CASE REPORT

The treatment of psychiatric disorders in Parkinson’s disease

Tratamentul tulburărilor psihiatrice în boala Parkinson

Data publicării: 30 Septembrie 2024
Editorial Group: MEDICHUB MEDIA
10.26416/Psih.78.3.2024.10094

Abstract

Affective disorders (depression and anxiety), psychosis, impulse control disorders, apathy and dementia are common and sometimes disabling psychiatric conditions in Parkinson’s disease (PD). Psychiatric aspects of PD are associated with numerous adverse outcomes, yet in spite of this and their high frequency, there remains incomplete understanding of epidemiology, presentation, risk factors, neural substrate, and management strategies. Psychiatric features are typically co- or multimorbid, and there is great intra- and interindividual variability in presentation. There is evidence that psychiatric disorders in PD are still under-recognized and undertreated, and although psychotropic medication use is common, randomized controlled trials demonstrating efficacy and tolerability are largely lacking. Future research on neuropsychiatric complications in Parkinson’s disease should be oriented toward determining modifiable correlates or risk factors and, most importantly, establishing efficacious and well-tolerated treatment strategies.
 

Keywords
Parkinson’s diseasetreatment of psychiatric disordersimpulse control disorders

Rezumat

Tulburările afective (depresia şi anxietatea), psihoza, tulburările de control al impulsului, apatia şi demenţa sunt comune şi uneori reprezintă condiţii psihiatrice dizabilitante în boala Parkinson (BP). Aspectele psihiatrice ale BP sunt asociate cu numeroase rezultate adverse. În ciuda acestui fapt şi a frecvenţei lor înalte, epidemiologia, prezentarea, factorii de risc, substratul neurologic şi strategiile de management sunt incomplet înţelese. Trăsăturile psihiatrice sunt tipic comorbide sau multimorbide şi există o mare variabilitate în prezentarea intra- şi interindividuală. Există dovezi că tulburările psihiatrice în BP sunt încă subrecunoscute şi subtratate. Deşi utilizarea medicaţiei psihotrope este comună, studiile controlate randomizate ce demonstrează eficacitatea şi tolerabilitatea lipsesc în mare măsură. Cercetări viitoare asupra complicaţiilor neuropsihiatrice în boala Parkinson ar trebui orientate spre determinarea corelaţiilor modificabile sau a factorilor de risc şi, cel mai important, spre stabilirea strategiilor de tratament eficace şi bine tolerat.
 
Cuvinte Cheie
boala Parkinsontratamentul tulburărilor psihiatricetulburări de control al impulsurilor

Introduction

The overall management of Parkinson’s disease (PD) depends on the status of symptoms, functioning of the patients, impairment, disability, and its impact on the quality of life(1).

The therapeutic efforts in PD are dominantly symptomatic, while some recent neuroprotective agents that might slow or reverse the natural cause of the disease are under investigation. Dopamine agonists (DA) are commonly used agents that exert substantial anti-parkinsonian symptomatic efficacy(2). In the earlier days, DA were first successfully used as an adjunct therapy to established and more potent L-DOPA treatment(6). However, they are now often utilized as a first-line medication for symptomatic treatment of early Parkinson’s disease among younger patients (below 60 years old), since they can delay motor complications, the onset of dyskinesia, and the L-DOPA treatment institution. Some authors explicitly argue that the treatment of PD should start with a dopamine agonist(7). It is important to highlight that DA therapy yields no results in patients who are unresponsive to L-DOPA. In terms of dopamine agonists, newer extended-release formulations have shown better safety profiles for patients than immediate-release ones. MAO-B inhibitors such as selegiline or rasagiline may also be used as monotherapy in patients who are in the early stage of the disease and have mild symptoms. L-DOPA is a more potent drug than dopamine agonists; however, it is commonly associated with “on-off” periods (fluctuating motor responses), dyskinesia, and serious psychiatric side effects(7). Some authors suggest the use of L-DOPA as an initial mode of treatment in all patients with PD (except young), particularly for those with serious cognitive or motor impairments that significantly interfere with daily living. Modern therapeutic approaches toward Parkinson’s disease often include dopamine agonists as the initial monotherapy for the earlier stages of PD, while they are then commonly combined with L-DOPA in later, chronic stages of the disease. In this case, doses of L-DOPA should be titrated to the lowest possible amount that is effective, to avoid dyskinetic abnormalities and motor fluctuations. Additionally, the treatment with L-DOPA should never be stopped abruptly, as this might cause malignant hyperthermia (Parkinson hyperpyrexia syndrome)(7).

Dopamine agonists are commonly divided into two groups: ergoline-derived and non-ergoline-derived agonists. Ergoline agonists are the first generation of DA, derived from ergot, and are associated with specific risks of peritoneal, pulmonary, and cardiac/valvular fibrosis(7). The most common drugs in ergoline class are bromocriptine, cabergoline, pergolide, and lisuride. Out of this group, bromocriptine is a cheap drug that is now rarely prescribed, but can be used in combination with L-DOPA in both early and late PD(7). Cabergoline and pergolide are frequently reserved for the progressive phase of Parkinson’s disease, although they can be used as monotherapy in the early phase. However, ergot-derived dopamine agonists are generally rarely used these days, due to their established risk of valvular and lung fibrosis. A responsible clinician needs to bear in mind that ergoline-derived agonists should not be prescribed to patients who have a positive history of heart, valvular, lung, or abdominal fibrosis. Thus, patients receiving ergoline-derived DA should be monitored with echocardiography before treatment is started and regularly during treatment(7).

The National Institute for Health and Care Excellence (NICE) guidelines now give an advantage to non-ergot DA over ergoline class agonists. Likewise, if a dopamine agonist is indicated in the elderly, a non-ergot drug should be preferred. The drugs in this group that are commonly used are pramipexole and ropinirole; these are the most common dopamine agonists prescribed in the United States of America, while others include rotigotine, piribedil and apomorphine(7).

General insights on DA therapy and observed side effects

Therapy with dopamine agonists often precipitates a wide spectrum of side effects in patients with Parkinson’s disease, especially among elderly patients (above 65 years old). Such side effects may range from mild and frequent to serious and debilitating. Constipation, nausea and headaches are commonly associated with DA therapy(7). The development of excessive daytime sleepiness (EDS) has been associated with dopamine agonists therapy, as well as the higher incidence of sleep-disordered breathing (SDB). Some of the dramatic side effects include hallucinations (both visual, tactile, and auditory), somnolence, peripheral edema, valvular heart disease, fibrosis, and heart failure. Recently, the association between higher doses of dopamine agonists therapy and impulse control disorders has been established in a plethora of studies(7). Abrupt and sudden withdrawal of antiparkinsonian drugs is associated with dangerous conditions such as neuroleptic malignant syndrome. It is important to monitor for these side effects when administering DA therapy to elderly patients(7).

Depression in PD

Depression in Parkinson’s disease predicts greater cognitive decline, deterioration in functioning and progression of motor symptoms, possibly reflecting more advanced and widespread neurodegeneration involving multiple neurotransmitter pathways. Depression may also occur after the withdrawal of dopamine agonists. Preexisting dementia is an established risk factor for the development of depression(8).

Recommendations for treatment

Step1. Exclude/treat organic causes such as hypothyroidism (the prevalence of which is relatively high in PD)(8).

Step 2. SSRIs are considered the first-line treatment, although the effect size is modest. Some patients may experience a worsening of motor symptoms, even though the absolute risk is low. Care must be taken when combining SSRI with selegiline, as the risk of serotonin syndrome is increased. The SNRIs venlafaxine and duloxetine also appear to have some effect although venlafaxine may modestly worsen motor symptoms(8). TCAs are generally poorly tolerated because of their anticholinergic (can worsen cognitive problems, constipation) and alpha-blocking effects (can worsen symptoms of autonomic dysfunction). SSRIs were the most effective treatments, significantly better than MAOIs and dopamine agonists. Limited evidence supports the safe use of agomelatine. Atomoxetine is not effective. Cognitive behavioral therapy (CBT) should always be considered(8).

Step 3. Consider augmentation with dopamine agonists/releasers such as pramipexole. Note though that these drugs increase the risk of impulse control disorders. They have also rarely been associated with the development of psychosis(8).

Step 4. Consider electroconvulsive therapy (ECT). Depression and motor symptoms respond well, but the risk of inducing delirium is high, particularly in patients with preexisting cognitive impairment(8). ECT may alleviate the affective disorder. Delirium is seen in a huge proportion of PD patients who have received ECT. However, it can be used for severe, treatment-refractory depression in PD and suicidal or life-threatening affective disorders. ECT can also be used in patients where rapid treatment response is required and the time needed for the treatment response using medications is difficult(1).

Step 5. Follow the algorithm for treatment-resistant depression. Be aware of the increased propensity for adverse effects and drug interactions in this patient group(8).

The stimulation therapies such as rTMS might be useful. The treatment would need to be repeated, as the treatment effect is short term(1).

Deep brain stimulation (DBS), especially focused on the subthalamic nucleus (STN), can be considered useful in the short term for managing depressive symptoms. However, with time, the effect can wane off. Some studies have reported an higher risk of suicide behaviors with the use of DBS in Parkinson’s disease(1).

Suicide

The pathogenesis of suicidal ideation has been shown to be the hypodopaminergic syndrome caused by dopamine agonist withdrawal, which is associated with depression, anxiety, apathy and anhedonia, resulting in suicide attempts. After DBS at subthalamic nucleus, reduced dopaminergic stimulation after drug dose reduction may be related to suicide. The treatment of suicide ideation is targeting the underlying suicide-related psychiatric symptoms, such as depression or anxiety. Proper management of motor fluctuation is also important to prevent suicide for relatively young, cognitively well-functioning patients with few comorbidities. Preoperative assessment, including psychosocial assessments, focusing on the potential suicidal risks before DBS at subthalamic nucleus, is recommended as a preventive measure(3).

Anxiety in PD

Among the various antianxiety medications, SSRIs and SNRIs are regarded as the first line of treatment. TCAs are better avoided in the elderly(1).

Benzodiazepines have been noted to be effective in treating anxiety in patients with Parkinson’s disease. At high doses, benzodiazepines are associated with a higher risk of falls and subsequent fractures along with a higher risk of cognitive impairment in the elderly population and abuse and dependence(1).

Anxiety, secondary to various causes, needs to be managed according to the underlying causes. In case of anxiety secondary to anti-parkinsonian medications, it is vital to adjust the dose, and if the anxiety symptoms are not tolerated, replacement of the medication should be considered(1).

Parkinson’s disease psychosis

The most important aspect of the management of Parkinson’s disease psychosis (PDP) includes finding out the modifiable risk factors and managing them. Ensuring the functioning of sensory modalities, such as visual and auditory, should be done. Keeping the patient in low stimulations areas with adequate lighting (to avoid minor visual hallucinations), maintaining the circadian rhythm, and reassuring the patients about symptoms are a few important steps(1).

Step 1. Possibilities of delirium should be ruled out, and the role of drugs having a high propensity of causing delirium should be evaluated. Other causes such as dehydration and electrolyte imbalances should be ruled out and managed, if any(1).

Step 2. Review of medications: reduce or stop non-parkinsonian drugs that could cause psychosis. Discontinue any nonessential centrally acting medications. Choose medications with a low risk of worsening mental status(3).

Step 3. Reduce or stop adjunctive anti-parkinsonian drugs in the following order: anticholinergics, monoamine oxidase B inhibitors, amantadine, dopamine agonists, COMT inhibitors, levodopa. Adjustment of anti-parkinsonian medications as motor function will tolerate. Careful consideration of the drug’s benefits for motor function and risks for psychosis. Adjustment of dopamine agonists and levodopa dosage: caution for the development of dopamine agonist withdrawal syndrome and neuroleptic malignant syndrome, respectively(3).

The primary objective of pharmacological treatment is to eliminate polypharmacy and optimum use of essential medications to treat PDP symptoms. The choice of medications should be based on (1) to avoid worsening of motor symptoms and cognitive impairment and (2) to decrease the hallucinations. Among atypical antipsychotics, clozapine and quetiapine are highly prescribed, but only clozapine has evidence of a needed therapeutic effect on hallucinations. However, the evidence suggesting the efficacy of quetiapine in treating PDP is not clear, and many studies have shown a very minimal or no benefit with quetiapine treatment. Atypical antipsychotics are advisable for patients with minimal or low cognitive impairment, while in patients with severe cognitive impairments, rivastigmine and donepezil are advisable(1).

A newer drug, pimavanserin, received FDA approval in 2016 for PDP treatment, and it has shown efficacy without worsening motor or cognitive symptoms. The usual dose is 34 mg once per day. The absorption is not affected by food, and there is no need of titration or dosage adjustment for sex, age, weight, ethnicity, or mild-to-moderate renal failure (CrCL >30 mL/min)(1).

Cognitive dysfunction and dementia

Cognitive impairment risk in Parkinson’s disease increases with disease progression and poses a significant burden to the patients, their families and society(9). There are no disease-modifying therapies or preventative measures for Parkinson’s disease mild cognitive impairment (PD-MCI), or Parkinson’s disease dementia (PDD). This article reviews current and previously investigated treatments and those under investigation, including pharmacologic, nonpharmacologic and surgical procedures.

There are currently no effective pharmacologic or nonpharmacologic treatments for PD-MCI. The only recommended treatment for PDD currently is rivastigmine, a cholinesterase inhibitor. Donepezil and galantamine – other cholinesterase inhibitors – are possibly useful. Memantine, an N-methyl-D-aspartate (NMDA) receptor antagonist, is considered investigational in PDD. Drug repurposing (atomoxetine, levodopa, insulin, atomoxetine for PD-MCI; ambroxol and ceftriaxone for PDD) and novel medications (SYN120, GRF6021, NYX-458 for PD-MCI; ANAVEX2-73, LY3154207, ENT-01, DAAOI-P for PDD) currently have insufficient evidence. There is growing research supporting exercise in the treatment of PD‑MCI, but most nonpharmacological approaches have insufficient evidence for use in PD-MCI (cognitive rehabilitation, deep brain stimulation, transcranial direct current stimulation, transcranial ultrasound, vestibular nerve stimulation) and PDD (cognitive intervention, deep brain stimulation, transcranial alternating current stimulation, transcranial ultrasound, temporal blood brain barrier disruption). Research is needed for both disease-modifying and symptomatic treatments in PD cognitive impairment(9).

There are no medications approved by the U.S. Food and Drugs Administration (FDA) or the European Medicines Agency (EMA) for PD-MCI. Rivastigmine is the only FDA-approved and EMA-approved medication for PDD. Current treatments for PD-related cognitive impairment primarily focus on symptom management, such as treating mood disorders, behavioral disturbance, sleep disorder, and lifestyle modification to improve the quality of life (e.g., physical activities, healthy diet and social engagement). While Parkinson’s disease is more common in men than women, there currently exist no differences in treatment approaches in men and women with PD(9).

Treating cognitive changes in PD starts with an assessment for potentially reversible contributors to cognitive changes(9). Major pharmacologic culprits are anticholinergic medications (e.g., antihistamines, antispasmodics), benzodiazepines, and opioids. Medications used to treat motor symptoms in PD can also contribute to cognitive symptoms. In the context of cognitive complaints, the general order in which PD medications are discontinued is as follows: anticholinergics, MAO-B inhibitors, amantadine, dopamine agonists, and COMT inhibitors, followed by reduced levodopa. Laboratory assessment for contributors to cognitive impairment commonly includes a complete blood count, serum electrolytes, glucose, blood urea nitrogen/creatinine, folate, B12, and thyroid function testing. Addressing depression and hearing loss are also part of a comprehensive approach to addressing cognitive impairment(9).

Studied treatments for Parkinson’s disease – mild cognitive impairment

Pharmacologic treatments for Parkinson’s disease – mild cognitive impairment

Researchers assessed atomoxetine, a selective norepinephrine reuptake inhibitor commonly used in attention deficit hyperactive disorder, in multiple studies of individuals with PD. In a randomized controlled trial (RCT) involving individuals with PD-MCI (n=30), atomoxetine (80 mg/day) showed no difference between the treatment and control groups in the primary cognitive outcome, a composite score based on a battery of standardized executive function tests, but the atomoxetine group had significant improvement on CAARS(9).

Creatine and coenzyme Q10 are important substrates involved in energy conversion in the mitochondria and have an indirect antioxidant effect(9).

Nonpharmacologic treatments for Parkinson’s disease – mild cognitive impairment

Cognitive interventions

Cognitive interventions are divided into three types: cognitive stimulation, cognitive training, and cognitive rehabilitation. Cognitive stimulation consists of nonspecific stimulation of cognitive and social functioning. Cognitive training uses standardized cognitive tasks on the computer or on paper. Cognitive rehabilitation targets specific areas of difficulty in activities of daily living to improve function(9).

The interventions included tailored exercises that stimulated executive function, attention, shifting ability, visuospatial function, and multi-domain online computer-based training over 4-8 weeks. The review concluded that there was no significant improvement in global cognition with the investigated approaches. One RCT in the systematic review (n=70) investigated a structured cognitive training program, NEUROvitalis, that focused on the cognitive domains frequently impaired in Parkinson’s disease (attention, memory, executive functions)(9).

Exercise and physical therapy

Different types of physical exercises have been evaluated for their effects on cognition, including treadmill training, dance, stationary bicycle, Wii Fit, and Tai chi. A systematic review of RCTs on the effects of physical exercise on cognition in PD (those with normal cognition and PD-MCI) showed that physical exercise improved global cognition, processing speed, attention and mental flexibility(9).

Device-related interventions

Transcranial magnetic stimulation (TMS) has been studied in PD for the treatment of motor, mood and cognitive symptoms. There is no definitive evidence for repetitive TMS (rTMS) in improving cognition in PD-associated cognitive impairment. One study showed that repeated intermittent “theta burst” stimulation of the left dorsolateral prefrontal cortex (DLPFC) improved cognition and visuospatial function lasting up to one month in persons with PD-MCI(9).

Transcranial direct current stimulation (tDCS) over the prefrontal cortex improved executive function, as measured in trail-making tasks, but not others (e.g., Stroop test, Wisconsin Card Sorting Test) in individuals with PD without dementia. An RCT (n=22) showed that the combination of cognitive training and transcranial direct current stimulation (tDCS) to the left DLPFC in individuals with PD-MCI (five days per week for two weeks) improved phonemic verbal fluency compared to cognitive training alone, and this effect persisted at three months(9).
 

Pathologic oscillatory activities exist in the thalamocortical region in PD, thus transcranial alternating current stimulation (tACS) was investigated for potential disease modulation. An RCT (n=15) using personalized transcranial alternating current stimulation, or tACS (location of stimulation was individually defined based on EEG data), five days per week for two weeks, did not show significant cognitive benefit in persons with PD with MMSE≥23(9).

Clinical treatment approaches for PD-MCI

The 2019 Movement Disorders Society update on evidence-based treatments for non-motor symptoms of PD concluded that there is currently insufficient evidence to support any pharmacologic (rivastigmine, rasagiline) or nonpharmacologic (transcranial direct-current stimulation, cognitive rehabilitation) treatment for non-dementia cognitive impairment in Parkinson’s disease. All reviewed approaches were labeled investigational(9).

Studied treatments for Parkinson’s disease dementia

Pharmacologic treatments for Parkinson’s disease dementia

Cholinesterase inhibitors are the most frequently studied medications for PDD. Rivastigmine is the only cholinesterase inhibitor that is approved by the FDA for use in Parkinson’s disease dementia. It is also approved for such use by the EMA, Canada and Japan(9).

Donepezil showed conflicting results in PDD studies. An RCT (n=16) found that donepezil 2.5-10 mg/day improved memory in persons with PD-MCI and PDD on the Dementia Rating Scale (DRS) but resulted in no significant changes in global cognitive status, attention, executive function, memory or visuospatial functions(9).

Memantine is an NMDA receptor antagonist considered investigational for use in PDD(9).

Nonpharmacologic treatments for Parkinson’ disease dementia

Studies on the effects of nonpharmacologic approaches on cognition in individuals with PDD are scarce. One systemic review that examined the effect of exercise in Lewy body dementia (LBD) included five studies, and only three included individuals with PDD (a total of 10 individuals with PDD)(9).

Deep brain stimulation (DBS): an RCT (n=6) evaluating bilateral NBM DBS in persons with PDD found no differences in the primary cognitive outcomes(9). Other RCTs are ongoing to evaluate subthalamic nucleus (STN) and NBM stimulation in treating motor and cognitive symptoms in PDD (NCT02589925). Other nonpharmacologic treatments that are being studied for PDD include transcranial ultrasound (NCT04250376) and temporary blood brain barrier (BBB) disruption using noninvasive ultrasound (NCT03608553)(9).

Clinical treatment approaches for Parkinson’s disease dementia

The 2019 Movement Disorders Society update on evidence-based treatments for non-motor symptoms of PD concluded that there is only sufficient evidence to support rivastigmine as efficacious for PD dementia. There is insufficient evidence of the efficacy of donepezil, galantamine or memantine. The update identified rivastigmine as clinically useful. The other cholinesterase inhibitors were classified as possibly useful, given their anti-dementia benefit outside PD. Memantine was labeled as investigational. Research on nonpharmacologic approaches for PDD are lacking, and there is insufficient evidence to support the use of nonpharmacological procedures (DBS, tACS) for PDD(9).

Apathy in Parkinson’s disease

Apathy remains an extremely common affliction, especially in subjects recently diagnosed with Parkinson’s disease, and is a major determinant of the quality of life for PD patients(10).

That said, apathy is a difficult symptom to manage in PD patients, as well-studied treatment options are currently limited. Our meta-analysis demonstrated that pharmacologic therapies have significant beneficial effects on apathy in PD patients, with no difference between dopaminergic agonists (such as rotigotine and piribedil) and other drug classes (including monoamine oxidase inhibitors and selective norepinephrine reuptake inhibitors)(10). Whilst the role of these agents in managing the motor symptoms of Parkinson’s disease remain disputed, these medications could be useful adjuncts for managing the nonmotor aspect of PD. However, while these medications may result in substantial improvements in apathy scores (and even other mood-related comorbidities), there may be challenges implementing such treatment regimens in clinical practice. Many of the studied medications are neurotropic agents which require transition across the blood-brain barrier and then interact with various receptors within the central nervous system. Such medications are also prone to drug-drug interactions, which range from altered pharmacokinetics to potentially life-threatening ones such as serotonin syndrome and sedation. Furthermore, polypharmacy is highly prevalent in Parkinson’s disease, as patients tend to have multiple medical comorbidities(10). Pharmacotherapeutic options for apathy must hence be systematically studied in future research to understand their risk profiles and potential interactions(10).

Despite having limited RCTs performed, exercise-based interventions are especially promising, given their potential to decrease the PD risk and, possibly, they even have disease-modifying effects. For example, higher levels of physical activity were linked with a lower risk of developing Parkinson’s disease, and even amongst PD patients, physical activity appears to improve symptoms severity, function and quality of life(10).

That being said, with the mounting evidence supporting the benefits of exercise, treatment regimens involving various types of exercises (such as aerobic and resistance training) represents a promising frontier, not to mention an excellent safety profile, unlike medications and invasive brain stimulation(10).

Noninvasive brain stimulation is an interesting up-and-coming treatment option of mood-related symptoms across both psychiatric and neurological disorders. Like exercise, the safety profile of noninvasive brain stimulation is excellent, with minimal (if any) clinically significant side effects. Examples of such stimulation include transcranial direct current simulation, transcranial alternating current simulation, and transcranial magnetic simulation. Though the evidence supporting its use remains limited in Parkinson’s disease, it has been systematically studied in other psychiatric and neurological disorders and has demonstrated promising results(10).

Sleep disorders in Parkinson’s disease

Insomnia

The treatment for insomnia (pharmacological or behavioral) must be preceded by a correct identification of the type of insomnia (initial, of maintenance, or terminal) and of possible disorders and factors causing it. It is necessary to rule out and treat motor or sleep breathing disorders, if present. If insomnia is iatrogenic or due to motor complications of PD, it is useful to modify the therapy. Levodopa-carbidopa controlled-release (LD-CR) improves sleep-associated motor symptoms that may contribute to insomnia, although data documenting an objective improvement in sleep parameters or in sleep satisfaction are insufficient. A double-blind crossover study, comparing the effect of a single dose of 100/25mg LD-CR with placebo, in 40 fluctuating PD patients, showed an improvement in nocturnal akinesia and only a not-significant trend of increase in total sleep time without any improvement in sleep latency and sleep fragmentation(11).

Nonpharmacologic treatment for insomnia consists of sleep hygiene measures and cognitive behavioral therapy. These have consistently been demonstrated as effective in primary (psychophysical insomnia), and also some forms of secondary insomnia (although they may be less effective than for primary insomnia). Good sleep hygiene should be advised in people with Parkinson’s disease with any sleep disturbance, including: avoidance of stimulants (e.g., coffee, tea, caffeine) in the evening; establishment of a regular pattern of sleep; comfortable bedding and temperature; provision of assistive devices, such as a bed lever or rails to aid with moving and turning, allowing the person to get more comfortable; restriction of napping in the late afternoon and early evening; advice about taking regular and appropriate exercise to induce better sleep; advice to avoid remaining in bed for long periods of time if unable to sleep; a review of all medication and avoidance of any drugs that may affect sleep or alertness, or may interact with other medication (e.g., selegiline, antihistamines, H2 antagonists, antipsychotics and sedatives)(5).

The effect of dopamine agonists on sleep disorders in Parkinson’s disease has been evaluated usually as secondary endpoint in many randomized controlled trials, showing an improvement in sleep parameters. Ropinirole 24-hour prolonged release (2-24mg/day), as adjunctive therapy to levodopa, significantly improved PDSS scores in 93/198 patients with motor fluctuations enrolled in a randomized, placebo-controlled study. A double-blind, double-dummy, randomized, placebo-controlled trial, comparing the efficacy of pramipexole (up to 4.5mg/day) and transdermal rotigotine patch (up to 16mg/day) on advanced-stage PD patients treated with LD, reveales for both drugs a small but significant improvement in sleep parameters assessed by PDSS. Rotigotine transdermal patch (2-16mg/day) improved early morning motor function and PDSS-2 scores in a multinational, randomized double-blind placebo-controlled study on 287 PD patients with unsatisfactory early morning motor symptom control and motor symptoms during the night(11).

Finally, rasagiline, a monoamine oxidase B inhibitor, can improve insomnia, probably increasing endo­genous melatonin levels. A single-center, prospective, observational study compared 19 PD patients treated with LD 200-300mg/day associated with rasagiline 1mg/day with 19 PD patients treated only with LD 200-300mg/day. After 12weeks of treatment, the group treated with LD and rasagiline showed a significant reduction in mean sleep latency and an increase in mean total sleep time(11).

If insomnia is not iatrogenic and not due to PD motor complications, the main therapy remains the cognitive behavioral therapy. This treatment comprises advice on sleep-wake behavior hygiene, stimulus control, sleep restriction, relaxation, and cognitive techniques(11).

In the cases in which pharmacological therapy is necessary, eszopiclone, doxepin, zolpidem, trazodone, ramelteon and melatonin could be useful, although these drugs are investigational for the treatment of insomnia in Parkinson’s disease, because there is insufficient evidence regarding their efficacy. To avoid tolerance, hypnotic drugs should ideally be used for no longer than 4-5weeks. Eszopiclone (2-3mg/day) was tested in 30 PD patients with insomnia in a placebo-controlled trial. This drug does not increase total sleep time but reduces awakenings during the night and improves sleep quality. Thirteen percent of patients reported mild adverse events such as dizziness and sedation(11).

Excessive daytime sleepiness

The treatment of excessive daytime sleepiness (EDS) in Parkinson’s disease is a challenge. First of all, it is necessary to identify and treat any possible sleep disorders that could disrupt nocturnal sleep and to withdraw or reduce any possible drugs causing hypersomnia, such as antidepressants, antipsychotics, or sedatives. At the same time, it is important to educate patients to apply the sleep hygiene rules. All dopamine agonists cause more EDS than LD, without differences between drugs but with a direct relationship with drug dose. Combination therapy with LD and dopamine agonists shows the highest risk of EDS. Instead, selegeline, amantadine, and entacapone had no influence on EDS. The association between orally dispersible selegiline and dopamine agonists may reduce or resolve EDS. If the above strategies do not improve EDS, the use of stimulating drugs such as modafinil (100-400mg/day) should be a solution. It seems to improve patients’ perception of wakefulness without any objective confirmation(11).

Possible adverse events related to modafinil therapy are headache, dry mouth, dizziness, nausea, nervousness, insomnia, and generalized itching. These side effects seem to be mild and decrease with dose reduction. Nocturnally administered sodium oxybate 3-9g/night in two split doses (at bedtime and 4hours later) may improve excessive daytime sleepiness and fatigue in PD, but further and larger studies are needed to prove its efficacy and safety, considering also its depressant function on the respiratory centers and its abuse potential(11).

Methylphenidate (1mg/kg three times daily, for threemonths) was effective after a night of LD withdrawal and after an acute administration of LD, in reducing ESS in 17 patients with advanced Parkinson’s disease. Unlike modafinil and sodium oxybate, which did not influence motor PD symptoms, methylphenidate improved them and, in particular, gait. Finally, caffeine (200mg/bid) seems to improve motor symptoms after threeweeks of treatment, in the absence of any real influence on EDS, in a randomized, double-blind, crossover, placebo-controlled, multicenter trial on 61 patients(11).

Parasomnias

NREM parasomnias (non-REM)

NREM parasomnias are undesired events characterized by an incomplete arousal from NREM sleep and include confusional arousals, sleepwalking and sleep terrors. The prevalence of NREM parasomnias in Parkinson’s disease is not clear. A questionnaire study on 661 PD patients showed that sleepwalking had a prevalence of 1.8%, while night terrors had a prevalence of 3.9%. In PD patients with RBD, the prevalence of NREM parasomnias (parasomnia overlap disorder) is higher, reaching, respectively, 4.3% and 8.7%. Somnambulism in Parkison’s disease is associated with higher incidence of depression and advanced PD stage(11).

The first approach to a patient with NREM para­somnias, independently of its causes, is to secure the bedroom in which the patient sleeps, closing and locking doors or windows, blocking stairways, and removing all potentially dangerous objects.

It is also important to reduce all the possible precipitating and predisposing factors, such as alcohol consumption, stress, fever, sleep deprivation, sleeping in unfamiliar or noise-exposed bedrooms. If present, it is necessary to treat OSA and reduce or withdraw psychotropic drugs such as phenothiazines, anticholinergic agents, and sedative/hypnotic agents(11). Clonazepam (CNZ; 0.25-2mg at bedtime) is the first-line pharmacologic treatment for NREM parasomnias in adults, but its efficacy has not been proved in randomized controlled trials. CNZ was effective in 90% of a series of 20 patients with parasomnia overlap disorder, but there are no studies in PD patients. Only four sleepwalkers were identified in a set of 165 PD patients.

After a two-year follow-up, two patients had a spontaneous remission of sleepwalking, one patient responded to topiramate treatment (100mg/day), and one patient showed a resolution of the episodes after clozapine treatment (25/mg day)(11).

REM parasomnias

Nightmares

Nightmares are vivid and unpleasant dreams recurring in REM sleep and causing awakening. Their prevalence in PD patients seems to be 17.2%, but these data are only based on questionnaires. Dream contents in PD patients seem to be different from controls in particular regarding violence, misfortune, and presence of animals.

Some authors explain that these contents in relation to the cognitive and frontal impairment of PD patients. Traumatic events, stress, use of antidepressants, alpha-agonists, beta-blockers, and cholinergic antagonists are all predisposing and precipitating factors for nightmares(11).

The first-line treatment for nightmares is cognitive behavioral therapy – in particular, the imagery rehearsal therapy (IRT), but these techniques have not been systematically tested in PD patients and need to be confirmed. A placebo-controlled study showed that prazosin (9.5mg/at bedtime) reduced nightmares in 10 Vietnam veterans. Other studies proved prazosin efficacy, but its real effectiveness needs to be tested in larger placebo-controlled trials. Side effects such as orthostatic hypotension could discourage its use in PD patients(11).

REM sleep behavior disorder (RBD)

REM sleep behavior disorder is a REM parasomnia characterized by complex, sometimes violent, and dangerous motor behaviors during which the patient acts out the content of his/her dream. RBD is present in 30% of patients with Parkinson’s disease and often precedes the onset of motor symptoms(1).

Independent of pharmacological therapy, in order to guarantee the patient’s and bed partner’s safety, securing the bedroom is necessary. It is also necessary to withdraw or reduce drugs potentially causing RBD, such as monoamine oxidase inhibitors, antidepressants, beta blockers (bisoprolol), opioids (tramadol), and centrally acting alpha-agonist hypotensive agents (clonidine). If RBD causes sleep disruption or if it influences the patient and bed partner’s safety, pharmacological treatment is indicated. CNZ (0.25-2mg, 30minutes prior to bedtime) has been a first-line therapy for RBD(11). CNZ is contraindicated in moderate and severe OSAS. The mechanism of action of CNZ is unknown(11).

In PD patients in which CNZ is contraindicated (for example, patients with OSAS, cognitive impairment, and a high baseline risk of falling), melatonin (3-12mg, before sleeping) could be the treatment of choice. CNZ and melatonin appear comparably effective for RBD symptoms and injury prevention(11).

Melatonin mechanisms of action are still not completely known, but its use seems to reduce RBD and decrease muscle tone during REM sleep. Side effects (morning headache, morning sleepiness, and delusions/hallucinations) are usually related to high doses. Pramipexole (0.2-1mg/night), paroxetine (10-40mg), donepezil (10-15mg), and rivastigmine (4.5-6mg) may be effective in some refractory cases, but the evidence of their efficacy is inconclusive due to the lack of randomized controlled.

Ramelteon was effective in RBD in PD patients in two recent open trials, conducted, respectively, in 24 and 12 PD patients, but these promising results could be confirmed in larger populations and for longer follow-up. Daytime sleepiness, nausea, delirium, giddiness, and worsening of constipation are possible ramelteon side effects(11).

Sleep-related breathing disorders

Obstructive sleep apnea

Obstructive sleep apnea (OSA) is characterized by snoring and repetitive episodes of complete (apnea) or partial (hypopnea) upper airway obstruction occurring during sleep. The patient typically complains of lack of breath, gasping or choking, insomnia, non-restorative sleep, and excessive daytime sleepiness. The prevalence of OSA in PD is highly controversial, widely ranging from 20% to 60%. At the same time, sleep fragmentation and intermittent hypoxemia due to OSA may contribute to or worsen Parkinson’s disease(11).

The gold standard therapy for OSA is the continuous positive airway pressure (CPAP), which normalizes nocturnal respiration, improving nighttime oxygenation, sleep architecture (particularly deepening sleep), and daytime sleepiness(11). The control of body weight and sleeping on one’s side during the night could be useful. In this case, to relieve the difficulties of turning around, adapted physiotherapy and increased dopaminergic treatment at night by extra nocturnal doses or sustained release drugs may improve OSA. Recently, mandibular advancement devices have been shown to be similarly beneficial to CPAP in improving OSA. There are contradictory reports on the modulation of respiratory function by anti-parkinsonian treatment and the real effect of DAs remains unknown. Dopamine agonists seem to enhance the risk of central sleep disorders of breathing. On the contrary, bedtime long-acting LD seems to improve OSA in PD patients, as shown in a polygraphic study in 57 patients, even though the real mechanism of action of LD has not been proven(11).

Sleep-related movement disorders

Restless legs syndrome

If restless legs syndrome (RLS) is mild, it can be managed by only lifestyle changes. Therefore, before initiating any pharmacological treatment, it is necessary to evaluate the frequency and duration of symptoms and their impact on the patient’s quality of life. Chronic renal failure, iron, vitamin B12 and folic acid deficiency, serum glucose, and HbA1C need to be investigated in order to exclude secondary forms. The serum ferritin level should be measured, and if the concentration is below 50-75µg/mL, or if transferrin saturation is less than 20%, supplementation with oral iron is recommended. If oral iron is poorly tolerated or contraindicated, the intravenous administration can also be considered. The withdrawal of drugs that potentially exacerbate RLS such as antidopaminergic drugs, antihistamines, and antidepressants (except for bupropion) is also recommended(11).

Dopamine agonists have proven effective for RLS. The lowest possible cumulative daily dose is recommended to prevent augmentation, which is a side effect characterized by an overall increase in RLS symptoms severity during therapy. To prevent such augmentation, long-acting DAs should be preferred to short acting ones. Alternatively, α2δ ligands (pregabalin 150-450mg/day, gabapentin 900-2400mg/day, or enacarbil 600-1.800mg/day) are useful. Dizziness, somnolence and fatigue are common α2δ ligands side effects. In resistant cases, low doses of opioids such as long-acting oxycodone or methadone should be considered, except for patients with high risk of addiction or with preexisting severe constipation, sleep apnea syndrome, or prolonged QTc. Finally, patients may obtain temporally relief by rubbing or massaging the affected limbs, bathing in hot or cold water, physical activity, or distracting themselves with mental exercises (for example, reading an interesting book at the onset of the symptoms)(11).

Periodic limb movements

Periodic limb movements (PLMs) are stereotyped and repetitive movements affecting the limbs – in particular, the legs – which can cause nonrestorative sleep. More than 15 movements per hour of sleep are considered pathological, although the prevalence of PLMs increases with age also in the normal population. In elderly, the prevalence of PLMs is estimated between 25% and 58%(11). Subjects with PLMs may or may not be aware of the movements reported by the bed partner. Some authors reported a possible link between the presence of PLMs and frequent awakenings, daytime sleepiness, fatigue or, more rarely, excessive daytime sleepiness. Periodic limb movements are often associated with RLS, narcolepsy, or sleep apnea. Eighty percent or more of all RLS patients have PLMs(11). It is not clear, if prevalence of periodic limb movements in Parkison’s disease is higher than in the general population. Age, secondary causes such as hyposideremia and the loss of dopaminergic cells may explain the link existing between PLMs and Parkinson’s disease. Antidepressants, neuroleptics, and lithium could be other potential inducing factors(11). In RLS patients, randomized placebo-controlled studies have established the efficacy of DAs for both improvement of RLS symptoms and reduction in PLMs. In a cross-sectional study on 19 untreated PD patients, the introduction of dopamine agonists therapy almost totally suppressed periodic limb movements(11).

Impulse control disorders  

Although the frequency of impulsivity and compulsive behavior in PD patients before the initiation of dopamine receptor agonists is similar to the frequency in healthy controls, it is conceivable that dopamine receptor agonists may turn impulsive personality traits into clinically disorders. Specifically, affinity of pramipexole and ropinirole for the D3 receptors is much greater than for the D2 receptor (100 and 25 times, respectively), as well as for D1 receptor (above 1000 and 300 times, respectively). Other dopamine agonists commercially available in only some countries, such as piribedil, may also lead to impulse control disorders (ICDs). At the same time, the oral dopamine agonists (pramipexole and ropinirole) have been found to have a greater risk for causing ICDs than the transdermal dopamine agonist rotigotine, which might be partially explained by the theory that transdermal delivery bypasses erratic gastric emptying, and it may avoid other changes in gastrointestinal motility, leading to the stability of plasma level. In a post-hoc analysis about Parkinson’s disease treated with rotigotine, although no definite conclusion can be reached on any dose-response relationship between rotigotine and impulse control disorders, the incidence of ICDs appeared to increase with the dosage increase, as increased with longer exposure to rotigotine and recommend active surveillance with increased duration of treatment and dose reduction when impulse control disorders are present(4).

In addition to dopamine agonists, levodopa, particularly in high dosages, has been also associated with ICDs. In patients taking dopamine agonist, concurrent levodopa usage is reported to increase the odds of impulse control disorders by approximately 50%. This multicenter study indicated that there is no association with higher dopamine agonists dose but a link with higher levodopa dose with ICDs, suggesting an intrinsic role for levodopa. And also, patients with Parkinson’s disease treated by levodopa show impulse control disorders more frequently and more severely than patients without levodopa, thereby suggesting the levodopa’s significance in a way(4). In ICDs patients with Parkinson’s disease, caregivers suffer huge burden from mental stress specifically on spousal safety. Impulse control disorders are associated with a high rate of separation and divorce, child abuse, and neglect. It is important to recognize the disease and treat it without delay(4).

As discussed above, impulse control disorders are considered to have strong relationship with dopamine agonists. Decreasing or even withdrawing dopamine agonists is usually the first choice for clinicians. For PD patients who have developed ICDs on account of dopamine agonist treatment, they will get remission significantly after decreasing dosages. One longitudinal study suggested that ICDs resolved after one year in about 50% of the patients who stopped dopamine agonists and continued to improve. Patients can increase levodopa dosage instead to avoid worsening of motor symptoms. However, the treatment is still challenging, as patients may experience dopamine agonist withdrawal syndrome(4). Considering the benefit from reducing dose of dopamine agonists such as pramipexole or ropinirole, it is recommended that temporary replacement of pramipexole by bromocriptine instead may relieve or reverse the impulse control disorders while the D2 stimulation needed for motor symptoms are still maintained(4).

Subthalamic nucleus (STN) deep brain stimulation (DBS) as a treatment for impulse control disorders is considered a controversial method, according to reported literature. STN-DBS and the following tapering of dopaminergic treatment can change personality traits in PD patients. A few studies are in favor of DBS surgery as a treatment for impulse control disorders and even suggest that ICDs may be considered as new indication for STN-DBS(4). ICDs patients exhibited a complex outcome after STN-DBS, with a tendency for overall reduction, but with several factors affecting its effect. It is believed that the effective management of medication and the correct stimulation parameters may explain these results better than previous literature. Successful surgery allows a marked decrease of total dopaminergic medication. The subthalamic nucleus stimulation may also have specific effect on limbic part of the STN. In general, fine-tuning of stimulation parameter after DBS surgery, accompanied with a drastic reduction of dopaminergic medication are considered as an effective method to give remission to ICDs patients, especially in the advanced-stage subgroup.

Meanwhile, some studies disapprove the using of STN-DBS, because impulse control disorders may persist or even worsen after DBS surgery. Even more, some evidence shows that impulse control disorders may emerge following DBS surgery regardless of unilateral or bilateral deep brain stimulation. Stimulation by DBS might sensitize the brain to the impulsive behaviors induced by dopamine agonists, especially in patients with addictive behavior history. Besides, stimulation with electrode contacts located mainly within the sensorimotor territory can result in spread of current to limbic and associative area. Failed surgery, with misplaced electrodes outside the STN, would result in failure to reduce dopaminergic medication, or even causing new onset of dopaminergic treatment. Stimulation intensity increased too rapidly will elicit impulse control disorders in the same way as dopaminergic treatment. Therefore, we should be careful when choosing deep brain stimulation treatment in clinical practices(4).

Amantadine, acting as a dopaminergic and glutamatergic modulator, was reported to have a great effect on reversing ICDs symptoms without aggravating motor function. Amantadine add-on therapy is considered to reduce hypersensitivity in ICDs patients, therefore a decrease is a risky choice. However, amantadine was associated with an increased risk for impulse control disorders in another multicenter study(4). As ICDs are thought to be linked to oral dopamine agonists, strategies utilizing intrajejunal levodopa which utilize continuous drug delivery may decrease the risk of developing ICDs. This therapy may become a popular treatment of impulse control disorders, not only because of its positive effect on behavioral disorders, but also on motor complications(4).

Clozapine was reported as a potential treatment for refractory impulse control disorders. There have been several cases reporting beneficial responses to clozapine in ICDs patients(4).

There has been an emerging method to treat impulse control disorders using transcranial magnetic stimulation (TMS). A study reported that low-frequency repetitive TMS was used to treat four PD patients with punding behavior whose symptoms were reversed magically. TMS deserves more studies to explore the best pattern and more indications(4).

To date, there have been few studies regarding the role of cognitive behavioral therapy in ICDs. Studies found that the combined treatment, with cognitive behavioral therapy and medical care, was more effective in reducing the severity of impulse control disorders, compared with medical care alone(4).    

 

 

 

Autori pentru corespondenţă: Raluca Pretorian E-mail: pretorianraluca@yahoo.com

CONFLICT OF INTEREST: none declared.

FINANCIAL SUPPORT: none declared.

This work is permanently accessible online free of charge and published under the CC-BY.

Bibliografie


  1. Tripathi A, Gupta Pk, Bansal T. Management of Psychiatric Disorders in Patients with Parkinson’s Diseases. Indian J Psychiatry. 2022;64(Suppl 2):S330-S343.

  2. Dujardin K, Sgambato V. Neuropsychiatric Disorders in Parkinson’s Disease: What Do We Know About the Role of Dopaminergic and Non-dopaminergic Systems?. Front Neurosci. 2020;14:25. Published 2020 Jan 29.

  3. Han JW, Ahn YD, Kim WS, et al. Psychiatric Manifestation in Patients with Parkinson’s Disease. J Korean Med Sci. 2018;33(47):e300.

  4. Zhang JF, Wang XX, Feng Y, Fekete R, Jankovic J, Wu YC. Impulse Control Disorders in Parkinson’s Disease: Epidemiology, Pathogenesis and Therapeutic Strategies. Front Psychiatry. 2021;12:635494. Published online 2021, Feb 9.

  5. Canadian Guideline for Parkinson Disease, Second Edition, 2020. www.ParkinsonClinicalGuidelines.ca

  6. Weintraub D. Management of psychiatric disorders in Parkinson’s disease: Neurotherapeutics - Movement Disorders Therapeutics. Neurotherapeutics. 2020;17(4):1511-1524.

  7. Borovac JA. Side effects of a dopamine agonist therapy for Parkinson’s disease: a mini-review of clinical pharmacology. Yale J Biol Med. 2016;89(1):37-47.

  8. Taylor DM, Barnes TRE, Young AH (Eds.). The Maudsley Prescribing Guidelines in Psychiatry,14th Edition. Wiley-Blackwell, 2021.

  9. Sun C, Armstrong MJ. Treatment of Parkinson’s Disease with Cognitive Impairment: Current Approaches and Future Directions. Behav Sci (Basel). 2021;11(4):54. 

  10. Mai AS, Lee YS, Yong JH, Teo DCYJ, Wan YM, Tan EK. Treatment of apathy in Parkinson’s disease: A bayesian network meta-analysis of randomised controlled trials. Heliyon. 2024;10(4):e26107.

  11. Loddo G, Calandra-Buonaura G, Sambati L, et al. The Treatment of Sleep Disorders in Parkinson’s Disease: From Research to Clinical Practice. Front Neurol. 2017;8:42. Published 2017, Feb 16.

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