Drug-Induced Parkinsonism in the Elderly

Incidence, Management and Prevention

Jose Luis Lopez-Sendon,
1,2
Mar a Angeles Mena
2,3
and Justo Garc a de Yebenes
1,2
1 Department of Neurology, Hospital Ramo n y Cajal, Madrid, Spain
2 CIBERNED (Centro de Investigacion Biomedica en Red. Enfermedades Neurodegenerativas), Madrid, Spain
3 Department of Neurobiology, Hospital Ramo n y Cajal, Madrid, Spain
Contents
Abstract. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106
2. Definition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107
3. Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107
4. Risk Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108
5. Clinical Features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109
6. Causal Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111
7. Pathogenic Mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112
8. Prevention and Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114
9. Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114
Abstract Drug-induced parkinsonism (DIP) has been claimed to be the most pre-
valent cause of secondary parkinsonism in clinical practice in the Western
world. Since the first descriptions in the early 1950s the prevalence of DIP
seems to be increasing and approaching that of idiopathic Parkinsons disease
(iPD) due to the aging of the population and the rising of polypharmaco-
therapy. Despite the wide interest this subject has raised in the past, it seems
to be frequently overlooked by the medical community.
It is particularly burdensome for the elderly and its management includes
recognition of symptoms and identification of risk factors and offending agents.
Prompt discontinuation of the causative agent leads to a marked improvement,
although the condition might persist or remit slowly in up to 10%of the patients.
Risk factors for developing DIP include older age; female sex; cognitive im-
pairment; potency, dose and length of treatment; pre-existing extrapyramidal
signs; and, very likely, a background of inherited predisposition. The main
causative agents are dopamine receptor antagonists but the list of drugs without
such a well known and straightforward mechanism of action is large. All anti-
psychotics, including atypicals (except clozapine) may produce parkinsonism.
Although many drugs cause parkinsonism in a dose-related manner, there is an
enormous variation in individual susceptibility. The clinical syndrome is less
likely to produce tremor than iPD, and is more likely to be symmetrical, but the
two syndromes might not be distinguished in any individual patient. Functional
neuroimaging tests, which use ligands that bind to the dopamine transporter, are
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useful for distinguishing iPD from DIP in doubtful cases in patients treated with
antipsychotics. The estimated presynaptic dopamine secreting neurons should
be diminished in iPD but normal in DIP produced by dopamine receptor
blockers, as assessed by molecular imaging techniques evaluating striatal dop-
amine transporters (DATs). Prompt recognition and discontinuation of the
culprit are the keys to the management of DIP. In persistent cases, specific
therapies including anticholinergics and amantadine may provide symptomatic
relief. Levodopa and dopamine receptor agonists might be an option in selected
cases in which dopamine nerve terminal defects are present.
The weight and scope of DIP varies with the age and underlying health of
the patient, imposing a significant burden on the elderly who, in many cases,
experience significant functional deterioration that leads to hospitalization
and has vast economic consequences.
This article reviews the epidemiology, pathogenic mechanisms, implicated
drugs, clinical features and management of DIP and highlights the need for
increased awareness of this iatrogenic condition.
1. Introduction
Drug-induced parkinsonism (DIP) was recog-
nized in the early 1950s, with the use of chlor-
promazine for the treatment of psychosis and
reserpine for high blood pressure.
[1]
Animal
studies demonstrated that reserpine induces an
akinetic state as well as bradykinesia by depleting
brain monoamines.
[2]
In fact, it was the reversal
of reserpine-induced akinesia by levodopa, but
not by 5-hydroxytryptophan (5-HTP), in the
animal model used by Carlsson and colleagues
that demonstrated that parkinsonism was related
to dopamine but not to serotonin depletion.
[3]
That finding provided a tremendous impetus for
the treatment of idiopathic Parkinsons disease
(iPD) since it was soon recognized that reserpine
caused a parkinsonian state in humans undis-
tinguishable from iPD.
[4]
This observation, cou-
pled with the known histopathology, led to the
discovery that dopamine and its metabolites are
severely reduced in iPD
[5]
and to its effective
treatment with dopamine precursors and dopa-
mine receptor agonists.
A large number of drugs have been identified
as potential culprits responsible for DIP and
today it is widely accepted that virtually all dop-
amine receptor antagonists as well as many other
drugs that interfere with dopamine synthesis or
release have the potential to cause DIP in predis-
posed individuals. Furthermore, other widely used
compounds outside the treatment of psychiatric
illnesses and with diverse pharmacological mech-
anisms of action are known to either induce or
exacerbate parkinsonism. DIP has been considered
the second leading cause of parkinsonism in the
elderly after iPD.
[6]
Neuroimaging studies per-
formed in iPD patients have shown that younger
onset iPD patients progress more slowly and seem
to endure substantially more damage to the ni-
grostriatal dopamine system before the first motor
symptoms appear.
[7]
This suggests that younger
patients have more efficient pre- and post-synaptic
compensatory mechanisms aimed at maintaining
normal dopamine neurotransmission.
[7]
There is
an age-related diminution in the number of nigral
dopaminergic neurons and increased Lewy body-
like neuronal inclusions, which may suggest
presymptomatic iPD in the elderly.
[8]
Also, this
particular group is more frequently subject to
polypharmacotherapy and treatment with antipsy-
chotics for behaviour-related disorders. Further-
more, the prognostic implications of recognizing
DIP in this age group are fundamental since the
disorder might be particularly burdensome
and imply a higher mortality.
[9]
Therefore, special
care should be taken in the use of potential
DIP-inducing agents in this population. Several
106 Lopez-Sendon et al.
2012 Adis Data Information BV. All rights reserved. Drugs Aging 2012; 29 (2)
factors that might indicate a high risk for devel-
oping DIP, other than age, have been suggested
and include female sex, exposure time and type of
offending drug, and multiple drug therapy.
[10]
Nevertheless, all the studies have demonstrated a
remarkable individual variation in the suscepti-
bility to develop DIP.
[11]
It is essential to bear in mind that the presence of
DIP is frequently overlooked, not only by general
practitioners and psychiatrists,
[12,13]
but also by
neurologists.
[14]
Recovery following withdrawal of
offending agents may take from weeks to months or
even years. In some cases, the persistence of clinical
deficits might suggest that, in some patients, the of-
fending drugs either unmask pre-existing subclinical
parkinsonism or produce irreversible progressive
deficits in the nigrostriatal dopamine pathway. This
last possibility has been supported by some radio-
nuclide studies performed in patients with DIP,
which revealed a reduced striatal uptake suggestive
of lesions of the presynaptic dopamine terminals
indicating that the DIP might be multifactorial.
[15]
It
has also been found that some of the drugs that
cause DIP may also cause direct neurotoxic damage
to the nigrostriatal dopamine neurons,
[16,17]
causing
an irreversible toxic parkinsonism.
The main steps for the management of DIP are
prevention, early recognition, withdrawal or re-
placement of offending drugs and, in certain
cases, pharmacological therapy.
A literature search was performed using the
terms drug-induced and parkinsonism to iden-
tify articles published from 1960 to 2011 on the
epidemiology of and agents causing DIP. Studies
were identified through electronic MEDLINE and
PubMed databases. Manual review of biblio-
graphies allowed for the detection of additional
articles. This article reviews the drugs that cause
DIP; the epidemiology, clinical features, patho-
genic mechanisms and management of DIP; and
the special role of aging in this syndrome.
2. Definition
DIP is defined as an akinetic-rigid syndrome
induced by pharmacological agents.
[16]
The term
parkinsonism refers to a clinical syndrome char-
acterized by the presence of tremor, rigidity and
bradykinesia in addition to loss of postural re-
flexes and freezing. DIP falls into the category of
secondary parkinsonisms.
[18]
This definition im-
plies a difference between primary or neurode-
generative parkinsonisms such as iPD and other
secondary parkinsonisms caused by environ-
mental agents such as cerebrovascular disease,
infections, tumours and toxic agents. DIP is
usually considered reversible, at least partially,
when the offending drug is withdrawn. However,
this is not always the case and long-term studies
indicate that up to 20% of patients develop
persistent and progressive deficits despite drug
discontinuation.
[19]
3. Epidemiology
The estimates for the prevalence and incidence
of DIP are greatly variable depending on the type
of study, the clinical scenario and the drugs in-
volved in the analysis. Its epidemiology clearly
reflects the characteristics of the population being
treated (e.g. an elderly population of institutiona-
lized patients or a psychiatric ward). Neverthe-
less, it seems clear that DIP represents one of the
most frequent causes of secondary parkinsonism
among certain populations. Approximately 15% of
patients on long-term antipsychotic therapy develop
DIP,
[20]
but the prevalence might reach as much as
60%depending on the potency and dose of the drug
or the sharp eye of the examining neurologists. A
study performed in the setting of a geriatric clinic
prospectively reviewed all new cases of parkinson-
ism.
[21]
It was noted that up to 51% of a total of 95
newly diagnosed parkinsonisms were considered re-
lated to prescribed drugs. The most common of-
fending agent was prochlorperazine, an antiemetic,
which the investigators thought was not indicated in
any case. Many epidemiological investigations
have addressed the prevalence of DIP in the gen-
eral population. The figures reported are rather
heterogeneous and reflect the different contexts in
which the studies were conducted. A study of a
population of 208 000 in a district located in the
English Midlands showed a PD prevalence of
108.4 per 100000,
[22]
which is comparable to fig-
ures from Rochester (MN), USA
[23]
and south-
west Finland.
[22]
In this population, DIP was very
Drug-Induced Parkinsonism in the Elderly 107
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uncommon. Different findings have been reported
in Japan, where DIP represents the second leading
cause of parkinsonism after iPD.
[24]
In a pop-
ulation-based survey performed in eight Italian
municipalities, DIP represented only 10%of all the
cases of parkinsonism.
[25]
A door-to-door, two-
phase-approach study of parkinsonism prevalence
in three elderly (age >65 years) population groups
of central Spain showed that of 118 subjects with
parkinsonism, 26 were considered to have DIP crite-
ria (22%).
[26]
In a community-based survey in Brazil
involving an aged population (aged 65 years), the
prevalence of parkinsonism (all types) was 7.2%.
DIP was the second most common cause (2.7%)
after Parkinsons disease (3.3%).
[27]
A recent pub-
lication reviewed the spontaneous notifications of
DIP in a French regional pharmacovigilance
centre (French Midi-Pyre ne es area of approxi-
mately 2 900 000 inhabitants) between 1993 and
2009.
[28]
During this time, 155 cases of drug in-
duced or worsened parkinsonism were reported.
In a door-to-door survey in Spain in 2004 to
determine the prevalence of parkinsonism in an
island community, the rate of DIP matched that of
presumed iPD.
[29]
Other large prospective epide-
miological studies have estimated the overall in-
cidence of DIP after the initiation of antipsychotics
(both typical and atypical) at about 4%.
[30]
Inter-
estingly, some studies have observed a change in
the prevalence and type of compounds implicated
in certain populations, highlighting perhaps the
importance of prescribing tendencies and an im-
proved knowledge of the side effect profiles of
these drugs.
[31]
However, it is clear that much par-
kinsonism is underdiagnosed, even in a healthcare
setting.
[32]
Another source of data for understand-
ing the epidemiology of DIP are drug trials, which
tend to use the Simpson-Angus Scale clearly
weighted toward rigidity and other scales that are
neither ideal nor fully validated.
[33]
As a result, it is
possible that the true prevalence of DIP is even
greater than reported in these studies.
4. Risk Factors
Many epidemiological studies have addressed
the identification of risk factors for the develop-
ment of DIP. While some of these risk factors have
been confirmed, contradictory reports are not un-
common. Only one fact remains unambiguous: all
studies have demonstrated a remarkable individual
variation in the susceptibility to extrapyramidal
side effects with dopamine receptor antagonist
drugs. Clearly, older patients are more susceptible
to DIP, presumably reflecting the known decline in
nigral neurons and striatal dopamine that occurs
with normal aging.
[34]
Among a group of elderly
patients, those with associated dementia are at
greater risk for development of DIP than patients
without dementia.
[35]
Patients with iPD and de-
mentia with Lewy bodies are particularly sensitive
to the effects of dopamine receptor antagonist
drugs. It is proven that younger psychotic patients,
who usually require more drugs than older patients,
are less likely to develop DIP.
[36]
There may also be
different sensitivities to antipsychotic motor side
effects with different psychiatric disorders as well as
with age of onset of the psychiatric disorder.
[37]
Most but not all studies have shown a higher
incidence of DIP in women,
[38,39]
but the reason
for this is not understood given the predominance
of iPD among males. The influence of a hereditary
predisposition has also been studied as a risk fac-
tor for developing DIP. Genetic differences in the
functional polymorphisms of the genes coding
for dopamine receptors and other proteins in-
volved in dopamine neurotransmission are a hy-
pothetical explanation for the variability of the
interindividual susceptibility to DIP.
[40,41]
Wide
genome analysis and genotype studies have iden-
tified several polymorphisms associated with DIP
severity in patients with schizophrenia taking an-
tipsychotics. Some of these found associations of
DIP with dopamine and serotonin receptor and
transporter polymorphisms.
[42]
Also, isolated re-
ports have suggested that there may be a familial
susceptibility to DIP
[43]
based on the identification
of affected family members. Other studies that
performed HLA typing in schizophrenic White
men taking antipsychotics found that a single an-
tigen was significantly more common in the group
with DIP than in the group without it.
[44]
In sup-
port of the hypothesis of a familial predisposition
is the observation that single heterozygous muta-
tions of the park-2 gene or polymorphisms of par-
kin have been found in some cases of DIP.
[45]
DIP
108 Lopez-Sendon et al.
2012 Adis Data Information BV. All rights reserved. Drugs Aging 2012; 29 (2)
can be considered a multifactorial process in which
potential neurotoxicity of drugs acts upon a back-
groundof inheritedpredisposition.
[46]
AIDSpatients
are more prone to develop DIP when exposed to
compounds liable to induce parkinsonism
[47]
and
HIVshould always be considered in young patients
with secondary parkinsonism. Histopathological
examinations of the pars compacta of the sub-
stantia nigra of autopsied AIDS cases found that
the total number of neuronal cell bodies was 25%
lower in AIDS patients than in age-matched
controls, which could possibly explain the higher
susceptibility of some of these patients to DIP.
[48]
Cigarette smoking has been considered to have
a protective effect against iPD.
[49]
Similarly,
schizophrenic patients who smoke have signifi-
cantly less cognitive impairment and a lower pre-
valence of DIP compared with non-smokers,
suggesting that cigarettes might play a protective
role against the development of dementia and
DIP in schizophrenia.
[50]
5. Clinical Features
The clinical features of DIP are variable, but by
definition, all patients must present with a rigid-
akinetic syndrome induced by pharmacological
agents. This variability can be attributed to both
individual factors such as age, sex and individual
susceptibility to a certain type of drug and also to
drug factors such as potency, dose and length of
exposure. Although the clinical characteristics
might overlap with those of iPD and other pri-
mary and secondary parkinsonisms, making the
syndromes undistinguishable in a particular sub-
ject, subtle clinical signs might provide help in the
differential diagnosis of DIP (table I). Patients
tend to be unaware of their parkinsonism when
mild except for tremor.
[51]
Since DIP is a drug-
induced syndrome, it is usually considered to be
symmetrical (on both sides of the body), but some
studies have observed asymmetry in up to half of
the patients.
[52,53]
Not all the cardinal features of
iPD are necessarily present, and they are variably
severe in an idiosyncratic manner. The complete
triad of tremor, rigidity and bradykinesia is seen
only in a limited number of cases. Akinesia with
loss of arm swing can be the earliest feature.
Bradykinesia can also be an early common symp-
tom, causing lack of expression in the face, slow
initiation of movement and speech difficulties. It is
less likely to be associated with tremor, which is
uncommon with drugs that selectively involve
dopamine neurotransmission, such as dopamine
D
2
receptor antagonists, and much more frequent
with other compounds that act through a less
Table I. Clinical features of DIP and iPD
Main features DIP iPD
Age at onset More often in the elderly Sixth decade
Symptoms at onset Typically symmetrical Typically asymmetrical
Onset Acute or subacute Chronic
Course with treatment Reversible Progressive
Response to causative
drug withdrawal
Variable Poor
Response to levodopa Poor Marked
Other features Orofacial dyskinesia, akathisia
Rest tremor Uncommon Common
Sex More common in females More common in males
Freezing Uncommon Common
DaTscan Normal Abnormal
PET/SPECT imaging Normal uptake of presynaptic markers, reduced
uptake of dopamine receptor ligands
Reduced uptake of presynaptic markers, normal
uptake of dopamine receptor ligands
DaTscan=ioflupane
123
I; DIP=drug-induced parkinsonism; iPD= idiopathic Parkinsons disease; PET=positron emission tomography;
SPECT= single proton emission computerized tomography.
Drug-Induced Parkinsonism in the Elderly 109
2012 Adis Data Information BV. All rights reserved. Drugs Aging 2012; 29 (2)
selective mechanism, such as calcium channel an-
tagonists or amiodarone.
[54]
The presence of other
drug-induced movement disorders, such as akathisia
and buccal-lingual-masticatory syndromes, might
accompany the clinical picture, indicating previous
exposure to dopamine receptor antagonists. The
nature of these associated movement disorders
might be acute, such as acute dystonic reactions and
akathisia, or tardive disorders that appear after
long-term treatment with the causative drug. Gait
abnormalities are common in DIP
[55]
but appear
only after many years of progression in Parkinsons
disease. Interestingly, freezing is frequently observed
in secondary parkinsonisms such as normal-pressure
hydrocephalus and vascular parkinsonism, and
generally in patients with neurodegenerative par-
kinsonism such as supranuclear gait palsy, multiple
system atrophy and corticobasal degeneration.
[56]
Nonmotor features of iPD have not been well
studied in DIP. Olfactory tests are reported to be
normal in DIP,
[57]
but other studies have reported
conflicting results.
[58]
Cognitive impairment re-
versible with the withdrawal of the offending
drug and associated with the severity of the
motor symptoms of DIP has been observed in a
recent study.
[59]
The course of DIP is also variable. It usually
develops within the 3 months after the patient is
exposed to the drug.
[16]
Most patients maintained
on antipsychotics without antiparkinson drugs
improve over time, but what percentage or to
what degree is unclear. Most patients reach a
plateau on a stable dose of antipsychotics and
maintain this level or improve. After the causa-
tive drug is withdrawn, parkinsonian signs usu-
ally begin to improve in several weeks and
patients are relieved from their symptoms within
several months,
[24]
although complete resolution
may take over a year.
[60]
The explanation for the
persistence of parkinsonism could be that iPD
was unmasked by blockade of dopamine recep-
tors or by drugs that interfere with dopamine
neurotransmission by other mechanisms. In sup-
port of this is the clinical observation that in some
patients DIP may recover, only to be followed
months later by the appearance of iPD.
[61]
In
some cases it could be that the offending agent
has not only a reversible functional property but
also an irreversible toxic potential that persists
after the withdrawal. For instance, dopamine
receptor antagonists increase the firing of dop-
amine neurons and the synthesis and metabolism
of catecholamines.
[62]
In addition, some dop-
amine receptor antagonists, such as haloperidol,
have direct toxic effects on neurons due to their
inhibition of mitochondrial function and could
contribute to the death of nigrostriatal dopamine
cells.
[63]
Other pharmaceutical compounds, in-
cluding atypical antipsychotics, may share both
mechanisms, that is, pharmacological inhibition
and neurotoxic effects on dopamine neurons. On
rare occasions an unexplained form of DIP can
be caused by antipsychotic withdrawal, known as
withdrawal emergent parkinsonism.
[64,65]
No
adequate explanation for this phenomenon has
been provided but it clearly contradicts the sim-
plistic theory that antipsychotics act primarily by
blocking dopamine receptors and suggests a
more complex mechanism of action for these
compounds.
Although the diagnosis is chiefly clinical and
history based, several ancillary tests may aid in the
differential diagnosis of DIP. It should be empha-
sized that the diagnosis of iPD should not be made
in patients who have received dopamine receptor
antagonists within the past year or longer unless the
parkinsonism has slowly worsened while off the
drug. The assumption that the parkinsonism was
produced by a certain drug would be straightfor-
ward in the case of drugs blocking dopamine re-
ceptors or those that deplete dopamine stores or
when the symptoms disappear after discontinua-
tion of the putative responsible agent. There are,
however, many cases attributed to certain com-
pounds in which the mechanisms of interaction
with the dopamine system are unknown and the
suspicion of causality is based on the observation
that the symptoms appear during the treatment
and disappear after its suppression. In this situa-
tion, the possible drug effect can only be taken into
account once the parkinsonism has developed.
When the awareness of the clinician about the
harmful effects of the offending drug is insufficient
to lead to a correct diagnosis, functional neuroimag-
ing might provide information with high sensitivity
about the integrity of the nigrostriatal pathway.
110 Lopez-Sendon et al.
2012 Adis Data Information BV. All rights reserved. Drugs Aging 2012; 29 (2)
Normal dopamine transporter-single proton emis-
sion computerized tomography (DAT-SPECT)
findings are helpful in supporting a diagnosis of DIP
by excluding underlying true nigrostriatal dysfunc-
tion.
[66]
Antidopaminergic drugs may unmaskactual
Parkinsons disease
[15]
and underlying Parkinsons
disease can be detected throughDATimaging. Also,
cardiac scintigraphy is normal in patients with DIP,
but abnormal in Parkinsons disease, implying intact
sympathetic function in DIP.
[67]
Transcranial ultra-
sound studies showed that patients with a pattern of
elevated echogenicity of the substantia nigra might
be more susceptible to DIP.
[66]
This might not aid in
the differential diagnosis but shows the importance
of individual susceptibility to DIP.
6. Causal Agents
The drugs that most frequently cause DIP are
primarily drugs that block dopamine receptors,
particularly D
2
receptors. These are most often
antipsychotic drugs, such as first-generation anti-
psychotics (haloperidol, chlorpromazine and tri-
fluoperazine) and newer atypical antipsychotics
such as risperidone or olanzapine (table II). It
should be noted that these drugs have different
degrees of parkinsonismassociated with them, that
is, none for clozapine and probably quetiapine,
and progressively more for olanzapine and risper-
idone.
[68-70]
However, several double-blind, placebo-
controlled studies carried out by movement disorder
experts showed no significant motor worsening
compared with placebo with the use of quetiapine
in iPD patients.
[71-73]
The propensity for these
agents to cause DIP relates to their degree of D
2
receptor occupancy.
[74,75]
Despite this, the devel-
opment of DIP remains highly unpredictable and
it is not uncommon to see patients receiving high
doses of antidopaminergics but without parkin-
sonism. Other compounds that interfere with
Table II. Potential causes of DIP
Potential risk of
DIP
Pharmacological group/mechanism of
action
Drug
High Dopamine D
2
receptor blockers Typical antipsychotics (haloperidol, prochlorperazine, thioxantenes,
amisulpride, flupentixol, fluphenazine, levomepromazine, pimozide promazine,
sulpiride, thioridazine, zuclopenthixol)
Atypical antipsychotics (at higher doses) [risperidone, olanzapine, aripiprazole]
Dopamine depleters Tetrabenazine, reserpine
Dopamine synthesis blockers a-Methyldopa
Calcium channel antagonists
(P-channel)
Flunarizine, cinnarizine
Intermediate Atypical antipsychotics Ziprasidone
Calcium channel antagonists
(L-channel)
Diltiazem, verapamil
Antiepileptics Valproate, phenytoin, levetiracetam
Antiemetic and gastric motility agents Prochlorperazine, metoclopramide, substituted benzamides
Mood stabilizers Lithium
Lower Antiarrhythmics Amiodarone, procaine
Immunosuppressants Ciclosporin, tacrolimus
Antidepressants SSRIs: fluoxetine, sertraline
Tricyclic: phenelzine
MAOIs: moclobemide, phenelzine
Antibacterials Cotrimoxazole
Antivirals Aciclovir, vidarabine, anti-HIV
Statins Lovastatin
Antifungals Amphotericin B
Hormones Levothyroxine sodium, medroxyprogesterone, epinephrine (adrenaline)
DIP=drug-induced parkinsonism; MAOIs = monoamine oxidase inhibitors; SSRI =selective serotonin reuptake inhibitors.
Drug-Induced Parkinsonism in the Elderly 111
2012 Adis Data Information BV. All rights reserved. Drugs Aging 2012; 29 (2)
dopamine are the antiemetics prochlorperazine
and droperidol, and agents used for gastrointes-
tinal complaints such as metoclopramide, clebo-
pride and similar substances. Of this group of
peripheral receptor blockers the only one that
poses no risk of DIP is domperidone, a con-
sequence of the fact that its high polarity does not
allow its penetration across the blood brain bar-
rier (BBB).
[76]
Domperidone, however, could be
equally toxic in subjects with BBB lesions, such
as those with recent cerebral infarcts or intracere-
bral surgery. In addition, medications that block
the synthesis of dopamine such as a-methyldopa
or the dopamine depleters reserpine and tetra-
benazine are also frequently associated with DIP
through a well known mechanism of action re-
lated to their ability to interfere with normal
nigrostriatal dopamine function.
[16]
Some calcium channel antagonists available
in Europe and South America (flunarizine and
cinnarizine), which are piperazine derivates, are
thought to cause DIP by blocking dopamine re-
ceptors.
[77,78]
Other calcium channel antagonists
(diltiazem and verapamil)
[79]
have been consid-
ered responsible for DIP with a less straightforward
mechanism of action. Reports of parkinsonism
induced by other compounds such as lithium
[80,81]
and amiodarone
[82]
are rare but appear con-
sistently over time. In some cases, DIP appears
in patients treated with very commonly used
drugs that rarely produce this complication and
whose interaction with the dopamine system is
not well understood. In these cases, the relation-
ship with the drug can be discerned only once the
parkinsonism has developed. These include some
antiepileptics, particularly valproic acid,
[83]
and
antidepressants including serotonin reuptake in-
hibitors (fluoxetine, sertraline, paroxetine).
[84-86]
Cholinesterase inhibitors, widely used to treat
dementia, may have increased tremor but did not
worsen motor function as measured by the Uni-
fied Parkinsons Disease Rating Scale in several
clinical trials.
[71,87]
A recent study reviewed the
spontaneous notifications of DIP and worsening
of parkinsonism over a period of 17 years in a
region that included 2 900 000 inhabitants.
[28]
Among the suspected drugs most involved were
central dopaminergic antagonists (49%), antide-
pressants (8%), calcium channel antagonists (5%),
peripheral dopaminergic antagonists (5%) and
histamine H
1
receptor antagonists (5%). Cases
involving lithium, valproic acid, amiodarone and
trimetazidine were also found.
[28]
The distribu-
tion of potential culprits might vary over time
depending on the prescription tendencies of each
region. Indeed, other studies have observed that
flunarizine and cinnarizine were amongst the
most common causes of DIP in countries in
which they were available in the past decades,
[88]
but their role in DIP has decreased in more recent
years probably because of prescribers improved
knowledge of the side effect profiles of these
drugs.
[31]
However, new potential culprits might
appear in the future.
7. Pathogenic Mechanisms
The mechanisms associated with the appearance
of DIP have a common final result: diminished D
2
receptor stimulation in the striatum. This occurs
primarily with the blockade of D
2
receptors by
antipsychotics and related drugs, but also occurs
with decreased dopamine release produced by
compounds that deplete dopamine storage vesicles
such as tetrabenazine, with medications that block
the synthesis of dopamine or block the dopamine
entry into the vesicles that are released into the sy-
napse or with compounds that have a reversible or
irreversible neurotoxic effect on dopamine neurons.
Several positron emission tomography (PET)
studies have shown that the pharmacological ef-
fect of antipsychotics is achieved with a blockade
of 6070% of dopamine receptors and that anti-
psychotic-induced parkinsonism appears when
the blockade of dopamine receptors is >75%.
[89]
Numerous mechanisms have been proposed to
explain the age-related increase in prevalence of
DIP in the elderly.
[90]
Some of these include ab-
normal pharmacokinetics associated with aging
as well as age-related reduction in the numbers of
dopamine neurons.
[91]
Supporting that is the fact
that the prevalence of iPD is lower in Asian
Indians who do not have age-related drop-out
of nigrostriatal dopamine neurons than in other
races.
[92]
112 Lopez-Sendon et al.
2012 Adis Data Information BV. All rights reserved. Drugs Aging 2012; 29 (2)
Recent studies from our laboratory have pro-
vided data about the molecular mechanisms im-
plicated in age-related increased prevalence of iPD
and DIP. Parkin null mice have normal KCl-
dependent release of dopamine but abnormal release
of the cytoplasmic pool of this neurotransmitter
mediated by stress and amphetamine.
[93]
As a result
of this abnormality these animals have an increased
intracellular, monoamine oxidase-mediated metab-
olism of dopamine and an increased production of
H
2
O
2
and other free radicals. These molecular ab-
normalities are compensated for by an enhanced
production of glutathione (GSH) and the animals
do not show a significant drop-out of nigrostriatal
dopamine neurons during the first year of age. Par-
kin null mice are, however, more susceptible to
dopamine neurotoxic drugs, such as cinnarizine,
than wild-type animals. Cinnarizine, which blocks
dopamine receptors and increases the vesicular re-
lease of dopamine, further increased dopamine me-
tabolism. Parkin null mice further increased GSH
levels as a compensatory mechanism against free
radicals. Neuronal markers, such as b-tubulin,
slightly increased in parkin null mice and more so
with cinnarizine. Astroglial markers decreased in
parkin null mice, and this effect was potentiated by
cinnarizine. Microglia were hyperactivated in parkin
null midbrain, suggesting inflammation in these
animals. Proapoptotic proteins were increased by
cinnarizine.
[94]
However, these compensatory mech-
anisms disappear with aging. Parkin null mice aged
>18 months do not have compensatory increased
GSH levels and the compensatory effects of astro-
glia disappear. As a result, the number of nigros-
triatal dopamine neurons drop out.
[95,96]
Therefore,
the increased susceptibility of elderly people to par-
kinsonizing drugs could be related to multiple
mechanisms including alterations in pharmacokine-
tics, age-related drop-out of dopamine neurons, lack
of compensatory mechanisms in the production of
free radical chelating agents and lack of neuropro-
tective effects of glia.
Antipsychotics can be categorized by potency.
In general, the more potent drugs have greater
affinity for the D
2
receptor, fewer anticholinergic
effects, and both greater antipsychotic effects and
more parkinsonian effects at lower doses.
[97]
The
severity of the DIP reflects the combined effects of
the patients sensitivity, presumably reflecting the
untreated state of the striatum, the D
2
-receptor
blocking effects of the drug, counterbalanced by the
drugs effects on other neurotransmitter systems,
which usually include some degree of anticholin-
ergic, antihistaminergic activity as well as effects on
neuropeptides and other systems. Atypical anti-
psychotics also block D
2
receptors; however, there
is no apparent correlation between the degree of
this blockade and the risk of inducing parkinson-
ism. One current hypothesis is the fast off theory,
which postulates that the duration of D
2
receptor
blockade, rather than the percentage of receptors
blocked, determines the likelihood of parkinson-
ism.
[75]
Another theory is that the ratio of serotonin
5-HT
2A
receptor blockade versus the D
2
receptor
blockade is critical because of the interplay between
the serotonin and dopamine systems in the brain.
Also, the rapidity of dose escalation, the target dose
and the patients intrinsic vulnerability play a key
role in the pathogenesis of DIP.
Several studies have shown that compounds
responsible for DIP may produce not only phar-
macological impairment of dopamine neurotrans-
mission, but also neurotoxic effects on dopamine
neurons. Short-term blockade of D
2
receptors
inhibits the production of neurotrophic sub-
stances for dopamine neurons, such as brain-
derived neurotrophic factor
[98]
and increases the
firing of dopamine neurons, which is associated
with a rise in the metabolism of dopamine and
enhanced production of neurotoxic free radi-
cals.
[99]
The direct toxic effects on dopamine
neurons have been investigated in the case of
haloperidol. DIP by haloperidol has been related
to the levels of the haloperidol piridinium ion, a
metabolite of haloperidol toxic to dopamine
neurons.
[100,101]
The clinical course of DIP, reaching a plateau
and then remitting, is thought to be due to two
factors known to occur in animals. Initially the
dopamine neurons release increased amounts of
dopamine in response to receptor blockade; over
time, upregulation of D
2
receptors occurs, thus
bypassing some of the blockade effects.
[102]
It is also
likely that changes develop inother neurotransmitter
systems as well as in the neurophysiology of basal
ganglia neuronal populations.
Drug-Induced Parkinsonism in the Elderly 113
2012 Adis Data Information BV. All rights reserved. Drugs Aging 2012; 29 (2)
8. Prevention and Treatment
The best treatment of DIP is prevention, in-
cluding the avoidance of prescription of causative
drugs whenever this is not strictly necessary or
when these could be substituted with compounds
with a safer profile. Other important considera-
tions are to preclude prescribing drugs with no
evidence of their usefulness
[103]
and to avoid
maintenance of drugs for longer than they remain
valuable. The risk of developing DIP should be
weighed in each patient and special monitoring is
warranted in individuals with higher risk, such as
elderly and demented patients, those with extra-
pyramidal signs such as tremor, patients with a
family history of parkinsonismand those who are
being treated with multiple drugs. Therefore, the
medical staff should be vigilant in advance of the
appearance of parkinsonian signs upon initiation
of certain medications. After the identification of a
DIP, the first step would be to ponder the degree of
the problem in each patient. DIP is a problem only
if it is troublesome for the patient, either socially or
functionally. By itself, it might not necessarily need
to be treated since it has no implications for the
treatment of underlying psychosis and is not ne-
cessarily a forerunner of a worse movement dis-
order. For a time, it was theorized that proper
control of psychosis could only be achieved once
DIP occurred, but this has been clearly disproved,
leaving DIP as an undesirable adverse effect of
some antipsychotic drugs. The first treatment strat-
egy would be to substitute the suspected com-
pounds with a related drug with a more favourable
side effect profile. Since DIP is related to potency
and dosage, the severity of DIP can be prevented
or reduced by using low-potency drugs at the
lowest effective dose of whatever drug is chosen. If
it is possible to discontinue the offending agent,
recovery usually occurs over several weeks. DIP
may improve with the use of anticholinergics,
[104]
and there seems to be no difference between the
efficacy of the two most popular anticholinergics
benztropine and trihexyphenidyl. The controversy
centres on whether the side effects of these drugs,
including dry mouth, constipation, urinary reten-
tion, blurred vision and memory impairment, are
offset by the benefit. They might be of some
symptomatic value when underlying psychiatric
illness precludes antipsychotic discontinuation, but
they must be used with great caution in the elderly
because of the risk of delirium and amnesia. It is,
therefore, good practice to continue these drugs
only if their use provides clear improvement.
Amantadine is an alternative to anticholinergic
drugs, being equally effective as trihexifenidyl for
the treatment of DIPbut associated with fewer and
less severe side effects.
[105]
Medical therapy should
be indicated when withdrawal of the offending
substance does not result in improvement or if the
patient requires therapy with the offending drug.
Levodopa or dopamine receptor agonists are usu-
ally ineffective due to striatal D
2
receptor blockade
and have been implicated in exacerbating psy-
chosis.
[53]
However, patients with a DIP secondary
to a loss of dopamine nerve terminals in the context
of a progressive degenerative parkinsonism (as as-
sessed by functional neuroimaging) may benefit
from levodopa therapy.
[15]
Parkinsonism due
to drugs such as tetrabenazine that deplete pre-
synaptic dopamine may also be amenable to
treatment with levodopa.
[106]
Resolution of the
DIP may take considerable time, however. An
alternative approach for refractory cases would be
the use of electroconvulsive therapy when appro-
priate, which temporarily ameliorates parkinson-
ism and treats psychosis
[107,108]
and depression.
[109]
9. Conclusions
With increasing prevalence due to the ageing
of the population and increasing polypharmaco-
therapy in the elderly, DIP threatens to be a health
problem of great magnitude in the future. The claim
that second-generation antipsychotic agents
cause less parkinsonismthan their predecessors has
made many physicians believe that the atypical
antipsychotics are safe and well tolerated in the
elderly. It has been demonstrated that DIP is fre-
quently misdiagnosed as iPD, and that in many
cases dopaminergic treatment is given to patients
who do not require it. The primary reason for fail-
ure to recognize DIP relates to under-recognition
of atypical antipsychotics as the possible cause.
DIP is a reversible condition that adversely
affects quality of life in the elderly. It can result in
114 Lopez-Sendon et al.
2012 Adis Data Information BV. All rights reserved. Drugs Aging 2012; 29 (2)
falls and related hospitalizations, lead to nursing
home placement, increased mortality and is re-
versible when the causative agent is discontinued.
In a study performed in a geriatric clinic,
[21]
51%
of 95 new cases of parkinsonism were associated
with prescribed drugs, 25% of patients with DIP
could not walk when first seen and 45% required
hospital admission. The clinical features of DIP
resolved permanently in two-thirds of cases in a
mean of 7 weeks.
It is essential for clinicians to be aware of the
extrapyramidal side effects of medications, to pre-
vent and manage DIP. The risk of side effects
should be evaluated in each patient and the selec-
tion of antipsychotic and antidepressant agents
should be tailored according to the basal char-
acteristics of each subject. For example, quetiapine
and clozapine should be preferred to other atypi-
cal and conventional antipsychotics when treat-
ing psychosis in Parkinsons disease.
[110]
Cessation
of the offending agent results in improvement
of symptoms in the majority of cases and would
eliminate the need for dopaminergic agents, which
are known to commonly cause side effects in the
elderly.
DIP remains a common problem despite the
development of atypical antipsychotic drugs, and is
undoubtedly under-recognized. Physicians have the
duty to remain vigilant to its possibility and man-
age it appropriately when present.
Acknowledgements
This study has been supported in part by grants from the
Spanish Ministry of Health, FIS 2010/172, CIBER (Centro de
Investigacio n Biome dica en Red) 2006/05/0059, CIBER
2010/05. The authors have no conflicts of interest that are
directly relevant to the content of this review. The authors
thank Ms C.D. Marsden for editorial assistance in the pre-
paration of this review.
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Correspondence: Dr Mar a Angeles Mena, Department of
Neurobiology, Hospital Ramo n y Cajal, Carretera de
Colmenar, Km 9,100, Madrid 28034, Spain.
E-mail: maria.a.mena@hrc.es
118 Lopez-Sendon et al.
2012 Adis Data Information BV. All rights reserved. Drugs Aging 2012; 29 (2)