Neuroleptic-Induced Movement Disorders

46
Neuroleptic-Induced Movement
Disorders
Manuchair Ebadi
Departments of Pharmacology and of Neurosciences, University of North Dakota School of
Medicine and Health Sciences
CONTENTS
Abstract
Types of Abnormal Movements
Tremor
Chorea
Dystonia and Athetosis
Hemiballismus
Myoclonus
Tics
Basal Ganglia and Movement Disorders
Dopaminergic Transmission Involved in Movement Disorders
The Mesolimbic- and Mesolimbic-Cortical Dopamine Pathways
The Nigrostriatal Dopamine Pathway
Neuroleptic-Induced Regulation of Dopamine-Receptor Subtypes and
Its Implication in Schizophrenia
The Modulatory Actions of Acetylcholine, Adenosine, Glutamate, and -Opioid on
Striatal Dopaminergic Transmission
Regulation of Central Dopaminergic Neurons by Opioid Receptors
The Striatal Blockade of the Adenosine A2A Receptor in Parkinsons Disease
The Neuropathology of Movement Disorders
The Pyramidal System
The Extrapyramidal System
The Cerebellar System
Diverse Classification of Drugs Causing Movement Disorders
Neuroleptic-Induced Movement Disorders
Neuroleptic-Induced Akathisia
Conditions Resembling Akathisia
Classification of Akathisia
Differential Diagnosis of Akathisia
Treatment of Neuroleptic-Induced Akathisia
Antiparkinsonian Agents
Amantadine .
Benzodiazapine Derivatives
Beta-Adrenergic Receptor Blocking Agents
Alpha-Adrenergic Receptor Blocking Agents
L-Tryptophan
Bupropion
Neuroleptic-Induced Dystonia
Iatrogenic Dystonia
Copyright 2005 by CRC Press LLC
580
Parkinsons Disease
Incidence of Acute Dystonia

Enhanced Susceptibility to Develop Dystonia
Tardive Dystonia
Idiopathic Orofacial Dystonia (Meiges Syndrome)
Treatment of Dystonias
Baclofen in the Treatment of Dystonia
Botulinum Toxin in the Treatment of Dystonia
Phenylalanine in Dopa-Response Dystonia (DRD)
Neuroleptic Malignant Syndrome
Differential Diagnosis of Neuroleptic Malignant Syndrome
Events Leading to or Enhancing the Severity of Neuroleptic Malignant Syndrome
Complications of Neuroleptic Malignant Syndrome
The Pathogenesis of Neuroleptic Malignant SyndromeThe Role of Dopamine
Treatment of Neuroleptic Malignant Syndrome
General Treatments
Specific Treatments
L-Dopa/Carbidopa
Bromocriptine
Dantrolene Sodium (Dantrium)
Amantadine
Anticholinergic Agents
Benzodiazepine Derivatives
Neuroleptic-Induced Parkinsonism
Incidence of Parkinsonism
Treatment of Parkinsonism
Antitremor Effects of Clozapine
Parkinsonism, Schizophrenia, and Dopamine
Neuroleptic-Induced Tardive Dyskinesia
Drugs and Conditions Causing Dyskinesia
Heterogeneity of Tardive Dyskinesia
Tardive Dyskinesia and Diabetes
L-Dopa-Induced Dyskinesia
Tardive Oculogyric Crisis
Tardive Dyskinesia and Type II Schizophrenia
Mechanisms of Neuroleptic-Induced Dyskinesia
-Aminobutyric Acid in the Pathogenesis of Tardive Dyskinesia
Dopamine, Peptides, Schizophrenia, and Neuroleptics
Neuroleptic-Cholecystokinin Interaction
Neuroleptic-Opioid Interaction
Treatment of Tardive Dyskinesia
Buspirone in L-Dopa-Induced Dyskinesias
Vitamin E and Dyskinesia
Amantadine in Tardive Dyskinesia
Clozapine in Axial Tardive Dystonia
Cholecystokinin in Tardive Dyskinesia
Risperidone and Tardive Dyskinesia
Conclusions
Acknowledgments
References
ABSTRACT
Parkinsonism, tremor, chorea-ballismus, dystonia, tardive
dyskinesia, myoclonus, tics, and akathisia can be induced
by many drugs. The drugs that are most frequently implicated in movement disorders are antipsychotics, calcium
channel antagonists, orthopramides and substituted benzamides (e.g., metoclopramide, sulpiride, clebopride,
domperidone), CNS stimulants, antidepressants including

the selective serotonin uptake inhibitors, anticonvulsants,
antiparkinsonian drugs, and lithium. Moreover, extrapyramidal reactions (EPR) have also been reported to occur
with the selective serotonin-reuptake inhibitors, and motor
dysfunction is caused by tacrine.117 It is possible for a
single drug, such as one of the antipsychotics, to induce
two or more types of movement disorders in the same
patient. Movement disorders are not always reversible
after drug withdrawal.
Strong positive correlations exist between hyperkinetic forms of four extrapyramidal syndromes (EPS), tardive dyskinesia, parkinsonism, akathisia, and tardive
dystonia. More specifically, the probability of having
akathisia, which is often neglected or misdiagnosed, is
markedly increased in a patient suffering from tardive
dyskinesia.
Furthermore, it is quite common for chronic psychiatric inpatients to suffer from combinations of EPS. Therefore, it is definitely advisable that neurologists and
psychiatrists dealing with such patient groups should be
familiar with treatment strategies for minimizing these
EPS and should regularly check on the state of the EPS.
Another group of drugs that physicians must deal with,
which are also commonly associated with neurologic complications, are the street drugs. Most of these agents
modulate central neurotransmitters, and some have direct
cerebrovascular effects. These characteristics are the bases
of their potential to produce neurologic symptoms. Of
these agents, the most notorious for its neurologic effects
and also one of the most commonly used is cocaine.
In addition to nonhemorrhagic infarctions, subarachnoid hemorrhage, intraparenchymal hemorrhage, and
intraventricular hemorrhage;18 single seizures, multiple
seizures, and status epileptics;19,20 migraine-like headache
caused by blockade of serotonin uptake mechanism;21
optic neuropathy associated with osteolytic sinusitis;22
and acute femoral neuropathy,23 cocaine produces acute
dystonia during administration24 and after withdrawal.24,25
In addition, cocaine-induced tics can occur in first-time
and chronic users.26 The tics may be multifocal and both
vocal and motor in character. In some instances, the tics
merely represent an uncovering of symptoms in a patient
previously diagnosed as having Tourettes syndrome, but
in others, tics occur for the first time during cocaine use.
Abstinence from cocaine usually results in resolution of
this syndrome.
Ecstasy is the name commonly used for 3,4-methylenedioxymethamphetamine (MDMA), a ring-substituted
amphetamine derivative. Although patented in 1914 as an
appetite suppressant, the drug did not become popular
until the 1970s, when it was marketed as an adjunct to
psychotherapy because of its effects in lowering the
defensiveness of the patient, thus breaking the barriers
between the patient and the therapist. Because of conCopyright 2005 by CRC Press LLC
581
cerns for its abuse potential and reports of neurotoxicity

in animal studies, it was declared illegal in the mid-1980s.
Despite its well-established neurotoxicity in animals, the
acute or chronic effects of this drug have not been well
studied in humans. Its recreational use, especially on college campuses, and reports of cases associated with
severe toxicity and death have increased awareness of the
drug.
Overlapping symptoms of neuroleptic malignant syndrome and serotonin syndrome have occurred in patients
taking MDMA.27 Recognition of the potential neurologic
complications of either prescription or illicit drugs is
extremely important. Familiarity with the neurologic
symptoms that can result from prescription drugs used to
treat neuropsychiatric patients makes it easier to determine whether a given neurologic finding is a drug effect
or part of an underlying syndrome for which the drug has
been prescribed.
In this chapter, a brief description of the types of
abnormal movements seen by physicians is provided, followed by a comprehensive discussion of drug-induced
movement disorders.
TYPES OF ABNORMAL MOVEMENTS

Movement disorders (sometimes called extrapyramidal
disorders) impair the regulation of voluntary motor activity without directly affecting strength, sensation, or cerebellar function. They include hyperkinetic disorders associated with abnormal, involuntary movement. Movement
disorders result from dysfunction of deep subcortical gray
matter structures termed the basal ganglia. While there is
no universally accepted anatomic definition of the basal
ganglia, for clinical purposes, they may be considered to
comprise the caudate nucleus, putamen, globus pallidus,
subthalamic nucleus, and substantia nigra. The putamen
and globus pallidus are collectively termed the lentiform
nucleus; the combination of lentiform nucleus and caudate
nucleus is designated the corpus striatum.28 Abnormal
movements can be classified as tremor, chorea, athetosis
or dystonia, ballismus, myoclonus, or tics.29
TREMOR
A tremor is a rhythmic oscillatory movement best characterized by its relationship to voluntary motor activity,
i.e., according to whether it occurs at rest, during maintenance of a particular posture, or during movement.
Tremor that occurs when the limb is at rest is generally
referred to as static tremor, or resting tremor. If present
during sustained posture, it is called a postural tremor.
While this tremor may continue during movement, movement does not increase its severity. When present during
movement but not at rest, a tremor is generally called an
intention tremor. Both postural and intention tremors are
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also called action tremors. The causes of tremor are indicated in Table 46.1.
CHOREA
The word chorea denotes rapid, irregular muscle jerks
that occur involuntarily and unpredictably in different
parts of the body. In florid cases, the often forceful involuntary movements of the limbs and head and the accompanying facial grimacing and tongue movements are
Parkinsons Disease
unmistakable. Voluntary movements may be distorted by

the superimposed involuntary ones. In mild cases, however, patients may exhibit no more than a persistent restlessness and clumsiness. Power is generally full, but there
may be difficulty in maintaining muscular contraction
such that, for example, hand grip is relaxed intermittently
(milkmaid grasp). The gait becomes irregular and
unsteady, with the patient suddenly dipping or lurching
to one side or the other (dancing gait). Speech often
becomes irregular in volume and tempo and may be
TABLE 46.1
Major Causes of Tremor
Postural tremor
Physiologic tremor
Enhanced physiologic tremor
Anxiety or fear
Excessive physical activity or sleep deprivation
Sedative drug or alcohol withdrawal
Drug toxicity (e.g., lithium, bronchodilators, tricyclic antidepressants)
Heavy metal poisoning (e.g., mercury, lead, arsenic)
Carbon monoxide poisoning
Thyrotoxicosis
Familial (autosomal dominant) or idiopathic (benign essential) tremor
Cerebellar disorders
Wilsons disease
Intention tremor
Brain stem or cerebellar disease
Drug toxicity (e.g., alcohol, anticonvulsants, sedatives)
Wilsons disease
Rest tremor
Parkinsonism
Wilsons disease
Heavy metal poisoning (e.g., mercury)
Four separate groups of symptoms are now described as part of the symptom complex of parkinsonism. These groups are tremor, akinesia, rigidity,
and loss of normal postural reflexes.
The tremor consists of rhythmatically alternating contractions of a given muscle group and of its antagonists. It is insidious in onset. Most
commonly, the tremor affects the distal parts of the extremity earlier and to a greater extent than the proximal parts. It is most prominent in the
fingers, often less prominent in the wrists, and involves the forearm or upper arm only infrequently. The rate of the tremor averages about three
to five oscillations per second. A number of descriptive terms such as pill-rolling or cigarette-rolling have been used to describe these movements,
but the rotary component is often lacking, so the term to-and-fro is more applicable. The tremor can also involve the leg, where again it is usually
more marked distally in the foot than it is proximally in the hip. The head, jaw, and pectoral structures can also become involved.
While the manifestations of the disease invariably involve the entire body, the symptoms can be markedly asymmetric. This is especially true
of the tremor, which frequently begins in one arm or leg and can remain predominantly unilateral for several years. It can become disabling on
one side while the other side is affected only slightly.
One of the classic features of this tremor is its presence during rest and its disappearance on purposeful movement. The tremor usually is
aborted by the initiation of any willed act but tends to reappear a few moments later, despite the continuation of the action. In most cases, however,
the tremor is less prominent on action than it is during rest. The tremor is characteristically absent during sleep. All extrapyramidal hyperkinesias
stop during sleep with the exception of certain cases of hemiballismus. A number of psychologic factors increase the tremor. These include
fatigue, cold, emotional stress of any sort, and almost anything that makes the patient nervous, including visits to his doctor. (For a review and
reference, see Reference 29.)
583
explosive in character. In some patients, athetotic movements or dystonic posturing may also be prominent. Chorea disappears during sleep. Table 46.2 shows the major
causes of chorea.
psychotic drugs), ischemic anoxia, focal intracranial disease, progressive supranuclear palsy, idiopathic torsion
dystonia (hereditary, sporadic), and formes frustes or idiopathic torsion dystonia.
DYSTONIA
HEMIBALLISMUS
AND
ATHETOSIS
The term athetosis generally denotes abnormal movements that are slow, sinuous, and writhing in character.
When the movements are so sustained that they are better
regarded as abnormal postures, the term dystonia is used,
and the terms are often used interchangeably. The abnormal movements and postures may be generalized or
restricted in distribution. In the latter circumstance, one
or more of the limbs may be affected (segmental dystonia),
or the disturbance may be restricted to localized muscle
groups (focal dystonia). The causes of dystonia and athetosis include static perinatal encephalopathy (cerebral
palsy), Wilsons disease, Huntingtons disease, Parkinsons disease, encephalitis lethargia drugs (levodopa, anti-
Hemiballismus is unilateral chorea that is especially violent because the proximal muscles of the limbs are
involved. It is due most often to vascular disease in the
contralateral subthalamic nucleus and commonly resolves
spontaneously in the weeks following its onset. It is sometimes due to other types of structural disease, and it was
an occasional complication of thalamotomy. Pharmacologic treatment is similar to that for chorea.
MYOCLONUS
Myoclonic jerks are sudden, rapid, and twitch-like muscle
contractions. They can be classified according to their
distribution, relationship to precipitating stimuli, or etiol-
TABLE 46.2
Causes of Chorea
Heredity
Huntingtons disease
Benign hereditary chorea
Wilsons disease
Paroxysmal choreoathetosis
Familial chorea with associated acanthocytosis
Static encephalopathy (cerebral palsy) acquired antenatally or perinatally (e.g., from anoxia, hemorrhage, trauma, kernicterus)
Sydenhams chorea
Chorea gravidarum
Drug toxicity
Levodopa and other dopaminergic drugs
Antipsychotic drugs
Lithium
Phenytoin
Oral contraceptives
Miscellaneous medical disorders
Thyrotoxicosis, hypoparathyroidism, or Addisons disease
Hypocalcemia, hypomagnesemia, or hypernatremia
Polycythemia vera
Hepatic cirrhosis
Systemic lupus erythematosus
Encephalitis lethargia
Cerebrovascular disorders
Vasculitis
Ischemic or hemorrhagic stroke
Subdural hematoma
Structural lesions of the subthalamic nucleus
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Parkinsons Disease
ogy. Generalized myoclonus has a widespread distribution, while focal or segmental myoclonus is restricted to
a particular part of the body. Myoclonus can be spontaneous, or it can be brought on by sensory stimulation,
arousal, or the initiation of movement (action myoclonus).
Myoclonus may occur as a normal phenomenon (physiologic myoclonus) in a healthy person, as an isolated abnormality (essential myoclonus), or as a manifestation of
epilepsy (epileptic myoclonus). It can also occur as a feature of a variety of degenerative, infectious, and metabolic
disorders (symptomatic myoclonus). The causes of general
myoclonus are shown in Table 46.3.
TABLE 46.3
Causes of General Myoclonus
Physiologic myoclonus
Nocturnal myoclonus
Hiccup
Essential myoclonus
Epileptic myoclonus
Symptomatic myoclonus
Degenerative disorders
Dentatorubrothalamic atrophy (Ramsay Hunt syndrome)
TICS
Tics are sudden, recurrent, quick, coordinated abnormal
movements that can usually be imitated without difficulty.
The same movement occurs again and again and can be
suppressed voluntarily for short periods, although doing
so may cause anxiety. Tics tend to worsen with stress,
diminish voluntary activity or mental concentration, and
disappear during sleep. Tics can be classified into four
groups, depending on whether they are simple or multiple
and transient or chronic. Transient simple tics are very
common in children, usually terminate spontaneously
within 1 year (often within a few weeks), and generally
require no treatment. Chronic simple tics can develop at
any age but often begin in childhood, and treatment is
unnecessary in most cases. The benign nature of the disorder must be explained to the patient. Persistent simple
or multiple tics of childhood or adolescence generally
begin before age 15 years. There may be single or multiple
motor tics, and often vocal tics, but complete remission
occurs by the end of adolescence. The syndrome of
chronic multiple motor and vocal tics is generally referred
to as Gilles de la Tourettes syndrome, after the French
physician who was one of the first to describe its clinical
features.29
Storage diseases (e.g., Lafora body disease)

Wilsons disease
Huntingtons disease
Alzheimers disease
Infectious disorders
Creutzfeldt-Jakob disease
AIDS dementia complex
Subacute sclerosing panencephalitis
Metabolic disorders
Drug intoxications (e.g., penicillin, antidepressants, anticonvulsants)
Drug withdrawal (ethanol, sedatives)
Hypoglycemia
Hyperosmolar nonketotic hyperglycemia
Hyponatremia
Hepatic encephalopathy
Uremia
Hypoxia
Myoclonic jerks are sudden, rapid, twitch-like muscle contractions.
They can be classified according to their distribution, relationship to
precipitating stimuli, or etiology. Generalized myoclonus has a widespread distribution, while focal or segmental myoclonus is restricted
to a particular part of the body. Myoclonus can be spontaneous, or
it can be brought on by sensory stimulation, arousal, or the initiation
of movement (action myoclonus). Myoclonus may occur as a normal
phenomenon (physiologic myoclonus) in healthy persons, as an isolated abnormality (essential myoclonus), or as a manifestation of
epilepsy (epileptic myoclonus). It can also occur as a feature of a
variety of degenerative, infectious, and metabolic disorders (symptomatic myoclonus). (For a review and reference, see Reference 29.)
BASAL GANGLIA AND MOVEMENT

DISORDERS
Great strides have been made in the last five decades
toward elucidating the neurochemistry of the pathways
involved in motor function and movement disorders.28,3035
These pathways include those connecting motor cortex,
brain stem, basal ganglia, and spinal cord. The basal ganglia play an important role in the control of movement
and complex motor behavior. Figure 46.1 shows a simplified schematic diagram of the primary connections of the
basal ganglia. Each area of cerebral cortex, from the most
primitive olfactory structures to the most highly organized
association cortex, has projections to one of a number of
deep telencephalic gray matter nuclei, which include the
putamen, caudate nucleus, nucleus accumbens, and the
outer layers of the olfactory tubercle. These nuclei all have
similar histochemical appearances and neurochemical
properties. In addition, each of these nuclei also gets input
from dopaminergic neurons in the midbrain and from the
interlaminar nuclei of the thalamus. The caudate nucleus,
putamen, nucleus accumbens, and outer tubercle can comprise the striatum.
The principal components of the basal ganglia are
the striatum, the pallidum, the substantia nigra, and the
subthalamic nucleus. The basal ganglia are neither a
major sensory relay nor a coordinating neuronal system,
such as the cerebellum, and they do not have direct
access to the motor neurons of the spinal cord. Because
585
FIGURE 46.1 The basic circuit of basal ganglia. The major subcortical input to area 6 arises in a nucleus of the dorsal thalamus,
called the ventral lateral nucleus (VL). The input to this part of VL, called VLo, arises from the basal ganglia buried deep within
the telencephalon. The basal ganglia, in turn, are targets of the cerebral cortex, particularly the frontal, prefrontal, and parietal cortex.
Thus, we have a loop where information cycles from the cortex through the basal ganglia and thalamus and then back to the cortex,
particularly the supplementary motor area. One of the functions of this loop appears to be the selection and initiation of willed
movements.
The basal ganglia consist of the caudate nucleus, the putamen, the globus pallidus, and the subthalamus. In addition, we can add
the substantia nigra, a midbrain structure that is reciprocally connected with the basal ganglia of the forebrain. The caudate and
putamen together are called the striatum, which is the target of the cortical input to the basal ganglia. The globus pallidus is the
source of the output to the thalamus. The other structures participating in various side loops that modulate the direct path are:
Cortex Striatum Globus pallidus VLo Cortex (SMA)
The neurons of the striatum appear randomly scattered, with no apparent order such as that seen in the layers of the cortex. But this
bland appearance hides a degree of complexity in the organization of the basal ganglia that we are only now beginning to appreciate.
It appears that the basal ganglia participate in a large number of parallel circuits, only a few of which are strictly motor. Other circuits
are involved in certain aspects of memory and cognitive function. (For reviews and references, see References 28 and 30 through 35.)
they lie just under the cerebral cortex and directly among
the flow of corticifugal fibers, the basal ganglia are ideally located to interact or act in conjunction with the
cerebral cortex.
Anatomically, this set of subcortical structures is
involved in a closed corticobasal ganglia-thalamo-cortical
loop, whose major axis is composed of sequentially
arranged elements, namely the striatum, the globus pallidus or pallidum, the substantia nigra, and the ventral tier
nuclei of the thalamus. Despite their privileged relationship with the cortex, it is not yet known how the basal ganglia complement the function of the cerebral cortex (for a
review, see Reference 34). In addition to the anatomical
substrate that allows information from the cerebral cortex
to flow along the corticobasal ganglia-thalamocortical
loops, there exist other structures that exert a profound

modulatory influence upon the activity of the core structures of the basal ganglia. These structures are the subthalamic nucleus, the pars compacta of the substantia nigra,
the centromedian/parafascicular thalamic complex, the
dorsal raphe nucleus, and pedunculopontine tegmental
nucleus (for a review, see Reference 36). These ancillary
structures provide the basal ganglia with a wide variety of
neurochemical inputs: (a) the subthalamic nucleus and the
centromedian/parafascicular thalamic complex provide a
glutamatergic entry;3739 (b) the dorsal raphe nucleus is the
origin of a serotoninergic input;40 (c) the pedunculopontine tegmental nucleus gives rise to a dual cholinergic and
glutamatergic afferent;41,42 and the substantia nigra is a
major source of dopamine at basal ganglia levels.43 Each
586
Parkinsons Disease
element of the main axis of the basal ganglia is thus the

focus of a highly complex interplay between these various
chemospecific inputs and the striatal afferents that use
GABA as a transmitter (see Figure 46.1). Diseases affecting one or more of the marked neurochemical imbalances
are the hallmark of several basal ganglia disorders, including Parkinsons disease.29,44
DOPAMINERGIC TRANSMISSION
INVOLVED IN MOVEMENT
DISORDERS
Drugs causing movement disorders influence dopaminergic transmission. The main dopaminergic neurons in the
brain are the following:
1. The ultrashort dopaminergic fibers, such as the
interplexiform amacrine-like neurons, which
link inner and outer plexiform layers of the
retina, and the periglomerular dopamine cells
of the olfactory bulb
2. The intermediate-length dopaminergic fibers,
such as tuberohypophysial dopamine cells,
incertohypothalamic neurons, and the medullary peri ventricular neurons
3. The long dopaminergic fibers linking the ventral tegmental and substantia nigra dopamine
cells with three principal sets of targets: the
neostriatum (principally the caudate and putamen); the limbic cortex (medial prefrontal, cingulate, and entorhinal areas); and other limbic
structures (the regions of the septum, olfactory
tubercle, nucleus accumbens septi, amygdaloid
complex, and piriform cortex)
These latter two groups have been termed the mesocortical
and mesolimbic dopamine projections, respectively.45
THE MESOLIMBIC- AND MESOLIMBIC-CORTICAL

DOPAMINE PATHWAYS
These pathways originate primarily from the A10 dopamine neuron group (ventral tegmental area). The mesolimbic tract mainly innervates the nucleus accumbens and
olfactory tubercle and is considered to be involved in
arousal, locomotor activity, and motivational and affective
states. The mesolimbic-cortical pathway innervates septum, hippocampus, amygdala, and many cortical regions
(such as the prefrontal and cingulate cortices) and is
important in higher cortical functions. It has been suggested that blockade of, in particular, limbic and prefrontal
dopamine D2 receptors might be the mode of action for
the therapeutic effects of antipsychotic compounds.
THE NIGROSTRIATAL DOPAMINE PATHWAY

The nigrostriatal dopamine pathway originates from the
A9 dopamine neuron group (substantia nigra) and projects
primarily to the striatum (nucleus caudatus, putamen, and
globus pallidus). The striatum is thought to be critically
involved in the regulation of movement and may also
subserve some cognitive processes. The nigrostriatal tract
is believed to be associated with the production of extrapyramidal side-effects by antipsychotic drugs46 (see
Figure 46.2).
NEUROLEPTIC-INDUCED REGULATION OF DOPAMINERECEPTOR SUBTYPES AND ITS IMPLICATION IN

SCHIZOPHRENIA
Dopamine receptors (DA-R) belong to the G protein-coupled receptor family, which includes many receptors such
as adrenergic, serotoninergic, and neuropeptidergic receptors. The common structural features of the G proteincoupled receptors are (a) the seven hydrophobic transmembrane domains, (b) the extracellular N-terminus
domain with glycosylation sites, (c) the cytoplasmic Ctenninus domain, and (d) the G protein coupling sites in
the third cytoplasmic loop. All the known DA-R subtypes
consist of a polypeptide chain containing about 400 amino
acids (50 kDa) and carbohydrate chains (for review, see
References 4752). The size of most receptor molecules
detected with anti-D2-R antibodies (anti-D2-R) varies
within the range of 90 to 120 kDa, depending on the
tissues,53,54 which is far larger than the molecular weight
expected from the amino acid sequence. Therefore, D2-R
is likely to contain carbohydrate chains of various sizes.
Although these carbohydrate chains are believed to have
no effect on ligand affinity, it is important to clarify their
roles in the receptor function.
Dopamine receptors were initially classified into various subtypes on the basis of pharmacological properties,
but more recently they have been grouped into two types:
the D1-R group, which activates adenylate cyclase, and
the D2-R group, which inhibits (or has no effect on) the
activity of adenylate cyclase.55,56 Cloning of receptor
genes in recent years has led to the identification of new
subtypes not previously identified by conventional pharmacological and biochemical methods. At present, there
are five DA-R subtypes, and they are classified into the
D1-R family (D1-R and D5-R) and D2-R family (D2-R, D3R and D4-R) based on their structures and pharmacological features. The third cytoplasmic loop is short in the
D1-R family and long in the D2-R family. It is generally
believed that receptors with a short third cytoplasmic loop
couple to stimulatory G proteins (Gs) and activate adenylate cyclase. On the other hand, receptors with a long
third cytoplasmic loop react to G1 and Go, which inhibit
adenylate cyclase, and Gq, which couples with phospholi-
587
FIGURE 46.2 The main ascending dopaminergic pathways in rat brain. Dopaminergic neurons with intermediate-length axons
include the tuberoinfundibular and hypophysial, incertohypothalamic cells, and the medullary peri ventricular group. The tuberoinfundibular neurons have a neurohumoral function; they secrete dopamine into a portal vascular system that supplies the anterior
pituitary. This dopamine is responsible for inhibiting secretion of the anterior pituitary hormone, prolactin.
The final subdivision of dopaminergic neurons includes the midbrain groups from the substantia nigra and the ventral tegmental
area. These systems have long axons that innervate the basal ganglia, parts of the limbic system, and the frontal cortex. The neostriatal
system, which has cell bodies in the substantia nigra, innervates the caudate and putamen. This suggests that dopamine released from
neostriatal areas has motor functions. The motor problems associated with Parkinsons disease are caused by a decrease in dopamine
in these areas. Administration of the dopamine precursor L-Dopa bypasses tyrosine hydroxylase and alleviates some of the motor
disturbances of Parkinsons disease. The specificity and complexity of the dopaminergic systems is further demonstrated by the
mesolimbic system. These neurons originate in the ventral tegmental area of the midbrain, next to the substantia nigra. Long axons
from these neurons project to many parts of the limbic system, including the nucleus accumbens, olfactory tubercle, septum, amygdala,
and limbic cortex (e.g., frontal and cingulate cortex). These areas are associated with mood alterations and cognitive function,
indicating another important role of central dopamine. The nucleus accumbens is involved with reward, and the release of dopamine
in this area provides positive feelings of reinforcement. (For review and reference, see Reference 46.)
pase C.57 D2-R also activates K+ channels.57 While the

structures of the extra- and intracellular loops of the DAR vary with each receptor, the trans-membrane domains
are highly homologous among most receptors. The subtypes belonging to the D1-R and D2-R families show overall sequence homology of about 50% within the families
and 30% between the families. It is believed that an aspartate in the third transmembrane domain forms an ion pair
with the protonated amine group of DA and that two
serines in the fifth transmembrane domain form a hydrogen bonding interaction with two phenol groups of
DA.57,58 The latter interaction is specific for DA and its
agonist. On the other hand, an aspartate in the second
transmembrane domain of D2-R has been shown to interact with antagonists.59 In humans, the genes of the five
DA-R subtypes are located on different chromosomes. In
general, the genes for G protein-coupled receptors have
no introns. The genes of the D1-R family (D1-R and D5-R)
also lack introns. On the other hand, a specific feature of
the genes of the D2-R family is the presence of introns in
their coding regions; the D2-R, D3-R, and D4-R genes
have 6, 5, and 4 introns, respectively.60,61 The presence of
these introns strongly suggests that the gene products of

each subtype of the D2-R family undergo post-translational splicing, resulting in a greater number of receptor
isoforms.
The dopaminergic hypothesis of schizophrenia postulates that an aberration of the brains dopamine transmitter systems is key to the pathophysiology of
schizophrenia. A cornerstone of this hypothesis, which
has guided research in the field of neuropsychiatry for
more than four decades, is the observation that therapeutic potency of antipsychotic drugs directly correlates with
their affinity for dopamine D2-R. This observation implies
that the different antipsychotics achieve their therapeutic
effects at doses that produce similarly high levels of D2-R
occupancy, an effect which, under chronic treatment conditions, can be expected to result in receptor up-regulation.
Indeed, antipsychotic drugs at clinically recommended doses occupy at least 70% of striatal D2-R and
significantly up-regulate these sites.62 While the dopaminergic hypothesis of schizophrenia has not lost its currency, its original premise has been challenged by the
588
Parkinsons Disease
discovery that therapeutically effective doses of the most

beneficial atypical antipsychotic, clozapine, are significantly smaller than would be predicted on the basis of its
relatively low affinity for D2-R. The D2- R occupancy of
this drug in the striatum is only 50 to 66% of that produced by other antipsychotics, and clozapine does not upregulate striatal D2-R. Evidence from studies of receptor
occupancy and regulation in postmortem brains of
patients with neuropsychiatric disorders and in nonhuman

primates is providing new leads in the ongoing quest to
understand the pathophysiology and causes of schizophrenia and to develop more effective methods of treatment (Table 46.4).
These studies suggest that the cerebral cortex is the
site of action of antipsychotic medications and indicate
that chronic treatment with these drugs differentially reg-
TABLE 46.4
Effect of Chronic Treatment with Antipsychotics on the Levels of mRNAs Encoding Different Dopamine
Receptor Subtypes in the Cortex and Neostriatum
Drugs
Chemical Class
Receptor Regulation
Striatum
D2 long
D2 short
D4
D1
D5
Antipsychoticstypical
Chlorpromazine
Haloperidol
Melindone
Pimozide
Phenothiazines
Butyrophernones
Indoles
Diphenylbutyl-piperidines
Antipsychoticsatypical
Clozapine
Olanzapine
Remoxipride
Risperidone
Dibenzodiazepines
Thienobenzodiazepines
Substituted benzamides
Benzisoxazoles
Nonantipsychotic D2 receptor antagonist

Tiapride
Antipsychoticstypical
Chlorpromazine
Haloperidol
Melindone
Pimozide
Phenothiazines
Butyrophernones
Indoles
Diphenylbutyl-piperidines
Antipsychoticsatypical
Clozapine
Olanzapine
Remoxipride
Risperidone
Dibenzodiazepines
Thienobenzodiazepines
Benzisoxazoles
Nonantipsychotic D2 receptor antagonist

Tiapride
= increase, = decrease, and = remains the same.

Data have been modified with permission from Lidow et al., 1997a, b.
For about three decades, the dopamine (DA) hypothesis of schizophrenia has been the reigning biological hypothesis of the neural mechanisms
underlying this disorder. The DA hypothesis has undergone numerous revisions but has proven remarkably resistant to obliteration. In its original
formulation, the hypothesis stated that schizophrenia is due to a central hyperdopaminergic state. This was based on two complementary lines of
indirect pharmacological evidence: the DA releaser amphetamine as well as other DA-enhancing agents such as the DA precursor L-dopa or
methylphenidate, produced and exacerbated schizophrenic symptoms, whereas drugs that were effective in the treatment of amphetamine-induced
psychosis and schizophrenia [neuroleptics or antipsychotic drugs (APDs)] decreased DA activity, and their clinical potency was correlated with
their potency in blocking D2 receptors.
Recently, it has been suggested that schizophrenia may involve a hypodopaminergic state in the dorsal striatum coupled with a hyperdopaminergic
state in the dorsal striatum coupled with a hyperdopaminergic state in the ventral striatum modes of DA activity within the prefrontal cortex, i.e.,
decreased phasic and increased tonic release. (For review and reference, see Reference 62.)
ulates both families of dopamine receptors in this structure. Up-regulation of the cortical dopamine D2-R is
accompanied by a down-regulation of the D1 sites. Balancing the opposing actions of dopamine D1 and D2-R
regulation may hold the key to optimal drug therapy and
to understanding the pathophysiology of schizophrenia
(see Reference 62 and Table 46.4).
THE MODULATORY ACTIONS OF ACETYLCHOLINE,

ADENOSINE, GLUTAMATE, AND -OPIOID ON
STRIATAL DOPAMINERGIC TRANSMISSION
The striatum is viewed as a structure performing fast neurotransmitter-mediated operations through somato-topically organized projections to medium-size spiny neurons.
Modulatory influences act indirectly by setting the excitability of the neuron to incoming phasic input mediated
by fast neurotransmitter actions. Modulatory influences
have relatively long kinetics of action/desensitization,
being related to modulation by voltage-operated ion channels as in the case of muscarinic and DA receptors or to
operation of voltage-gated ion channels as in the case of
N-methyl-D-aspartate (NMDA) receptors. Modulatory
influences on neuronal excitability might not even be
labeled as facilitatory (+) or inhibitory (), their actual
sign depending on the membrane potential. Modulatory
actions can have long-lasting transcriptional effects that
might be the basis for adaptive and plastic changes. The
caudate-putamen is one of the areas of the brain rich in
modulatory receptors such as acetylcholine, adenosine,
GABA, glutamate, neurotensin, opioid, substance P, and
somatostatin (for review, see References 35 and 63
through 65). A few examples will be cited to support this
contention. Parkinsons disease is a disease of extrapyramidal motor function characterized by difficulties in initiating and smoothly sustaining motions. It is associated
with severe loss of dopamine-containing neurons in the
substantia nigra. Parkinsons disease can be treated with
the dopamine precursor L-dopa, but this does not stop
disease progression, its effectiveness ultimately decreases,
and it may produce psychosis.66 Parkinsons disease is also
associated with a large (approximately 50%) loss of highaffinity nicotine binding sites from the brain.67,68
A central role in the modulatory operations taking
place in the striatum is played by acetylcholine neurons.
Acetylcholine neurons account for 1 to 2% of the striatal
neuronal population. In all species examined, they are
among the largest neurons of the striatum both for the size
of the perikaryon (about 30 m in its longest dimension)
and the area of distribution of the dendritic tree (up to
0.5 mm2). Striatal acetylcholine neurons are interneurons,
although a subpopulation of them also projects to neocortex. Striatal acetylcholine neurons receive three major
synaptic inputs: (1) from intrinsic medium-size spiny
neurons that use substance P and GABA as transmitters,
589
and project to the substantia nigra pars reticulata and

entopeduncular nucleus (medial pallidal segment of primates), (2) from extrinsic DA neurons of the mesencephalic tegmentum (A8, A9, and A10 groups), and (3) from
extrinsic excitatory (glutamate) neurons of the intralaminar thalamus (parafascicular complex) and, to a lesser
extent, of the cortex. The output of acetylcholine neurons
are the medium-size spiny neurons and the medium-size
spiny interneurons containing somatostatin/neuropeptide
Y (NPY) and neurotensin or GABA, which might be
interposed between the acetylcholine neurons and
medium-size spiny neurons (see Figure 46.3).
Stimulation of the striatum will evoke a short-latency
inhibitory postsynaptic potential in zona compacta
dopaminergic neurons and in zona reticulata neurons.69
However, overstimulation of the striatum will actually
cause an activation of DA neuron firing, and the said activation occurs with an inhibition of GABAergic neurons in
the zona reticulata that normally inhibit the activity of
dopaminergic neurons.69,70 These GABAergic inhibitory
neurons may represent collaterals of nigrothalamic
neurons71 or a short-axon interneuron located near the
zona compacta.
Therefore, stimulation of striatum exerts two electrophysiological actions on DA neurons, which are a direct
GABAergic inhibition and an indirect disinhibition.72 The
striatum is known to send a large number of GABAergic
inhibitory projections to the globus pallidus, which in turn
sends GABAergic fibers to the subthalamic nucleus.7375
Lesions of the nigrostriatal DA system activate the striatopallidal pathway, thereby disinhibiting the subthalamus.76,77 Single-pulse stimulation of the subthalamus has
been shown to produce short-latency excitation of both
dopaminergic and nondopaminergic neurons within the
substantia nigra,7880 and glutamatergic excitatory
postsynaptic potentials have been associated to DA neurons recorded in vitro72,81,82 (see also Figure 46.3).
The operations performed by cortico-striatal projections and medium-size spiny neurons are regarded to be
of a fast-neurotransmitter-like nature. Thus, cortically
elicited fast EPSPs recorded from medium-size spiny
neurons are mediated by glutamate receptors of the D, L-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid
(AMPA) subtype; in turn, these neurons use GABA as
their fast inhibitory transmitter. Transmission through
NMDA receptors can be regarded as modulatory in view
of its voltage dependency and of its ability to act as a gain
amplifier of excitatory phasic input, thus promoting burst
firing. This transmission is largely inoperative in resting
striatal medium-size spiny neurons, due to Mg2+ blockage
of NMDA channels in hyperpolarized conditions. By contrast, acetylcholine neurons are already tonically active
and depolarized to near threshold in basal conditions,
making NMDA transmission fully operative in acetylcholine neurons and therefore capable of promotion burst fir-
590
Parkinsons Disease
FIGURE 46.3 Striatal cholinergic transmission. Acetylcholine is the familiar transmitter at the neuromuscular junction, at synapses
in autonomic ganglia, and at postganglionic parasympathetic synapses. Cholinergic interneurons also exist within the brain, in the
striatum and the cortex, for example. In addition, there are two major diffuse modulatory cholinergic systems in the brain, one of
which is called the basal forebrain complex. It is a complex because the cholinergic neurons lie scattered among several related
nuclei at the core of the telencephalon, medial and ventral to the basal ganglia. The best known of these are the medial septal nuclei,
which provide the cholinergic innervation of the hippocampus, and the basal nucleus of Meynert, which provides most of the
cholinergic innervation of the neocortex. (For reviews and references, see References 69, 81, and 82.)
ing in response to low amplitude excitatory input. Fully

active NMDA transmission might thus contribute to a
major property of striatal acetylcholine neurons, that
being, in contrast with medium-size spiny neurons,
exquisitely sensitive to excitatory phasic input. This phenomenon supports the suggestion that, although mediumsize spiny neurons express NMDA receptors and receive a
massive glutamate projection, they are likely to be influenced by noncompetitive NMDA-receptor antagonists
only indirectly as a result of a primary action of acetylcholine neurons.64
REGULATION OF CENTRAL DOPAMINERGIC NEURONS

BY OPIOID RECEPTORS
Manzanares et al.63 and Pan65 have discussed the regulation of central dopaminergic neurons by opioid receptors.
Three pharmacologically distinct subtypes of opioid
receptors (, , and ) have been identified in the CNS.
Until recently, the study of the regulation of dopaminergic
neurons by subtypes of opioid receptors has been limited
by the lack of specific agonists and antagonists for these
receptors. The development of selective , , and opioid receptor agonists and antagonists has now permitCopyright 2005 by CRC Press LLC
ted exploration of the role played by each of these opioid

receptor subtypes in the modulation of central dopaminergic neurons. To date, much of what is known regarding
the effects of opioids on dopaminergic neurons has been
based on studies using compounds that act at either - or
-opioid receptors (see Figure 46.1).
Activation of -opioid receptors stimulates mesolimbic, nigrostriatal, and incertohypothalamic dopaminergic
neurons; inhibits tuberoinfundibular dopaminergic neurons; and has no effect on periventricular-hypophysial
dopaminergic neurons. On the other hand, activation of opioid receptors inhibits the basal activity of peri ventricular-hypophysial dopaminergic neurons and the pharmacologically stimulated activities of mesolimbic,
nigrostriatal, and tuberoinfundibular dopaminergic neurons. In contrast, comparatively less is known about the
role of -opioid receptors in regulating dopaminergic
neuronal systems in the brain. Administration of the opioid selective agonist [D-Pen2, D-Pen5] enkephalin
(OPDPE) increases the release of DA in the nucleus
accumbens but has no effect in the striatum. No information is available regarding the effects of activation or
blockade of -opioid receptors on the activities of hypothalamic dopaminergic neurons.
THE STRIATAL BLOCKADE OF THE ADENOSINE A2A

RECEPTOR IN PARKINSONS DISEASE
The GABA-enkephalin neurons (see Figure 46.1) are
excited by cortical inputs and inhibited by recurrent collaterals (via GABAA receptors). In Parkinsons disease,
the feedback inhibition of striatal neurons by the recurrent
collaterals may be insufficient to control the overactivity
of these neurons. This overactivity probably arises from
a reduction in the DA-R-mediated control of acetylcholine
and glutamate release (from cortical and thalamic afferents) and in D2-R-mediated inhibition of striatal neurons.
Such overactivity may also be partly due to reduced D1R-mediated stimulation of striatal GABA release, and to
the action of muscarinic acetylcholine receptors that stabilize an excitable state of the striatal neurons. It has been
recently shown that blockage of the A2A receptor increases
the release of GABA from striatal synaptosomes and
increases inhibitory input into medium spiny neurons.
Therefore, A2A receptor blockage serves to increase the
GABA-mediated feedback control of the striatal output
neurons.
This mode of action is intrinsically different from that
of the DA-related modulators used in most parkinsonian
therapies, as feedback inhibition is a function of the
degree of excitation of individual striatal neurons. Thus,
the effect of an A2A receptor antagonist may be restricted
to the control of the recurrent collaterals of those neurons
that are highly active. The reduction in acetylcholine
release caused by A2A receptor blockage may also contribute to this inhibition of medium spiny neurons, by
reducing cholinergic stimulation and thus the ability of
acetylcholine to maintain the excitable state of the output
neurons. In the absence of DA, the facilitatory drive of the
D1 receptors on the striatal GABAergic, substance P-containing neurons of the direct pathway is also lost, causing
these cells to become less excitable. Although the A2A
receptor probably has no direct effect on this pathway, it
opposes the behavioral effects of D1-R stimulation, striatal neurons and the cholinergic interneurons.35
THE NEUROPATHOLOGY OF MOVEMENT

DISORDERS
The term extrapyramidal system to be described in the
following section was first coined by Samuel Alexander
Kinnier Wilson in 1912 in describing the neurological
disorder of hepatolenticular degeneration (Wilsons disease). Lesions in the pyramidal system, extrapyramidal
system, or cerebellar system result in distinctive disturbances of motor activity.29.83
THE PYRAMIDAL SYSTEM

The pyramidal tract derives its name from the fact that
constituent fibers pass through the medullary pyramid, a
591
prominent bulge on the ventral surface of the medulla

oblongata. Its fibers arise in the cerebral cortex, principally
from that area around the central sulcus that constitutes
the motor cortex. The fibers then descend through the
brain stem and, after a partial decussation in the medulla,
continue through the spinal cord and finally terminate
about the lower motor neurons. Injury to this tract produces paralysis of voluntary movement. As a result, the
pyramidal system is believed to be concerned with the
initiation of voluntary movements.
THE EXTRAPYRAMIDAL SYSTEM

The extrapyramidal system is made up of a number of
paired nuclei and associated pathways. The major structures of this system include putamen, globus pallidus,
substantia nigra, and subthalamic nuclei (corpus Luysii)
(Figure 46.1). The caudate and putamen together are
referred to as the striatum or neostriatum, whereas the
globus pallidus is often referred to as the pallidum. The
term basal ganglia is often used to refer to the extrapyramidal system. Strictly speaking, the basal ganglia are a
number of large, paired masses of gray matter in the
forebrain and include the caudate, putamen, and globus
pallidus, as well as the amygdala. This latter structure is
functionally a part of the limbic system so that the term
basal ganglia usually refers only to the first three pairs of
nuclei. Lesions of the extrapyramidal system often result
in abnormal movements that usually are present at rest.
Such lesions also result in abnormalities of station and
postural reflexes. The extrapyramidal system then is
thought to be concerned with maintenance of posture as
opposed to initiation or coordination of voluntary movement.
THE CEREBELLAR SYSTEM

The cerebellar system is composed of the cerebellum and
its afferent and efferent pathways, as well as associated
structures such as the red nuclei and the inferior olives.
Lesions of this system result in tremor with movement,
incoordination, dyssynergia, and ataxia. The cerebellar
system is believed to be concerned with the coordination
of movements as opposed to the initiation of involuntary
movement. Although clinical experience has demonstrated
a high degree of interdependence among these three motor
systems, the term extrapyramidal disease, however, still
serves the useful purpose of tying together a number of
clinically defined disease states of diverse etiology and
obscure pathogenesis. Causing abnormal movements,
these states share a number of related symptoms, and the
major pathological changes noted in these diseases are all
present within the extrapyramidal nuclei. The clinical
signs and symptoms that help to tie these disease states
together fall into the following groups: (a) hyperkinesia,
592
abnormal involuntary movements, (b) akinesia, slowness

or poverty of spontaneous movement, (c) rigidity, and (d)
loss of normal postural reactions.83 Movement disorders
may be classified broadly as the syndrome of parkinsonism or an akinetic rigid syndrome and those disorders
causing a variety of abnormal involuntary movements or
dyskinesias, including tremor, dystonia, athetosis, chorea, ballism, tics, and myoclonus. For a comprehensive
classification of parkinsonism, diseases causing parkinsonism and dementia, differential diagnosis of tremor, etiological classification of chorea, features distinguishing
tardive dyskinesia and Huntingtons disease, causes of
ballism, etiological classification of dystonia, classification of tics, etiological classification of myoclonus, differential diagnosis of paroxysmal dyskinesia, startle and
related syndrome, and finally, abnormal involuntary movements in sleep, refer to a review by Lang and Weiner.5
DIVERSE CLASSIFICATION OF DRUGS

CAUSING MOVEMENT DISORDERS
Drugs causing or aggravating movement disorders have
diversified classification (Table 46.5) and mechanisms of
actions.14 For example: Norpseudoephedrine causes persistent dyskinetic syndromes such as spasmodic torticollis
and cranial dystonia.14 Tiagabine, an indirect GABA
receptor agonist, has been shown to inhibit haloperidolinduced oral dyskinesias,84
A variety of neurological syndromes, involving particularly the extrapyramidal motor system, occur following the use of almost all antipsychotic drugs. These
reactions are particularly prominent during treatment with
the high-potency agents (tricyclic piperazines and butyrophenones). There is less likelihood of acute extrapyramidal side effects with clozapine, thioridazine, or low
doses of risperidone. Six varieties of neurological syndromes are characteristic of antipsychotic drugs. Four of
these (acute dystonia, akathisia, parkinsonism, and the
rare neuroleptic malignant syndrome) usually appear
soon after administration of the drug, and two (rare perioral tremor and tardive dyskinesias or dystonias) are lateappearing syndromes that occur following prolonged
treatment.
Mianserin, a tetracyclic antidepressant, which
increases the release of noradrenaline by blocking alpha-2
adrenoceptors,85,86 has been shown to activate a latent
involuntary movement disorder in predisposed persons.87
NEUROLEPTIC-INDUCED MOVEMENT
DISORDERS
The treatment of schizophrenic patients with neuroleptics
(antipsychotics) has had a decisive impact on psychiatry
in that the number of patients hospitalized has decreased
Parkinsons Disease
dramatically, and the number treated on an outpatient basis

has increased steadily. However, a variety of neurological
syndromes, involving particularly the extrapyramidal system, occur after either acute or chronic administration of
neuroleptics, and the most serious syndromes include
akathisia, dystonia, neuroleptic malignant syndrome, parkinsonism, and tardive dyskinesia.8890 Despite awareness
that neuroleptics could produce extrapyramidal side
effects, these drugs remain the most effective means of
treating schizophrenic patients. Moreover, atypical neuroleptics such as clozapine (8-chloro-11 (4-methyl-1-piperazinyl)-5H-dibenzo (b,e)(1,4)diazepine) and risperidone, which cause substantially fewer numbers of
potentially incapacitating side effects such as neuroleptic
malignant syndrome, have been synthesized and marketed. In addition to accepting the involvement of dopaminergic receptors in the pathogenesis of neurolepticinduced movement disorders, recent reports have implicated serotoninergic, GABAergic, glutamatergic, and peptidergic transmissions in the appearance, manifestation,
and treatment of neuroleptic-induced movement disorders.
By having a comprehensive understanding of pharmacokinetic and pharmacodynamic principles unique to antipsychotics, the neuroleptic-induced movement disorders
may be minimized vastly and their potentially lethal neurotoxicity averted altogether.
NEUROLEPTIC-INDUCED AKATHISIA
Kathisia is a Greek word that may be translated as the act
of sitting, and akathisia means literally an inability to
remain seated.91,92 Patients with neuroleptic-induced
akathisia may describe vague feelings such as inner tension, emotional uneasiness, all wound up like a
spring, unable to relax, having a hurry-up feeling, or
uncomfortable in any position. In addition to an inability
to sit still, akathisia is characterized by shifting of legs
and tapping of feet while sitting, and by rocking and
shifting weight while standing. Although the term akathisia was first used by Haskovec,93 spontaneously occurring
syndromes of restlessness were reported long before the
introduction of neuroleptics in 1955. For example, in
1880, Beard described it as a fidgetiness and nervousness,
inability to keep stilla sensation that amounts to painis sometimes unspeakably distressing. When the legs feel
this way, the sufferer must get up and walk or run, even
if he is debilitated. This was confirmed 75 years later by
a warning that akathisia can be more difficult to endure
than any of the symptoms for which the patient was originally treated.94
Akathisia may occur after administration of any neuroleptic but is especially found with more potent neuroleptics.9597 The prevalence has been reported as 12.5%,
20%,96,9899 or 75%100 with more potent neuroleptics such
as haloperidol. Indeed, by lowering the dose of a potent
TABLE 46.5
Examples of Drug-Induced Movement Disorders
1. Drugs associated with induction of akathisia:
Metoclopramide
Dopamine storage and transport inhibitors: a-methyltyrosine, reserpine, tetrabenazine
Levodopa and dopamine agonists
Antidepressants:
selective serotonin reuptake
inhibitors, tricyclic antidepressants
Lithium
2. Drugs associated with induction of chorea:
Dopamine antagonists (including antipsychotics)
Dopamine agonists:
levodopa, direct dopamine agonists
CNS stimulants:
amphetamines, pemoline, methylphenidate, cocaine, xanthines Anticholinergics
HI antihistamines H2 antihistamines
Oral contraceptives
Anticonvulsants:
phenytoin
3. Drugs that can induce myoclonus:
Antidepressants:
cyclic antidepressants
selective serotonin reuptake inhibitors, monoamine oxidase inhibitors, Levodopa
Bismuth salts
Anticonvulsants:
valproic acid (sodium valproate), carbamazepine, phenytoin
Lithium
Morphine or its derivatives, antineoplastic drugs
Bromocriptine
4. Drugs associated with induction or aggravation of Parkinsonism
Antipsychotics
Calcium channel antagonists:
flunarizine, cinnarizine, diltiazem, verapamil, amlodipine, manidipine, orthopramides and substituted benzamides:
metoclopramide, sulpiride, clebopride, cisapride, domperidone, veralipride, and Dopamine agonists
Biogenice amine storage and transport inhibitors:
reserpine, tetrabenazine
Antiemetic/antivertiginous agents:
thiethylperazine, prochlorperazine
Methyldopa
5. Drugs associated with the development of tardive dyskinesia
Antipsychotic drugs
Orthopramides and substituted benzamides:
metoclopramide, clebopride, sulpiride, veralipride
flunarizine, cinnarizine
Antidepressants:
cyclic antidepressants
6. Drugs associated with induction of acute and/or tardive dystonia
Antipsychotic drugs
Orthopramides and substituted benzamides:
metoclopramide, sulpiride, tiapride, cisapride, domperidone, veralipride, and dopamine agonists: levodopa
Direct dopamine agonists
Antidepressants:
selective serotonin reuptake inhibitors, tricyclic antidepressants, monoamine oxidase inhibitors
Anticonvulsants:
carbamazepine, phenytoin
593
594
Parkinsons Disease
Table 46.5 (continued)

7. Drugs associated with induction or aggravation of postural tremor
Anticonvulsant drugs
Tricyclic antidepressants, -adrenergic agonists, levodopa
Amphetamines
Thyroxine
Antihyperglycemic drugs
Caffeine
Corticosteroids
flunarizine, cinnarizine
Amiodarone
A variety of neurologic syndromes, involving particularly the extrapyramidal system, occur following shorter long-term use of neuroleptic
(antipsychotic) drugs. These include akathisia, dystonia, neuroleptic malignant syndrome, parkinsonism, and tardive dyskinesia.
Akathisia is characterized by an inability to sit still, by shifting of the legs and tapping of feet while sitting, and by rocking and shifting of the
weight while standing. Reducing the total dosage of neuroleptic medications and the addition of either an anticholinergic drug, one of the
benzodiazepine derivatives, or propranolol have been shown to reduce the severity of akathisia.
Dystonia is characterized by an exaggerated posturing of the head, neck, or jaw; by spastic contraction of the muscles of the lips, tongue, face,
or throat, which makes drinking, eating, swallowing, and speech difficult; by torticollis, retrocollis, opisthotonus, distress, and ultimately anoxia.
Neuroleptic-induced dystonia, which may occur in children treated actively with phenothiazine derivatives for their antiemetic properties,
disappears in sleep and is treated effectively with diphenhydramine hydrochloride (Benadryl), which possesses both anticholinergic and antihistaminic properties.
Parkinsonian symptoms may be characterized by postural instability, stooped posture, shuffling and festinating gate, or rigidity, due to enhanced
muscle tone, with, at times, cogwheel or ratchet resistance to passive movements in any direction. There is also tremor at rest with regular
rhythmic oscillations of the extremities especially in the hands and fingers as well as akinesia (poverty of movement) or bradykinesia (slowness
in initiating volitional activities). These symptoms, which are due to blockade of dopaminergic receptor sites in the striatum, are lessened by
reducing the dosage of neuroleptics and by the oral administration of anticholinergic compounds, such as trihexyphenidyl hydrochloride (Artane)
or benztropine mesylate (Cogentin).
Tardive dyskinesia is characterized by abnormal involuntary movements frequently involving the facial, buccal, and masticatory muscles and often
extending to the upper and lower extremities, including the neck, trunk, fingers, and toes. With continuous blockade, the dopaminergic receptors
in the striatum up-regulate. Following the discontinued use of neuroleptics or a reduction in dosage, the dyskinesia becomes apparent. In the
therapeutic management of neuroleptic-induced tardive dyskinesia, reserpine, lithium, diazepam, baclofen, and vigabatrin have all been used with
unsatisfactory results. Therefore, in the absence of an effective treatment, the best prevention of tardive dyskinesia is to prescribe the neuroleptics
at their lowest possible doses, have patients observe drug-free holidays, and avoid prescribing anticholinergic agents solely to prevent parkinsonism.
Neuroleptic Malignant Syndrome
Among the complications of neuroleptic chemotherapy, the most serious and potentially fatal complication is malignant syndrome, which is
characterized by extreme hyperthermia; lead pipe skeletal muscle rigidity that causes dyspnea, dysphagia, and rhabdomyolysis; autonomic
instability; fluctuating consciousness; leukocytosis; and elevated creatine phosphokinase levels.
The treatments of neuroleptic malignant syndrome consists of immediately discontinuing the neuroleptic agent and administering dantrolene
sodium and dopamine function-enhancing substances such as levodopacarbidopa, bromocriptine, or amantadine. (For reviews and references,
see References 3 and 4.)
neuroleptic,99 or by switching the patient to a lowerpotency neuroleptic,96 it is possible to treat akathisia. The
syndrome of akathisia is composed of both subjective
feelings and the psychological experience of inner restlessness and objective motor signs such as jiggling or
shaking of the legs when seated and rocking from foot to
foot when standing.92 In milder forms of akathisia, the
patients may only have subjective complaints, whereas, in
moderate and severe forms, both subjective feelings of
restlessness and objective movements exist.91,101 Akathisia
can be a quite common and very troubling side effect of

psychotropic treatment. Clinicians have become steadily
more aware of this disorder, owing to descriptions of restless movement disorder originating in the first half of this
century. Delineation of acute akathisia is crucial for providing patients with the best interventions.
The pathophysiology of akathisia is not completely
understood but likely arises from complex interactions in
subcortical and possibly spinal DA/norepinephrine systems. There are now valid and reliable methods to assess
akathisia using standardized scales; doing so helps track

the progress of treatment interventions. The secondary
complications of akathisia are numerous. The most notable ones are noncompliance and assaultive or suicidal ideation or behavior. Causative agents of akathisia include all
currently available neuroleptics, various other psychoactive medications, and occasionally other nonpsychotropics. Treatment first should include stopping the
offending agent (if possible), lowering the dose, or changing to a lower-potency neuroleptic. If these strategies are
not feasible, then there are a host of medications that are
variably effective. The most common are -adrenergic
receptor blockers, anticholinergics, clonidine, or benzodiazepines. Less commonly prescribed agents such as opiates, amantadine, buspirone, piracetam, amitriptyline, and
dopamine depleters can be tried in more treatment-refractory patients.
CONDITIONS RESEMBLING AKATHISIA

Ekbom (1944) described an idiopathic syndrome that he
originally called asthenia crurum paraesthetica and later
renamed restless leg syndrome.102 Similar to akathisia,
the patients descriptions are: it feels like ants were running up and down in my bones, it feels like an internal
itch, and it is a diabolical feeling that I would not wish
on my worst enemy. Akathisia-like syndromes have also
been reported in encephalitis lethargica103 and in patients
with both postencephalitic and idiopathic parkinsonism.104
Nocturnal myoclonus, or periodic movements in
sleep, causes intense and repetitive muscle jerking during
sleep. Treatment with 100- to 200-mg L-dopa105 or with
L-dopa plus bromocriptine106 has been reported to be beneficial in this movement disorder. Leg restlessness also
occurs after withdrawal from narcotic analgesics, and this
opioid-related restlessness responds to treatment with
clonidine 107109 or treatment with propranolol.110 Propranolol is also effective in treating neuroleptic-induced
akathisia.
CLASSIFICATION
OF
AKATHISIA
Akathisia has been divided into the three categories of

chronic akathisia, acute akathisia, and pseudoakathisia:
1. Chronic akathisia (tardive akathisia). The term
denotes that akathisia developed late in the
course of neuroleptic therapy and both subjective restlessness and objective motor movements are present. Furthermore, it is frequently
associated with tardive dyskinesia, does not
respond to anticholinergic drugs99 and, like tardive dyskinesia, is difficult to treat.111
2. Acute akathisia. The term acute denotes that
akathisia developed recently (within 6 months)
595
and is related to an increase in the doses of

neuroleptics. It is not associated with dyskinesia.
3. Pseudoakathisia. The term was coined by
Munetz and Comes.112 The condition resembles
chronic akathisia without subjective feelings of
inner restlessness.113 This characteristic makes
it difficult to differentiate among chronic
akathisia, pseudoakathisia, and tardive dyskinesia.
In an effort to differentiate among these problems, it has
been suggested that, if the patient is restless and therefore
is moving, he suffers from akathisia. If the patient moves
and therefore is restless, he suffers from tardive dyskinesia.114
DIFFERENTIAL DIAGNOSIS
OF
AKATHISIA
Anxiety and agitated depression are often associated with

restlessness. In akathisia, unnatural or abnormal restlessness is confined mostly to the legs.115,116 It is interesting
that the anxiolytic agent lorazepam is less effective than
propranolol in treating neuroleptic-induced akathisia.92
Although five major rating scales have been developed to
measure akathisia (see Reference 117 for review), the
differentiation between subjective and objective akathisia
is difficult. The Chouinard extrapyramidal rating scale118
and the 23-item rating scale for akathisia developed by
Braude et al.99 do attempt to assess both subjective and
objective akathisia.
TREATMENT OF NEUROLEPTIC-INDUCED
AKATHISIA
Because the incidence of neuroleptic-induced akathisia is
higher with more potent neuroleptics such as haloperidol,
switching patients to a lower-potency neuroleptic such as
chlorpromazine may improve akathisia.96,97 Braude et al.99
reported that the only consistently effective treatment of
akathisia was a reduction in the dose of neuroleptic. In
addition to this general guideline, the other agents used
to treat akathisia are (a) antiparkinsonian agents, (b) anxiolytic agents, (c) alpha- and beta-adrenergic receptor
blocking agents, and (d) to a limited extent, L-tryptophan.
ANTIPARKINSONIAN AGENTS
Unlike drug-induced parkinsonism (rigidity, akinesia, and
tremor), neuroleptic-induced akathisia responds incompletely and unpredictably to anticholinergic medications.
Clinical experience using benztropine and procyclidine,119
benztropine,120 benztropine or trihexyphenidyl,100 and
biperiden121 indicates that the response is more satisfactory if akathisia coexists with parkinsonism, but less satisfactory if akathisia exists alone.
596
AMANTADINE
Amantadine, in a daily dose of 200 to 300 mg, has been
shown to be as effective as, or more effective than, a daily
dose of 2 to 4 mg of benztropine in treating neurolepticinduced akathisia.122124 However, tolerance develops to
the beneficial effects of amantadine.125
BENZODIAZAPINE DERIVATIVES
Moderate to marked improvement has been reported in
treating neuroleptic-induced akathisia after daily administration of 5 to 15 mg diazepam,126,127 1.5 to 5.0 mg
lorazepam,128 and 0.5 mg clonazepam.129
BETA-ADRENERGIC RECEPTOR BLOCKING AGENTS

The most promising treatment of akathisia consists of
beta-adrenergic receptor blocking agents. Lipinski et al.130
were the first to treat 12 patients with propranolol
(30 mg/day) and to report improvement in all patients. The
beneficial effects of propranolol were confirmed by Kulik
and Wilbur131 and by Lipinski et al.130 Adler et al.92,132
compared the effectiveness of lorazepam (2 mg/day) with
propranolol (20 to 30 mg/day) and concluded that propranolol decreased both subjective feelings of restlessness
and objective motor signs, whereas lorazepam decreased
subjective but not objective signs. Furthermore, they133
showed that propranolol was far superior to benztropine
in treating akathisia. Moreover, Reiter et al.134 successfully
treated a patient suffering from sinus bradycardia and
akathisia with pindolol, a beta-adrenergic receptor blocking agent that possesses an intrinsic sympathomimetic
activity. The unexplained selectivity of beta-adrenergic
receptor blocking agents in treating akathisia may be cited
by studies that showed metoprolol was less effective than
propranolol,135 whereas atenolol was ineffective.136,137
Finally, propranolol has been used successfully for neuroleptic-induced akathisia resistant to treatment with anticholinergics and benzodiazepines.
Selective or nonselective, centrally acting beta-adrenergic antagonists reduce haloperidol-induced emotional
defecation in rats, and this effect parallels the reported
anti-akathisia effect of these drugs in humans.139
ALPHA-ADRENERGIC RECEPTOR BLOCKING AGENTS

Clonidine, a central alpha-2 adrenergic receptor agonist,
was shown to be effective in treating akathisia in a daily
dose of 0.2 to 0.8 mg138 and in a daily dose of 0.15 to
0.40 mg.117
L-TRYPTOPHAN
After an initial report by Sandyk et al.,140 Kramer et al.141
reported that L-tryptophan appeared to reduce both the
Parkinsons Disease
subjective and the objective components of akathisia in

most of the patients in their study.
BUPROPION
Neuroleptic-induced akathisia responds dramatically to
bupropion (300 mg/day/5 days) treatment.142
NEUROLEPTIC-INDUCED DYSTONIA
Dystonia is characterized by an exaggerated posturing of
head, neck or jaw; by spastic contraction of muscles of
the lips, tongue, face or throat, making drinking, eating,
swallowing and speech difficult; by torticollis, retrocollis,
opisthotonos, and oculogyric crisis; and by laryngeal and
pharyngeal spasm potentially leading to respiratory distress and ultimately anoxia. The term dystonia was first
coined by Oppenheim143 and the full spectrum of the disease has been reviewed by Eldridge,144 Marsden,145
Lang,146 McGeer and McGeer,147 Dickey and Morrow,148
and Lang and Weiner.5 The acute dystonias are quite dramatic in their presentation. Usually precipitated by the
neuroleptic phenothiazines and butyrophenone compounds, dystonic movements and postures take various
forms.
Most commonly, these drug-induced dystonias occur
in the acute phase of treatment with phenothiazines and
butyrophenones and often affect patients under the age of
40, although this is not a hard-and-fast rule. The salient
clinical features accompanying these neuroleptic-induced
dystonias are oculogyric crisis and abnormal posturing of
the head and neck. Patients with oculogyric crisis often
complain of an inability to move their eyes in the vertical
plane; they also complain of double vision and blurred
vision, but rarely of pain on attempted gaze.
Most often, the eyes maintain a sustained upward
gaze. The symptom complaints appear to result from the
patients attempt to maintain full visual field by manipulating head and neck musculature in an uncoordinated
fashion. The abnormal posture of the head and neck
including opisthotonos, in which the head and neck are in
a retrocolic position, give the patient a most bizarre
appearance. Other muscles may be involved in acute
drug-induced dystonia, but these presentations are much
less common than the opisthotonos and oculogyric crisis.149
Drug-induced dystonia is caused primarily by medications that affect dopaminergic mechanisms. For example, patients with Parkinsons disease treated with L-dopa
might develop typical dystonic movements and postures.150153 In addition to dystonia caused by
neuroleptics154 or by metoclopramide,155 dystonic-like
reactions have also occurred with many other drugs
including high doses of carbamazepine,156 phenytoin,157
or propranolol.158 Neuroleptic-induced dystonia is
divided into acute dystonia and tardive dystonia.159 The

two dystonic reactions may be differentiated by the fact
that acute dystonia responds well to anticholinergic medications, whereas tardive dystonia does not, suggesting
different underlying mechanisms.
597
trauma,173 hypothyroidism,174 and certain degenerative

disorders of the central nervous system (e.g., neuronal
ceroidlipofuscinosis)175 are thought to enhance ones
chances of developing neuroleptic-induced dystonia.
Chronic administration of cocaine enhances the concentration of dopamine.176
IATROGENIC DYSTONIA
Dystonia in various forms, including torticollis, blepharospasm, and oromandibular movements, has occurred
after administration of many drugs (Table 46.5147). These
dystonic reactions are idiosyncratic, occurring in susceptible patients, with the susceptibility decreasing with age.
Indeed, diphenhydramine, an antihistaminic substance
with anticholinergic properties, and benztropine, an anticholinergic agent, have been used successfully in treating
n e u r o l e p t i c - i n d u c e d a c u t e d y s t o n i a . Ye t ,
diphenhydramine160,161 and benztropine162 have caused
dystonia in susceptible individuals. It is clearly seen that
the complexity of these responses militates against provision of a unified concept regarding drug-induced dystonia.
Therefore, only the most commonly occurring dystonias
will be described.
INCIDENCE
OF
ACUTE DYSTONIA
The incidence of neuroleptic-induced dystonia has been

reported to be as low as 2 to 3%163 to as high as 50%.164
However, it is generally agreed that incidence is considerably higher in children and young adults.165167
ENHANCED SUSCEPTIBILITY
TO
DEVELOP DYSTONIA
Cocaine addiction,168 hypoparathyroidism,169 alcoholism,170 excess stress,171,172 childhood convulsion or birth
TARDIVE DYSTONIA
Dystonias may be a group of disorders with multiple etiology in which both dopamine excess and deficiency are
implicated. Furthermore, treatment of dystonias is generally empiric, defying generalization. The following comments in Table 46.6, are illustrative. A simplified presentation of the involvement of neurotransmitters in the
genesis of dystonia is not possible at this time.146,147,193195
IDIOPATHIC OROFACIAL DYSTONIA (MEIGES

SYNDROME)
Ortiz196 reported that a patient with Meiges syndrome
responded best to a combination of haloperidol (a dopamine receptor blocking agent, hence reducing dopamine
excess) and benztropine (acetylcholine receptor blocking
agents, hence reducing acetylcholine excess).
This syndrome, usually occurring within 24 to 72 hr
after initiation of neuroleptic therapy, must be differentiated from late-onset tardive dystonia.197,198 Neurolepticinduced tardive dystonia may or may not respond to anticholinergic agents,199 whereas anticholinergic agents
exacerbate neuroleptic-induced tardive dyskinesia.200
Furthermore, in contrast to tardive dyskinesia, tardive
dystonia decreases with age and shows no female preponderance.201
TABLE 46.6
Treatment of Dystonia
Potent neuroleptics such as haloperidol may cause dystonia, asphyxiation, and death.177181 Neuroleptic-induced dystonia is relieved by
diphenhydramine or benztropine.167,182,183
Thioridazine-induced dystonia in a patient with neuronal ceroidlipofuscinosis was refractory to most drugs but improved with baclofen, 175 which
acts by inhibiting the release of glutamate and other neurotransmitters.
In a double-blind, placebo-controlled crossover study, six patients with different forms of dystonia were treated with -vinyl GABA, an inhibitor
of GABA-transaminase. -vinyl GABA therapy (2 g/day for 2 weeks) was compared with placebo by weekly assessments. There were no
consistent changes in three evaluation scores. Based on this study, agents that augment central nervous system GABA are unlikely to benefit
patients with generalized dystonia.184
Dystonia of the paroxysmal type, lasting only a few minutes (also called basal ganglia epilepsy), responds to anticonvulsants such as phenytoin,
carbamazepine, or clonazepam.147
Juvenile dystonia parkinsonism185 or progressive dystonia with marked diurnal fluctuations (also called Segawa syndrome), and sometimes aberrant
juvenile parkinsonism,186 responds well to L-dopa or anticholinergic agents.187
Botulinum toxin has been used for temporary relief of focal dystonia such as blepharospasm,188190 torticollis,147 and writers cramp.191
Pancuronium bromide, a skeletal muscle relaxant, has been used in patients with acute torticollis.192
Dystonias may be a group of disorders with multiple etiology in which both dopamine excess and deficiency are implicated. Furthermore, treatment
of dystonias is generally empiric, defying generalization. A simplified presentation of the involvement of neurotransmitters in the genesis of
dystonia is not possible at this time.
598
Parkinsons Disease
TREATMENT OF DYSTONIAS
High-dose anticholinergic therapy for childhood-onset
dystonia, botulinum toxin injections for focal dystonia,
and L-dopa for diurnal dystonia provide symptomatic
relief in some patients.147
BACLOFEN
IN THE
TREATMENT
OF
DYSTONIA
Greene,202 by reviewing the literature, summarized the

beneficial effects of baclofen, a presynaptically acting
GABA receptor agonist, in the management of dystonia.
Dramatic improvement in symptoms, especially in gait,
was found in almost 30% of 31 children and adolescents
with idiopathic dystonia in one retrospective study using
doses ranging from 40 to 180 mg daily. The response to
baclofen in adults with focal dystonia is less dramatic.
One series of 60 adults with cranial dystonia found sustained benefit in only 18%, and smaller series have not
consistently found significant benefit in adults. Baclofen
has been used to treat several secondary dystonias; tardive
dystonia has occasionally been reported to improve with
administration of baclofen, and there are isolated reports
of improvement in dystonia occurring in Parkinsons disease and in glutaric aciduria.
BOTULINUM TOXIN
IN THE
TREATMENT
OF
DYSTONIA
Botulinum toxin acts presynaptically at nerve terminals to

prevent the calcium-mediated release of acetylcholine.203
When botulinum toxin is injected locally, the effect is that
of a chemical denervation.204 Injected locally into extraocular muscles, botulinum toxin has been used to treat
strabismus205 and, injected subcutaneously over orbicularis oculi, has been used to treat blepharospasm.189,206213
Botulinum toxin has been used to treat hemifacial
spasm.214216 In addition, botulinum toxin has been used
to treat spasmodic torticollis,217 oromandibular-laryngeal
cervical dystonia,218 and stiff-person syndrome.219
overlap in clinical features, some have recommended that

all children and young adults with dystonia and athetoiddystonic cerebral palsy be given a trial of levodopa to
exclude DRD. However, response to levodopa in patients
with DRD is not always immediate, especially in earlyonset and severe cases, and levodopa can provide significant symptomatic benefit in some patients with secondary
dystonia who do not have DRD.
Hyland et al.220 measured plasma levels of phenylalanine, tyrosine, biopterin, and neopterin at baseline, and 1,
2, 4, and 6 hr after an oral phenylalanine load
(100 mg/kg). Seven adults with DRD, two severely
affected children with DRD, and nine adult controls were
studied. All patients had phenylalanine and tyrosine concentrations within the normal range at baseline. In the
adult patients, phenylalanine levels were higher than in
controls at 2, 4, and 6 hr post-load (p < 0.0005); tyrosine
concentrations were lower than control levels at 1, 2, and
4 hr post-load (p < 0.05). Phenylalanine-to-tyrosine ratios
were elevated in patients at all times post-load (p <
0.0005). Biopterin levels in the patients were decreased at
baseline and 1, 2, and 4 hr post-load (p < 0.005). Pretreatment with tetrahydrobiopterin (7.5 mg/kg) normalized
phenylalanine and tyrosine profiles in two adult patients.
In the children with DRD, phenylalanine-to-tyrosine
ratios were slightly elevated at baseline. Following phenylalanine loading, the phenylalanine profiles were similar to those seen in the adult patients, but there was no
elevation in plasma tyrosine. Baseline biopterin levels
were lower in the children with DRD than in the adult
patients or the controls, and there was no increase in biopterin post-load. In both the children and adults with DRD,
neopterin concentrations did not differ from control values at baseline or after phenylalanine load. These results
are consistent with decreased liver phenylalanine hydroxylase activity due to defective synthesis of tetrahydrobiopterin in patients with DRD. The findings show that a
phenylalanine load may be useful in the diagnosis of this
disorder.
PHENYLALANINE IN DOPA-RESPONSE DYSTONIA

(DRD)
NEUROLEPTIC MALIGNANT SYNDROME
The syndrome of autosomal dominant dystonia that is

exquisitely responsive to levodopa, termed hereditary progressive dystonia with diurnal fluctuation or dopa-responsive dystonia (DRD), is not well known outside the fields
of pediatric neurology and of movement disorders and is
likely to be underdiagnosed. The disease is classically
present as a dystonic gait disorder in childhood, with an
average age of symptom onset of 5 to 6 years, but the
spectrum of clinical manifestations is broad. Some children have presented in the first 2 years of life with developmental motor delay. In older children, prominent upper
motor neuron findings, including spastic diplegia, have
led to the misdiagnosis of cerebral palsy. Because of this
Among the complications of neuroleptic chemotherapy,

the most serious and potentially fatal complication is
malignant syndrome, which is characterized by extreme
hyperthermia; lead pipe skeletal muscle rigidity causing
dyspnea, dysphagia, and rhabdomyolysis; autonomic
instability; fluctuating consciousness; leukocytosis; and
elevated creatine phosphokinase (see References 3, 4, and
221 through 232).
Neuroleptic malignant syndrome, which is sometimes
associated with abrupt withdrawal of anticholinergic
agents,233 may occur without muscular rigidity.234 Furthermore, an acute imbalance of sodium in the central nervous system has been proposed to play a role in the
pathophysiology of neuroleptic malignant syndrome,235

and dehydration and hot weather are additional factors for
the development of neuroleptic malignant syndrome.236
Neuroleptic malignant syndrome associated with dysarthric disorders has been reported.237 Pure akinesia is a
syndrome characterized by akinesia without rigidity,
tremor, and supranuclear gaze palsy. Yoshikawa et al.238
reported a patient with pure akinesia-manifested in neuroleptic malignant syndrome. Clozapine, an atypical neuroleptic, was initially reported not to cause neuroleptic
malignant syndrome. As a matter of fact, chronic schizophrenic patients should be considered for clozapine treatment.239 However, it is evident that clozapine
monotherapy may cause neuroleptic malignant syndrome.240,241 Moreover, withdrawal from clozapine has
caused catatonia.242
Neuroleptic malignant syndrome, as the most serious
but the rarest and least known of the complications of
neuroleptic chemotherapy,243 is viewed as a triad of fever,
movement disorder, and altered mentation.226 Pulmonary
abnormalities, including tachypnea, dyspnea, stridor, and
pulmonary edema, are probably secondary complications
resulting from movement disorder, alteration in the functions of the autonomic nervous system (tachycardia, diaphoresis, and labile blood pressure), and changes in
mental status (stupor, lethargy, and coma).
In 115 cases of neuroleptic malignant syndrome studied by Addonizio et al.,228 the primary psychiatric diagnoses, in descending order of occurrence, consisted of
schizophrenia (44%), bipolar mania (26%), major depression (10%), schizoaffective disorder (6%), atypical psychosis (3%), alcohol abuse (3%), bipolar depression
(2%), mental retardation (2%), organic mental syndrome
(1%), Alzheimers disease (1%), and sedative abuse (1%).
Among these 115, there were 72 men (63%) and 43
women (37%). Furthermore, greater than 50% of the
cases were patients 40 years or younger. Unlike the more
familiar neuroleptic-induced movement disorders, which
occur in 15 to 50% of patients, neuroleptic malignant syndrome is relatively rare, and the annual incidence of the
syndrome has been reported to be 0.15%,244 0.4 to
1.4%,223,245247 or 2.4%.227,247 Among the 115 cases
reported by Addonizio et al.228 and 52 cases analyzed by
Kurlan et al.,227 the incidence of neuroleptic malignant
syndrome seems to be considerably higher with haloperidol than with any other neuroleptic.
DIFFERENTIAL DIAGNOSIS OF NEUROLEPTIC

MALIGNANT SYNDROME
Many diseases and toxic reactions mimic the cardinal
features of neuroleptic malignant syndrome, namely fever,
muscular rigidity, changes in mental status, and autonomic
dysfunction. Therefore, care must be taken to differentiate
neuroleptic malignant syndrome from malignant hyperCopyright 2005 by CRC Press LLC
599
thermia, lethal catatonia, heat stroke, central anticholinergic toxicity, central nervous system infection, severe
dystonic reaction, drug- and food-related allergic reactions, electrolyte imbalance, thyrotoxicosis, strychnine
poisoning, rabies, tetanus, polymyositis, rhabdomyolysis,
and stiff-person syndrome.248
EVENTS LEADING TO OR ENHANCING THE SEVERITY OF

NEUROLEPTIC MALIGNANT SYNDROME
The contributing factors leading to and/or enhancing the
incidence or severity of neuroleptic malignant syndrome
are dehydration,249 exhaustion,250 pre-existing organic
brain syndrome,251 external heat load,252 large dosage and
rapid dose titration of neuroleptics,253 excessive sympathetic discharge,254,255 concurrent lithium therapy, and
abrupt discontinuation of antiparkinsonian agents.
COMPLICATIONS OF NEUROLEPTIC MALIGNANT

SYNDROME
In addition to respiratory failure, acute renal failure, and
cardiovascular collapse, which occur frequently in inadequately treated or untreated patients with neuroleptic
malignant syndrome, other serious complications have
occurred, even in patients treated well with dantrolene and
dopamine-enhancing substances. The reported complications are myocardial infarction,256 periarticular ossification,257 peripheral neuropathy,258 respiratory distress syndrome and disseminated intravascular coagulation,259 and
necrotizing enterocolitis.260 The cluster of aforementioned
symptoms occurred in 52 patients who received neuroleptics for schizophrenia (24), for affective disorder (13), for
other psychiatric disorders (13), for preinduction anesthesia (1), and for withdrawal from sedative-hypnotic drugs
(1). Receiving more than one neuroleptic significantly
increases the incidence of neuroleptic malignant syndrome. Furthermore, it is generally believed that the incidence of malignant syndrome is higher with high-potency
neuroleptics than low-potency ones.
THE PATHOGENESIS OF NEUROLEPTIC MALIGNANT

SYNDROMETHE ROLE OF DOPAMINE
Although the pathogenesis of neuroleptic malignant syndrome is not entirely clear, a blockade of dopaminergic
receptors in the corpus striatum is thought to cause muscular contraction and rigidity-generating heat, and a
blockade of dopaminergic receptors in the hypothalamus
is thought to lead to impaired heat dissipation. Therefore,
the excess heat production along with a lack of heat dissipation produces pronounced hyperthermia, which is the
hallmark of the syndrome. Furthermore, a blockade of
dopamine receptors in the spinal cord is thought to be
responsible for dysautonomia. The involvement of dopam-
600
ine in the genesis of malignant syndrome is further supported by the observation that, in addition to neuroleptics,
which block dopamine receptors, dopamine-depleting
agents such as reserpine, dopamine storage blocking
agents such as tetrabenazine, and dopamine synthesis
inhibitors such as -methylparatyrosine might also produce neuroleptic malignant syndrome. The rapid (4-hr)
reversal of hyperthermia of neuroleptic malignant syndrome by L-dopa/carbidopa also indicates that an alteration in the metabolism or function of dopamine and/or
its receptors may be responsible for the hyperthermia.
Because dopamine plays a role in central thermoregulation
in mammals261263 and, because neuroleptics block dopamine receptor sites, the hyperthermia associated with neuroleptic malignant syndrome might result from a blockade
of dopamine target sites within the preoptic-anterior hypothalamus.264,265 A stereotaxic injection of dopamine into
the preoptic-anterior hypothalamus causes a reduction in
core temperature, and this effect is blocked by haloperidol.262 Histidylproline diketopiperazine [cyclo(His-Pro)],
an endogenously occurring cyclic dipeptide, shares certain
properties with dopamine in that it causes hypothermia
and is found in preoptic-anterior hypothalamus and in
striatum.266
In addition to hyperthermia, the parkinsonism
(98%) and alteration in mental status (8 to 27%) seen in
patients with neuroleptic malignant syndrome may
result from blockade of dopaminergic receptors in the
nigrostriatal system and from disruption of dopaminergic function in the mesocortical system.264 The gradual
(1 to 5 days) disappearance of parkinsonism seen in
patients with neuroleptic malignant syndrome and the
resumption of normal physiological functions after
treatment with L-dopa/carbidopa support this contention. In addition to Sinemet, other dopamine-functionenhancing drugs, such as bromocriptine98,267276 and
amantadine277282 have shown efficacy in treating neuroleptic malignant syndrome.
TREATMENT OF NEUROLEPTIC
MALIGNANT SYNDROME
GENERAL TREATMENTS
The most important factor in treatment of neuroleptic
malignant syndrome is the early recognition of the incipient syndrome and prompt discontinuation of neuroleptic
medication.283 Allsop and Twigley284 described a psychotic patient who developed neuroleptic malignant syndrome after administration of fluphenthixol. Because the
treatment with dantrolene sodium was instituted too late,
the patient died after massive intestinal hemorrhage, intraabdominal sepsis, and disseminated intravascular coagulation. In addition to blocking dopamine receptors in the
hypothalamus, basal ganglia, and spinal cord, neuroleptics
Parkinsons Disease
cause excessive release of calcium from the sarcoplasmic

reticulum in peripheral muscle fibers, resulting in exaggerated muscular contraction and in enhanced thermogenesis.223 Dantrolene or other muscle relaxants are useful285
when used in conjunction with dopamine-enhancing substances. Furthermore, every attempt should be made to
reduce morbidity and to avert mortality, which are related
to the development of cardiac problems, pneumonia, pulmonary embolus, and renal failure, secondary to myoglobinuria.286 Airway intubation and other supportive care
might be required in some patients. Lack of fluid intake
along with diaphoresis may result in dehydration requiring
fluid supplementation. Furthermore, vigorous fluid therapy is needed to combat myoglobinuria. Although dialysis
may improve renal failure, neuroleptic agents are protein
bound and are not removed readily by dialysis. In treating
neuroleptic malignant syndrome, it should be recalled that
significant variations might occur in patients. For example, it is generally presumed that neuroleptic malignant
syndrome lasts for 5 to 10 days after discontinuation of
oral neuroleptic.287 However, if the syndrome is caused
by a long-acting neuroleptic, such as fluphenazine enanthate, a more prolonged and severe case may be anticipated.281 Patients who are receiving neuroleptics and suffer from heat stroke may present with fever, rigidity, and
elevated creatine kinase. However, their skin is dry, and
their blood pressure is low or normal.288,289 Neuroleptic
malignant syndrome may occur in a milder form after the
administration of weaker dopamine-depleting substances
such as reserpine, and later develop fully in the same
patient after the administration of a potent dopamine
receptor blocking agent such as haloperidol.290 Finally,
neuroleptic malignant syndrome may be superimposed
upon tardive dyskinesia,291 making both diagnosis and
treatment difficult.
SPECIFIC TREATMENTS
In neuroleptic malignant syndrome, central dopaminergic
receptors are blocked, and altered levels of dopamine
metabolites such as 3,4-dihydroxyphenylacetic acid and
homovanillic acid have been found postmortem.292 Therefore, the treatment of choice is to reverse the hypodopaminergic state by administration of L-dopa/carbidopa, bromocriptine, or amantadine.
L-DOPA/CARBIDOPA
L-dopa/carbidopa (Sinemet 25:100) is often effective in
reversing hyperthermia and making the patient afebrile in
hours. Treatment, however, may need to be continued for
several days.226 Harris et al.293 reported a patient in whom
malignant syndrome developed after taking haloperidol
(15 mg/day), and therapy was initiated with dantrolene
(10 mg/kg/24 hr). In this case, severe muscle rigidity
resolved and temperature was reduced from 107 to 102

after the administration of dantrolene. Twenty-four hours
after carbidopa-L-dopa (25:100) treatment was started, the
temperature dropped to 100. When subsequent carbidopaL-dopa was inadvertently not given, the temperature
increased, despite continuous treatment with dantrolene.293 Hirschorn and Greenberg294 reported a case of
L-dopa-induced myoclonus combined with L-dopa withdrawal-induced neuroleptic malignant syndrome, which
was successfully treated with L-dopa/carbidopa along
with 2 mg/day of methysergide (a serotonin receptor
antagonist). It has been suggested that prolonged L-dopa
therapy may result in deregulation of serotonergic transmission producing myoclonus.295
BROMOCRIPTINE
In 1983, several investigators269,272,274,276 explored the beneficial effects of bromocriptine in reversing neuroleptic
malignant syndrome. The recommended initial dose is 5.0
to 7.5 mg three times daily.296 If the syndrome has progressed to the point at which the patient is unable to
swallow the orally available bromocriptine, it is necessary
to produce muscular relaxation by dantrolene (3 mg/kg
four times daily). However, it should be stated that the
hyperthermia in malignant syndrome does not respond to
muscle relaxation alone.297 Because dantrolene produces
a rare but potentially fatal idiosyncratic hepatocellular
injury, bromocriptine may be administered by a nasogastric tube in patients in whom a pre-existing liver disease
may preclude the use of dantrolene.
Dhib-Jalbut et al.269 reported that the amount of bromocriptine mesylate to be given to a patient depends on
body temperature, autonomic and extrapyramidal signs,
and symptoms. Therefore, in treating five patients with
malignant syndrome, they used 7.5 to 45.0 mg/day in
three divided doses for 10 days. In all five patients, significant improvement in vital signs and reduction in creatine
kinase was noted within 24 to 72 hr after initiation of bromocriptine treatment. Resolution of confusion and mutism was noted within 24 to 48 hr, and resolution of
extrapyramidal rigidity occurred within 1 week. In two
patients, early discontinuation of bromocriptine resulted
in a relapse of neuroleptic malignant syndrome, which
responded to reinstitution of the drug.269
DANTROLENE SODIUM (DANTRIUM)

Dantrolene, a nitrophenylamino hydantoin derivative, is a
unique skeletal muscle relaxant in that, unlike competitive
neuromuscular blocking agents (e.g., D-tubocurarine),
depolarizing blocking agents (e.g., succinylcholine and
decamethonium), and agents enhancing or mimicking
GABAergic transmission (e.g., diazepam and baclofen),
dantrolene exerts its effects by direct action on excitationcontraction coupling and by reducing the amount of calCopyright 2005 by CRC Press LLC
601
cium released from sarcoplasmic reticulum.298 Dantrolene,

which depresses the central nervous system, does not
affect neuromuscular transmission, nor does it change the
electric properties of skeletal muscle membranes.299
Although the hepatotoxicity of dantrolene precludes its
widespread and chronic usage, it has proven beneficial in
treating patients with spasticity associated with stroke,
cerebral palsy, spinal cord injury, and multiple sclerosis.
Furthermore, it is effective in reducing the muscular rigidity associated with malignant hyperthermia300,301 and in
neuroleptic malignant syndrome.285,302 In malignant hyperthermia, a dose of 2.4 mg/kg is given by intravenous
infusion for prophylaxis or initial treatment of hyperthermia.300 Britt301 recommended that dantrolene should be
administered at a rate of 1 mg/kg/min while monitoring
electroencephalogram and until heart rate and temperature
begin to fall and muscle stiffness starts to subside. If
necessary, treatment may be repeated every minute, or a
maintenance infusion of 1 to 2 mg/kg per 3 to 4 hours
initiated until all evidence of hyperthermia has disappeared. Similar to L-dopa or bromocriptine, dantrolene
sodium may produce rapid reversal of neuroleptic malignant syndrome.246,248,272,296,303306 The initial usual recommended dose of dantrolene, which may vary depending
on the severity of the problem and the perceived need of
the patient, to be decided by the attending physician (see
Reference 307), is between 0.8 and 2.5 mg/kg given intravenously every 6 hr308 or between 0.25 and 3.0 mg given
intravenously every 6 hr.272,304 When symptoms abate and
the patient is able to swallow, oral doses in the range of
100 to 200 mg/day may be substituted.305 Rapid resolution
of symptoms (within 24 hr) is possible if treatment is
begun early,309 although the usual course of treatment is
5 to 10 days.248
AMANTADINE
Although universal agreement on its efficacy does not
exist, amantadine has been tried in the management of
neuroleptic malignant syndrome.272,277281
ANTICHOLINERGIC AGENTS
Anticholinergic drugs such as benztropine (Cogentin) are
usually ineffective in treating the rigidity of neuroleptic
malignant syndrome and do not affect or may even aggravate the associated hyperthermia.310 However, Schrehla
and Herjanic311 reported a schizoaffective patient who
developed neuroleptic malignant syndrome and did not
respond completely with bromocriptine (5 mg p.o. t.i.d.)
but improved dramatically with 2 mg benztropine (i.m.)
after initial treatment with bromocriptine.
BENZODIAZEPINE DERIVATIVES
Benzodiazepine derivatives, which enhance GABAergic
function, have produced transient relief of symp-
602
Parkinsons Disease
toms.222,214,264,306,312,313 Benzodiazepine derivatives have

also been recommended to control agitated patients
while being treated for neuroleptic malignant syndrome.248,296
NEUROLEPTIC-INDUCED PARKINSONISM
The cardinal features of Parkinsons disease are tremor at
rest, rigidity, akinesia, and postural abnormalities. A small
number of patients, however, might display only akinesia
without rigidity or tremor.314317 Drug-induced parkinsonism is common but under-recognized.318 A majority of
patients initially diagnosed as having Parkinsons disease
were subsequently shown to have drug-induced syndrome.319,320 By far the most frequent causes of druginduced parkinsonism are neuroleptics that block dopamine receptors in nigrostriatal dopaminergic pathways. Furthermore, there is a direct relationship between the
potency of neuroleptics as antipsychotics and the incidence of parkinsonism. The more potent agents, such as
haloperidol, produce more frequent pseudoparkinsonism
than the less potent agents such as chlorpromazine.
INCIDENCE
OF
PARKINSONISM
Although the severity of neuroleptic-induced parkinsonism varies with class of drug, potency of drug, dosage
level, and the length of treatment, the factors enhancing
ones susceptibility to develop parkinsonism are not
known.96,97,321 Some patients do not develop parkinsonism, even after taking potent neuroleptics for a long
period of time, whereas others experience severe and disabling symptoms after a few doses of relatively weak
neuroleptics. Neuroleptic-induced parkinsonism is reversible and disappears after discontinuation or lowering of
drug dosage.
TREATMENT OF PARKINSONISM
Neuroleptic-induced parkinsonism is best treated by
reducing doses of neuroleptic and by adding an anticholinergic agent such as benztropine or trihexyphenidyl.
Anticholinergic drugs should not be used prophylactically,
because the incidence of tardive dyskinesia is far higher
in patients who receive neuroleptics and an anticholinergic
drug given prophylactically to prevent parkinsonism. Ldopa is contraindicated, because it might aggravate the
underlying psychiatric problem for which neuroleptic
treatment was initiated. In animal models of Parkinsons
disease, glutamate receptor antagonists diminish
levodopa-associated motor fluctuations and dyskinesia.322
ANTITREMOR EFFECTS
OF
CLOZAPINE
Tremor at rest is a classic symptom of Parkinsons disease

that causes significant disability and distress for the
patient and is generally only weakly responsive to conventional treatment such as anticholinergic or amantadine. Jansen323 reported that clozapine (18 mg/day)
improved tremor.
PARKINSONISM, SCHIZOPHRENIA,
AND
DOPAMINE
The coexistence of Parkinsons disease and schizophrenia

is of theoretical interest and of therapeutic importance.
Parkinsons disease is known to be a striatal dopamine
deficiency syndrome. On the other hand, schizophrenic
patients are thought to suffer from a dopaminergic hyperactivity state.324329 Clozapine along with L-dopa/carbidopa may be used in the management of patients with
Parkinsons disease who also suffer from schizophrenia,330331 or in patients with L-dopa-induced psychosis.332
Moreover, clozapine therapy may allow an increase in
antiparkinson therapy leading to further amelioration of
parkinsonism.333 Clozapine has also been advocated to be
of value in treating resistant schizophrenics334 and in a
paranoid subgroup of schizophrenics.335
NEUROLEPTIC-INDUCED TARDIVE
DYSKINESIA
Persistent dyskinesia, which was initially described in
1956,336,337 also became known as reversible and irreversible drug-related dyskinesia.338 This neuroleptic-induced
movement disorder is characterized by abnormal involuntary movements frequently involving the facial, buccal,
and masticatory muscles and extending often to the upper
and lower extremities, including the neck, trunk, fingers,
and toes. The typical abnormal facial movements include
opening and protrusion and retrieval of the tongue and
closing of the mouth, chewing, licking, sucking, puckering, smacking, panting, and grimacing. Abnormal movements associated with the disorder, which might involve
any part of the body, can be ataxic, myoclonic, dystonic,
dyskinetic, or choreiform in nature. The neurolepticinduced dyskinesias, which have been reported and studied extensively in adult patients,339341 occur also in children.342
Steen et al.343 believe that autosomal inheritance of
two polymorphic Ser 9 Gly alleles (2-2 genotype), but not
homozygosity for the wild-type allele (1-1 genotype), is a
susceptibility factor for the development of tardive dyskinesia.
DRUGS
AND
CONDITIONS CAUSING DYSKINESIA
In addition to neuroleptics339,340342 dyskinesias have been

reported to occur after exposure to antidepressants,344,345
anxiolytic agents,346 anticonvulsants,156 antihistaminics,161,347 narcotics, L-dopa,340 amphetamine,348 lithium,349
metoclopramide155,350 used in the treatment of gastrointes-
tinal motor dysfunctions, and allegedly nicotine,351 inasmuch as the incidence of tardive dyskinesia is higher
among smokers. However, because smoking induces the
activity of the hepatic microsomal enzymes and enhances
the metabolism of neuroleptics, it necessitates the use of
higher-than-ordinary doses of neuroleptics for patients.352
The reported higher incidence of tardive dyskinesia in
smokers taking neuroleptics might be due to higher doses
of neuroleptics themselves. In addition to drug-induced
movement disorders, dyskinesias have been reported to
take place occasionally in infantile autism, in Huntingtons
chorea, in some elderly individuals, and in some patients
with mental retardation.353 As a matter of fact, a positive
correlation between cognitive impairment and tardive dyskinesia has been suggested.354
HETEROGENEITY
OF
TARDIVE DYSKINESIA
Tardive dyskinesia, a late-developing side effect syndrome

arising as a consequence of chronic neuroleptic treatment,
is pharmacologically heterogenous, and this heterogeneity
is seen between individual patients (and groups of
patients) as well as within body areas of individual patients
(and groups of patients) as well as within body areas of
individual patients.355 For example, tardive dyskinesia
most often involves the oral-lingual-facial regions but can
affect all other body areas as well. The symptoms of
tardive dyskinesia are most commonly choreoathetoid in
nature but can have dystonic as well as other features (e.g.,
tics, akathisia, myoclonus). Symptoms of tardive dyskinesia vary widely in severity, but the majority of cases are
mild. In addition, the syndrome varies in its duration with
symptoms being transient in some patients, whereas, in
others, they persist and in some cases may be irreversible.
Although disturbances in dopamine and acetylcholine
seem to be involved in these disorders, they do not in all
cases exist in functionally opposite relationships. The
observed pharmacologic heterogeneity in tardive dyskinesia response reflects the limitations of the dopamine/acetylcholine model of tardive dyskinesia, which oversimplifies the neuroanatomy of the basal ganglia (Figure 46.1)
and the pathophysiology of tardive dyskinesia. The chemical and anatomical complexity of this region suggests that
other neurotransmitter systems such as glutamate356 and
neuronal circuits within and extending from the basal ganglia might be disturbed in the pathogenesis (Figure 46.2).
Consistent with these views is the observation that
although trihexyphenidyl is effective in the treatment of
neuroleptic-induced parkinsonism, a subpopulation of
patients with tardive dyskinesia also shows improvement
after anticholinergic treatment.357
TARDIVE DYSKINESIA
AND
DIABETES
Diabetic patients have been shown to exhibit a greater

incidence of tardive dyskinesia.358 Hyperglycemia supCopyright 2005 by CRC Press LLC
603
presses the basal firing of dopamine-containing neurons,359 and insulin reduces the severity of symptoms in
tardive dyskinesia.360
L-DOPA-INDUCED DYSKINESIA
L-dopa-induced dyskinesias are a heterogeneous phenomenon, which might be difficult to explain on the basis of
a single pathological mechanism. For example, Luquin et
al.361 classified L-dopa-induced dyskinesias into on dyskinesias, diphasic dyskinesia, and off periods. Chorea, myoclonus, and dystonic movements occurred during
the on period. Dystonic postures, particularly affecting
the feet, were mainly present in the off period, but a
few patients had a diphasic presentation. Repetitive stereotyped movements of the lower limbs always corresponded to diphasic dyskinesia. Moreover, Luquin et al.361
have shown that dopamine agonists enhanced on dyskinesias and markedly reduced or abolished off period
dystonia and diphasic dyskinesia. Dopamine receptor
antagonists reduced all types of L-dopa-induced dyskinesia but also aggravated parkinsonism. These data indicate
that L-dopa-induced dyskinesias in Parkinsons disease is
a heterogeneous phenomenon difficult to explain on the
basis of a single pathophysiological mechanism.361
TARDIVE OCULOGYRIC CRISIS

The syndrome of oculogyric crisis was originally
described in association with epidemic encephalitis
lethargica.362 Oculogyric crisis is now most commonly
seen as a side effect of neuroleptic medication.363 It is
recognized as a form of acute dystonia involving primarily
the ocular muscles, although retrocollis, blepharospasm,
contraction of the frontalis, jaw opening, and other movements might be associated with it. The importance of the
syndrome lies in the fact that it is common, being reported
in 10% to more than 60% of patients recently treated with
neuroleptic medication, and very distressing to the patient
and onlookers. It usually occurs within a few days of
starting the drug or increasing its dose, with one report
suggesting that 90% of patients experienced it in the first
4 days of drug treatment. Sachdev364 reported on six
patients with chronically recurring oculogyric crisis; three
of the patients developed tardive side effects, and in one
patient the episodes persisted for some months after cessation of neuroleptic.
TARDIVE DYSKINESIA
AND
TYPE II SCHIZOPHRENIA
Davis et al.365 found a significant association between

tardive dyskinesia, cognitive impairment, some negative
symptoms, and formal thought disorders. These associations were independent of other illnesses and treatment
variables. The severity of tardive dyskinesia correlated
significantly with that of cognitive impairment.
604
Parkinsons Disease
MECHANISMS OF NEUROLEPTIC-INDUCED
DYSKINESIA
Long-term administration of neuroleptics and other drugs
causes tardive dyskinesia, which closely resembles Ldopa-induced dyskinesias and is brought about through
complex mechanisms that are ill defined. It is generally
believed that its pathogenesis involves blockade of dopamine receptor sites and that its pathophysiology results from
a hypersensitivity of dopamine receptors (see Reference
366). This hypothesis, however, is not universally
accepted, for the reasons presented in Table 46.7. The
aforementioned studies, when examined collectively, indicate that the hypothesis proposing dopaminergic hyperactivity cannot explain completely the etiology of schizophrenia and/or the pathogenesis of tardive dyskinesia,
hence making treatment difficult.
-AMINOBUTYRIC ACID IN THE PATHOGENESIS

TARDIVE DYSKINESIA
OF
GABA has been shown to interact with nigrostriatal

dopaminergic neurons.367370 Defective GABAergic transmission has been advanced as a possible etiologic factor
in the pathogenesis of tardive dyskinesia.371,372 There is a
reduction in the concentration of GABA in the cerebral
spinal fluid of patients with tardive dyskinesia, and

GABA-mimetic drugs improve dyskinetic symptoms.
Moreover, it has been suggested that diminished neural
activity in efferent GABAergic tracts from the substantia
nigra pars reticulata to the thalamus underlies tardive dyskinesia in human beings (Figures 46.1 and 46.3). The
repeated administration of neuroleptics reduces the activity of glutamic acid decarboxylase only in substantia nigra
of animals developing dyskinesia.373,374 Therefore, one of
the recent therapeutic regimens advocates the administration of substances that functionally enhance GABAergic
transmission, such as diazepam, or of agents that act as
GABA receptor agonists, such as muscimol. GABArelated pharmacological treatment is based on the observation in experimental animals that the GABAergic efferent tract in the striatum constitutes a segment of the striatonigral feedback loop (Figure 46.3) with the ability to
modulate the activity of dopaminergic cells in the substantia nigra.375378 Based on this concept, it has been shown
that muscimol,379 a GABA receptor agonist, and -acetylenic-GABA380 or -vinyl-GABA,195 substances that elevate the concentration of GABA by inhibiting GABAtransaminase, were effective in alleviating the severity of
tardive dyskinesia. Singh et al.381 have shown that diazepam significantly improved tardive dyskinesia and that
TABLE 46.7
The Pathogenesis of Tardive Dyskinesia and Chronic Blockade of Dopamine Receptor Sites
The pathophysiology of L-dopa-induced dyskinesia and of neuroleptic-induced dyskinesia is not identical because progabide, a GABA receptor
agonist, is only beneficial in treating neuroleptic-induced (but not L-dopa-induced) dyskinesia.401
In addition to dopamine, noradrenergic overactivity might contribute to the pathogenesis of tardive dyskinesia. 402
The hyperactivity of brain dopaminergic systems, especially in the cortical and limbic regions, has been postulated to play a definite role in the
etiology of schizophrenia (reviewed in Reference 328). However, a study by Karoum et al.403 suggests that the output of dopamine and its
metabolites is lower in schizophrenia. Furthermore, at postmortem, no significant differences in D1 and D2 receptors have been found in
schizophrenic patients with or without tardive dyskinesia.404
Because the blockade and hypersensitivity of dopamine receptors induced by neuroleptics are thought to play crucial roles in the etiology and
manifestation of tardive dyskinesia, all pharmacotherapeutic interventions have concentrated on modifying the expression of dopaminergic
transmission. Reserpine, which depletes dopamine in the brain and blocks its uptake into the intraneuronal storage vesicles, has been shown to
benefit some patients with tardive dyskinesia.405 Identical palliative effects have also been reported with tetrabenazine, which possesses reserpinelike properties.406409 A therapeutic regimen advocating step-wise and progressively smaller doses of neuroleptics to slowly desensitize the
dopamine receptor sites has also been shown to be effective in many, but not all, schizophrenic patients with tardive dyskinesia. 410
The neuroleptic-induced increase in the number of striatal dopamine receptors occurs rapidly within 1 week, whereas the appearance of tardive
dyskinesia is observed months or years after initiation of neuroleptic treatment.
Dyskinesia is one of the main adverse events related to long-term dopa therapy in patients with Parkinsons disease. Generally, most drugs with
reliable antidyskinetic properties, such as classical neuroleptics, also reduce the antiparkinsonian efficacy of dihydroxyphenyl-alanine (L-dopa),
thus markedly limiting their clinical usefulness. L-dopa-induced dyskinesia is characterized by abnormal, involuntary movements such as chorea
and dystonia. It can affect several body parts and can occur when the patient is on or off treatment. On-treatment dyskinesia can be apparent at
the start of dose, at the peak dose, or at the end dose. Heterogeneity of the disorder has made it extremely difficult to determine the neural
mechanisms underlying L-dopa-induced dyskinesia. In the past, it was suggested that L-dopa-induced dyskinesia might represent a symptom of
the progression of Parkinsons disease, but data from 1-methy-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated primates, which do not show
progression of parkinsonian symptoms, strongly suggest that the appearance of L-dopa-induced dyskinesia results from the treatment. D 1 receptor
blockade improves L-dopa-induced dyskinesia but worsens parkinsonism in MPTP monkeys.
some of the improvement persisted after discontinuation

of the administration of diazepam. Studies by Sandyk382
have shown that baclofen and clonazepam were effective
in the treatment of neuroleptic-induced akathisia. These
observations suggest, but do not confirm, a direct link
between dopaminergic transmission, GABAergrc transmission, the pathogenesis of neuroleptic-induced dyskinesia, and the treatment of the dyskinesia with diazepam
or GABA-mimetic agents.
An attempt has been made to demonstrate this association by studying the effects of treatment with diazepam
alone, with haloperidol alone, and with haloperidol in
combination with diazepam on the activity of glutamic
acid decarboxylase and on the metabolism of dopamine
and serotonin in discrete regions of the rat brain at the end
of treatment with drugs and in brains of animals allowed
to undergo a drug-free holiday.386 During a 3-day withdrawal period, after daily administration of 3 mg/kg of
haloperidol (i.p.) for 3 weeks, the activity of glutamic
acid decarboxylase in the striatum increased from 72.6
7.8 to 92.6 10.2 nmol 14CO2/mg/protein/hr, and the concentration of dopamine in the striatum increased from
7.87 0.23 to 8.86 0.38 g/g wet tissue. Diazepam (5
mg/kg, i.p.), given during the withdrawal period from
haloperidol, was able to nullify the enhancement in the
concentration of dopamine but not in the activity of
glutamic acid decarboxylase in the striatum. The results
of these studies were interpreted to indicate that the
reported beneficial effects of diazepam and GABAmimetic agents in ameliorating the symptoms of tardive
dyskinesia might occur through a mechanism that does
not necessarily link transmission involving both dopamine and GABA.383 In another study, Mithani et al.384 have
shown that neuroleptic-induced chewing movements and
decreases in nigral glutamic acid decarboxylase activity
were not causally related.
DOPAMINE, PEPTIDES, SCHIZOPHRENIA,

NEUROLEPTICS
AND
The metabolism of neuropeptides including opioids, neurotensin, metenkephalin, substance P, and cholecystokinin
in the spinal fluids of control and neuroleptic-treated
schizophrenic patients has been reviewed.385394 The lack
of detailed knowledge describing the exact nature of the
interaction between dopamine and these neuropeptides
militates against a comprehensive discussion of their
involvement either in the pathogenesis of schizophrenia
or in the pharmacodynamics of neuroleptics. Nevertheless,
a few fragmentary yet interesting items will be outlined.
NEUROLEPTIC-CHOLECYSTOKININ INTERACTION
The possible involvement of cholecystokinin (CCK) in the
pathogenesis of schizophrenia has been reviewed.395 CCK,
605
a 33-amino acid peptide, originally characterized in the

porcine gastrointestinal tract, was first detected in the vertebrate central nervous system by Vanderhaeghen et al.396
In the brain, the majority of CCK-gastrin-like peptides
exist as the sulfated form of CCK octapeptide
(CCK8S).397400 CCK8S may serve as a neurotransmitter
or a neuromodulator, influencing, among other functions,
dopaminergic transmission.
The coexistence of dopamine and CCK8S in a subpopulation of mesolimbic dopaminergic neurons has been
demonstrated,411,412 suggesting that this peptide might
modulate dopamine function. This observation is of interest in view of the suggested hyperactive dopaminergic
transmission in schizophrenia; the beneficial antipsychotic effect of neuroleptics, which allegedly block the
hyperactive dopamine receptors; and, as discussed previously, of neuroleptic-induced tardive dyskinesia, postulated to result from denervation supersensitivity of
dopaminergic neurons in the striatum.413,414 Other evidence pointing to a dopamine-CCK-linked transmission
are the observations that CCK elevates the density of
brain D2 receptors415 and that intrastriatally injected CCK
is able to stimulate dopamine-mediated transmission.416
In an attempt to study further the possibility of dopamineCCK cotransmission, Hama and Ebadi417 determined the
CCK binding sites in the mouse brain. By using a synaptosomal fraction isolated from the mouse cerebral cortex
and [propionyl-3H]CCK8-sulfate ([3H]CCK8S) as a
ligand, a single binding site for [3H]CCK8S with a KD
value of 1.04 nM and a Bmax value of 42.9 fmol/mg/protein was identified. The competitive inhibition of
[3H]CCK8S binding by related peptides produced an
order of potency of CCK8-sulfated (IC50 = 5.4 nM) >
CCK8-unsulfated (IC50 = 40 nM) > CCK4 (IC50 =
125 nM). The regional distribution of [3H]CCK8S binding in the mouse brain was highest in the olfactory bulb
(34.3 5.6 fmol/mg/protein) > cerebral cortex> cerebellum> olfactory tubercle> striatum> pons-medulla> midbrain> hippocampus> hypothalamus (12.4 2.1
fmol/mg/protein).417
CCK peptides share certain properties with neuroleptics in that they induce catalepsy, antagonize conditioned
avoidance behavior, antagonize stereotyped behavior,
induce hypothermia, induce ptosis, and antagonize certain
actions of amphetamine. In addition, ceruletide, CCK8, or
CCK33 may produce rapid, effective, and persistent
antipsychotic effects, especially in some neurolepticresistant patients.414
The aforementioned data led neuroscientists to study
the effects of acute or chronic administration of neuroleptics, including haloperidol, on the concentrations of CCK
and its receptor sites. The results of these studies provided
interesting but inconclusive observations. The varied
effects of haloperidol on the concentration of CCK418420
might depend on the varied mammalian species studied,
606
Parkinsons Disease
the areas of brain examined, the nature of the experiments

conducted, and especially the ligand used to determine
either the content or the density of receptor sites for the
octapeptide. Indeed, a study by Zetler421 has shown that
CCK-like peptides with neuroleptic activity were able to
antagonize stereotyped behaviors caused by dopaminergic receptor agonists, but the mechanism of action of the
peptides was not due to a simple clear-cut neuroleptic-like
blockade of postsynaptic dopamine receptors. The coexistence of CCK peptides in the nigrostriatal and mesolimbic dopaminergic systems might modulate the synthesis,
storage, and/or functions of dopamine and provide additional insight into the efficacy of neuroleptics and the psychopathology of schizophrenia. However, the nonuniform
distribution of CCK8S receptors in the central nervous
system signifies a broader function for the octapeptide
than once anticipated, deserving further in-depth investigation.416
TABLE 46.8
Experimental Evidence Suggesting Close
Interaction between Neuroleptic Therapy and the
Endogenous Opioid Peptides
Areas of the central nervous system, such as striatum and nucleus
accumbens, contain high concentrations of both dopamine and
opioid receptors.430434
The interrelationship between dopaminergic and enkephalinergic
neurons435 is further extended by studies showing that the number
of mesolimbic opioid binding sites is reduced after denervation of
dopaminergic neurons.436
Chronic injection of haloperidol,434 but not clozapine,435 increased
the concentration of enkephalins selectively in the striatum.
Neuroleptic-induced supersensitivity in the mesolimbic
dopaminergic receptor is reduced by naloxone, an opioid receptor
antagonist.436
NEUROLEPTIC-OPIOID INTERACTION
Opioids might participate in the pathogenesis of neuroleptic-induced

akathisia.437,438
Experimental evidence suggests close interaction between

neuroleptic therapy and the endogenous opioid peptides140
(see Table 46.8). The experimental evidence and clinical
findings strongly support the contention that a modification in the metabolism and/or action of dopamine-opioid
and dopamine-CCK transmission in part might have both
beneficial and harmful effects with regard to the neuroleptic-induced movement disorders.
Methadone, a narcotic used to detoxify individuals addicted to

heroin, can produce choreic movements.439 Conversely, naloxone,
an opioid receptor antagonist, has been reported to palliate the
symptoms associated with tardive dyskinesia.440,441
Cortical and basal ganglia levels of opioid receptor binding are
altered in L-dopa-induced dyskinesia. Moreover, the fact that
dyskinetic and nondyskinetic animals often show opposite changes
in opioid radioligand binding suggests that the motor response to
L-dopa is determined, at least in part, by compensatory adjustments
of brain opioid receptors.
TREATMENT OF TARDIVE DYSKINESIA

BUSPIRONE
IN
L-DOPA-INDUCED DYSKINESIAS
Buspirone is an azaspirodecandeione drug with an anxiolytic efficacy comparable to that of the benzodiazepines,
but without any sedative, muscle relaxant, or anticonvulsant effects.422,423 Unlike the benzodiazepines, buspirone
does not interact with GABA-benzodiazepine chloride
channel complex, is thought to exert its neuropharmacological properties as an agonist for serotonin 5-HT1A
receptor subtype, and blocks presynaptic dopamine D2
receptors.424 By stimulating 5-HT1A autoreceptors located
on raphe neurons, buspirone inhibits the firing of serotonergic neurons, leading to a decrease of serotonin transmission in the brain. Moreover, it interacts directly with 5HT1A postsynaptic receptors in the hippocampus, an action
that has been invoked to explain, at least in part, its anxiolytic effects.425 Bonifati et al.425 reported that buspirone
(10 mg orally twice a day) for 3 weeks significantly lessened the severity of the L-dopa-induced dyskinesia without worsening parkinsonism. Buspirone in relatively large
doses of 180 mg/day (the recommended dosage of buspirone in anxiety is 20 to 60 mg/day) has been shown to
be effective in the treatment of tardive dyskinesia.
Improvement was also observed in neuroleptic-induced

parkinsonism and akathisia. Although the dosages administered were considerably higher than those used in the
treatment of anxiety, drug side effects were reported to be
mild.426 Although dyskinetic movements may improve
with reduction in anxiety,427 Moss et al.426 believed that
the observed antidyskinetic effect associated with buspirone treatment occurred independently of buspirones
effects on anxiety.
VITAMIN E
AND
DYSKINESIA
Vitamin E (1200 mg daily) for 1 month significantly ameliorated the severity of tardive dyskinesia.428 Moreover,
Dannon et al.429 treated 16 patients with tardive dyskinesia
with vitamin E in an open trial of on-off-on design. Abnormal involuntary movement scale (AIMS) ratings were performed in every phase of the study. The patients exhibited
a significant reduction in their mean AIMS scores during
vitamin E treatment. Thus, this finding may suggest a
possible role for vitamin E in the treatment of tardive
dyskinesia.
AMANTADINE
IN
TARDIVE DYSKINESIA
Angus et al. 442 reported that amantadine, initially

100 mg/day during the first week and then 300 mg/day
during the third week, produced an improvement in dyskinesia without exacerbation of psychosis even with prolonged administration.
CLOZAPINE
IN
AXIAL TARDIVE DYSTONIA
Functionally disabling tardive dystonia is a well recognized subtype of tardive dyskinesia for which treatment
is often ineffective.159,443445 Trugman et al.446 reported a
patient with severe axial tardive dystonia who showed
improvement for 4 years after treatment with the atypical
antipsychotic drug clozapine (625 mg/day). Clozapine differs from conventional neuroleptics in that it has higher
affinity for dopamine D1 and lower affinity for dopamine
D2 receptors than do conventional antipsychotics, which
are relatively selective dopamine D2 antagonists.
CHOLECYSTOKININ
IN
TARDIVE DYSKINESIA
CCK is known to modulate the nigrostriatal and mesolimbic dopamine neuronal system.2,416 Kojima et al.447 in a
double-blind, placebo-controlled, and matched-pairs
study, reported on the effectiveness of ceruletide
(0.8 g/kg/week), an analog of CCK, in suppressing the
symptoms of neuroleptic-induced tardive dyskinesia. Global evaluation of the severity of tardive dyskinesia symptoms over the 8-week study period revealed a significant
improvement with ceruletide as compared with placebo.
Analysis of the therapeutic response to ceruletide over the
course of treatment revealed a slow but long-lasting
improvement of tardive dyskinesia symptoms. Side
effects, which were mild and transient, consisted mainly
of nausea and epigastric discomfort. The incidence of side
effects did not differ between the ceruletide- and placebotreated groups. Ceruletide appears to be a novel and practical treatment that can substantially alleviate the symptoms of dyskinesia.
RISPERIDONE
AND
TARDIVE DYSKINESIA
Risperidone is a novel benzisoxazole derivative that is

characterized as a potent central serotonin receptor antagonist with less potent dopamine D2 receptor antagonist
properties.448,449 The incidence of tardive dyskinesia with
risperidone is low. In all studies to date, no cases of tardive
dyskinesia have been conclusively attributed to risperidone. For example, in a Canadian multicenter, doubleblind clinical trial of risperidone, 135 hospitalized chronic
schizophrenic patients were randomly assigned to one of
six parallel treatment groups for 8 weeks: risperidone, 2,
6, 10, or 16 mg/day, haloperidol, 20 mg/day; or placebo.
Risperidone (6 to 16 mg)-treated patients showed signifCopyright 2005 by CRC Press LLC
607
icantly (P < 0.05) lower dyskinetic scores than those

receiving placebo, whereas in haloperidol- and placebotreated patients, no significant differences for dyskinetic
symptoms were noted.450
The efficacy of risperidone versus haloperidol and
amitriptyline in the treatment of patients with a combined
psychotic and depressive syndrome has been studied.451
In a multicenter, double-blind, parallel group trial, the
efficacy of risperidone was compared with a combination
of haloperidol and amitriptyline over 6 weeks in patients
with coexisting psychotic and depressive symptoms with
either a schizoaffective disorder, depressive type, a major
depression with psychotic features, or a nonresidual
schizophrenia with major depressive symptoms according
to DSM-III-R criteria. A total of 123 patients (62 risperidone; 61 haloperidol and amitriptyline) were included;
the mean daily dosage at endpoint was 6.9 mg risperidone
versus 9 mg haloperidol combined with 180 mg amitriptyline. Efficacy results for those 98 patients (47 risperidone; 51 haloperidol/amitriptyline) who completed at
least 3 weeks of double-blind treatment revealed, in both
treatment groups, large reductions in the Positive and
Negative Syndrome Scale-derived Brief Psychiatric Rating Scale (risperidone 37%; haloperidol/amitriptyline
51%) and the Bech-Rafaelsen Melancholia Scale total
scores (risperidone 51%; haloperidol/amitriptyline 70%).
The reductions in the Brief Psychiatric Rating Scale and
the Bech-Rafaelsen Melancholia Scale scores in the total
group were significantly larger in the haloperidol/amitriptyline group than in the risperidone group (P < 0.01),
mostly because of significant differences in the subgroup
of patients suffering from depression with psychotic features, whereas treatment differences in the other diagnostic subgroups were not significant.
The incidence of extrapyramidal side effects as
assessed by the Extrapyramidal Symptom Rating Scale
was slightly higher under risperidone (37%) than under
haloperidol/amitriptyline (31%). Adverse events were
reported by 66% of risperidone and 75% of haloperidol/amitriptyline patients. The results of this trial suggest
that the therapeutic effect of haloperidol/amitriptyline is
superior to risperidone in the total group of patients with
combined psychotic and depressive symptoms. However,
subgroup differences have to be considered.451 Risperidone also causes neuroleptic malignant syndrome.452454
CONCLUSIONS
A variety of neurological syndromes, involving particularly the extrapyramidal motor system, occur following
the use of many drugs, but especially with almost all
antipsychotic drugs. These drug-induced movement disorders are particularly prominent during treatment with
the high-potency agents (tricyclic piperazines and butyrophenones). There is less likelihood of acute extrapyra-
608
midal side effects with clozapine, thioridazine, or low

doses of risperidone.
Six varieties of neurological syndromes are characteristic of antipsychotic drugs. Four of these (acute dystonia,
akathisia, parkinsonism, and the rare neuroleptic malignant syndrome) usually appear soon after administration
of the drug, and two (rare perioral tremor and tardive dyskinesias or dystonias) are late-appearing syndromes that
occur following prolonged treatment.
The pharmacodynamics of drug-induced movements
are ill defined, and treatments are often unsatisfactory.
ACKNOWLEDGMENTS
The author gratefully acknowledges, appreciates, and
admires the unique, dedicated, and excellent secretarial
skills of Mrs. Dani Stramer. The studies cited in this paper
have been supported by a grant from USPHS no.
NS34566.
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Incidence of Acute Dystonia