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. Other primary
sleep disorders should he evaluated with appropriate polysomnongraphy
and mean sleep latency testing studies. Treatment with methylphenidate
or selegiline can be beneficial. Occasionally caffeine produces
increased alertness.
 
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