Review

Drug-induced parkinsonism
Jose Lopez-Sendon, Maria A Mena & Justo G de Yebenes

Hospital Ramon y Cajal, Servicio de Neurologa, CIBERNED, Madrid, Spain

1. Introduction
Introduction: Drug-induced parkinsonism (DIP) is the second most common
cause of parkinsonism after idiopathic Parkinsons disease (iPD). Initially
2. Drug-induced parkinsonism
reported as a complication of antipsychotics, it was later recognized as a
3. Conclusions common complication of antidepressants, calcium channel antagonists, gas-
4. Expert opinion trointestinal prokinetics, antiepileptic drugs and many other compounds.
Despite being a major health problem in certain populations, it seems to be
frequently overlooked by the medical community.
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Areas covered: This paper approaches the concept of DIP, reviews its
epidemiology, clinical features and ancillary tests recommended for a correct
diagnosis. The authors discuss the different drugs and its pathogenic
mechanisms. The relevance of an early recognition and recommendations
for a correct management are commented.
Expert opinion: Prescribers need to remain vigilant for DIP, particularly in the
elderly, patients taking multiple drugs and those with genetic risk factors
involved in iPD. Cessation of the causing agent is the main treatment and
there is no evidence of benefit for the use of anticholinergics or levodopa.
If the medication cannot be withdrawn, it should be switched to agents
with a lower risk of DIP.
For personal use only.

Keywords: antipsychotics, calcium channel blockers, dopamine receptor blocker, drug-induced,

extrapyramidal side effects, neuroleptics, parkinsonism

Expert Opin. Drug Saf. [Early Online]

1. Introduction

Drug-induced parkinsonism (DIP) was recognized in the early 1950s as a common

complication of antipsychotic therapy [1,2]. Initially considered to be present in
4 -- 40% of patients treated with the first neuroleptics [3,4], it has been reported as
a complication of treatments with diverse compounds including new generation
antipsychotics, calcium channel antagonists, gastrointestinal prokinetics, antiar-
rhythmics, antidepressants and others [5]. Two decades ago, parkinsonism related
to calcium channel antagonists reached epidemic proportions in some countries,
accounting for 75% of the cases of DIP and up to 40% of the total cases of
parkinsonism [6,7].
DIP is considered reversible after drug suppression. Persistency of the clinical
deficits after culprit withdrawal may indicate a previous subclinical parkinsonism
unmasked by the involved drugs. Studies with presynaptic uptake dopamine
markers using single photon emission tomography (SPECT) have shown that there
are two groups of DIP patients: those with normal SPECT (suggesting normal den-
sity of dopamine terminals) and patients with reduced striatal uptake (suggestive of
lesion of the presynaptic dopamine terminals) [8]. These findings are in agreement
with the hypothesis of a multifactorial origin of DIP. In addition, some of the drugs
that produce DIP may also cause direct neurotoxic damage to the nigrostriatal
dopamine neurons [9,10]. It is now evident that some individuals, perhaps with
genetic variants of genes involved in familial Parkinsons disease (PD), are especially
susceptible to this complication [11].
Here, the authors review DIP, the drugs that cause it, its pathogenic mechanisms,
individual risk factors, diagnosis and management.

10.1517/14740338.2013.787065 2013 Informa UK, Ltd. ISSN 1474-0338, e-ISSN 1744-764X 1

All rights reserved: reproduction in whole or in part not permitted
 J. Lopez-Sendon et al.

treatments. Population studies have detected incidences of

Article highlights.
. Despite advances in ancillary tests, the clinical course of
parkinsonism after drug discontinuation is paramount
for a correct differential diagnosis.
. Management of DIP includes prevention, early
recognition and withdrawal of the offending drug.
. Certain variables such as age, use of multiple drugs or
previous vascular damage to the nigrostriatal pathway
increase the risk of DIP. However, DIP susceptibility is
highly variable and unpredictable among different
subjects.
.
DIP is the second cause of parkinsonism but is still
perceived as a neglected pathology on the day-to-day
clinics by most of the studies.
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DIP among the 50 -- 99 years age group of 22.94 per
100,000 person-years [17]. The extrapolation of these results
to the total population of the USA would provide an estima-
tion of 20,000 -- 25,000 incident cases of DIP per year.
Another study focused on an elderly population of 64 years
or older patients estimated the prevalence of DIP to be
3.3%, representing a 37% of all cases of parkinsonism [18].
The figures of DIP among clinical series of movement dis-
orders units place DIP as the second cause of parkinsonism
after iPD with a prevalence of 20 -- 56% [19].
Antipsychotics are the prototypical and most common
compounds producing DIP. The first study of the prevalence

of DIP with chlorpromazine found that about 40% of these

This box summarizes key points contained in the article. patients had parkinsonism. A recent study has shown a
prevalence of DIP in 1 out of 126 patients taking antipsy-
chotics [20]. This figure is probably underestimated as it was
2. Drug-induced parkinsonism
obtained from patient self-reported complications to Medi-
care. Another study including > 250,000 patients on typical
2.1 Definition
and atypical antipsychotics, aged > 66 years, followed for a
DIP is defined by the appearance of a parkinsonian syndrome
mean period of 6 months, totaling a follow-up of 11,000
in patients treated with drugs that impair dopamine function.
person-years, detected a total of 449 patients with DIP, 4%
Also, there should be no previous history of parkinsonism
per year [21]. The risk of DIP in patients treated with low
before the use of the offending drug. This implies a distinc-
doses of atypical antipsychotics (< 1 mg of risperidone daily,
tion with idiopathic Parkinsons disease (iPD) and other
For personal use only.

or equivalent dose of related compounds) is lower than that

parkinsonisms related to neurodegenerative disorders or envi-
of the classical neuroleptics, but the difference of risk
ronmental agents (such as cerebrovascular disease, infections,
disappears when typical and atypical antipsychotics are used
trauma, tumors, etc.). The majority of the compounds
at high doses.
responsible for DIP interfere with the nigrostriatal dopamine
In conclusion, it is now widely accepted that DIP is the
neurotransmission. In others, this interaction with the
second most common etiology of parkinsonism in spite of
dopamine system is unclear and the consideration of DIP rises
being underrecognized and frequently misdiagnosed as iPD.
when there is a tight-close temporal relationship with
the syndrome.
2.3 Clinical features and ancillary tests
The clinical course after drug withdrawal is important in
The clinical features of DIP are variable, but a summary of the
the differential diagnosis. DIP is considered reversible after
most characteristic ones is presented in Table 2. By definition,
drug withdrawal but up to 25% of the patients with suspected
all patients do have an akinetic rigid syndrome. The severity
DIP develop a progressive or persistent parkinsonism in spite
of the deficit and the presence of other clinical findings
of drug discontinuation [12,13]. Persistence and eventual wors-
depend on different variables including the type of causative
ening or a full remission but subsequent reappearance of the
drug, age of the patient, length of exposure and dose [12].
symptoms suggests the existence of a preclinical stage of iPD
However, neurological deficits tend to be more severe in
or other neurodegenerative parkinsonism unmasked by the
DIP than in iPD.
drug (Table 1). Persistent non-progressive parkinsonism may
The differential diagnosis between DIP and other types of
indicate an irreversible damage to the nigrostriatal dopamine
parkinsonism is not always easy and may not be possible based
system due to a toxic pharmacological exposure. Also, certain
solely on the clinical symptoms. iPD is characterized by
compounds can produce a progressive parkinsonism after a
asymmetric involvement of body limbs. Asymmetry is less
single non-persistent exposure [14]. In fact, only those with a
characteristic of DIP although it may happen. In contrast
full and long-lasting recovery can be diagnosed as pure
with vascular parkinsonism, which severely involves the legs
DIP. Ancillary tests such as dopamine transporter (DAT)
and produces frequent impairment of gait, DIP produces a
imaging and transcranial sonography [15,16] are helpful in
less severe gait disorder and a relatively more pronounced
identifying patients with underlying nigrostriatal dysfunction.
masked facial expression. Occasionally, the first symptom
is a decrease in arm swing when walking, rather than a
2.2 Epidemiology difficulty to rise from a low seat. The presence of tremor is
The prevalence of DIP has been studied in the general popu- variable. It is uncommon with drugs that selectively involve
lation, in specific groups such as clinical series of movement the dopamine neurotransmission, such as dopamine D2
disorders units and in cohorts of patients under specific blockers, and much more frequent with other compounds

2 Expert Opin. Drug Saf. [Early Online]

 Drug-induced parkinsonism

Table 1. Clinical course and DAT characteristics in the differential diagnosis of DIP.

Clinical entity Response to drug withdrawal PET/SPECT

Pure DIP Reversible Presynaptic markers: normal dopamine

Toxic-irreversible DIP (e.g., reserpine,
MPTP, typical antipsychotic)
Unmasked iPD
Primary parkinsonism worsened
by drugs (PSP, DLB)
receptor ligands: reduced
Irreversible, may progress Variable
Remission and later worsening Reduced uptake of presynaptic markers,
Partial improvement and later worsening normal uptake of dopamine receptor ligands
Partial improvement and later worsening Variable

DIP: Drug-induced parkinsonism; DLB: Dementia with Lewy bodies; iPD: idiopathic Parkinsons disease; PET: Positron emission tomography; PSP: Progressive
supranuclear palsy; SPECT: Single proton emission tomography.
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Table 2. Clinical characteristics of iPD and DIP.

iPD DIP

Age at onset Mean age at sixth decade More often in the elderly
Symmetry of deficits Asymmetric Often symmetric
Lower/upper body involvement Both More severe involvement of the upper part
Less gait disorder
Tremor Variable Variable
Depression Common Common
Dementia Rare at onset, frequent with May be present before onset of parkinsonism
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prolonged evolution
Clinical response to L-DOPA Good Poor
or dopamine agonists

DIP: Drug-induced parkinsonism; iPD: Idiopathic Parkinsons disease; PD: Parkinsons disease.

that act through a less selective mechanism, such as amiodar-
one or calcium channel blockers [12,13,17-19]. The appearance
of concomitant movement disorders induced by drugs such
as tardive dyskinesia is frequent in DIP patients whereas is
rare in drug-nave iPD patients.
The clinical outcome after discontinuing the offending
drug is essential in the diagnosis. Although most patients
with DIP improve at least partially after withdrawal of the
offending drug, lack of improvement or even disease progres-
sion after discontinuation of the offending drugs may happen.
Mart Masso and Poza, for instance, found that approximately
90% of patients with cinnarizine-induced parkinsonism
eventually recovered after a follow-up of up to 10 years [12].
The recovery rate, in fact, changes with different definition
criteria. Patients not achieving full recovery after a long period
of time should be excluded from the diagnosis of pure DIP.
However, there is evidence supporting that certain drugs can
induce a persistent and even progressive parkinsonism.
Vingerhoets et al. have shown with F18-F-DOPA studies
that short-term exposure of young individuals to chemicals
toxic for the dopamine neurons, in that case to MPTP
(1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), leads to a
protracted decline in nigrostriatal dopaminergic function
that progresses more rapidly than in normal aging and is sim-
ilar to the progression of patients with PD [14]. Therefore,
similar evolution could take place after limited exposure of
patients to certain drugs, which could produce toxic effects
on dopamine neurons. Several drugs related to DIP interfere
with cellular mechanisms related to cell survival and it is con-
sidered that long exposure to these compounds may not only
interfere with dopamine neurotransmission but also induce a
permanent lesion of this system. Lack of reversibility can
also be explained considering that at least some patients
with DIP are individuals in the presymptomatic phase of
PD who, in any case, would develop the disease, and whose
clinical symptoms are only accelerated by the offending drugs.
In support of this hypothesis, the authors have found single
heterozygous mutations of the Park-2 gene or polymorphisms
of parkin in some cases of DIP.
Depression is a very common early symptom in many
patents with DIP, but it is also common in the elderly, a
population at special risk for DIP, so at times it is difficult to
understand whether depression is due to DIP or to the initial
disease that was treated with drugs which cause DIP. Cognitive
deficits are not typical of DIP but many drugs, including
sodium valproate [22] and several antipsychotics -- particularly
first-generation antipsychotics -- may worsen cognitive
function. However, in many cases cognitive deficits should
not be related to the drugs that produce DIP but rather to
the concomitant diseases of the patient.

Expert Opin. Drug Saf. [Early Online] 3

 J. Lopez-Sendon et al.
Patients with DIP respond to treatment with L-DOPA and
dopamine agonists less well than patients with iPD. Most
patients improve, at least partially, with the limitations
explained above, after the withdrawal of the offending drug.
2.4 Drugs
Drugs can be classified according to their relative risk of
producing DIP. Certain drugs have a high risk and are consis-
tently associated with DIP with well-identified causative
mechanisms that, in many cases, have been tested in animal
models of PD. That is the case of classical antipsychotics [1-9]
and other compounds that block dopamine receptors such
as gastrointestinal prokinetics (Table 3). First-generation
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antipsychotics are associated with a different risk of DIP
depending on their muscarinic antagonism. In this sense,
zuclopenthixol or haloperidol are expected to be associated
with a higher risk of extrapyramidal side effects with respect
to chlorpromazine or levomepromazine. Atypical antipsy-
chotics produce parkinsonism in certain individuals when
used at moderate or high doses [23-28]. An exception is
clozapine that has the same risk of DIP as placebo [27]. The
lower risk of DIP of second-generation antipsychotics, com-
pared with neuroleptics, probably derives from the fact that
classic antipsychotics are potent blockers of striatal D2
For personal use only.
dopamine receptors whereas second- and third-generation
antipsychotics, in addition to certain partial agonist action
on dopamine receptors, have preference for other subtypes
of receptors.
Other dopamine receptor blockers, such as the
benzamine derivatives, used for the treatment of nausea and
vomiting [29-37], or the phenothiazide derivatives, used for
the treatment of vertigo [38-44], frequently produced DIP.
Similarly, drugs that interfere with vesicular storage of
monoamines, such as tetrabenazine and reserpine [45,46], are
frequently associated with DIP.
The most important calcium channel antagonists associated
with DIP were cinnarizine and flunarizine [6,7,12,19,47-69]. The
first was removed from the market in most countries. Flunar-
izine, still widely used and very valuable for the preventive
treatment of vascular headaches, has also been associated
with DIP. Diltiazem [70] and verapamil [71], both calcium
channel antagonists, have also been considered responsible
for DIP.
Other compounds that interact with the dopamine neuro-
transmission and that are often associated with DIP include
the following: the antiarrhythmic amiodarone [72-76],
lithium [77-80] (commonly used for the treatment of bipolar
disorder or the prevention of cluster headache) and alfametil-
dopa [81], an inhibitor of catecholamine synthesis formerly
used for the treatment of high blood pressure and still
valuable in the treatment of tardive dyskinesias.
Parkinsonism has also been related to an array of abuse
substances. Alcohol has been associated with withdrawal
parkinsonism. Cocaine is known to cause parkinsonism due
to direct vascular damage and is a major risk factor for
4 Expert Opin. Drug Saf. [Early Online]
antipsychotic-induced extrapyramidal side effects while other
stimulants such as methamphetamine and other amphetamine-
type stimulants (meth/amphetamine) can cause a direct
damage to dopamine neurons [82].
Sometimes parkinsonism appears in patients treated with
very commonly used drugs that rarely produce DIP and whose
interaction with the dopamine system is unknown. Among
this group of drugs one should mention antiepileptics [22,83-86],
antidepressants [87-93], anticholinergics such as propiver-
ine [94,95] and drugs used for the treatment of postmenopausal
syndrome such as veralipride [96]. In these cases it is conceiv-
able that the disease is related to several mechanisms including
the following: i) simultaneous administration of several
mutually potentiating drugs; ii) pharmacokinetic peculiarities
of the subject and iii) special individual susceptibility.
2.5 Pathogenic mechanisms
The mechanisms causing DIP may interfere with the nigros-
triatal pathway at several levels but share a common final
result: diminished D2 receptor stimulation in the striatum.
The majority of compounds responsible for DIP block
striatal dopamine D2 receptors [97]. Positron emission tomog-
raphy (PET) studies have shown that the pharmacological
effect of antipsychotics are achieved with a blockade of a
60 -- 70% of the dopamine receptors and that parkinsonism
appears when the blockade reaches 75 -- 80% [98]. These fig-
ures may vary since the occupancy of the receptors is not equal
to antagonism. For instance, the atypical antipsychotic aripi-
prazol rarely produces parkinsonism with occupancy rates as
high as 95% due to its weak antagonistic effects.
Other compounds act by inhibiting uptake of dopamine
into granular vesicles of presynaptic neurons. Monoamines
are concentrated from the cytoplasm into vesicles by vesicular
monoamine transporters (VMATs). There are two isoforms of
VMATs [99,100]: VMAT1 is located predominantly in periph-
eral endocrine and paracrine cells while VMAT2 is located in
the brain and sympathetic neurons [101]. Many compounds
may bind to VMATs but three drugs are known to do so
selectively: tetrabenazine (TBZ), reserpine and ketanserin.
TBZ and reserpine bind to the same site on the VAMT2
but to different conformations. While reserpine binds
irreversibly being potentially toxic, TBZ displays reversible
binding. Inhibiting the uptake of monoamines -- including
dopamine -- into synaptic vesicles diminishes their output at
synapse producing DIP.
Certain calcium channel antagonists decrease neuronal
activity [102], reduce monoamine neurotransmission and
dopaminergic viability [10] and reduce the levels of homovanil-
lic acid (HVA) in the cerebrospinal fluid (CSF) of healthy pri-
mates [103] suggesting that, even without previous dopamine
dysfunction, they can produce a calcium-dependent reduction
of dopamine release. Both cinnarizine and flunarizine are
potent uncouplers of the vacuolar H+-ATPase in catechol-
amine storage vesicles [104]. This could alter the intracellular
metabolism of dopamine, a mechanism that has been reported

Table 3. Drugs associated with DIP.
Risk of DIP Mechanism of action
High D2 receptor blockade
Dopamine depletion
Dopamine synthesis blockade
Ca2+ channel antagonism
Antiemetics
Intermediate D2 receptor blockade (atypical)
Ca2+ channel antagonism
Antiepileptics
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Intermediate Mood stabilizers
Low Antiarrhythmics
Immunosuppressants
Antidepressants
Antivirals
Statins
Antifungals
Hormones
DIP: Drug-induced parkinsonism; MAOIs: Monoamine oxidase inhibitors; MPTP: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; SSRIs: Selective serotonin
reuptake inhibitors.
For personal use only.
as neurotoxic for dopamine cells in parkin null mice [105,106],
and could also be neurotoxic for patients with abnormal
parkin function.
Other compounds responsible for DIP may produce not
only a reversible pharmacological impairment of dopamine
neurotransmission, but also neurotoxic effects on dopamine
neurons. Short-term blockade of dopamine D2 receptors
inhibits the production of neurotrophic substances for dopa-
mine neurons, such as brain-derived neurotrophic factor [107]
and stimulates the firing of dopamine neurons increasing
the metabolism of dopamine and production of free radicals.
After chronic treatment, haloperidol dampens the activity of
the dopamine neurons [108] through a mechanism related to
K+ channels. Downregulation of dopamine firing after long
treatment with haloperidol correlates with reduction of
HVA levels in CSF, but this effect does not always take place,
and its failure may be associated with DIP. Other persistent
toxic effect on the nigrostriatal dopamine neurons produced
by haloperidol is related to the levels of haloperidol pyridi-
nium ion [109], which may be produced locally in the brain.
Treatment with haloperidol -- but not clozapine -- increases
oxidative metabolism in the brain, reduces the phosphoryla-
tion of Akt and activates caspase-3 [110]. Haloperidol has
been shown to change the nigral expression of the transcrip-
tion factor nuclear factor-kappaB (NF-kB), which responds
directly to oxidative stress [111] and plays a role in the activa-
tion of several genes involved in immune and inflammatory
function. Individual pharmacokinetic has explained inter-
individual differences in susceptibility to DIP by haloperidol
variability related to CYP34A and the polymorphic CYP3A5
isoenzyme systems, which metabolize haloperidol to its
Expert Opin. Drug Saf. [Early Online]
Drug-induced parkinsonism
Pharmacological group/drug
Typical antipsychotics (haloperidol, prochlorperazine, thioxantenes,
amisulpride, flupentixol, fluphenazine, levomepromazine,
pimozide promazine, sulpiride, thioridazine, zuclopenthixol)
Atypical antipsychotics (risperidone, olanzapine, ziprasidone, aripiprazole)
Tetrabenazine, reserpine
Alfametildopa
Flunarizine, cinnarizine
Metoclopramide, levosulpiride, clebopride
Quetiapine, clozapine
Diltiazem, verapamil
Valproate, phenytoin, levetiracetam
Lithium
Amiodarone, procaine
Cyclosporine, tracrolimus
SSRIs: fluoxetine, sertraline
MAOIs: moclobemide, phenelzine
Acyclovir, vidarabine, anti-HIV
Lovastatin
Amphotericin B
Levothyroxine sodium, medroxyprogesterone, epinephrine (adrenaline)
pyridinium ion. Compounds interacting with this system such
as antidepressants may enhance toxicity related to the pyridi-
nium ion in patients treated with haloperidol. This mechanism
is not an important genetic contributor to the inter-individual
variability in CYP3A-mediated haloperidol clearance pathway.
The influence of hereditary predisposition in DIP has been
known for more than a lustrum [112]. Several studies have
addressed the risk factors and mechanism underlying this
genetic predisposition [113-115]. Parkin knockout mice are
more susceptible to the toxic effects of cinnarizine than
wild-type controls [105]. In parkin-deficient mice, cinnarizine
produced changes in the metabolism of dopamine and
increased the expression of proapoptotic proteins and reduced
the proportion of astroglia and hyperactivated microglial cells,
suggesting that in these genetically modified animals, cinnar-
izine selectively triggers the expression of neurotoxic factors
that could produce an irreversible damage to the nigrostriatal
dopamine system. This suggests that heterozygote parkin
mutation carriers may be more susceptible to DIP.
2.6 Management
Prevention is a key element in the management of DIP. Physi-
cians should be aware of which drugs might produce DIP and
prescribe them only under clear indication. Before the
description of calcium antagonist-related parkinsonism, up
to 6% of the Spanish population over 60 years of age was
treated with cinnarizine [116]. A similar high prescription rate
was found in other countries in Latin America, producing
DIP in epidemic proportions in these areas. Also, many
patients with cognitive impairment or communication
disorders are given antipsychotics larga manu to cover lack
5
 J. Lopez-Sendon et al.
of adequate behavioral stimulation, medical attention or to
play a calming effect on medical problems such as pain,
constipation or urinary retention, which are not adequately
evaluated and treated. In some clinical series, up to 50% of
the patients with DIP were found to be treated with antipsy-
chotic drugs for conditions unrelated to psychosis including
insomnia, anxiety or depression [117]. The first preventative
approach, therefore, is not to prescribe compounds that are
not useful and avoid maintaining the prescription for longer
than it remains necessary.
The second management strategy is to substitute certain
compounds by a related drug with a better side-effect profile.
For instance, the substituted benzamides used for the treat-
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ment of nausea should be substituted by domperidone, which
does not cross the blood--brain barrier nor produces DIP [118].
Also, typical antipsychotics should be preferred to atypical
antipsychotics particularly when higher doses are required.
The choice of antipsychotic is a complex decision that depends
on a number of factors including diagnosis, profile of potential
side effects, concomitant medication and conditions such as
predisposition to suffer DIP. Clozapine is a useful agent for
the treatment of drug-induced psychosis in PD [119,120], but
it can also improve the clinical symptoms of DIP induced by
other D2 antagonists. However, treatment with clozapine is
For personal use only.
associated with agranulocitosis and neutropenia, which appear
at a rate of 0.16 -- 0.18%, mostly in young patients with
schizophrenia during the first months of treatment, and
require monitoring of hematological levels. This complication
has also been described with perazine derivatives, olanzapine
and risperidone [121]. Aside from hematological side effects,
clozapine is one of the most effective antipsychotics available
for the treatment of psychosis in conditions such as PD, but
its dangerous side effects should always be pondered against
its low risks of causing DIP [122,123].
The third strategy would be to carefully monitor individu-
als with special risk factors for developing DIP. Senior indi-
viduals, those with family history of parkinsonism, dementia
or tremor and those under treatment with multiple drugs
are more prone to suffer DIP. Once the treatment with a
potential culprit for DIP is initiated, the patients should be
periodically examined for initial symptoms of DIP. The
most sensitive tests are those related to quantitative
measurement of specific age-averaged, motor tests such as
computerized versions of tapping or walking. As soon as any
deterioration on performance is detected, the drug should be
tampered or discontinued. In some cases, discontinuation
requires a slow down titration. When improvement is incom-
plete after several months, iPD or other parkinsonian syn-
drome should be suspected and treatment with dopamine
agonists or L-DOPA might produce benefit. For more than
half a century, it has been common to prescribe anticholiner-
gics as a preventive treatment of DIP in patients treated with
antipsychotics. Although anticholinergics are very effective for
the treatment of acute dystonic reactions in patients treated
with neuroleptics, there is neither evidence nor rational
6 Expert Opin. Drug Saf. [Early Online]
support for the idea that these compounds could alleviate
DIP [124].
The prognosis of complete recovery is uncertain and
10 -- 30% of the patients will continue to have symptoms
several months after the discontinuation of the causative
drug. At least 10% of patients will develop a persistent and
progressive parkinsonian syndrome.
3. Conclusions
DIP is a very important health problem with a prevalence
approaching that of idiopathic PD and increasing. Its high
prevalence and frequent irreversibility require an active sur-
veillance from the prescribing physicians. Precautions and
careful monitoring of the clinical symptoms are especially
important in individuals with risk factors.
4. Expert opinion
This review discusses the latest findings on DIP, focusing on
relevant aspects for clinical practice. An array of different clin-
ical scenarios is possible when confronting DIP and, despite
some advances, the clinical course is still crucial to differenti-
ate patients with pure DIP from other parkinsonisms. Some
techniques such as DAT imaging may be useful to identify the
prognosis and the underlying pathogenesis of this disorder,
but they are pricey and not always available in the non-
specialized practice. Measurement of echogenicity of the sub-
stantia nigra with transcranial ultrasonography as a risk
marker for DIP has been explored but further studies are
needed to evaluate its usefulness. Also, certain variables such
as age, previous vascular damage to the nigrostriatal pathway,
treatment with multiple drugs and genetic variants have been
identified as risk factors for the appearance of DIP, but we
still lack the knowledge to determine why some people are
so resistant to astonishingly high doses of dopamine blockers
and others are incredibly sensible to lower doses of the
same agents.
With regards to the epidemiological studies conducted so
far, either on the general population or in specialized move-
ment disorder units, they seem to agree on their conclusions:
i) DIP is the second cause of parkinsonism, ii) it is frequently
overlooked by the clinical community and iii) it is a great
source of potentially reversible functional impairment. So,
despite being a classical topic of the neurological literature
and a major public health threat, DIP is perceived by many
authors as a neglected pathology on the day-to-day clinics.
Many drugs causing DIP are still prescribed for inappropriate
reasons such as dizziness or dyspepsia and, in many cases,
maintained for prolonged periods of time.
The pathogenic mechanisms of DIP are also well under-
stood, particularly those involving the dopamine modifying
agents, namely dopamine receptor blockers and dopamine
depleters. Several mechanisms including a more antagonistic
effect toward serotonin-2A receptors than toward dopamine
 Drug-induced parkinsonism

receptors, and a faster dissociation from D2 receptors explain
the lower frequency of DIP with second- compared with
first-generation antipsychotics. However, the ways of interac-
tion of other compounds clearly associated with DIP such as
lithium or valproate are less understood and need to be
further investigated.
Regarding management, some principles are universally
accepted: the culprits have to be looked for and withdrawn
if possible, second- and third-generation are preferred to
first-generation antipsychotics, there is no evidence support-
ing the use of levodopa, dopamine agonists or anticholinergics
for the treatment of DIP and gastrointestinal motility drugs
not crossing the blood--brain barrier (such as domperidone)
Expert Opin. Drug Saf. Downloaded from informahealthcare.com by University of Queensland on 05/12/13
low rates of DIP. Others, such as clozapine, have not been
associated with DIP but entail a spectrum of undesirable
side effects. Third-generation antipsychotics such as
aripiprazol have failed to become a competitive substitute
due to a higher rate of extrapyramidal side effects but the
pipeline of newer drugs will hopefully bring better agents in
the future.
Declaration of interest
This study has been supported in part by grants from the
Spanish Ministry of Health, FIS 2010/172; CIBER (Centro
de Investigacion Biomedica en Red) C2006/05/59 and

are preferred to those with central effects. Second-generation CAM 2011/BMD-2308. The authors have no conflict of
antipsychotics such as quetiapine are associated with very interest that are directly relevant to the content of this review.

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Affiliation
Jose Lopez-Sendon1, Maria A Mena2 &
Justo G de Yebenes1
Author for correspondence
1
Hospital Ramon y Cajal,
Servicio de Neurologa, CIBERNED,
Ctra de Colmenar Km 9,100,
Madrid, 28034, Spain
Tel: +0034 913368821;
E-mail: jgyebenes@yahoo.com
2
Hospital Ramon y Cajal,
Neurobiologia, CIBERNED,
Ctra de Colmenar Km 9,100,
Madrid, 28034, Spain