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The most potent neuroleptic agent that can be used without fear of worsening parkinsonian symptoms is clozapine.[141,142] This atypical neuroleptic is a less potent blocker of striatal dopamine receptors than other drugs in its class and it appears to be specific for the subclass of dopamine-receptor mediated psychosis. The dosages required to treat dopaminergic-induced hallucinosis are much lower than those required in schizophrenia. A starting dose of 12.5 mg at bedtime is appropriate. If upward titration is required in patients with PD, the final dosage seldom exceeds 50 mg per day. Even at these low dosages, side effects such as sedation and hypotension are seen. One additional approach to the treatment of levodopa-induced hallucinosis is the use of the serotonin antagonist ondansetron.[143] Early experience indicates that this agent may be effective for this purpose, but high cost may inhibit its use except under extreme circumstances.
Other medical conditions. If psychiatric symptoms in a patient with PD are unrelated to antiparkinsonian medications or represent activation of an underlying, preexistent psychotic disorder, larger dosages of clozapine likely will be required. Additional side effects may be seen with higher dosages, most notably severe sialorrhea and the induction of seizures. The most serious complication, agranulocytosis, is not dose-related and occurs in approximately 2% of patients who receive this agent.
SLEEP DISORDERS
One of the most common problems for patients with moderate to advanced PD is disruption of normal sleep patterns.[144-146] In his initial monograph, James Parkinson recognized sleep disturbance as an important component of paralysis agitans.[147] While poor sleep is common in the elderly, patients with PD have a unique set of difficulties that require accurate diagnosis and often improve with correct intervention. The physiologic basis for disrupted sleep arises from three neurotransmitter systems. Nigral dopamine cell loss causes poor mobility, while dorsal raphe serotonergic cell loss and locus ceruleus noradrenergic cell loss contribute to depression and sleep cycle disruption.[148,149] (See the algorithm and the corresponding text for specific symptom management.)
INSOMNIA. The first branch point of the sleep disorder portion of the algorithm covers difficulty with sleep initiation and sleep maintenance (breakout 23). Initiation and maintenance problems may be primary sleep disorders or be associated with dementia, secondary to PD mobility impairment or tremor, or may result from medication-induced dyskinesia or depression. Idiopathic insomnia. Inability to fall asleep is common among patients with PD. A diagnosis of idiopathic insomnia usually is made clear by the initial description, although a diary can provide useful information. Evaluation may include all-night polysomnography (PSG) in select patients. Patients should he asked about their ability to turn over in bed or adjust sheets without assistance, frequency of nocturia, and occurrence of nightmares. If the bed partner reports any unusual behaviors by the patient (eg, semipurposeful actions, aggression, wandering), PSG may reveal REM Behavior Disorder (RBD). This syndrome is most frequent in older males with neurologic illness and may result in injury to patient or spouse. Case reports of RBD and PD are in the literature and in our clinical practice. RBD in patients with PD may he treated with low-dose clonazepam (0.25 to 1.0 mg nightly).
Pharmacologic options for idiopathic insomnia are listed in table 1, along with typical dosages. Long-term use of sedative hypnotics is generally not good practice, as physical dependence and cognitive side effects are common. Pharmacologic profiles and side effects of these medications are discussed in a recent review.[151] Nocturnal PD symptoms. Attention should be directed first to any PD symptoms or motor fluctuation.[152] Trouble getting comfortable or turning in bed often is caused by underdosage of dopaminergic medications or "wearing off" of their effects. One of the long-acting levodopa preparations carbidopa-levodopa CR 50/200 or CR 25/100) at bedtime may be an appropriate treatment for certain of these patients.[153] Alternatively, dopamine agonists such as pergolide or bromocriptine may be employed. These agents, because of their longer half-lives, also have the advantage of reducing early morning dystonia. Occasionally, dyskinesias interfere with normal sleep. If such is the case, bedtime dopaminergic dosages should be decreased. Physical aids such as satin sheets for greater ease of movement and condom catheters may he helpful. Medication-induced. If patients are taking selegiline twice daily, the second dose should be given no later than noon. If that is already the practice, consider elimination of the second dose or discontinuation of the drug altogether. Insomnia is not uncommon with selegiline and this may result from the amphetamine metabolites of the parent compound. Amantadine may also produce insomnia because of its stimulatory effects. Dosage reduction or drug discontinuation should he considered. Dementia associated with PD. (See sleep-related problems within the "Dementia" sections to follow.) Depression. Patients with insomnia should be questioned about possible depression and, if indicated, a treatment program initiated. Such a program may include increased daytime activities, counseling, or antidepressant medications. The soporific effects of tricyclic agents often work to promote sleep onset and sleep consolidation. Typical choices include amitriptyline or nortriptyline at 10 to 25 mg at bedtime. Maximum dosages are usually less than 100 mg, because of the higher frequency of side effects in elderly patients.
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Table 1. Medications used for the short-term treatment of insomnia (dose at bedtime)
Diphenhydramine 25-75 mg
Chloral hydrate 250-750 mg
Tricyclic agents 10-100 mg
Temazepam 15-30 mg
Diazepam 1-5 mg
Clonazepam 0.5-1 mg
Zolpidem 10 mg
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EXCESSIVE DAYTIME SLEEPINESS. Many factors contribute to daytime sleepiness (breakout 24). For the person with PD, several common problems emerge as outlined in the table 2. Depression. If untreated depression exists, then treatment with an alerting antidepressant (eg, bupropion, 75 to 300 mg per day in divided doses) or low bedtime doses of a tricyclic may help to alleviate daytime sleepiness (see subsection on depression under "Behavioral impairment" in the "Neuropsychiatric problems" section). Often, depression in patients with PD lacks some of the classic vegetative signs and may be mistaken as bradykinesia. Psychologic assessment or an empiric trial of medical therapy is warranted. Electroencephalography may reveal reduced sleep latency in PD patients with depression.[154] Medication-induced. Perhaps the most simple form of daytime sleepiness to address is medication-induced. Use of anxiolytics or other sedating agents should be minimized during the day. Levodopa-induced sleepiness is a well-characterized but uncommon phenomenon. Patients with moderate to advanced stages of PD sometimes describe the overwhelming urge to sleep as a dose of levodopa takes effect. This may occur more often with sustained-release carbidopa-levodopa. The mechanism for this effect is unclear, although stimulation of dopamine receptors may induce sleep at low levels.[155] Perhaps the more gradual onset of the CR formulation is responsible for this phenomenon. One occasionally can reduce this effect by switching from a CR to a short-acting form of carbidopa-levodopa during the daytime.
