also are employed frequently for treatment of depression in patients with PD. These agents are activating rather than sedating in their action, which might be desirable in certain patients. The dosages for the treatment of depression in PD are the same as those for non-PD-associated depression (eg, 20 mg daily for fluoxetine). Some concern has been raised that the symptoms of PD could worsen after fluoxetine treatment, but this is not a common problem.[134] The potential does exist, however, for an adverse interaction between selective serotonin reuptake inhibitors and selegiline and concurrent use usually is discouraged.[135] Electroconvulsive therapy (ECT) is another treatment modality available for the therapy of depression in PD.[136] Typically, ECT is considered either for severe depression that is unresponsive to medical therapy or for temporary amelioration of severe depressive symptoms during the 1- to 3-week latency before antidepressant drugs take effect. A fringe benefit of this approach is that transient improvement might occur in the motor signs of PD, as well.[137] Anxiety and panic reactions. Like depression anxiety or panic might appear predominantly during "off" periods in some patients but in others can be present throughout the day, irrespective of control of parkinsonian symptoms. Using DSM-III-R criteria, a recent study found that 38% of PD patients manifested clinically significant anxiety.[138] When anxiety occurs predominantly during "off" periods, its intensity tends to parallel the difference in motoric function between the "on" and "off" states.[139] In patients who experience anxiety largely while "off," therapeutic attention first should be directed to improving fluctuations in motor performance before considering pharmacologic intervention. In patients who suffer persistent anxiety or whose fluctuations cannot be sufficiently controlled to improve their "off"-period anxiety, anxiolytic drugs are indicated. The most useful agents for this purpose are the benzodiazepines, such as diazepam, alprazolam, and lorazepam. Typical dosages for this purpose are 0.5 to 1 mg three times daily for alprazolam or 2.5 to 5 mg four times daily for diazepam. Still lower dosages are often required at the initiation of therapy in the elderly. For patients who do not benefit from the benzodiazepines, imipramine or buspirone can be considered, but it must be recognized that the former agent can have undesirable side effects, such as confusion or hypotension, and that the latter has mild dopamine-blocking properties. Panic disorder consists of a severe state of anxiety that occurs episodically and is characterized by a variety of psychologic, a utonomic, and somatic symptoms. These include, among others, breathlessness, nausea and vomiting, diaphoresis, dizziness, choking, and the fear of dying or going insane. In occasional patients, such symptoms coincide with their levodopa "off" states. For these individuals, dosage adjustment of their antiparkinsonian drugs, as described in the section, "Motor problems," is the appropriate treatment. In other patients, treatment directed at panic disorder, per se, is necessary. Benzodiazepines also may be useful in these cases, but higher dosages may be required to achieve the desired result. A specific benzodiazepine, clonazepam, may be especially useful in panic disorder. Should these agents be ineffective, the serotonin reuptake inhibitors can also be used to good advantage. For refractory cases, ECT may be effective. HALLUCINATIONS. Treatment related psychosis can cause severe disability in a patient with PD. Both anticholinergic and dopaminergic antiparkinsonian medications can induce psychotic symptoms, such as paranoia and hallucinations (breakout 22). Medication-induced. When related to dopaminergic agents, this complex of symptoms presumably results from stimulation of mesolimbic dopamine receptors. It has been estimated that the overall incidence of hallucinosis in levodopa-treated PD patients is 20%.[129] In these patients, the earliest sign of psychosis is often the appearance of restlessness, vivid dreams, and nightmares. More advanced symptomatology consists of hallucinations and paranoid ideation. With further progression, a state of delirium can develop. Hallucinations that develop under these circumstances are usually visual and more common at night. They are typically nonthreatening and often involve family members (alive or deceased) or nonferocious animals such as cats or dogs. As is the case with other treatment-related neuropsychiatric side effects, reduction or discontinuance of potentially causative medications should be the first means of therapy starting with those adjunctive agents that have relatively less efficacy in the treatment of the motor symptoms of PD. Thus, selegiline or amantadine should be the first agents to be discontinued, followed by anticholinergic agents and then the dopamine agonists. Next, if needed, carbidopa-levodopa should be titrated downward to the point of improvement in psychotic symptomatology, but at the same time this improvement must be balanced against the inevitable reemergence of bradykinesia, rigidity, or tremor. If hallucinations are predominantly nocturnal, an attempt should be made to remove or reduce dosing of antiparkinsonian agents administered in the late evening or at bedtime. When hallucinations persist despite the maximally tolerated reduction of antiparkinsonian medication, pharmacologic antipsychotic therapy is indicated. Neuroleptic agents are the most effective drugs for this purpose, but most of these preparations--such as haloperidol, perphenazine, or chlorpromazine--are potent dopamine blockers whose potential for inducing parkinsonian symptoms limits their usefulness. Low-potency neuroleptic agents, however, can be very useful for treating hallucinosis in patients with PD. Three such agents are thioridizine, molindone, and risporidone. These drugs often can be used at low dosages (eg, 20 to 30 mg per day for thioridizine or 0.5 to 1 mg per day for risporidone), with little or no noticeable effect on parkinsonian symptoms but with clear improvement in hallucinations. This approach is especially useful for patients who have vivid dreams nightmares, or nocturnal hallucinations, it whom the drug can be administered late in the evening or at bedtime. It should be noted that among these three low-potency neuroleptics, risperidone is relatively new. Significant experience with its use in patients with PD has not yet been accumulated. 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-close 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. ---------------------------------------------------------------- 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 ---------------------------------------------------------------- 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. ---------------------------------------------------------------- Table 2. Causes of excessive daytime sleepiness associated with Parkinson's disease Drug-induced Levodopa Anxiotytics Antidepressants Selegiline-induced insomnia Primary steep disorder Obstructive sleep apnea Restless leg syndrome Periodic limb movements of sleep REM behavior disorder Endocrine dysfunction (eg hypoparathyroidism) Circadian cycle disruption with dementia PD, lack of zeitgebers ----------------------------------------------------------------- Dementia. Disruption of normal circadia rhythms occurs with the dementia of PD when patients lose the normal environmental an temporal clues, or "zeitgebers" about time passage.[156] This problem is common in nursing homes and other institutional settings. In all patients, sleep hygiene should be reviewed. For some, restoration of consistent schedules (eg lights out, meals, medication times, exposure to sunlight) is adequate for normalizing circadian cycles. Idiopathic. Nighttime insomnia should be corrected if possible. Other primary sleep disorders, such as obstructive sleep apnea[157] or narcolepsy should be evaluated with appropriate PSG and mean sleep latency testing studies. Treatment with methylphenidate, 5 to 10 mg one to two times daily, or selegiline, 5 mg at morning and noon, can be beneficial. Occasionally, caffeine (as coffee or tablets, 100 to 200 mg per day) produces increased alertness. Hypothyroidism and other metabolic causes for excessive daytime sleepiness should he investigated, NIGHTMARES. Nightmares can be induced by medications, a precursor of dementia, or idiopathic (breakout 25). Medication induced. Dopaminergic medications frequently induce vivid dreams. In fact, patients with PD often note a return of previously absent dreaming shortly after initiation of carbidopa-levodopa therapy. It is only after several years of treatment, with higher dosages of levodopa, that vivid dreams become problematic, Simple reductions in nighttime dopaminergic drugs should alleviate the nightmares, Elimination or reduction of tricyclic medications also can be beneficial. A distinction between vivid dreams and RBD may be important in certain patients, Manifestations of the former are reported by the patient, whereas complaints relating to RBD typically are voiced by the bed partner. Dementia, Increasing nightmares are harbingers of cognitive impairment and possible daytime drug-induced psychosis. If optimal motor function can only be obtained with dopaminergic dosages that produce psychosis, treatment with low-dose clozapine may produce a striking benefit.[158,159] This drug is associated with a 1 to 2% risk of neutropenia (and death from overwhelming infection), Therefore, weekly monitoring of the white blood count is mandatory.[160] The dosage of clozapine is much lower than that used for schizophrenia. Typically, 12.5 mg is prescribed nightly. The maximum dose is 75 mg nightly but most patients do quite well in the 12.5- to 25-mg range. Some patients require treatment only three to four nights per week, The most common side effects associated with clozapine are lethargy and hypotension, with the former most often seen in patients with frank dementia. Alternative antipsychotics can be employed. Those with the least specific D2 receptor blockade produce less exacerbation of parkinsonism. Molindone, 5 to 25 mg nightly, or thioridazine, 10 to 50 mg nightly has been used for many years to this end, Little experience has been gained with the recently released drug risperidone. Idiopathic. If aggressive behavior or wandering occurs during sleep PSG may confirm RBD and appropriate treatment can be started, If RBD is not present on PSG, then reduction of dopaminergic medications is often necessary. RESTLESS LEG SYNDROME AND PERIODIC LIMB MOVEMENTS OF SLEEP. This primary sleep disorder has such high prevalence in the PD population that all clinicians should be aware of its varied manifestations.[161] Restless leg syndrome (RLS) consists of uncomfortable sensations in the legs (eg parasthesias, aches cramping, and an overwhelming need to move or walk). Symptoms are at the worst in the evening or when the patient attempts to rest, and they transiently improve while the patient is walking, stretching, or exercising. RLS can be related to medications being taken, a symptom of PD itself, or idiopathic (breakout 26). Medication-related. RLS seems distinct from akathisia, which is most often related to underdosage or "wearing off" of the levodopa effect.[162] If akathisia is suspected, then adjustment of antiparkinsonian medications is appropriate. Simply increasing carbidopa-levodopa doses at bedtime (the CR forms are particularly useful) maybe beneficial. It remains unclear whether or not PD-related leg restlessness should be considered idiopathic RLS. Clozapine has been reported to reduce akathisia.[163] Differential diagnosis also should include nocturnal dyskinesia. This may be reduced by lowering bedtime doses of dopaminergic medications. Idiopathic. Approximately 50% of patients with RLS have associated periodic limb movements of sleep (PLMS).[161] Termed "nocturnal myoclonus" in the past-perhaps inappropriately-this syndrome can be so mild as to be detectable only with PSG or so severe that it forces bed partners to sleep in separate rooms. The movements resemble fragments of the triple flexion or Babinski reflex. They last 0.5 to 6 seconds and occur every 20 to 40 seconds. These movements can profoundly disrupt normal sleep architecture and produce insomnia and excessive daytime sleepiness. The dramatic response to levodopa and dopaminometic medications implies reduced dopamine activity in the brain or spiral cord. [164] However, the specific neuronal systems involved have yet to be determined.[165] Regardless, it is clear that patient symptoms worsen with insufficient carbidopa-levodopa treatment and are relieved with increased medication. In particular, sustained-release carbidopa-levodopa can effectively halt RLS symptoms and markedly reduce PLMS. Unfortunately, overflow of RLS symptoms into the daytime is often a problem with levodopa therapy and requires additional doses during the waking hours. A long-acting dopamine agonist, such as pergolide, is an effective alternative in many patients. Other treatment options include low-dose clonazepam or opiates (eg, codeine, 30 to 60 mg nightly). Tricyclic agents may exacerbate RLS and PLMS. For nocturnal symptoms, direct attention to any Parkinson's disease symptoms or motor fluctuation. One of the long-acting levodopa preparations at bedtime may be an appropriate. Alternatively dopamine agonists may be employed. If dyskinesias interfere with normal sleep, bedtime dopaminergic dosages should be decreased. If insomnia is medication-induced and patients are taking selegiline twice daily, the second dose should be given no later than noon. If this is already the practice, consider elimination of the second dose or discontinuation of the drug altogether. Patients with insomnia should be questioned about possible depression and, if indicated, a treatment program initiated. 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. Patients with moderate to advanced stages of Parkinson's disease may describe an overwhelming urge to sleep as a dose of levodopa takes effect. This effect can occasionally be reduced by switching from a CR to a short-acting form of carbidopa-levodopa during the daytime. Disruption of normal circadian rhythms occurs with the dementia of Parkinson's disease when patients lose the normal environmental and temporal clues about time passage. For some, restoration of consistent schedules is adequate for normalizing circadian cycles. Nighttime insomnia should be corrected if possible. 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