Atypical Antipsychotic Drugs in the

Treatment of Parkinsons Disease

Journal of Pharmacy Practice

24(6) 534-540
The Author(s) 2011
Reprints and permission:
sagepub.com/journalsPermissions.nav
DOI: 10.1177/0897190011426556
http://jpp.sagepub.com

Joseph H. Friedman, MD1

Abstract
Parkinsons disease (PD) patients often develop psychotic symptoms that severely affect quality of life and limit the use of
medications to ameliorate motor symptoms. Psychotic symptoms are a major cause for nursing home placement. While these
symptoms do not always require treatment, they often do but antipsychotic drugs all share the common pharmacological
mechanism of blocking dopamine D2 receptors which may worsen motor problems in this very vulnerable population.
Double blind, placebo controlled trials (DBPCT) have shown that clozapine is effective at controlling the psychotic symptoms
at doses far below those used in schizophrenia, without worsening motor function, even improving tremor. DBPCT have
demonstrated that olanzapine worsens motor function without improving psychosis. Quetiapine has been shown in DBPCT to
be free of motor side effects in PD patients but not effective, whereas many open label studies have indicated that quetiapine is
effective. The other atypical have been the subjects of conflicting open label reports. The effects of the atypicals in PD psychosis
is reviewed.
Keywords
Parkinsons disease, atypical antipsychotic drugs, neuroleptics, first-generation antipsychotics, second-generation antipsychotics,
Parkinsons disease psychosis, hallucinations, delusions

Introduction
Atypical Antipsychotic Drugs: an overview
The introduction of the term atypical antipsychotic (AA) has
been, from the viewpoint of movement disorder neurology,
unfortunate. When clozapine was introduced, its freedom from
extrapyramidal side effects (EPSs) made it unique. It was classified as an AA drug, presumably with the thought that there
either were not other drugs in development that would have
a similar lack of motor side effects or that the drugs in development would have the same lack of side effects. Unfortunately, almost all of the later drugs had a relative lack of
motor side effects, not an absolute lack and there are questions
about how significant these reductions actually are.1 Thus,
when newer drugs were developed and billed by their manufacturers as atypical, the US Food and Drug Administration (FDA) refused to endorse this label and instead has had
every antipsychotic subsequent to clozapine classified by its
chemical family and not as an AA. Clozapine remains the
only antipsychotic designated by the FDA as atypical. The
other second-generation antipsychotics are labeled as atypical by the marketing departments of their manufacturers
based on unspecified criteria.
There is no consensus definition of what it means for an
antipsychotic drug to be atypical.2 Probably the most
common notion is that an antipsychotic drug is atypical if it
is relatively free of EPSs,3 but what relatively means has

never been categorized, the general inference being that the

drug does not usually cause EPS when used at usual doses.
However, other proposed definitions for atypicality have
included efficacy for negative symptoms of schizophrenia,
although, since there is scarce evidence that any of the drugs
is particularly effective in this area, this would declassify many
or all of the so-called atypicals; lack of prolactin elevation;
relative potency of 5HT2A receptor antagonism to dopamine
receptor blockade.3 A proposal for the relative strengths of the
D2 and serotonin 5HT2A blockade, the fast off dissociation4
from D2 receptors, or the freedom from catalepsy in rodents, in
the presumed antipsychotic doses scaled to size,3 are other proposed definitions.
The effects of AA on people with Parkinsons disease (PD)
is important because the medications used to treat the motor
symptoms of PD induce psychotic symptoms in a large percentage of patients.5-9 Until the development of clozapine, there
was no tolerated treatment for this. Reduction of the anti-PD

1
Department of Neurology, Movement Disorders Program, Butler Hospital,
Alpert Medical School of Brown University, Providence, RI, USA

Corresponding Author:
Department of Neurology, Movement Disorders Program, Butler Hospital,
Alpert Medical School of Brown University, 345 Blackstone Blvd, Providence,
RI 02906, USA
Email: joseph_friedman@brown.edu

Friedman
medications resulted in worsened mobility as did the use of
low-potency, first-generation neuroleptics.10
An equally important, although much less common
challenge, is the treatment of primary psychotic disorders, such
as schizophrenia, when these patients develop idiopathic
Parkinsons disease (IPD). Although schizophrenia may have
an underlying dopamine disorder,11 this does not preclude the
development of IPD, and this unfortunate concordance has
been documented with autopsy. Since all antipsychotics block
dopamine D2 receptors, and the major drugs for treating IPD
enhance dopamine transmission, pharmacological treatment
poses an obvious theoretical conundrum.
The association of neuroleptics with parkinsonism was made
with the introduction of chlorpromazine in the 1950s, and the
startling variability of the sensitivities of patients to this and the
other motor side effects was noted early on.12 I have examined a
patient without parkinsonian signs who had been on 200 mg of
haloperidol daily for at least several weeks, while seeing others
develop obvious signs of parkinsonism on 0.5 mg per day.
To a movement disorders neurologist, an acceptable
definition for AA would be freedom of worsened motor function in someone with PD. This seemed appropriate and accurate
when clozapine was first introduced but became murkier with
the addition of the subsequent antipsychotics.

Parkinsons Disease Psychosis

Parkinsons disease psychosis (PDP) is defined as a syndrome of
psychotic symptoms present continuously or intermittently over
the course of a month in someone with IPD who has no primary
psychotic process.9 The presence of anti-PD medications is not
required, and several categories of PDP are suggested, including
with and without dementia and with and without PD medications. The symptoms are positive in nature, predominantly hallucinations.5-10,13 These are visual in most cases, with about half
the cases also having auditory hallucinations. The hallucinations
are also different than those in schizophrenia, being without
emotional content. They are usually of people, often strangers,
not threatening, and typically are the same in each recurrence,
for example, 3 girls dressed in ballet costumes dancing in the driveway 2 or 3 times/week at dinner time; a baby sitting in a stroller, smiling but making no sounds; a circus dog lying on a bed.
They tend to occur at night and almost always occur only in a
low-stimulus environment. Minor hallucinations are defined
as peripheral field images,9 usually shadows or small animals,
which disappear when the person turns to look at them; or presence hallucinations, defined as a strong feeling of someone,
occasionally an animal, being next to or behind the individual,
but not there when the person turns to look.9 Delusions are less
common, affecting about 5% to 10% of drug-treated patients and
are typically paranoid in nature with spousal infidelity being the
single most common delusion.
The presence of psychotic symptoms is a greater stress for
caregivers than motor14 and is the single greatest precipitant for
nursing home placement in the United States.15

535
While hallucinations are usually not very bothersome to the
patient, delusions always are, especially with their paranoid
content and their affecting a person who is often quite helpless.
Unfortunately, the emergence of hallucinations, even with
benign content, is a poor prognostic sign, for worsened psychotic symptoms,16 dementia,16 and death.17 Unlike most disorders
in which drug side effects occur, all of the drugs available for
treating motor problems in PD may generate psychotic symptoms. Interestingly, the one with the least likelihood of doing
so is levodopa, which is also the most potent, most important,
and least expensive.

Atypical Antipsychotics and PDP

Clozapine
Although clozapine was suggested as the ideal treatment of
PDP as early18 as 1978, the first report on its use in PD
appeared19 in 1985. Given the fact that clozapine was available
in Europe between 1978 and 1985, albeit in a limited fashion,
the fact that the drug was not studied for this purpose remains a
mystery. The next report on its use was a single case in a patient
with schizophrenia who developed IPD and became intolerant of
any antipsychotic because of extremely severe parkinsonism20
and whose psychosis worsened with the use of anti-PD medications when not on an antipsychotic. This patient did extremely
well in terms of both motor function and psychiatric condition
on clozapine. As early as 1991, a suggested protocol10 for treating PDP, based on clozapine, was published and became the
standard treatment regimen until quetiapine became available.
Once clozapine was made commercially available in the United
States, in 1992, many reports of the drugs benefits were
reported from open-label trials. However, the first doubleblind, placebo-controlled trial (DBPCT) reported a negative outcome.21 Two multicenter DBPCTs were ultimately performed,
the first multicenter DBPCT for any nonmotor symptom of
PD ever performed.22,23 The first trial was performed in the
United States and the second in France. The protocols were
almost identical and the results, too, were almost identical. Since
there is no generally accepted measure for rating psychosis in
PD, a number of different scales were used, and each, including
the clinical global impression scale, showed clinically and statistically significant benefit. The improvements seen in the clozapine PDP trials are far more robust than those seen in any of the
schizophrenia studies and tended to occur much faster. In both
studies, the dose was determined by clinical response. In the
American study, the mean dose used was 25 mg/d. In retrospect,
the reason the first double-blinded trial of clozapine was aborted
was that the drug was initiated and titrated as if it was for refractory schizophrenia, a much too rapid titration for old, frail
people. It induced severe sedation and was not tolerated.
Clozapine has a number of potential side effects. The hematological problem of agranulocytosis, which is why regular
blood monitoring is required, is not dose related so that even
doses as low as 6.25 mg/d (in contrast to the usual antipsychotic
doses in schizophrenia of 300-900 mg/d) still require the same

536
monitoring as the high doses. The other problems that make
clozapine such a difficult drug to use, namely weight gain and
the metabolic syndrome are, as best can be determined, not
seen in PD patients, presumably because of the low doses.
Sedation is still a significant side effect of clozapine, even at
low doses. This is usually, but not always advantageous, since
many PDP patients are awake at night when their symptoms
worsen. So clozapine is typically administered at bedtime. This
is sometimes supplemented with daytime doses but not usually.
An interesting theoretical point is that the dose of clozapine,
often as low as 6.25 mg at bedtime, to put a patient into complete remission, is thought to be so low that the dopamine
receptors are not likely affected.

Risperidone
Risperidones claim to atypicality is based on conflicting data.
In one head-to-head report in neuroleptic-naive patients,
treated open label,24 there were no differences in EPS between
risperidone and haloperidol, both used at low doses. Risperidone has been reported to produce parkinsonism, tardive dyskinesia in neuroleptic-naive patients, akathisia, acute dystonic
reactions, and elevated prolactin levels. The first report on risperidones use in PD was extremely positive, with 6 PD patients
treated successfully and without motor complications,25 but this
was followed closely by reports from the Movement Disorders
group at Columbia,26 then Brown,27 both reporting dramatic
worsening of motor function. In one report, all 6 PD patients
treated with risperidone experienced motor worsening despite
using doses similar to those used in the first publication. The second article included parkinsonian patients who did not all have
IPD and reported 5 of 6 developing worsened mobility. Later
reports were also in conflict with each other with some reporting
good tolerance and others not.28,29 The explanation for the discrepant results is not apparent. The various reports used similar
dosing and described similar patients. And while it is true that in
the general population, sensitivity to the motor side effects of
each dopamine blocking drug is extremely variable, one would
not expect this in IPD or primary parkinsonian disorders as the
dopamine-secreting neurons must be severely depleted before
one sees clinical signs of parkinsonism.

Olanzapine
The first report on olanzapines effect in PDP was an open-label
study with follow-up of 3 months.30 The results were similar to
those reported in the open-label clozapine publications. Based
on these observations, the manufacturer sponsored 4 DBCT.3133
Two of the studies were performed in parallel in Europe and
the United States, and constitute the largest studies completed to
date on PDP.32 A third study that compared olanzapine and clozapine was stopped halfway through at the request of the safety
monitoring board for the study.33 A fourth study was placebo
controlled and found that olanzapine caused worsened parkinsonism and was not helpful.31 The results of the DBPCT were
uniformly negative, with worsened motor function reported in

Journal of Pharmacy Practice 24(6)

each study, as well as a lack of improvement in psychosis. While
these studies were going on, some chart reviews were published
which also noted worsened motor function from olanzapine.34,35
The FDA mandated a black box warning for its use in PD.

Quetiapine
The data on quetiapine, like the data on the other AA, are interesting and difficult to understand. There have been 4 DBPCTs,
of which the 3 with substantial numbers of subjects, found no
benefit,36-38 whereas a small trial did report a statistically significant improvement.39 Two single-blinded trials comparing
quetiapine to clozapine reported equivalence in one40 and
nonequivalence in the other41 with clozapine being more
effective. One important observation from all the doubleblind controlled trials has been a lack of motor worsening
on the drug. Aside from clozapine, no other AA has data to
support this claim.
Why quetiapine should be helpful in open trials but fail
double-blind trials is uncertain. The design of the Shotbolt38
study that used dropout rate as the primary variable and dosed
the drug in a twice daily (bid) regimen rather than primarily a
bedtime dose is likely to explain this. The small positive study
is too small to rely on. The Rabey study37 enrolled 59 severely
psychotic patients, 80% of whom suffered paranoid delusions
and gave the drug on a bid regimen. Ultimate dosing was only
about 35 mg/d in each group, presumably due to intolerance
of the quetiapine in the active treatment arm but the fact that the
placebo group was not pushed to higher doses suggests a lack of
a sufficiently aggressive approach to treatment. Since the openlabel studies reported an average dose of around 65 mg,42 this
lack of efficacy is not surprising and the choice of a bid regimen
may, in retrospect, have been a methodological flaw. In clinical
practice, quetiapine is given initially at bedtime and this dose is
usually increased unless a morning hangover effect occurs or if
symptoms remain during the day, in which case a morning dose
is introduced. It is uncommon to start with bid dosing and to
keep the 2 doses the same, rather than giving the bulk of the dose
at bedtime. The Ondo study36 enrolled 29 subjects and titrated
quetiapine up to 200 mg/d and found no benefit, despite not
including dropouts in their analysis. While concluding the failure
of their study to prove efficacy, the authors nevertheless suggested that this may have been due to underpowering.
Thus quetiapine is safe to use in PD patients in terms of
motor function and orthostatic hypotension was not reported
as clinically significant. Other side effects, like weight gain
have not been reported but duration of the observations, especially the controlled trials, may not have continued long enough
to have allowed this to occur and weights were not reported.
For longer term, open-label chart reviews, weight gain may
have been offset by a tendency for weight loss in PD. Sedation
and weight gain side effects are often beneficial in PD patients
who sleep poorly at night and tend to lose weight.
The open-label experience with quetiapine, supported by the
lack of motor side effects, has made quetiapine one of two

Friedman
drugs to be considered for treating PDP by the American
Academy of Neurology task force on the treatment of PD.43

Ziprasidone
There are few reports on ziprasidone, presumably because of the
warning concerning the QT interval. One large open-label study
found ziprasidone to be both helpful and well tolerated,44 whereas
a few case reports describe significant motor worsening.45,46
Since ziprasidone has been shown to cause parkinsonism in schizophrenics and acute dystonic reactions and to reduce tics in
Tourettes syndrome,47 it is highly likely that PD patients will
show more sensitivity to the drug and suffer motor declines.

Aripiprazole
Aripiprazole has been characterized as a partial dopamine
agonist based on properties of being both a dopamine receptor
blocker and a partial dopamine stimulant. As such, it was hoped
that it might not only have antipsychotic properties in PDP but
also improve motor function. An open-label study funded by
the pharmaceutical company, planned as a pilot project for a
large, multicenter DBPCT, using doses lower than were commercially available at the time, was aborted after observations
of motor worsening in PD patients.48 Two small open-label
reports, one prospective and the other a chart review reported
motor complications and plans for a DBPCT, were abandoned.48,49 In addition, aripiprazole has subsequently been
reported to cause severe motor worsening in a PD patient,50
dose-dependent parkinsonism in schizophrenics,51,52 as well
as tardive dyskinesia when used in otherwise neurolepticnaive patients.53 These observations of EPS in people without
prior movement disorders underscore the likely propensity of
this drug to worsen motor function in people with IPD.

Melperone
This AA was reported several years ago to improve PDP without harming motor function54 and was the subject of a multicenter, DBPCT in the United States. The results were
reported only in the financial sections of newspapers but were
never presented in abstract or publication. The results were that
it was not beneficial but did not cause motor worsening (personal communication).

Newer AA
There are no reports on the effect of iloperidone, asenapine, or
paliperidone on PD patients. From the side effect reports of
these drugs in schizophrenia, one would predict that they are
unlikely to be well tolerated by PD patients.

Current Recommendations
The American Academy of Neurology set up a task to assess
the treatments of all aspects of PD. Their recommendations for
the management of PDP remain unchanged as of this writing,43

537
suggesting that sources of infection or other nonneurological
problems be evaluated and treated, followed by a reduction and
discontinuation of all psychoactive drugs, as tolerated. It is
common, for example, in this population that anticholinergic
agents are used to control bladder overactivity, and benzodiazepines for anxiety. When PD medications have been reduced
as much as tolerated, then quetiapine is to be considered. The
recommendation is very clear in acknowledging that this recommendation is not evidence based and is based on the experience of the task force members. The DBPCT indicate that
the drug does not work. Clozapine, despite level 1 evidence
to support its use, was also to be considered due to the logistical problem of blood monitoring. The committee felt that quetiapine, although not having DBCT data to support its use, did
have DBCT data to support its safety, whereas all other AA,
excepting clozapine, did not. Aripiprazole is the third line
agent, although data indicate that it is likely to worsen some
patients.
Cholinesterase inhibitors have also been used but not
reported nearly as extensively as the AA. The data suggest mild
benefit only, and the benefit may take weeks to develop.55-61
Rare case reports of electroconvulsive therapy (ECT) as an
effective treatment for psychosis have been published.62-64
ECT has been known for several decades to improve motor
function as a bonus when PD patients with severe depression
have been treated. Unfortunately, the motor benefit is sustained
only for days to weeks.
In assessing motor function, one must be sure that the
patient is not taking nonneuroleptics that may cause parkinsonian side effects such as valproic acid, metoclopramide, and
prochlorperazine. Lithium may also cause parkinsonism and
may not have a useful substitute in someone with a psychotic
bipolar disorder. While the selective serotonin reuptake inhibitors may cause parkinsonism or worsen parkinsonism in PD
patients, this is considered rare.

Epilogue
Clinical Equipoise: Evidence- Versus Experience-Based
Medicine in the Use of AAs
If one reviews the publications on the treatment of PDP, one is
left with the conclusions that clozapine has level 1 evidence for
efficacy and tolerance and is the only drug with anything
beyond level 3 evidence for its use; that quetiapine has level
1 evidence of freedom of worsening motor problems in PD
patients but only level 3 evidence of benefit; that olanzapine
has level 1 data that it is harmful for motor function and also
does not improve psychotic symptoms; that the other AA have
conflicting level 3 data with regard to their benefits and their
side effects. Different reviewers have interpreted the ambiguous results differently. Eng and Welty65 state that there is not
enough evidence for or against other atypical antipsychotics to
draw any conclusions regarding their use in these patients.
Hasnain et al66 believe risperidone at low doses of 0.25 mg
to 1 mg/d may be a reasonable second line option for psychosis

538
associated with early Parkinsons disease, while Aarsland
et al67 state that more novel antipsychotic drugs like ziprasidone and aripiprazole have not yet been tested systematically
and preliminary reports are inconclusive.
These comments are, if one limits ones focus to these
drugs published effects on PD justifiable, but ignore the larger
reality of these drugs motor side effects. All antipsychotic
drugs, excepting quetiapine and clozapine, produce dosedependent parkinsonism in non-PD patients. Few would argue
with the presumption that parkinsonism in normals predicts
worsened parkinsonism in those already parkinsonian. One is
reminded of the old maxim, absence of evidence is not the
same as evidence of absence. Simply because these drugs
have not undergone DBPCT does not mean they might work.
These drugs will never be studied in DBPCT because many
in the Parkinson community would consider such trials unethical due to the presumption of worsened motor function in
many. This is not to say that some PD patients will tolerate one
or more of these drugs without problem and that they should
never be used. These drugs should be used sparingly, only after
trying quetiapine, clozapine, and aripiprazole, with close
follow-up of motor function.
Declaration of Conflicting Interests
The author(s) declared the following potential conflicts of interest
with respect to the research, authorship, and/or publication of this article: lectures: Teva, Ingelheim Boehringer; Glaxo Smith Kline; consulting: United Biosource; Bubaloo, Halsted, Reitman LLC; EMD
Serono; Genzyme; Teva; Acadia; research: MJFox; NIH: Cephalon;
EMD Serono; Teva; Acadia Royalties: Demos Press.

Funding
The author(s) received no financial support for the research, authorship, and/or publication of this article.

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