prevalence of psychiatric symptomatology warrants labeling PD the quintessential neuropsychiatric disorder.⁶

Despite the prevalence of psychiatric complications associated with PD, the need for intervention is often delayed or missed all together. Patients may be reticent to discuss hallucinations or memory issues due to embarrassment or fear of being displaced from their homes. Patients and caregivers may not be aware that psychiatric symptoms are part of PD presentation, and thus may not volunteer information about their existence. In addition, because the motor symptoms are obvious manifestations of the disease, the majority of emphasis is often placed on their control while less obvious issues are forgotten or treated as secondary problems. Psychiatric morbidity is associated with worse quality-of-life scores than even severe motor symptoms for both patients and caregivers.^7,8 It is incumbent on healthcare providers to inquire about non-motor symptoms and document findings at each encounter regardless of their presence or absence to allow for early identification and monitoring throughout disease progression.

A summary of common neuropsychiatric comorbidities and considerations for each may be found in this Table.

DEPRESSION IN PD

RJ is a 73-year-old patient who was diagnosed with PD approximately 6 years ago. When he comes to pick up a refill of her carbidopa/levodopa, you ask how she is getting along. She becomes tearful and tells you that she is extremely anxious about the fact that his symptoms seem to be getting worse. Upon further inquiry, you find out that his medication is effective for less than 5 hours even though it is prescribed to be taken every 6 hours. What opportunities are there for maximizing the pharmacologic care of RJ?

The association between a diagnosis of PD and a diagnosis of depression has long been recognized. The two are interdependent such that the presence of one can have implications on the course of the other.⁹ Estimates are that upward of 50% of patients with PD have some degree of depression. Of those patients, between 10% and 30% have non-major (minor) depression whereas 5% to 20% have symptoms consistent with major depression.^10-13 A study of 124 individuals demonstrated that mild, moderate, and severe depression are all significantly more common in patients with PD than in healthy matched controls (P < .001 for all groups).¹⁴ Suicidal ideation was long considered a symptom unassociated with PD-related depression, but in reality is not infrequent.¹⁵ Although dementia and psychosis are typically associated with later-stage disease, depression can occur at any point during the disease process, including decades before motor dysfunction is recognized.^16,17 Depression has been identified as a potential predictor of a pending PD diagnosis.¹⁸ A cohort study of patients with newly diagnosed PD demonstrated a depression prevalence of nearly 14%, which was roughly double that seen in healthy controls.¹⁹

The etiology of depression in PD is multifactorial. Decreased functional connectivity between the cortical and limbic system has been demonstrated in patients with PD and depression, but the same is not noted in those without depression.²⁰ Dopamine is involved in cognition, as well as brain pathways controlling emotion and motivation. Patients with PD are noted to have less dopamine in the thalamus.²⁰ The thalamus serves as a relay station, projecting signals to multiple brain areas. One of these areas, the amygdala, plays a role in processing emotional information. It is believed that by the time patients present with frank motor dysfunction, upwards of 50% to 80% of dopaminergic neurons have been lost. While the body can compensate for dopaminergic loss as it pertains to functional movement until this threshold is reached, the same may not be said for depression. This may explain why the mood disorder pre-dates a PD diagnosis with such frequency.²¹ That said, reactions to increasing disability cannot be discounted as inconsequential in contributing to depression in these patients.²² Swings in mood may be present and coincide with when patients are in the off state (uncontrolled motor symptoms). Poorly controlled motor symptoms have been identified as a predictor of antidepressant treatment failure.²³ In particular, symptoms such as anxiety, feelings of panic, and dysphoria may be cyclically present. Motor function control assessment is necessary to determine whether inadequate treatment is the primary culprit or a potential contributing factor to depression symptoms.²⁴ Pain may also contribute to depression and is essential to control.¹⁴

Risk factors for development of depression include female sex, history of depression (personal or familial), early-onset PD, daytime somnolence, higher pain scores, greater motor dysfunction (and by extension higher levodopa doses), and other concomitant psychiatric diagnoses.^25-30 Of the psychiatric symptoms associated with PD, depression is by far the most studied. Even so, it remains undertreated. Most studies report that only 20% to 25% of patients with concomitant depression receive treatment, though a study of data collected in the United States between 2005 and 2011 evaluating antidepressant use in over 1.7 million patient visits suggested that treatment rates may be closer to 58%.³¹

Standardized diagnostic criteria for depression in patients with PD do not exist. Although structural brain changes have been identified in patients who are found to have depression before or shortly after PD diagnosis, there is no biomarker for testing, thus it is necessary to recognize symptoms and make a diagnosis based on clinical presentation alone once metabolic and other medical causes (e.g., decreased vitamin B12 levels, hypothyroidism, electrolyte disturbances, or anemia) have been ruled out.^32,33 Therein lies the biggest challenge to the diagnosis of depression. Because of the apparent overlap between symptoms of depression and symptoms of PD, the assumption that these symptoms are due to PD frequently results in missed opportunities to treat depression. Among symptoms of depression that may be mistaken for symptoms of PD are anhedonia, weight changes, changes in sleep patterns, generalized fatigue, cognitive impairment, lack of facial expression, and psychomotor slowing.³⁴ It is then prudent to focus on symptoms that do not overlap, including feelings of inappropriate guilt, worthlessness, and hopelessness.⁹ Caregiver interviews can also help to identify a patient in need of antidepressant intervention.

Treatment of Depression in Patients With PD

In general, the use of antidepressant therapy produces beneficial effects in patients with PD when considered in aggregate.³⁵ Individual drug classes are considered equally effective across the spectrum of PD depression, though there are few head-to-head studies to help drive treatment decisions.

Tricyclic antidepressants (TCAs) have generated positive data. Mechanistically, they potentiate the activity of serotonin (5-HT), dopamine, and norepinephrine by blocking neurotransmitter reuptake. Positive effects have been demonstrated with amitriptyline, imipramine, desipramine, and nortriptyline.³⁶ However, amitriptyline and imipramine have greater anticholinergic activity, resulting in a side-effect profile that is often difficult for patients, especially older ones, to tolerate. Drowsiness, dry mouth, urinary retention, and cardiac conduction abnormalities are associated with TCA use. In addition, problems already present for many patients with PD, including constipation, cognitive impairment, and hypotension, may be exacerbated by these medications. While desipramine and nortriptyline have less effect on muscarinic, histaminergic, and alpha-adrenergic systems, they are not without risk.³⁷ Overall, despite data demonstrating efficacy in alleviating symptoms of depression in patients with PD, TCAs are seldom considered first-line agents due to their propensity to cause adverse events.

The selective serotonin reuptake inhibitors (SSRIs) are by far the most prescribed antidepressants for patients with PD, with an estimated 70% of treated patients using an agent from this class.³¹ These medications work primarily to inhibit serotonin reuptake, though their selectivity varies by agent because other neurotransmitters and receptors can be affected. Data generated by a meta-analysis that included studies evaluating SSRIs, serotonin and norepinephrine reuptake inhibitors (SNRIs), TCAs, dopamine agonists, and trazodone suggest that while antidepressant use generally produces positive results, the SSRIs are the only class that produces a consistent statistically significant decline in symptoms.³⁵ It is important to keep in mind that the various agents within this class have their own unique side-effect profiles. For instance, paroxetine is a particularly anticholinergic SSRI known for its sedative properties. Like other highly anticholinergic agents, it can exacerbate cognitive impairment, constipation, and urinary retention. It is important to recognize that the choice of agent within the class can affect patients differently. Additionally, although rare, there have been reports of worsening motor function in some patients with PD who were treated with SSRI antidepressants.³⁸

Monoamine oxidase (MAO) inhibitors have been used in the treatment of depression for decades, though their use has declined significantly in favor of newer drug classes such as the SSRIs and SNRIs. The agents used in the treatment of depression are non-selective with affinity for MAO-A, which is primarily responsible for the large number of drug and food interactions and side effects associated with the class. There are currently 3 MAO inhibitors used in the treatment of PD: selegiline, rasagiline, and safinamide. Unlike their antidepressant counterparts, these medications are selective for MAO-B at normal doses.³⁹ While it is likely that at higher doses they might have some ability to decrease depressive symptoms in patients with PD, selectivity is likely to be lost, making them subject to the same interactions and adverse events as the non-selective agents.³⁴ For that reason MAO inhibitors are not considered viable options for the treatment of depression in patients with PD, regardless of whether they are used for control of motor symptoms. Of note, MAO-B inhibitors are not contraindicated when used with antidepressant medications, and the risk of serotonin syndrome when given with other agents that increase neurotransmitter levels is extremely small versus the non-selective MAO inhibitors.

A member of the dopamine agonist class of medications, which are used for motor control, has shown some promise for easing depression symptoms in patients with PD. Pramipexole has been suggested as an alternative to traditional antidepressants due to its affinity for dopamine (D₃ subtype) receptors, which are abundant in the mesolimbic area of the brain and are involved in motivation and reward-related behavior.³⁴ A systematic review of studies evaluating the use of pramipexole for PD-associated depression confirmed improvements in mood that were significant vs placebo (P < .001).⁴⁰ However, depression was measured via the United Parkinson’s Disease Rating Scale (UPDRS) mood score rather than a depression-specific scale. The UPDRS is not designed to detect depression or changes specific to antidepressant use. In addition, patients with depression that was deemed severe were routinely excluded from study participation. The available data are therefore probably not robust enough to suggest routine use of pramipexole as a first-line agent in the treatment of depression. However, if patients need better motor control and also display signs of depression, pramipexole may be a reasonable medication to use. It should be noted that depression may predispose patients to the emergence of impulse control disorders, which is a problem frequently encountered with the use of dopamine agonists for PD.⁴¹ Aside from pramipexole, no other dopamine agonists have shown consistently positive effects on depression.

There are additional data to suggest that some patients with PD and depression may benefit from treatment with the SNRIs venlafaxine and duloxetine.^42,43 Case studies and expert opinion also suggest potential efficacy with mirtazapine and bupropion.⁹ No clinical trials exist to explore the potential for augmentation therapy in the case of resistant depression. In the end, the choice of antidepressant should be driven by the needs of the patient and the characteristics of the individual medications.⁹ For instance, duloxetine may benefit a patient with concomitant pain, mirtazapine may stimulate appetite in a patient with anorexia, and sertraline is among the antidepressants that may be beneficial for the control of anxiety.

RJ’s tearful demeanor could be a sign that he is depressed. The pharmacist can inform RJ that depression is a common finding in patients with PD and suggest that he be evaluated to determine if medication therapy is warranted. Because symptoms of depression can be linked to uncontrolled motor symptoms in some patients, it is essential to optimize RJ’s medication by increasing his carbidopa/levodopa dose, shortening the drug interval, or adding on an additional antiparkinson drug. If antidepressant use is determined to be warranted, an agent with antianxiety properties may be a prudent choice for RJ.

PD PSYCHOSIS

AN has been having visual hallucinations for some time. At first, she recognized that what she was seeing wasn’t real. However, over time she began having frightening hallucinations of someone in her room, and she began attempting to fight with the person she was seeing. You note she started pimavanserin therapy approximately 2 weeks ago. Upon inquiring how AN is tolerating the medication, you are told that her daughter stopped giving it to her because it didn’t seem to make any difference. What advice can you offer AN and her daughter?

PD psychosis (PDP) is an independent predictor of mortality in patients and is the chief risk factor for placement of individuals in a nursing home environment.^44-46 A study of PDP and matched controls of patients with PD without psychosis illustrated the increased rate of escalation to the need for custodial care.⁴⁷ The risk in those with PDP was approximately triple that of those without a psychosis diagnosis (19.6% vs 6.5%), and the mean time to progression to needing custodial care was lower (416 vs 525 days). In addition, the cumulative incidence of death was greater by approximately 33% in the PDP group (P < .0001).

A PDP diagnosis is not typically made in the early stages of PD. However, estimates are that after a patient has lived with the disease for at least 20 years, 70% of patients will exhibit symptoms.⁴⁸ Risk factors for PDP development include longer duration of illness, presence of dementia, sensory impairment, insomnia, and the use of dopamine agonists for motor symptom control.⁴⁹ During the prodromal phase it is common for patients to disclose the appearance of vivid dreams or nightmares with or without rapid eye movement sleep behavior disorder.^50,51 As with motor symptoms, the indicators of PDP are progressive.⁴⁹ Many patients will advance to experiencing illusions (misinterpretations of perception such that inanimate objects are mistaken for something else). A false sense of presence (a feeling that one is not alone in a room) is also common at this stage. Hallucinations, defined as a sensory perception in the absence of a real stimulus, often follow from this point, and are mostly visual in nature. However, auditory, tactile, and olfactory hallucinations are sometimes reported.⁵² It is typical for patients with PDP to retain insight into the false nature of their hallucinations in the beginning, but over time this insight is often lost and the patient begins to perceive the hallucinations as real. Delusions, which are usually persecutory in nature (e.g., spousal infidelity, monetary theft) may also begin to form during this later stage.^48,49

From a pathophysiological standpoint, several neurotransmitters have been implicated in PDP including dopamine, 5-HT, and acetylcholine.²⁵ Other intrinsic factors that are likely linked to psychosis include visual processing deficits with a decrease in acuity, difficulty recognizing color and contrast between light and dark, and brain pathology in the vision center. The deposition of Lewy bodies and genetic components (e.g., apolipoprotein E epsilon 4 allele and tau H1H1 genotype) have also been connected to PDP.⁵³ The inclusion of medication therapy for motor symptoms must always be considered in the list of potential culprits as well because cognitive deficits and hallucinations have been associated with dopaminergic treatment.

Before other steps are employed, down-titration of antiparkinson medications is typically advised to determine if the symptoms are caused by the medication. The order of discontinuation is not determined by any official recommendation, but a typical approach would be to begin with medications that are more likely to cause psychotic symptoms while taking into account the likely degree of efficacy in controlling motor symptoms. A sample order for discontinuation might be to begin with anticholinergic medications (sometimes employed for tremor-predominant disease), followed by amantadine, dopamine agonists, MAO-B inhibitors, catechol-o-methyltransferase inhibitors, and finally levodopa.⁵⁴ However, given that most of these patients will be in a stage of advanced disease, exacerbation of motor symptoms is likely to hamper successful discontinuation, or even downward tapering of many medications. In fact, halting of the first medications on the list may result in the need for an escalation in levodopa therapy to compensate for lost efficacy in the control of motor symptoms.⁴⁹ If minimization of medications proves unsuccessful in controlling PDP symptoms, antipsychotic therapy may need to be started.

Treatment of PD Psychosis

In the earlier stages of PDP, it may not be necessary to treat hallucinations if the patient is aware of their false nature, unless the hallucinations are particularly disturbing or frightening to the patient.⁴⁹ However, continued and frequent monitoring is essential to offering prompt treatment because if this circumstance changes, uncontrolled hallucinations with loss of insight may result in behavior that is dangerous to both the patient and caregivers.

The majority of traditional antipsychotic medications and many of the atypical antipsychotic medications are poor choices for the treatment of PDP due to their mechanism of actions, which frequently include dopaminergic (D₂ receptor) blockade, which may make the exacerbation of motor symptoms and the antagonism of dopaminergic therapy possible.⁵⁵ In addition, the dopamine blocking antipsychotic treatments have been associated with an increased risk in both morbidity (e.g., stroke) and mortality in older individuals, including those with PD.^56,57 This leaves few options for treatment.

There are 3 antipsychotic medications typically used to treat PDP, including clozapine and quetiapine (both used off-label) and pimavanserin, which is the only medication approved by the US Food and Drug Administration (FDA) specifically for the treatment of PDP. Comparative efficacy data among the 3 medications are limited.⁵⁸

Mechanistically, clozapine is thought to exert its antipsychotic effects through blockade of 5-HT_2A receptors, as well as histamine receptors without any significant effects at D₂ receptors, making issues with motor symptom exacerbation unlikely.⁵⁹ Three studies have independently confirmed the efficacy of low-dose clozapine (typically given at a starting dose of 6.25 mg daily titrated to effect) in the treatment of PDP symptoms.^60-62 In addition, a meta-analysis comprising 12 placebo-controlled and 5 active-controlled studies suggested clozapine is the most effective of the oft-used antipsychotic medications.⁵⁸ Unfortunately, clozapine is a difficult agent to use because extensive ongoing monitoring is needed given the risk for the development of severe/life-threatening neutropenia, which occurs in roughly 1% of patients independent of dose.⁶³ Logistically, the ongoing need to keep appointments to monitor the patient’s absolute neutrophil count can be difficult for those with limited mobility. The drug is also highly anticholinergic and may cause related side effects, as previously discussed. For these reasons, despite the evidence supporting its efficacy, clozapine is not routinely used in clinical practice as a first-line agent for the treatment of PDP.

Data on the efficacy of quetiapine for treating PDP is equivocal at best. Its mechanism of action is similar to that of clozapine, and though it has shown some D₂ blockade, it rapidly dissociates from this site rendering it unlikely to exacerbate the motor symptoms of PD.⁶⁴ It is the most commonly used antipsychotic for this indication despite the fact that all randomized trials to date have either produced data that suggested a lack of efficacy or that did not allow for definitive conclusions about effectiveness to be drawn.^65-67 However, there are anecdotal reports of usefulness.⁵⁴ The dose range for PDP is typically 12.5 mg to 150 mg daily. Quetiapine is easy to access than clozapine and pimavanserin, and requires no specific monitoring, making it an easy medication to use.

Pimavanserin received breakthrough therapy designation from the FDA, and it was approved based on the results of a single trial in April 2016 specifically for the treatment of PDP.^68,69 Pharmacologically it is an inverse agonist at 5-HT_2A receptors (meaning it induces a conformational change resulting in a functional decrease in the transduction of signals to a threshold below normal baseline levels) and an antagonist at 5-HT_2C receptors, though its binding to the former is substantially greater.^59,70 Affinity for other neurotransmitter receptor types has not been identified. An open-label trial of pimavanserin included data from 459 individuals who had been using the medication for a mean of 728 days.⁶⁸ Participants who had been complete responders in phase 3 trials at 6 weeks (n=43) demonstrated stability of Clinical Global Impression (CGI)-Severity scores. This is a 7-point clinician-rated scale that gages severity of illness at the time of assessment for comparison relative to past experience with patients with the same disease.⁷¹ Scores on the CGI-Improvement (rated according to patient improvement from baseline assessment while using an intervention) were stable through 192 weeks. Thus the data suggest that efficacy is maintained over several years. Twenty-nine percent of patients discontinued use of the medication due to adverse events including hallucinations (3.1%), PD (2%), psychiatric disorders (1.7%), confusion (1.3%), and pneumonia (1.1%). All other adverse events linked to discontinuation occurred in less than 1% of study subjects. The most common adverse events overall were falls (32%), urinary tract infection (19%), hallucination (13.7%), decreased body weight (12.4%), and confusion (11.1%). Sixty-one deaths were reported and determined by independent review to be unrelated to drug therapy. This is important as there were concerns in the post-marketing arena that pimavanserin was associated with an increased risk of mortality in users. However, FDA review did not identify correlation.⁷² In a study supported by the manufacturer, researchers determined the number needed to treat to identify positive effects vs placebo is 10, whereas the number needed to harm was not statistically different from placebo, indicating a favorable safety profile for the medication. Overall, the likelihood of response to pimavanserin is 5 times greater than the likelihood of discontinuation due to an adverse event.⁷³

One criticism that came out of the clinical trials was that after data collection was finalized, the evaluation tool was modified, resulting in the creation of a unique instrument never before used and exclusive to the pimavanserin studies.⁵⁹ The Scale for the Assessment of Positive Symptoms (SAPS) was shortened to include only certain subdomains including hallucinations and delusions and became the SAPS-PD. The threshold for the power analysis was a 3-point change, which loosely correlates to minimal improvement on the CGI-Improvement scale.⁷⁴ In the pivotal study, rates of efficacy did not exceed placebo until the 4-week evaluation and effectiveness continued to increase through week 6. As such, prescribers need to know that full effects may not be noted prior to a 4- to 6-week medication trial.^69,75 Positive attributes of the pimavanserin studies included the fact that participants underwent psychosocial therapy prior to commencing the drug trial so as to lessen the potential influence of placebo. Centralized raters were used to minimize bias. No new safety signals have emerged post-marketing, and as expected, no exacerbations in motor symptoms are anticipated with pimavanserin use.⁵⁹ In most cases the drug can be started at its optimal dose of 34 mg without the need for titration. Pimavanserin is only available through specialty pharmacies.

AN and her daughter need to be counseled about the lag time associated with pimavanserin effectiveness. It can take 4 to 6 weeks for benefit to be observed with this medication. They should be encouraged to restart therapy.

PD DEMENTIA

JB has had PD for approximately 8 years. She expressed concern that she is beginning to feel “absent minded.” The neurologist is considering initiating therapy with a cholinesterase inhibitor, but has asked you whether you recommend any medication changes in the meantime. Currently, JB takes carbidopa/levodopa for motor symptom control, extended-release amantadine for levodopa-induced dyskinesia, lisinopril for hypertension, and oxybutynin for overactive bladder.

Cognitive impairment in patients with PD is the most common non-motor feature. Dementia in patients with PD is associated with mortality rates up to 3 times higher compared with patients without dementia over 10 years in age- and sex-matched controls.⁷⁶ At any point in time, approximately 25% to 30% of all patients with PD have dementia.^77,78 Data suggest that if patients with PD lived long enough, everyone would inevitably meet the diagnostic criteria for dementia. Mild cognitive impairment is present in 15% to 25% of patients at the time of PD diagnosis, increasing their risk of conversion to dementia 6-fold.^8,79 Additional known risk factors for the development of PD dementia (PDD) include advanced age (both in general and at the time of PD diagnosis), predominant dysfunction of gait, and presence of hallucinations.^80-82 The occurrence of depression after diagnosis in 353 individuals with PD who were followed for 7 years revealed that there was a predisposition to dementia development when compared with those who had depression prior to their diagnosis.⁸³ Evidence suggests that it is prudent to have patients with PD and resistant depression undergo thorough cognitive testing.⁸⁴ Often, declines in short-term memory are dismissed by clinicians and caregivers as a part of the normal aging process. Although this is sometimes accurate, because of the prevalence of PDD, the American Academy of Neurology guidelines recommend formal evaluation of cognitive function occur at least yearly and that any complaints be routinely documented to track progression.⁸⁵

PDD is a dementia type associated with the deposition of alpha-synuclein in the brain. These deposits are collectively called Lewy bodies.¹⁴ There is an ongoing argument as to whether dementia with Lewy bodies (DLB), which is a diagnosis in and of itself, is different from PDD or if they are one and the same. Both are associated with similar features, including parkinsonian traits, hallucinations, and fluctuations in attention and arousal.⁸⁶ Differentiating between the two is generally based on the timeline of development with DLB diagnosed if symptoms occur within 1 year of the diagnosis of PD.⁸⁷ Later emergence of symptoms is considered PDD. Additional pathology is frequently noted post-mortem in the brains of patients with PD with 59% displaying tau (neurofibrillary tangles) consistent with Alzheimer disease.⁸⁸ Cerebrovascular changes that may be partially responsible for symptoms are also noted with regularity.

As with psychosis, it is prudent to rule out other potential reasons for symptoms before commencing with a treatment plan. Cardiovascular disease, vitamin B12 deficiency, thyroid dysfunction, autoimmune diseases, sequelae from head injury, subdural hematomas, and even impaired vision or hearing can result in symptoms that suggest dementia might be present.⁸ Acutely, infections, metabolic abnormalities, and medication changes should also be considered potential culprits.

Along with the risk factors already mentioned, there is a growing dataset emerging to implicate the use of anticholinergic medications in the development of dementia in patients with PD. One retrospective trial that used an active comparator model evaluated 1,232 patients.⁸⁹ Subjects were stratified according to whether they experienced anticholinergic exposure deemed mild vs moderate-severe (the designated exposure group) on the Anticholinergic Burden Scale. There was no difference in the rate of dementia development between the 2 groups (19.5% vs 17.7%, respectively). However, when looking at cumulative minimum doses, higher exposure was significantly associated with an increased risk for dementia development vs lower exposure. This suggests that regardless of the level of anticholinergic burden associated with a particular medication, length of exposure and higher doses over time correlate with the development of cognitive impairment.⁸⁹ Another study evaluating the risk of exposure to anticholinergic antiparkinson medications included 2 groups of 10,967 individuals.⁹⁰ One of the groups was exposed to the treatment while the other was not. No increased risk was noted in individuals who received medication for less than 6 months during the first year after their PD diagnosis. However, after the 6-month threshold was met, an increase in dementia risk was noted (P < .001). The exact reason why anticholinergics may trigger progression to dementia remains unknown, but decreased glucose metabolism and an increase in brain atrophy have been identified as potential contributing factors.⁹¹ Of the medications that might be used often in PD and are considered among those possessing a higher anticholinergic burden are the antidepressant paroxetine; the antipsychotics quetiapine and clozapine; amantadine (considered to have moderate burden); and the pure anticholinergics benztropine and trihexyphenidyl, which are approved for treatment of the motor symptoms of PD, particularly the tremor-predominant subtype.⁹²

The Movement Disorder Society Task Force has put forth criteria for a practical clinical approach to the diagnosis of PDD. Beyond meeting the official criteria for PD diagnosis, patients must have had PD prior to the onset of cognitive symptoms, score less than 26 on the Mini-Mental State Exam (MMSE), demonstrate a deficit of cognition severe enough to interfere with activities of daily living, and display an impairment in 2 of the following areas: attention, executive function, visuospatial function, and memory.^80,93

Treatment of PD Dementia

Few medications for the treatment of dementia are currently on the market, and those that are have been primarily approved for treatment of the Alzheimer subtype. There are currently 3 available cholinesterase inhibitors including rivastigmine, donepezil, and galantamine. Only rivastigmine has been approved by the FDA for use in PDD.⁸ The other drug that is used in the treatment of moderate-severe dementia symptoms is the glutamate receptor blocker memantine. It is not approved for use in PDD.

A meta-analysis comprising data drawn from studies of both cholinesterase inhibitors and memantine compared outcomes among the medications, though galantamine was not included because it has not been sufficiently studied in the PD population.⁹⁴ Several tools for measurement were used across the studies. Positive results were noted on both the MMSE and the Montreal Cognitive Assessment scale for global cognitive function, reaching statistical significance for both rivastigmine and donepezil (P < .00001). Memantine did not demonstrate a significant change. When evaluating the cognitive domain of memory, both cholinesterase inhibitors once again proved beneficial (P = .0003), as they did for language (P = .01). No positive effects were seen in visuospatial function. When the CGI-Change scale was used, only outcomes with rivastigmine use were significant, whereas donepezil and memantine failed to reach the threshold. The same was true for change in motor function with rivastigmine (P < .0001). No study reported a positive change in the frequency of falls. Adverse events among the studies, most of which were mild or moderate in nature, were consistent with cholinergic effects and dementia including nausea and vomiting, aggravation of parkinsonian tremor, somnolence, insomnia, and hallucinations. In addition to reaching efficacy thresholds in more categories than other medications, rivastigmine was also associated with a higher number of adverse events compared with placebo than donepezil or memantine. In clinical practice, donepezil is the most widely used cholinesterase inhibitor on the market. However, use in patients with PD is off-label. In addition to receiving approval for use in this population, rivastigmine has shown some propensity for decreasing hallucinations in a 24-week double-blind, placebo-controlled study.⁹⁵

There is currently no mention of hallucinations or other symptoms of psychosis associated with JB’s cognitive changes at this time, so tapering her antiparkinson medications is not necessary. However, JB is taking oxybutynin for overactive bladder. This medication is highly anticholinergic, and given that data demonstrate that long-term use of anticholinergic medications is associated with cognitive decline in patients with PD, and because the therapy that is being considered (a cholinesterase inhibitor) works to increase levels of acetylcholine, it is prudent to choose a medication that works via a different mechanism to control her bladder symptoms (e.g., a beta-3 adrenergic agonist).

NON-PHARMACOLOGIC APPROACHES TO THE TREATMENT OF NEUROPYSCHIATRIC SYMPTOMS IN PATIENTS WITH PD

There are several studies looking at the use of various non-pharmacologic methods for control of psychiatric symptoms in the PD population. However, it is difficult to draw conclusions about the effectiveness of most of these options with certainty due to low participant numbers and the heterogeneity of the interventions.

As previously stated, patients with resistant depression may have other undiagnosed psychiatric diagnoses. Consequently, those diagnoses must be ruled out or treated so that additional interventions can be effective. There is some positive evidence for the use of cognitive behavioral therapy (CBT) to alter maladaptive or harmful beliefs to alleviate emotional distress. Some effectiveness has been demonstrated when training has continued for at least 8 to 12 weeks.⁹⁶ Electroconvulsive therapy (ECT) is an option for patients with treatment-resistant depression when other interventions have proven inadequate. In a review of ECT treatment in 116 patients with PD, 93.1% of patients had positive results.⁹⁷ In addition, 83% of patients experienced improvement in motor scores in studies that included that assessment as an outcome measure. Cases of delirium or transient confusion rarely occurred, but discontinuation of therapy was occasionally needed. Some argue that ECT should be used earlier in the treatment algorithm, but additional data are required to determine the best timing. Strategies for ECT maintenance therapy remain undefined.

Well-studied nondrug approaches to the management of psychosis in PD are also limited, but some interventions are easy to use. As previously discussed, reversible causes must first be addressed. A simple first step is to optimize the living environment of patients with PDP.⁹⁸ For instance, because problems with visual processing and acuity are common in this population, improving issues with vision using corrective lenses and increasing the amount of light in the immediate environment may help reduce the frequency of hallucinations. Cognitive training, including patient self-talk and reassurance that the hallucinations are not real, can be helpful for some.⁹⁹ Patients can also be taught to focus harder on the hallucination in an effort to make the mind perceive what is really there, or to deliberately look away from it and focus on something in another part of the room. CBT may be beneficial as long as the patient still has insight into the false nature of their hallucinations.⁹⁸ Unlike hallucinations, delirium is unlikely to respond to non-medical interventions.

A recent review of nondrug strategies for individuals with PD and cognitive impairment revealed that no adequately powered studies are currently available, and no study specifically designed to assess improvement in cognitive function reached a class I level of evidence.¹⁰⁰ Of the interventions evaluated, cognitive training was the most likely intervention to demonstrate positive outcomes. Probable effectiveness for this training was noted as it pertains to improving attention, working memory, and maintaining memory performance. No intervention demonstrated results sufficient to be considered effective for improving executive function. However, physical training in the form of stationary cycling, faster-pace treadmill walking, and dance did produce some level C evidence (possibly effective) for this domain. The authors did note that a combination of physical and cognitive interventions appeared to be more beneficial than use of either one on its own.¹⁰⁰

ROLE OF THE PHARMACIST IN THE CARE OF PATIENTS WITH PD AND NEUROPSYCHIATRIC SYMPTOMS

It is often stated that pharmacists are the most accessible healthcare providers. In the case of patients with PD, due to issues with mobility and psychiatric disorders, pharmacists may interact with caregivers more often than patients depending on practice setting. This should not stop pharmacists from asking about the patient’s well-being (though a patient’s rights under the Health Insurance Portability and Accountability Act must be considered during such conversations).

Alterations in a patient’s mood or personality should be noted, and referral for follow-up suggested when appropriate. For individuals who are taking medications to alleviate depressive symptoms or pimavanserin for hallucinations, it is important to stress that there is a lag time to effectiveness for most agents. In addition, titration is often needed and trials of more than 1 drug may be necessary to identify the best treatment option for an individual patient. Both patients and caregivers must be made to understand that treatment of depression is a process and that in some cases, significant time will pass before treatment can be optimized. Furthermore, they must be made to understand that unless tolerance is an issue, drug therapy should continue even if immediate results are not perceived. For those who may be undertreated, pharmacists should offer encouragement to engage in ongoing discussions with the prescriber. Dose optimization for cholinesterase inhibitors used for the treatment of dementia is essential to their effectiveness. Continued inquiry about the effectiveness of an antidepressant is prudent given that PD is progressive with ever-changing brain chemistry that might cause a once beneficial antidepressant medication to become ineffective over time. Additionally, questions about other symptoms should be asked and suggestions made to prescribers about antidepressant selection if a particular agent’s characteristics might be beneficial in controlling other symptoms such as pain, insomnia, anorexia, or anxiety.

For patients who present with new prescriptions or medications on their profile, other treatments should be reviewed to determine if drugs are being prescribed to treat adverse events that might be alleviated with therapy changes. Medications for many disorders can negatively affect cognition, especially in the older PD population. Particular consideration should be given to the ongoing anticholinergic burden of a patient’s medications because many drugs that are not related to the treatment of PD (eg, antihistamines, sleep aids, medications for urinary frequency, antispasmodics, antiemetics, skeletal muscle relaxants) may contribute to acute cognitive changes and increase the risk for PDD over time. Optimization of motor symptom control should also be addressed with dose escalation or suggestions for medication additions; failing to do so has been shown to predict the failure of antidepressant therapy.¹⁰¹ To that end, interventions should be made to make medications for motor symptom control safer and more effective, such as suggesting changes in dosage form for patients who are having difficulty with safe swallowing or helping to schedule levodopa doses around mealtimes to optimize absorption.

CONCLUSIONS

Early recognition and treatment of neuropsychiatric symptoms associated with PD is essential to optimize patient outcomes. Pharmacists are in an ideal position to recognize mood and behavioral changes that may be secondary to treatment of motor symptoms or other concomitant conditions and to offer alternatives to prescribers when necessary. Knowledge of unique drug properties can be leveraged to tailor treatment to the needs of an individual and potentially alleviate multiple complaints. Counseling patients and caregivers about realistic expectations can go a long way to ensuring that treatment of neuropsychiatric symptoms is implemented for maximum benefit. In addition, pharmacists can help guide patients and caregivers through the process of procuring specialty medications such as pimavanserin and discuss options for financial assistance.

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