Neuroleptic-Induced Movement Disorders

Neuroleptic-Induced Movement Disorders

Manuchair Ebadi

Departments of Pharmacology and of Neurosciences, University of North Dakota School of Medicine and Health Sciences

CONTENTS

AbstractTypes of Abnormal Movements

TremorChoreaDystonia and AthetosisHemiballismusMyoclonusTics

Basal Ganglia and Movement DisordersDopaminergic Transmission Involved in Movement Disorders

The Mesolimbic- and Mesolimbic-Cortical Dopamine PathwaysThe Nigrostriatal Dopamine PathwayNeuroleptic-Induced Regulation of Dopamine-Receptor Subtypes and Its Implication in SchizophreniaThe Modulatory Actions of Acetylcholine, Adenosine, Glutamate, and

δ

-Opioid on Striatal Dopaminergic TransmissionRegulation of Central Dopaminergic Neurons by Opioid ReceptorsThe Striatal Blockade of the Adenosine A2A Receptor in Parkinson’s Disease

The Neuropathology of Movement DisordersThe Pyramidal SystemThe Extrapyramidal SystemThe Cerebellar System

Diverse Classification of Drugs Causing Movement DisordersNeuroleptic-Induced Movement DisordersNeuroleptic-Induced Akathisia

Conditions Resembling AkathisiaClassification of AkathisiaDifferential Diagnosis of Akathisia

Treatment of Neuroleptic-Induced AkathisiaAntiparkinsonian AgentsAmantadine .Benzodiazapine DerivativesBeta-Adrenergic Receptor Blocking AgentsAlpha-Adrenergic Receptor Blocking AgentsL-Tryptophan Bupropion

Neuroleptic-Induced DystoniaIatrogenic Dystonia

46

Copyright © 2005 by CRC Press LLC

580

Parkinson’s Disease

Incidence of Acute DystoniaEnhanced Susceptibility to Develop DystoniaTardive DystoniaIdiopathic Orofacial Dystonia (Meige’s Syndrome)

Treatment of DystoniasBaclofen in the Treatment of DystoniaBotulinum Toxin in the Treatment of DystoniaPhenylalanine in Dopa-Response Dystonia (DRD)

Neuroleptic Malignant SyndromeDifferential Diagnosis of Neuroleptic Malignant SyndromeEvents Leading to or Enhancing the Severity of Neuroleptic Malignant SyndromeComplications of Neuroleptic Malignant SyndromeThe Pathogenesis of Neuroleptic Malignant Syndrome—The Role of Dopamine

Treatment of Neuroleptic Malignant Syndrome General TreatmentsSpecific TreatmentsL-Dopa/CarbidopaBromocriptine Dantrolene Sodium (Dantrium)AmantadineAnticholinergic AgentsBenzodiazepine Derivatives

Neuroleptic-Induced ParkinsonismIncidence of Parkinsonism

Treatment of ParkinsonismAntitremor Effects of ClozapineParkinsonism, Schizophrenia, and Dopamine

Neuroleptic-Induced Tardive Dyskinesia Drugs and Conditions Causing DyskinesiaHeterogeneity of Tardive DyskinesiaTardive Dyskinesia and DiabetesL-Dopa-Induced DyskinesiaTardive Oculogyric CrisisTardive Dyskinesia and Type II Schizophrenia

Mechanisms of Neuroleptic-Induced Dyskinesia

γ

-Aminobutyric Acid in the Pathogenesis of Tardive DyskinesiaDopamine, Peptides, Schizophrenia, and NeurolepticsNeuroleptic-Cholecystokinin InteractionNeuroleptic-Opioid Interaction

Treatment of Tardive DyskinesiaBuspirone in L-Dopa-Induced DyskinesiasVitamin E and DyskinesiaAmantadine in Tardive DyskinesiaClozapine in Axial Tardive DystoniaCholecystokinin in Tardive DyskinesiaRisperidone and Tardive Dyskinesia

ConclusionsAcknowledgmentsReferences

ABSTRACT

Parkinsonism, tremor, chorea-ballismus, dystonia, tardivedyskinesia, myoclonus, tics, and akathisia can be induced

by many drugs. The drugs that are most frequently impli-cated in movement disorders are antipsychotics, calciumchannel antagonists, orthopramides and substituted ben-zamides (e.g., metoclopramide, sulpiride, clebopride,



581

domperidone), CNS stimulants, antidepressants includingthe selective serotonin uptake inhibitors, anticonvulsants,antiparkinsonian drugs, and lithium. Moreover, extrapyra-midal reactions (EPR) have also been reported to occurwith the selective serotonin-reuptake inhibitors, and motordysfunction is caused by

tacrine

.

1–17

It is possible for asingle drug, such as one of the antipsychotics, to inducetwo or more types of movement disorders in the samepatient. Movement disorders are not always reversibleafter drug withdrawal.

Strong positive correlations exist between hyperki-netic forms of four extrapyramidal syndromes (EPS), tar-dive dyskinesia, parkinsonism, akathisia, and tardivedystonia. More specifically, the probability of havingakathisia, which is often neglected or misdiagnosed, ismarkedly increased in a patient suffering from tardivedyskinesia.

Furthermore, it is quite common for chronic psychiat-ric inpatients to suffer from combinations of EPS. There-fore, it is definitely advisable that neurologists andpsychiatrists dealing with such patient groups should befamiliar with treatment strategies for minimizing theseEPS 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 com-plications, are the “street drugs.” Most of these agentsmodulate central neurotransmitters, and some have directcerebrovascular effects. These characteristics are the basesof their potential to produce neurologic symptoms. Ofthese agents, the most notorious for its neurologic effectsand also one of the most commonly used is

cocaine

.In addition to nonhemorrhagic infarctions, subarach-

noid hemorrhage, intraparenchymal hemorrhage, andintraventricular hemorrhage;

18

single seizures, multipleseizures, and status epileptics;

19,20

migraine-like headachecaused by blockade of serotonin uptake mechanism;

21

optic neuropathy associated with osteolytic sinusitis;

22

and acute femoral neuropathy,

23

cocaine produces acutedystonia during administration

24

and after withdrawal.

24,25

In addition, cocaine-induced tics can occur in first-timeand chronic users.

26

The tics may be multifocal and bothvocal and motor in character. In some instances, the ticsmerely represent an uncovering of symptoms in a patientpreviously diagnosed as having

Tourette’s syndrome

, butin others, tics occur for the first time during cocaine use.Abstinence from cocaine usually results in resolution ofthis syndrome.

Ecstasy

is the name commonly used for 3,4-methyl-enedioxymethamphetamine (MDMA), a ring-substitutedamphetamine derivative. Although patented in 1914 as anappetite suppressant, the drug did not become popularuntil the 1970s, when it was marketed as an adjunct topsychotherapy because of its effects in lowering thedefensiveness of the patient, thus breaking the barriersbetween the patient and the therapist. Because of con-

cerns for its abuse potential and reports of neurotoxicityin animal studies, it was declared illegal in the mid-1980s.Despite its well-established neurotoxicity in animals, theacute or chronic effects of this drug have not been wellstudied in humans. Its recreational use, especially on col-lege campuses, and reports of cases associated withsevere toxicity and death have increased awareness of thedrug.

Overlapping symptoms of neuroleptic malignant syn-drome and serotonin syndrome have occurred in patientstaking MDMA.

27

Recognition of the potential neurologiccomplications of either prescription or illicit drugs isextremely important. Familiarity with the neurologicsymptoms that can result from prescription drugs used totreat neuropsychiatric patients makes it easier to deter-mine whether a given neurologic finding is a drug effector part of an underlying syndrome for which the drug hasbeen prescribed.

In this chapter, a brief description of the types ofabnormal movements seen by physicians is provided, fol-lowed by a comprehensive discussion of drug-inducedmovement disorders.

TYPES OF ABNORMAL MOVEMENTS

Movement disorders (sometimes called

extrapyramidaldisorders

) impair the regulation of voluntary motor activ-ity without directly affecting strength, sensation, or cere-bellar function. They include

hyperkinetic disorders

asso-ciated with abnormal, involuntary movement. Movementdisorders result from dysfunction of deep subcortical graymatter structures termed the

basal ganglia

. While there isno universally accepted anatomic definition of the basalganglia, for clinical purposes, they may be considered tocomprise the caudate nucleus, putamen, globus pallidus,subthalamic nucleus, and substantia nigra. The putamenand globus pallidus are collectively termed the

lentiformnucleus

; the combination of lentiform nucleus and caudatenucleus is designated the

corpus striatum

.

28

Abnormalmovements can be classified as

tremor

,

chorea

,

athetosis

or

dystonia

,

ballismus

,

myoclonus

, or

tics

.

29

T

REMOR

A tremor is a rhythmic oscillatory movement best char-acterized by its relationship to voluntary motor activity,i.e., according to whether it occurs at rest, during main-tenance of a particular posture, or during movement.Tremor that occurs when the limb is at rest is generallyreferred to as

static tremor

, or

resting tremor

. If presentduring sustained posture, it is called a

postural tremor

.While this tremor may continue during movement, move-ment does not increase its severity. When present duringmovement but not at rest, a tremor is generally called an

intention tremor

. Both postural and intention tremors are


582


also called

action tremors

. The causes of tremor are indi-cated in Table 46.1.

C

HOREA

The word

chorea

denotes rapid, irregular muscle jerksthat occur involuntarily and unpredictably in differentparts of the body. In florid cases, the often forceful invol-untary movements of the limbs and head and the accom-panying facial grimacing and tongue movements are

unmistakable. Voluntary movements may be distorted bythe superimposed involuntary ones. In mild cases, how-ever, patients may exhibit no more than a persistent rest-lessness and clumsiness. Power is generally full, but theremay be difficulty in maintaining muscular contractionsuch that, for example, hand grip is relaxed intermittently(milkmaid grasp). The gait becomes irregular andunsteady, with the patient suddenly dipping or lurchingto one side or the other (dancing gait). Speech oftenbecomes irregular in volume and tempo and may be

TABLE 46.1Major 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

Wilson’s disease

Intention tremor

Brain stem or cerebellar disease

Drug toxicity (e.g., alcohol, anticonvulsants, sedatives)

Wilson’s disease

Rest tremor

Parkinsonism

Wilson’s 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 thefingers, often less prominent in the wrists, and involves the forearm or upper arm only infrequently. The rate of the tremor averages about threeto 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 usuallymore 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 trueof the tremor, which frequently begins in one arm or leg and can remain predominantly unilateral for several years. It can become disabling onone 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 isaborted 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 hyperkinesiasstop during sleep with the exception of certain cases of hemiballismus. A number of psychologic factors increase the tremor. These includefatigue, cold, emotional stress of any sort, and almost anything that makes the patient nervous, including visits to his doctor. (For a review andreference, see Reference 29.)



583

TABLE 46.2Causes of Chorea

Heredity

Huntington’s disease

Benign hereditary chorea

Wilson’s disease

Paroxysmal choreoathetosis

Familial chorea with associated acanthocytosis

Static encephalopathy

(cerebral palsy) acquired antenatally or perinatally (e.g., from anoxia, hemorrhage, trauma, kernicterus)

Sydenham’s chorea

Chorea gravidarum

Drug toxicity

Levodopa and other dopaminergic drugs

Antipsychotic drugs

Lithium

Phenytoin

Oral contraceptives

Miscellaneous medical disorders

Thyrotoxicosis, hypoparathyroidism, or Addison’s 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

explosive in character. In some patients, athetotic move-ments or dystonic posturing may also be prominent. Cho-rea disappears during sleep. Table 46.2 shows the majorcauses of chorea.

D

YSTONIA

AND

A

THETOSIS

The term

athetosis

generally denotes abnormal move-ments that are slow, sinuous, and writhing in character.When the movements are so sustained that they are betterregarded as abnormal postures, the term

dystonia

is used,and the terms are often used interchangeably. The abnor-mal movements and postures may be generalized orrestricted in distribution. In the latter circumstance, oneor more of the limbs may be affected (

segmental dystonia

),or the disturbance may be restricted to localized musclegroups (

focal dystonia

). The causes of dystonia and athe-tosis include static perinatal encephalopathy (cerebralpalsy), Wilson’s disease, Huntington’s disease, Parkin-son’s disease, encephalitis lethargia drugs (levodopa, anti-

psychotic drugs), ischemic anoxia, focal intracranial dis-ease, progressive supranuclear palsy, idiopathic torsiondystonia (hereditary, sporadic), and formes frustes or idio-pathic torsion dystonia.

H

EMIBALLISMUS

Hemiballismus is unilateral chorea that is especially vio-lent because the proximal muscles of the limbs areinvolved. It is due most often to vascular disease in thecontralateral subthalamic nucleus and commonly resolvesspontaneously in the weeks following its onset. It is some-times due to other types of structural disease, and it wasan occasional complication of thalamotomy. Pharmaco-logic treatment is similar to that for chorea.

M

YOCLONUS

Myoclonic jerks are sudden, rapid, and twitch-like musclecontractions. They can be classified according to theirdistribution, relationship to precipitating stimuli, or etiol-


584


ogy.

Generalized myoclonus

has a widespread distribu-tion, while

focal

or

segmental

myoclonus

is restricted toa particular part of the body. Myoclonus can be sponta-neous, or it can be brought on by sensory stimulation,arousal, or the initiation of movement (

action myoclonus

).Myoclonus may occur as a normal phenomenon (

physio-logic myoclonus

) in a healthy person, as an isolated abnor-mality (

essential myoclonus

), or as a manifestation ofepilepsy (

epileptic myoclonus

). It can also occur as a fea-ture of a variety of degenerative, infectious, and metabolicdisorders (

symptomatic myoclonus

). The causes of generalmyoclonus are shown in Table 46.3.

T

ICS

Tics are sudden, recurrent, quick, coordinated abnormalmovements that can usually be imitated without difficulty.The same movement occurs again and again and can besuppressed voluntarily for short periods, although doingso may cause anxiety. Tics tend to worsen with stress,diminish voluntary activity or mental concentration, anddisappear during sleep. Tics can be classified into fourgroups, depending on whether they are simple or multipleand transient or chronic.

Transient simple tics

are verycommon in children, usually terminate spontaneouslywithin 1 year (often within a few weeks), and generallyrequire no treatment.

Chronic simple tics

can develop atany age but often begin in childhood, and treatment isunnecessary in most cases. The benign nature of the dis-order must be explained to the patient.

Persistent simple

or

multiple tics

of childhood or adolescence generallybegin before age 15 years. There may be single or multiplemotor tics, and often vocal tics, but complete remissionoccurs by the end of adolescence. The syndrome of

chronic multiple motor and vocal tics

is generally referredto as

Gilles de la Tourette’s syndrome

, after the Frenchphysician who was one of the first to describe its clinicalfeatures.

29

BASAL GANGLIA AND MOVEMENT DISORDERS

Great strides have been made in the last five decadestoward elucidating the neurochemistry of the pathwaysinvolved in motor function and movement disorders.

28,30–35

These pathways include those connecting motor cortex,brain stem, basal ganglia, and spinal cord. The basal gan-glia play an important role in the control of movementand complex motor behavior. Figure 46.1 shows a simpli-fied schematic diagram of the primary connections of thebasal ganglia. Each area of cerebral cortex, from the mostprimitive olfactory structures to the most highly organizedassociation cortex, has projections to one of a number ofdeep telencephalic gray matter nuclei, which include theputamen, caudate nucleus, nucleus accumbens, and theouter layers of the olfactory tubercle. These nuclei all havesimilar histochemical appearances and neurochemicalproperties. In addition, each of these nuclei also gets inputfrom dopaminergic neurons in the midbrain and from theinterlaminar nuclei of the thalamus. The caudate nucleus,putamen, nucleus accumbens, and outer tubercle can com-prise the striatum.

The principal components of the basal ganglia arethe striatum, the pallidum, the substantia nigra, and thesubthalamic nucleus. The basal ganglia are neither amajor sensory relay nor a coordinating neuronal system,such as the cerebellum, and they do not have directaccess to the motor neurons of the spinal cord. Because

TABLE 46.3Causes of General Myoclonus

Physiologic myoclonus

Nocturnal myoclonus

Hiccup

Essential myoclonus

Epileptic myoclonus

Symptomatic myoclonus

Degenerative disorders

Dentatorubrothalamic atrophy (Ramsay Hunt syndrome)

Storage diseases (e.g., Lafora body disease)

Wilson’s disease

Huntington’s disease

Alzheimer’s 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 toprecipitating stimuli, or etiology.

Generalized myoclonus

has a wide-spread distribution, while

focal

or

segmental myoclonus

is restrictedto a particular part of the body. Myoclonus can be spontaneous, orit can be brought on by sensory stimulation, arousal, or the initiationof movement (

action myoclonus

). Myoclonus may occur as a normalphenomenon (

physiologic myoclonus

) in healthy persons, as an iso-lated abnormality (

essential myoclonus

), or as a manifestation ofepilepsy (

epileptic myoclonus

). It can also occur as a feature of avariety of degenerative, infectious, and metabolic disorders (

symp-tomatic myoclonus

). (For a review and reference, see Reference 29.)



585

they lie just under the cerebral cortex and directly amongthe flow of corticifugal fibers, the basal ganglia are ide-ally located “to interact or act” in conjunction with thecerebral cortex.

Anatomically, this set of subcortical structures isinvolved in a closed corticobasal ganglia-thalamo-corticalloop, whose major axis is composed of sequentiallyarranged elements, namely the striatum, the globus palli-dus or pallidum, the substantia nigra, and the ventral tiernuclei of the thalamus. Despite their privileged relation-ship with the cortex, it is not yet known how the basal gan-glia complement the function of the cerebral cortex (for areview, see Reference 34). In addition to the anatomicalsubstrate that allows information from the cerebral cortexto flow along the corticobasal ganglia-thalamo- cortical

loops, there exist other structures that exert a profoundmodulatory influence upon the activity of the core struc-tures of the basal ganglia. These structures are the subtha-lamic nucleus, the pars compacta of the substantia nigra,the centromedian/parafascicular thalamic complex, thedorsal raphe nucleus, and pedunculopontine tegmentalnucleus (for a review, see Reference 36). These ancillarystructures provide the basal ganglia with a wide variety ofneurochemical inputs: (a) the subthalamic nucleus and thecentromedian/parafascicular thalamic complex provide aglutamatergic entry;

37–39

(b) the dorsal raphe nucleus is theorigin of a serotoninergic input;

40

(c) the pedunculopon-tine tegmental nucleus gives rise to a dual cholinergic andglutamatergic afferent;

41,42

and the substantia nigra is amajor source of dopamine at basal ganglia levels

.

43

Each

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 withinthe 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 willedmovements.

The basal ganglia consist of the caudate nucleus, the putamen, the globus pallidus, and the subthalamus. In addition, we can addthe substantia nigra, a midbrain structure that is reciprocally connected with the basal ganglia of the forebrain. The caudate andputamen together are called the striatum, which is the target of the cortical input to the basal ganglia. The globus pallidus is thesource 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 thisbland 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 circuitsare involved in certain aspects of memory and cognitive function. (For reviews and references, see References 28 and 30 through 35.)


586 Parkinson’s Disease

element of the main axis of the basal ganglia is thus thefocus of a highly complex interplay between these variouschemospecific inputs and the striatal afferents that useGABA as a transmitter (see Figure 46.1). Diseases affect-ing one or more of the marked neurochemical imbalancesare the hallmark of several basal ganglia disorders, includ-ing Parkinson’s disease.29,44

DOPAMINERGIC TRANSMISSION INVOLVED IN MOVEMENT DISORDERS

Drugs causing movement disorders influence dopaminer-gic transmission. The main dopaminergic neurons in thebrain are the following:

1. The ultrashort dopaminergic fibers, such as theinterplexiform amacrine-like neurons, whichlink inner and outer plexiform layers of theretina, and the periglomerular dopamine cellsof the olfactory bulb

2. The intermediate-length dopaminergic fibers,such as tuberohypophysial dopamine cells,incertohypothalamic neurons, and the medul-lary peri ventricular neurons

3. The long dopaminergic fibers linking the ven-tral tegmental and substantia nigra dopaminecells with three principal sets of targets: theneostriatum (principally the caudate and puta-men); the limbic cortex (medial prefrontal, cin-gulate, and entorhinal areas); and other limbicstructures (the regions of the septum, olfactorytubercle, nucleus accumbens septi, amygdaloidcomplex, and piriform cortex)

These latter two groups have been termed the mesocorticaland mesolimbic dopamine projections, respectively.45

THE MESOLIMBIC- AND MESOLIMBIC-CORTICAL DOPAMINE PATHWAYS

These pathways originate primarily from the A10 dopam-ine neuron group (ventral tegmental area). The mesolim-bic tract mainly innervates the nucleus accumbens andolfactory tubercle and is considered to be involved inarousal, locomotor activity, and motivational and affectivestates. The mesolimbic-cortical pathway innervates sep-tum, hippocampus, amygdala, and many cortical regions(such as the prefrontal and cingulate cortices) and isimportant in higher cortical functions. It has been sug-gested that blockade of, in particular, limbic and prefrontaldopamine D2 receptors might be the mode of action forthe therapeutic effects of antipsychotic compounds.

THE NIGROSTRIATAL DOPAMINE PATHWAY

The nigrostriatal dopamine pathway originates from theA9 dopamine neuron group (substantia nigra) and projectsprimarily to the striatum (nucleus caudatus, putamen, andglobus pallidus). The striatum is thought to be criticallyinvolved in the regulation of movement and may alsosubserve some cognitive processes. The nigrostriatal tractis believed to be associated with the production of extra-pyramidal side-effects by antipsychotic drugs46 (seeFigure 46.2).

NEUROLEPTIC-INDUCED REGULATION OF DOPAMINE-RECEPTOR SUBTYPES AND ITS IMPLICATION IN SCHIZOPHRENIA

Dopamine receptors (DA-R) belong to the G protein-cou-pled receptor family, which includes many receptors suchas adrenergic, serotoninergic, and neuropeptidergic recep-tors. The common structural features of the G protein-coupled receptors are (a) the seven hydrophobic trans-membrane domains, (b) the extracellular N-terminusdomain with glycosylation sites, (c) the cytoplasmic C-tenninus domain, and (d) the G protein coupling sites inthe third cytoplasmic loop. All the known DA-R subtypesconsist of a polypeptide chain containing about 400 aminoacids (–50 kDa) and carbohydrate chains (for review, seeReferences 47–52). The size of most receptor moleculesdetected with anti-D2-R antibodies (anti-D2-R) varieswithin the range of 90 to 120 kDa, depending on thetissues,53,54 which is far larger than the molecular weightexpected from the amino acid sequence. Therefore, D2-Ris likely to contain carbohydrate chains of various sizes.Although these carbohydrate chains are believed to haveno effect on ligand affinity, it is important to clarify theirroles in the receptor function.

Dopamine receptors were initially classified into vari-ous 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, andthe D2-R group, which inhibits (or has no effect on) theactivity of adenylate cyclase.55,56 Cloning of receptorgenes in recent years has led to the identification of newsubtypes not previously identified by conventional phar-macological and biochemical methods. At present, thereare five DA-R subtypes, and they are classified into theD1-R family (D1-R and D5-R) and D2-R family (D2-R, D3-R and D4-R) based on their structures and pharmacologi-cal features. The third cytoplasmic loop is “short” in theD1-R family and “long” in the D2-R family. It is generallybelieved that receptors with a short third cytoplasmic loopcouple to stimulatory G proteins (Gs) and activate adeny-late cyclase. On the other hand, receptors with a longthird cytoplasmic loop react to G1 and Go, which inhibitadenylate cyclase, and Gq, which couples with phospholi-


Neuroleptic-Induced Movement Disorders 587

pase C.57 D2-R also activates K+ channels.57 While thestructures of the extra- and intracellular loops of the DA-R vary with each receptor, the trans-membrane domainsare highly homologous among most receptors. The sub-types belonging to the D1-R and D2-R families show over-all sequence homology of about 50% within the familiesand 30% between the families. It is believed that an aspar-tate in the third transmembrane domain forms an ion pairwith the protonated amine group of DA and that twoserines in the fifth transmembrane domain form a hydro-gen bonding interaction with two phenol groups ofDA.57,58 The latter interaction is specific for DA and itsagonist. On the other hand, an aspartate in the secondtransmembrane domain of D2-R has been shown to inter-act with antagonists.59 In humans, the genes of the fiveDA-R subtypes are located on different chromosomes. Ingeneral, the genes for G protein-coupled receptors haveno introns. The genes of the D1-R family (D1-R and D5-R)also lack introns. On the other hand, a specific feature ofthe genes of the D2-R family is the presence of introns intheir coding regions; the D2-R, D3-R, and D4-R geneshave 6, 5, and 4 introns, respectively.60,61 The presence of

these introns strongly suggests that the gene products ofeach subtype of the D2-R family undergo post-transla-tional splicing, resulting in a greater number of receptorisoforms.

The dopaminergic hypothesis of schizophrenia postu-lates that an aberration of the brain’s dopamine transmit-ter systems is key to the pathophysiology ofschizophrenia. A cornerstone of this hypothesis, whichhas guided research in the field of neuropsychiatry formore than four decades, is the observation that therapeu-tic potency of antipsychotic drugs directly correlates withtheir affinity for dopamine D2-R. This observation impliesthat the different antipsychotics achieve their therapeuticeffects at doses that produce similarly high levels of D2-Roccupancy, an effect which, under chronic treatment con-ditions, can be expected to result in receptor up-regula-tion.

Indeed, antipsychotic drugs at clinically recom-mended doses occupy at least 70% of striatal D2-R andsignificantly up-regulate these sites.62 While the dopamin-ergic hypothesis of schizophrenia has not lost its cur-rency, its original premise has been challenged by the

FIGURE 46.2 The main ascending dopaminergic pathways in rat brain. Dopaminergic neurons with intermediate-length axonsinclude the tuberoinfundibular and hypophysial, incertohypothalamic cells, and the medullary peri ventricular group. The tuberoin-fundibular neurons have a neurohumoral function; they secrete dopamine into a portal vascular system that supplies the anteriorpituitary. 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 tegmentalarea. These systems have long axons that innervate the basal ganglia, parts of the limbic system, and the frontal cortex. The neostriatalsystem, which has cell bodies in the substantia nigra, innervates the caudate and putamen. This suggests that dopamine released fromneostriatal areas has motor functions. The motor problems associated with Parkinson’s disease are caused by a decrease in dopaminein these areas. Administration of the dopamine precursor L-Dopa bypasses tyrosine hydroxylase and alleviates some of the motordisturbances of Parkinson’s disease. The specificity and complexity of the dopaminergic systems is further demonstrated by themesolimbic system. These neurons originate in the ventral tegmental area of the midbrain, next to the substantia nigra. Long axonsfrom 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 dopaminein this area provides positive feelings of reinforcement. (For review and reference, see Reference 46.)



discovery that therapeutically effective doses of the mostbeneficial atypical antipsychotic, clozapine, are signifi-cantly smaller than would be predicted on the basis of itsrelatively low affinity for D2-R. The D2- R occupancy ofthis drug in the striatum is only 50 to 66% of that pro-duced by other antipsychotics, and clozapine does not up-regulate striatal D2-R. Evidence from studies of receptoroccupancy and regulation in postmortem brains of

patients with neuropsychiatric disorders and in nonhumanprimates is providing new leads in the ongoing quest tounderstand the pathophysiology and causes of schizo-phrenia and to develop more effective methods of treat-ment (Table 46.4).

These studies suggest that the cerebral cortex is thesite of action of antipsychotic medications and indicatethat chronic treatment with these drugs differentially reg-

TABLE 46.4Effect 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

Antipsychotics—typicalChlorpromazineHaloperidolMelindonePimozide

PhenothiazinesButyrophernonesIndolesDiphenylbutyl-piperidines

↑↑↑↑

↑↑↑↑

↑↑←←

←←←←

←←←←

Antipsychotics—atypicalClozapineOlanzapineRemoxiprideRisperidone

DibenzodiazepinesThienobenzodiazepinesSubstituted benzamidesBenzisoxazoles

↑↑←←

↑↑←←

↑↑←↑

←←←←

←←←←

Nonantipsychotic D2 receptor antagonistTiapride Substituted benzamides ↑ ↑ ↑ ← ←

Antipsychotics—typicalChlorpromazineHaloperidolMelindonePimozide

PhenothiazinesButyrophernonesIndolesDiphenylbutyl-piperidines

↑↑↑↑

↑↑↑↑

↑↑←←

↓↓↓↓

↓↓↓↓

Antipsychotics—atypicalClozapineOlanzapineRemoxiprideRisperidone

DibenzodiazepinesThienobenzodiazepinesSubstituted benzamidesBenzisoxazoles

↑↑↑↑

↑↑

↑

↑↑←↑

↓↓↓↓

↓↓↓↓

Nonantipsychotic D2 receptor antagonistTiapride Substituted benzamides ← ↑ ↓ ↓

↑ = 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 mechanismsunderlying this disorder. The DA hypothesis has undergone numerous revisions but has proven remarkably resistant to obliteration. In its originalformulation, the hypothesis stated that schizophrenia is due to a central hyperdopaminergic state. This was based on two complementary lines ofindirect pharmacological evidence: the DA releaser amphetamine as well as other DA-enhancing agents such as the DA precursor L-dopa ormethylphenidate, produced and exacerbated schizophrenic symptoms, whereas drugs that were effective in the treatment of amphetamine-inducedpsychosis and schizophrenia [neuroleptics or antipsychotic drugs (APDs)] decreased DA activity, and their clinical potency was correlated withtheir potency in blocking D2 receptors.

Recently, it has been suggested that schizophrenia may involve a hypodopaminergic state in the dorsal striatum coupled with a hyperdopaminergicstate 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 struc-ture. Up-regulation of the cortical dopamine D2-R isaccompanied by a down-regulation of the D1 sites. Bal-ancing the opposing actions of dopamine D1 and D2-Rregulation may hold the key to optimal drug therapy andto understanding the pathophysiology of schizophrenia(see Reference 62 and Table 46.4).

THE MODULATORY ACTIONS OF ACETYLCHOLINE, ADENOSINE, GLUTAMATE, AND δ-OPIOID ON STRIATAL DOPAMINERGIC TRANSMISSION

The striatum is viewed as a structure performing fast neu-rotransmitter-mediated operations through somato-topi-cally organized projections to medium-size spiny neurons.Modulatory influences act indirectly by setting the excit-ability of the neuron to incoming phasic input mediatedby fast neurotransmitter actions. Modulatory influenceshave relatively long kinetics of action/desensitization,being related to modulation by voltage-operated ion chan-nels as in the case of muscarinic and DA receptors or tooperation of voltage-gated ion channels as in the case ofN-methyl-D-aspartate (NMDA) receptors. Modulatoryinfluences on neuronal excitability might not even belabeled as facilitatory (+) or inhibitory (–), their actualsign depending on the membrane potential. Modulatoryactions can have long-lasting transcriptional effects thatmight be the basis for adaptive and plastic changes. Thecaudate-putamen is one of the areas of the brain rich inmodulatory receptors such as acetylcholine, adenosine,GABA, glutamate, neurotensin, opioid, substance P, andsomatostatin (for review, see References 35 and 63through 65). A few examples will be cited to support thiscontention. Parkinson’s disease is a disease of extrapyra-midal motor function characterized by difficulties in ini-tiating and smoothly sustaining motions. It is associatedwith severe loss of dopamine-containing neurons in thesubstantia nigra. Parkinson’s disease can be treated withthe dopamine precursor L-dopa, but this does not stopdisease progression, its effectiveness ultimately decreases,and it may produce psychosis.66 Parkinson’s disease is alsoassociated with a large (approximately 50%) loss of high-affinity nicotine binding sites from the brain.67,68

A central role in the modulatory operations takingplace in the striatum is played by acetylcholine neurons.Acetylcholine neurons account for 1 to 2% of the striatalneuronal population. In all species examined, they areamong the largest neurons of the striatum both for the sizeof the perikaryon (about 30 µm in its longest dimension)and the area of distribution of the dendritic tree (up to0.5 mm2). Striatal acetylcholine neurons are interneurons,although a subpopulation of them also projects to neocor-tex. Striatal acetylcholine neurons receive three majorsynaptic inputs: (1) from intrinsic medium-size spinyneurons that use substance P and GABA as transmitters,

and project to the substantia nigra pars reticulata andentopeduncular nucleus (medial pallidal segment of pri-mates), (2) from extrinsic DA neurons of the mesencepha-lic tegmentum (A8, A9, and A10 groups), and (3) fromextrinsic excitatory (glutamate) neurons of the intralami-nar thalamus (parafascicular complex) and, to a lesserextent, of the cortex. The output of acetylcholine neuronsare the medium-size spiny neurons and the medium-sizespiny interneurons containing somatostatin/neuropeptideY (NPY) and neurotensin or GABA, which might beinterposed between the acetylcholine neurons andmedium-size spiny neurons (see Figure 46.3).

Stimulation of the striatum will evoke a short-latencyinhibitory postsynaptic potential in zona compactadopaminergic neurons and in zona reticulata neurons.69

However, overstimulation of the striatum will actuallycause an activation of DA neuron firing, and the said acti-vation occurs with an inhibition of GABAergic neurons inthe zona reticulata that normally inhibit the activity ofdopaminergic neurons.69,70 These GABAergic inhibitoryneurons may represent collaterals of nigrothalamicneurons71 or a short-axon interneuron located near thezona compacta.

Therefore, stimulation of striatum exerts two electro-physiological actions on DA neurons, which are a directGABAergic inhibition and an indirect disinhibition.72 Thestriatum is known to send a large number of GABAergicinhibitory projections to the globus pallidus, which in turnsends GABAergic fibers to the subthalamic nucleus.73–75

Lesions of the nigrostriatal DA system activate the striato-pallidal pathway, thereby disinhibiting the subthala-mus.76,77 Single-pulse stimulation of the subthalamus hasbeen shown to produce short-latency excitation of bothdopaminergic and nondopaminergic neurons within thesubstantia nigra,78–80 and glutamatergic excitatorypostsynaptic potentials have been associated to DA neu-rons recorded in vitro72,81,82 (see also Figure 46.3).

The operations performed by cortico-striatal projec-tions and medium-size spiny neurons are regarded to beof a fast-neurotransmitter-like nature. Thus, corticallyelicited fast EPSPs recorded from medium-size spinyneurons are mediated by glutamate receptors of the D, L-α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid(AMPA) subtype; in turn, these neurons use GABA astheir fast inhibitory transmitter. Transmission throughNMDA receptors can be regarded as modulatory in viewof its voltage dependency and of its ability to act as a gainamplifier of excitatory phasic input, thus promoting burstfiring. This transmission is largely inoperative in restingstriatal medium-size spiny neurons, due to Mg2+ blockageof NMDA channels in hyperpolarized conditions. By con-trast, acetylcholine neurons are already tonically activeand depolarized to near threshold in basal conditions,making NMDA transmission fully operative in acetylcho-line neurons and therefore capable of promotion burst fir-



ing in response to low amplitude excitatory input. Fullyactive NMDA transmission might thus contribute to amajor property of striatal acetylcholine neurons, thatbeing, in contrast with medium-size spiny neurons,exquisitely sensitive to excitatory phasic input. This phe-nomenon supports the suggestion that, although medium-size spiny neurons express NMDA receptors and receive amassive glutamate projection, they are likely to be influ-enced by noncompetitive NMDA-receptor antagonistsonly indirectly as a result of a primary action of acetyl-choline neurons.64

REGULATION OF CENTRAL DOPAMINERGIC NEURONS BY OPIOID RECEPTORS

Manzanares et al.63 and Pan65 have discussed the regula-tion of central dopaminergic neurons by opioid receptors.Three pharmacologically distinct subtypes of opioidreceptors (µ, κ, and σ) have been identified in the CNS.Until recently, the study of the regulation of dopaminergicneurons by subtypes of opioid receptors has been limitedby the lack of specific agonists and antagonists for thesereceptors. The development of selective µ−, κ−, and σ-opioid receptor agonists and antagonists has now permit-

ted exploration of the role played by each of these opioidreceptor subtypes in the modulation of central dopamin-ergic neurons. To date, much of what is known regardingthe effects of opioids on dopaminergic neurons has beenbased on studies using compounds that act at either µ- orσ-opioid receptors (see Figure 46.1).

Activation of µ-opioid receptors stimulates mesolim-bic, nigrostriatal, and incertohypothalamic dopaminergicneurons; inhibits tuberoinfundibular dopaminergic neu-rons; and has no effect on periventricular-hypophysialdopaminergic neurons. On the other hand, activation of κ-opioid receptors inhibits the basal activity of peri ventric-ular-hypophysial dopaminergic neurons and the pharma-cologically stimulated activities of mesolimbic,nigrostriatal, and tuberoinfundibular dopaminergic neu-rons. In contrast, comparatively less is known about therole of σ-opioid receptors in regulating dopaminergicneuronal systems in the brain. Administration of the σ-opioid selective agonist [D-Pen2, D-Pen5] enkephalin(OPDPE) increases the release of DA in the nucleusaccumbens but has no effect in the striatum. No informa-tion is available regarding the effects of activation orblockade of σ-opioid receptors on the activities of hypo-thalamic dopaminergic neurons.

FIGURE 46.3 Striatal cholinergic transmission. Acetylcholine is the familiar transmitter at the neuromuscular junction, at synapsesin autonomic ganglia, and at postganglionic parasympathetic synapses. Cholinergic interneurons also exist within the brain, in thestriatum and the cortex, for example. In addition, there are two major diffuse modulatory cholinergic systems in the brain, one ofwhich is called the basal forebrain complex. It is a “complex” because the cholinergic neurons lie scattered among several relatednuclei 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 thecholinergic innervation of the neocortex. (For reviews and references, see References 69, 81, and 82.)



THE STRIATAL BLOCKADE OF THE ADENOSINE A2A RECEPTOR IN PARKINSON’S DISEASE

The GABA-enkephalin neurons (see Figure 46.1) areexcited by cortical inputs and inhibited by recurrent col-laterals (via GABAA receptors). In Parkinson’s disease,the feedback inhibition of striatal neurons by the recurrentcollaterals may be insufficient to control the overactivityof these neurons. This overactivity probably arises froma reduction in the DA-R-mediated control of acetylcholineand glutamate release (from cortical and thalamic affer-ents) and in D2-R-mediated inhibition of striatal neurons.Such overactivity may also be partly due to reduced D1-R-mediated stimulation of striatal GABA release, and tothe action of muscarinic acetylcholine receptors that sta-bilize an excitable state of the striatal neurons. It has beenrecently shown that blockage of the A2A receptor increasesthe release of GABA from striatal synaptosomes andincreases inhibitory input into medium spiny neurons.Therefore, A2A receptor blockage serves to increase theGABA-mediated feedback control of the striatal outputneurons.

This mode of action is intrinsically different from thatof the DA-related modulators used in most parkinsoniantherapies, as feedback inhibition is a function of thedegree of excitation of individual striatal neurons. Thus,the effect of an A2A receptor antagonist may be restrictedto the control of the recurrent collaterals of those neuronsthat are highly active. The reduction in acetylcholinerelease caused by A2A receptor blockage may also con-tribute to this inhibition of medium spiny neurons, byreducing cholinergic stimulation and thus the ability ofacetylcholine to maintain the excitable state of the outputneurons. In the absence of DA, the facilitatory drive of theD1 receptors on the striatal GABAergic, substance P-con-taining neurons of the direct pathway is also lost, causingthese cells to become less excitable. Although the A2A

receptor probably has no direct effect on this pathway, itopposes the behavioral effects of D1-R stimulation, stri-atal neurons and the cholinergic interneurons.35

THE NEUROPATHOLOGY OF MOVEMENT DISORDERS

The term extrapyramidal system to be described in thefollowing section was first coined by Samuel AlexanderKinnier Wilson in 1912 in describing the neurologicaldisorder of hepatolenticular degeneration (Wilson’s dis-ease). Lesions in the pyramidal system, extrapyramidalsystem, or cerebellar system result in distinctive distur-bances of motor activity.29.83

THE PYRAMIDAL SYSTEM

The pyramidal tract derives its name from the fact thatconstituent fibers pass through the medullary pyramid, a

prominent bulge on the ventral surface of the medullaoblongata. Its fibers arise in the cerebral cortex, principallyfrom that area around the central sulcus that constitutesthe motor cortex. The fibers then descend through thebrain stem and, after a partial decussation in the medulla,continue through the spinal cord and finally terminateabout the lower motor neurons. Injury to this tract pro-duces paralysis of voluntary movement. As a result, thepyramidal system is believed to be concerned with theinitiation of voluntary movements.

THE EXTRAPYRAMIDAL SYSTEM

The extrapyramidal system is made up of a number ofpaired nuclei and associated pathways. The major struc-tures of this system include putamen, globus pallidus,substantia nigra, and subthalamic nuclei (corpus Luysii)(Figure 46.1). The caudate and putamen together arereferred to as the striatum or neostriatum, whereas theglobus pallidus is often referred to as the pallidum. Theterm basal ganglia is often used to refer to the extrapyra-midal system. Strictly speaking, the basal ganglia are anumber of large, paired masses of gray matter in theforebrain and include the caudate, putamen, and globuspallidus, as well as the amygdala. This latter structure isfunctionally a part of the limbic system so that the termbasal ganglia usually refers only to the first three pairs ofnuclei. Lesions of the extrapyramidal system often resultin abnormal movements that usually are present at rest.Such lesions also result in abnormalities of station andpostural reflexes. The extrapyramidal system then isthought to be concerned with maintenance of posture asopposed to initiation or coordination of voluntary move-ment.

THE CEREBELLAR SYSTEM

The cerebellar system is composed of the cerebellum andits afferent and efferent pathways, as well as associatedstructures such as the red nuclei and the inferior olives.Lesions of this system result in tremor with movement,incoordination, dyssynergia, and ataxia. The cerebellarsystem is believed to be concerned with the coordinationof movements as opposed to the initiation of involuntarymovement. Although clinical experience has demonstrateda high degree of interdependence among these three motorsystems, the term extrapyramidal disease, however, stillserves the useful purpose of tying together a number ofclinically defined disease states of diverse etiology andobscure pathogenesis. Causing abnormal movements,these states share a number of related symptoms, and themajor pathological changes noted in these diseases are allpresent within the extrapyramidal nuclei. The clinicalsigns and symptoms that help to tie these disease statestogether fall into the following groups: (a) hyperkinesia,



abnormal involuntary movements, (b) akinesia, slownessor poverty of spontaneous movement, (c) rigidity, and (d)loss of normal postural reactions.83 Movement disordersmay be classified broadly as the syndrome of parkin-sonism or an akinetic rigid syndrome and those disorderscausing a variety of abnormal involuntary movements or“dyskinesias,” including tremor, dystonia, athetosis, cho-rea, ballism, tics, and myoclonus. For a comprehensiveclassification of parkinsonism, diseases causing parkin-sonism and dementia, differential diagnosis of tremor, eti-ological classification of chorea, features distinguishingtardive dyskinesia and Huntington’s disease, causes ofballism, etiological classification of dystonia, classifica-tion of tics, etiological classification of myoclonus, dif-ferential diagnosis of paroxysmal dyskinesia, startle andrelated syndrome, and finally, abnormal involuntary move-ments in sleep, refer to a review by Lang and Weiner.5

DIVERSE CLASSIFICATION OF DRUGS CAUSING MOVEMENT DISORDERS

Drugs causing or aggravating movement disorders havediversified classification (Table 46.5) and mechanisms ofactions.14 For example: Norpseudoephedrine causes per-sistent dyskinetic syndromes such as spasmodic torticollisand cranial dystonia.14 Tiagabine, an indirect GABAreceptor agonist, has been shown to inhibit haloperidol-induced oral dyskinesias,84

A variety of neurological syndromes, involving par-ticularly the extrapyramidal motor system, occur follow-ing the use of almost all antipsychotic drugs. Thesereactions are particularly prominent during treatment withthe high-potency agents (tricyclic piperazines and buty-rophenones). There is less likelihood of acute extrapyra-midal side effects with clozapine, thioridazine, or lowdoses of risperidone. Six varieties of neurological syn-dromes are characteristic of antipsychotic drugs. Four ofthese (acute dystonia, akathisia, parkinsonism, and therare neuroleptic malignant syndrome) usually appearsoon after administration of the drug, and two (rare perio-ral tremor and tardive dyskinesias or dystonias) are late-appearing syndromes that occur following prolongedtreatment.

Mianserin, a tetracyclic antidepressant, whichincreases the release of noradrenaline by blocking alpha-2adrenoceptors,85,86 has been shown to activate a latentinvoluntary movement disorder in predisposed persons.87

NEUROLEPTIC-INDUCED MOVEMENT DISORDERS

The treatment of schizophrenic patients with neuroleptics(antipsychotics) has had a decisive impact on psychiatryin that the number of patients hospitalized has decreased

dramatically, and the number treated on an outpatient basishas increased steadily. However, a variety of neurologicalsyndromes, involving particularly the extrapyramidal sys-tem, occur after either acute or chronic administration ofneuroleptics, and the most serious syndromes includeakathisia, dystonia, neuroleptic malignant syndrome, par-kinsonism, and tardive dyskinesia.88–90 Despite awarenessthat neuroleptics could produce extrapyramidal sideeffects, these drugs remain the most effective means oftreating schizophrenic patients. Moreover, “atypical neu-roleptics” such as clozapine (8-chloro-11 (4-methyl-1-pip-erazinyl)-5H-dibenzo (b,e)(1,4)diazepine) and risperi-done, which cause substantially fewer numbers ofpotentially incapacitating side effects such as neurolepticmalignant syndrome, have been synthesized and mar-keted. In addition to accepting the involvement of dopam-inergic receptors in the pathogenesis of neuroleptic-induced movement disorders, recent reports have impli-cated serotoninergic, GABAergic, glutamatergic, and pep-tidergic transmissions in the appearance, manifestation,and treatment of neuroleptic-induced movement disorders.By having a comprehensive understanding of pharmaco-kinetic and pharmacodynamic principles unique to anti-psychotics, the neuroleptic-induced movement disordersmay be minimized vastly and their potentially lethal neu-rotoxicity averted altogether.

NEUROLEPTIC-INDUCED AKATHISIA

Kathisia is a Greek word that may be translated as the actof sitting, and akathisia means literally an inability toremain seated.91,92 Patients with neuroleptic-inducedakathisia may describe vague feelings such as “inner ten-sion,” “emotional uneasiness,” “all wound up like aspring,” “unable to relax,” “having a hurry-up feeling,” or“uncomfortable in any position.” In addition to an inabilityto sit still, akathisia is characterized by shifting of legsand tapping of feet while sitting, and by rocking andshifting weight while standing. Although the term akathi-sia was first used by Haskovec,93 spontaneously occurringsyndromes of restlessness were reported long before theintroduction of neuroleptics in 1955. For example, in1880, Beard described it as a fidgetiness and nervousness,inability to keep still—a sensation that amounts to pain-is sometimes unspeakably distressing. When the legs feelthis way, the sufferer must get up and walk or run, evenif he is debilitated. This was confirmed 75 years later bya warning that akathisia can be more difficult to endurethan any of the symptoms for which the patient was orig-inally treated.94

Akathisia may occur after administration of any neu-roleptic but is especially found with more potent neuro-leptics.95–97 The prevalence has been reported as 12.5%,20%,96,98–99 or 75%100 with more potent neuroleptics suchas haloperidol. Indeed, by lowering the dose of a potent



TABLE 46.5Examples of Drug-Induced Movement Disorders

1. Drugs associated with induction of akathisia:

MetoclopramideDopamine storage and transport inhibitors: a-methyltyrosine, reserpine, tetrabenazineLevodopa and dopamine agonistsAntidepressants:

selective serotonin reuptakeinhibitors, tricyclic antidepressants

Lithium2. Drugs associated with induction of chorea:

Dopamine antagonists (including antipsychotics)Dopamine agonists:

levodopa, direct dopamine agonistsCNS stimulants:

amphetamines, pemoline, methylphenidate, cocaine, xanthines AnticholinergicsHI antihistamines H2 antihistaminesOral contraceptivesAnticonvulsants:

phenytoin3. Drugs that can induce myoclonus:

Antidepressants:cyclic antidepressantsselective serotonin reuptake inhibitors, monoamine oxidase inhibitors, Levodopa

Bismuth saltsAnticonvulsants:

valproic acid (sodium valproate), carbamazepine, phenytoinLithiumMorphine or its derivatives, antineoplastic drugsBromocriptine

4. Drugs associated with induction or aggravation of Parkinsonism

AntipsychoticsCalcium 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

Methyldopa5. Drugs associated with the development of tardive dyskinesia

Antipsychotic drugsOrthopramides and substituted benzamides:

metoclopramide, clebopride, sulpiride, veraliprideCalcium channel antagonists:

flunarizine, cinnarizineAntidepressants:

cyclic antidepressants6. Drugs associated with induction of acute and/or tardive dystonia

Antipsychotic drugsOrthopramides and substituted benzamides:

metoclopramide, sulpiride, tiapride, cisapride, domperidone, veralipride, and dopamine agonists: levodopaDirect dopamine agonistsAntidepressants:

selective serotonin reuptake inhibitors, tricyclic antidepressants, monoamine oxidase inhibitorsAnticonvulsants:

carbamazepine, phenytoin



neuroleptic,99 or by switching the patient to a lower-potency neuroleptic,96 it is possible to treat akathisia. Thesyndrome of akathisia is composed of both subjectivefeelings and the psychological experience of inner rest-lessness and objective motor signs such as jiggling orshaking of the legs when seated and rocking from foot tofoot when standing.92 In milder forms of akathisia, thepatients may only have subjective complaints, whereas, inmoderate and severe forms, both subjective feelings ofrestlessness and objective movements exist.91,101 Akathisia

can be a quite common and very troubling side effect ofpsychotropic treatment. Clinicians have become steadilymore aware of this disorder, owing to descriptions of rest-less movement disorder originating in the first half of thiscentury. Delineation of acute akathisia is crucial for pro-viding patients with the best interventions.

The pathophysiology of akathisia is not completelyunderstood but likely arises from complex interactions insubcortical and possibly spinal DA/norepinephrine sys-tems. There are now valid and reliable methods to assess

Table 46.5 (continued)

7. Drugs associated with induction or aggravation of postural tremor

Anticonvulsant drugsTricyclic antidepressants, β-adrenergic agonists, levodopaAmphetaminesThyroxineAntihyperglycemic drugsCaffeineCorticosteroidsCalcium channel antagonists:

flunarizine, cinnarizineAmiodarone

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 theweight while standing. Reducing the total dosage of neuroleptic medications and the addition of either an anticholinergic drug, one of thebenzodiazepine 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 antihis-taminic properties.

Parkinsonian symptoms may be characterized by postural instability, stooped posture, shuffling and festinating gate, or rigidity, due to enhancedmuscle tone, with, at times, “cogwheel” or “ratchet” resistance to passive movements in any direction. There is also tremor at rest with regularrhythmic oscillations of the extremities especially in the hands and fingers as well as akinesia (poverty of movement) or bradykinesia (slownessin initiating volitional activities). These symptoms, which are due to blockade of dopaminergic receptor sites in the striatum, are lessened byreducing 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 oftenextending to the upper and lower extremities, including the neck, trunk, fingers, and toes. With continuous blockade, the dopaminergic receptorsin the striatum up-regulate. Following the discontinued use of neuroleptics or a reduction in dosage, the dyskinesia becomes apparent. In thetherapeutic management of neuroleptic-induced tardive dyskinesia, reserpine, lithium, diazepam, baclofen, and vigabatrin have all been used withunsatisfactory results. Therefore, in the absence of an effective treatment, the best prevention of tardive dyskinesia is to prescribe the neurolepticsat 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 ischaracterized by extreme hyperthermia; “lead pipe” skeletal muscle rigidity that causes dyspnea, dysphagia, and rhabdomyolysis; autonomicinstability; fluctuating consciousness; leukocytosis; and elevated creatine phosphokinase levels.

The treatments of neuroleptic malignant syndrome consists of immediately discontinuing the neuroleptic agent and administering dantrolenesodium and dopamine function-enhancing substances such as levodopacarbidopa, bromocriptine, or amantadine. (For reviews and references,see References 3 and 4.)



akathisia using standardized scales; doing so helps trackthe progress of treatment interventions. The secondarycomplications of akathisia are numerous. The most nota-ble ones are noncompliance and assaultive or suicidal ide-ation or behavior. Causative agents of akathisia include allcurrently available neuroleptics, various other psychoac-tive medications, and occasionally other nonpsychotro-pics. Treatment first should include stopping theoffending agent (if possible), lowering the dose, or chang-ing to a lower-potency neuroleptic. If these strategies arenot feasible, then there are a host of medications that arevariably effective. The most common are β-adrenergicreceptor blockers, anticholinergics, clonidine, or benzodi-azepines. Less commonly prescribed agents such as opi-ates, amantadine, buspirone, piracetam, amitriptyline, anddopamine depleters can be tried in more treatment-refrac-tory patients.

CONDITIONS RESEMBLING AKATHISIA

Ekbom (1944) described an idiopathic syndrome that heoriginally called “asthenia crurum paraesthetica” and laterrenamed “restless leg syndrome.”102 Similar to akathisia,the patients’ descriptions are: it feels like ants were run-ning up and down in my bones, it feels like an internalitch, and it is a diabolical feeling that I would not wishon my worst enemy. Akathisia-like syndromes have alsobeen reported in encephalitis lethargica103 and in patientswith both postencephalitic and idiopathic parkinsonism.104

Nocturnal myoclonus, or periodic movements insleep, causes intense and repetitive muscle jerking duringsleep. Treatment with 100- to 200-mg L-dopa105 or withL-dopa plus bromocriptine106 has been reported to be ben-eficial in this movement disorder. Leg restlessness alsooccurs after withdrawal from narcotic analgesics, and thisopioid-related restlessness responds to treatment withclonidine 107–109 or treatment with propranolol.110 Propra-nolol is also effective in treating neuroleptic-inducedakathisia.

CLASSIFICATION OF AKATHISIA

Akathisia has been divided into the three categories ofchronic akathisia, acute akathisia, and pseudoakathisia:

1. Chronic akathisia (tardive akathisia). The termdenotes that akathisia developed late in thecourse of neuroleptic therapy and both subjec-tive restlessness and objective motor move-ments are present. Furthermore, it is frequentlyassociated with tardive dyskinesia, does notrespond to anticholinergic drugs99 and, like tar-dive dyskinesia, is difficult to treat.111

2. Acute akathisia. The term acute denotes thatakathisia developed recently (within 6 months)

and is related to an increase in the doses ofneuroleptics. It is not associated with dyskinesia.

3. Pseudoakathisia. The term was coined byMunetz and Comes.112 The condition resembleschronic akathisia without subjective feelings ofinner restlessness.113 This characteristic makesit difficult to differentiate among chronicakathisia, pseudoakathisia, and tardive dyskine-sia.

In an effort to differentiate among these problems, it hasbeen suggested that, if the patient is restless and thereforeis moving, he suffers from akathisia. If the patient movesand therefore is restless, he suffers from tardive dyskine-sia.114

DIFFERENTIAL DIAGNOSIS OF AKATHISIA

Anxiety and agitated depression are often associated withrestlessness. In akathisia, unnatural or abnormal restless-ness is confined mostly to the legs.115,116 It is interestingthat the anxiolytic agent lorazepam is less effective thanpropranolol in treating neuroleptic-induced akathisia.92

Although five major rating scales have been developed tomeasure akathisia (see Reference 117 for review), thedifferentiation between subjective and objective akathisiais difficult. The Chouinard extrapyramidal rating scale118

and the 23-item rating scale for akathisia developed byBraude et al.99 do attempt to assess both subjective andobjective akathisia.

TREATMENT OF NEUROLEPTIC-INDUCED AKATHISIA

Because the incidence of neuroleptic-induced akathisia ishigher with more potent neuroleptics such as haloperidol,switching patients to a lower-potency neuroleptic such aschlorpromazine may improve akathisia.96,97 Braude et al.99

reported that the only consistently effective treatment ofakathisia was a reduction in the dose of neuroleptic. Inaddition to this general guideline, the other agents usedto treat akathisia are (a) antiparkinsonian agents, (b) anx-iolytic agents, (c) alpha- and beta-adrenergic receptorblocking agents, and (d) to a limited extent, L-tryptophan.

ANTIPARKINSONIAN AGENTS

Unlike drug-induced parkinsonism (rigidity, akinesia, andtremor), neuroleptic-induced akathisia responds incom-pletely and unpredictably to anticholinergic medications.Clinical experience using benztropine and procyclidine,119

benztropine,120 benztropine or trihexyphenidyl,100 andbiperiden121 indicates that the response is more satisfac-tory if akathisia coexists with parkinsonism, but less sat-isfactory if akathisia exists alone.



AMANTADINE

Amantadine, in a daily dose of 200 to 300 mg, has beenshown to be as effective as, or more effective than, a dailydose of 2 to 4 mg of benztropine in treating neuroleptic-induced akathisia.122–124 However, tolerance develops tothe beneficial effects of amantadine.125

BENZODIAZAPINE DERIVATIVES

Moderate to marked improvement has been reported intreating neuroleptic-induced akathisia after daily admin-istration of 5 to 15 mg diazepam,126,127 1.5 to 5.0 mglorazepam,128 and 0.5 mg clonazepam.129

BETA-ADRENERGIC RECEPTOR BLOCKING AGENTS

The most promising treatment of akathisia consists ofbeta-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. Thebeneficial effects of propranolol were confirmed by Kulikand Wilbur131 and by Lipinski et al.130 Adler et al.92,132

compared the effectiveness of lorazepam (2 mg/day) withpropranolol (20 to 30 mg/day) and concluded that propra-nolol decreased both subjective feelings of restlessnessand objective motor signs, whereas lorazepam decreasedsubjective but not objective signs. Furthermore, they133

showed that propranolol was far superior to benztropinein treating akathisia. Moreover, Reiter et al.134 successfullytreated a patient suffering from sinus bradycardia andakathisia with pindolol, a beta-adrenergic receptor block-ing agent that possesses an intrinsic sympathomimeticactivity. The unexplained selectivity of beta-adrenergicreceptor blocking agents in treating akathisia may be citedby studies that showed metoprolol was less effective thanpropranolol,135 whereas atenolol was ineffective.136,137

Finally, propranolol has been used successfully for neu-roleptic-induced akathisia resistant to treatment with anti-cholinergics and benzodiazepines.

Selective or nonselective, centrally acting beta-adren-ergic antagonists reduce haloperidol-induced emotionaldefecation in rats, and this effect parallels the reportedanti-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 dailydose of 0.2 to 0.8 mg138 and in a daily dose of 0.15 to0.40 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

subjective and the objective components of akathisia inmost of the patients in their study.

BUPROPION

Neuroleptic-induced akathisia responds dramatically tobupropion (300 mg/day/5 days) treatment.142

NEUROLEPTIC-INDUCED DYSTONIA

Dystonia is characterized by an exaggerated posturing ofhead, neck or jaw; by spastic contraction of muscles ofthe lips, tongue, face or throat, making drinking, eating,swallowing and speech difficult; by torticollis, retrocollis,opisthotonos, and oculogyric crisis; and by laryngeal andpharyngeal spasm potentially leading to respiratory dis-tress and ultimately anoxia. The term dystonia was firstcoined by Oppenheim143 and the full spectrum of the dis-ease 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 dra-matic in their presentation. Usually precipitated by theneuroleptic phenothiazines and butyrophenone com-pounds, dystonic movements and postures take variousforms.

Most commonly, these drug-induced dystonias occurin the acute phase of treatment with phenothiazines andbutyrophenones and often affect patients under the age of40, although this is not a hard-and-fast rule. The salientclinical features accompanying these neuroleptic-induceddystonias are oculogyric crisis and abnormal posturing ofthe head and neck. Patients with oculogyric crisis oftencomplain of an inability to move their eyes in the verticalplane; they also complain of double vision and blurredvision, but rarely of pain on attempted gaze.

Most often, the eyes maintain a sustained upwardgaze. The symptom complaints appear to result from thepatient’s attempt to maintain full visual field by manipu-lating head and neck musculature in an uncoordinatedfashion. The abnormal posture of the head and neckincluding opisthotonos, in which the head and neck are ina retrocolic position, give the patient a most bizarreappearance. Other muscles may be involved in acutedrug-induced dystonia, but these presentations are muchless common than the opisthotonos and oculogyric cri-sis.149

Drug-induced dystonia is caused primarily by medi-cations that affect dopaminergic mechanisms. For exam-ple, patients with Parkinson’s disease treated with L-dopamight develop typical dystonic movements and pos-tures.150–153 In addition to dystonia caused byneuroleptics154 or by metoclopramide,155 dystonic-likereactions have also occurred with many other drugsincluding high doses of carbamazepine,156 phenytoin,157

or propranolol.158 Neuroleptic-induced dystonia is



divided into acute dystonia and tardive dystonia.159 Thetwo dystonic reactions may be differentiated by the factthat acute dystonia responds well to anticholinergic medi-cations, whereas tardive dystonia does not, suggestingdifferent underlying mechanisms.

IATROGENIC DYSTONIA

Dystonia in various forms, including torticollis, ble-pharospasm, and oromandibular movements, has occurredafter administration of many drugs (Table 46.5147). Thesedystonic reactions are idiosyncratic, occurring in suscep-tible patients, with the susceptibility decreasing with age.Indeed, diphenhydramine, an antihistaminic substancewith anticholinergic properties, and benztropine, an anti-cholinergic agent, have been used successfully in treatingneu ro l ep t i c - i nduced acu t e dys ton i a . Ye t ,diphenhydramine160,161 and benztropine162 have causeddystonia in susceptible individuals. It is clearly seen thatthe complexity of these responses militates against provi-sion of a unified concept regarding drug-induced dystonia.Therefore, only the most commonly occurring dystoniaswill be described.

INCIDENCE OF ACUTE DYSTONIA

The incidence of neuroleptic-induced dystonia has beenreported to be as low as 2 to 3%163 to as high as 50%.164

However, it is generally agreed that incidence is consid-erably higher in children and young adults.165–167

ENHANCED SUSCEPTIBILITY TO DEVELOP DYSTONIA

Cocaine addiction,168 hypoparathyroidism,169 alcohol-ism,170 excess stress,171,172 childhood convulsion or birth

trauma,173 hypothyroidism,174 and certain degenerativedisorders of the central nervous system (e.g., neuronalceroidlipofuscinosis)175 are thought to enhance one’schances of developing neuroleptic-induced dystonia.Chronic administration of cocaine enhances the concen-tration of dopamine.176

TARDIVE DYSTONIA

Dystonias may be a group of disorders with multiple eti-ology in which both dopamine excess and deficiency areimplicated. Furthermore, treatment of dystonias is gener-ally empiric, defying generalization. The following com-ments in Table 46.6, are illustrative. A simplified presen-tation of the involvement of neurotransmitters in thegenesis of dystonia is not possible at this time.146,147,193–195

IDIOPATHIC OROFACIAL DYSTONIA (MEIGE’S SYNDROME)

Ortiz196 reported that a patient with Meige’s syndromeresponded best to a combination of haloperidol (a dopam-ine receptor blocking agent, hence reducing dopamineexcess) and benztropine (acetylcholine receptor blockingagents, hence reducing acetylcholine excess).

This syndrome, usually occurring within 24 to 72 hrafter initiation of neuroleptic therapy, must be differenti-ated from late-onset tardive dystonia.197,198 Neuroleptic-induced tardive dystonia may or may not respond to anti-cholinergic agents,199 whereas anticholinergic agentsexacerbate neuroleptic-induced tardive dyskinesia.200

Furthermore, in contrast to tardive dyskinesia, tardivedystonia decreases with age and shows no female prepon-derance.201

TABLE 46.6Treatment of Dystonia

Potent neuroleptics such as haloperidol may cause dystonia, asphyxiation, and death.177–181 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 γ-vinyl GABA, an inhibitor of GABA-transaminase. γ -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,188–190 torticollis,147 and writer’s 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.



TREATMENT OF DYSTONIAS

High-dose anticholinergic therapy for childhood-onsetdystonia, botulinum toxin injections for focal dystonia,and L-dopa for diurnal dystonia provide symptomaticrelief in some patients.147

BACLOFEN IN THE TREATMENT OF DYSTONIA

Greene,202 by reviewing the literature, summarized thebeneficial effects of baclofen, a presynaptically actingGABA receptor agonist, in the management of dystonia.Dramatic improvement in symptoms, especially in gait,was found in almost 30% of 31 children and adolescentswith idiopathic dystonia in one retrospective study usingdoses ranging from 40 to 180 mg daily. The response tobaclofen in adults with focal dystonia is less dramatic.One series of 60 adults with cranial dystonia found sus-tained benefit in only 18%, and smaller series have notconsistently found significant benefit in adults. Baclofenhas been used to treat several secondary dystonias; tardivedystonia has occasionally been reported to improve withadministration of baclofen, and there are isolated reportsof improvement in dystonia occurring in Parkinson’s dis-ease and in glutaric aciduria.

BOTULINUM TOXIN IN THE TREATMENT OF DYSTONIA

Botulinum toxin acts presynaptically at nerve terminals toprevent the calcium-mediated release of acetylcholine.203

When botulinum toxin is injected locally, the effect is thatof a chemical denervation.204 Injected locally into extraoc-ular muscles, botulinum toxin has been used to treatstrabismus205 and, injected subcutaneously over orbicu-laris oculi, has been used to treat blepharospasm.189,206–213

Botulinum toxin has been used to treat hemifacialspasm.214–216 In addition, botulinum toxin has been usedto treat spasmodic torticollis,217 oromandibular-laryngealcervical dystonia,218 and stiff-person syndrome.219

PHENYLALANINE IN DOPA-RESPONSE DYSTONIA (DRD)

The syndrome of autosomal dominant dystonia that isexquisitely responsive to levodopa, termed hereditary pro-gressive dystonia with diurnal fluctuation or dopa-respon-sive dystonia (DRD), is not well known outside the fieldsof pediatric neurology and of movement disorders and islikely to be underdiagnosed. The disease is classicallypresent as a dystonic gait disorder in childhood, with anaverage age of symptom onset of 5 to 6 years, but thespectrum of clinical manifestations is broad. Some chil-dren have presented in the first 2 years of life with devel-opmental motor delay. In older children, prominent uppermotor neuron findings, including spastic diplegia, haveled to the misdiagnosis of cerebral palsy. Because of this

overlap in clinical features, some have recommended thatall children and young adults with dystonia and athetoid-dystonic cerebral palsy be given a trial of levodopa toexclude DRD. However, response to levodopa in patientswith DRD is not always immediate, especially in early-onset and severe cases, and levodopa can provide signif-icant symptomatic benefit in some patients with secondarydystonia who do not have DRD.

Hyland et al.220 measured plasma levels of phenylala-nine, 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 severelyaffected children with DRD, and nine adult controls werestudied. All patients had phenylalanine and tyrosine con-centrations within the normal range at baseline. In theadult patients, phenylalanine levels were higher than incontrols at 2, 4, and 6 hr post-load (p < 0.0005); tyrosineconcentrations were lower than control levels at 1, 2, and4 hr post-load (p < 0.05). Phenylalanine-to-tyrosine ratioswere elevated in patients at all times post-load (p <0.0005). Biopterin levels in the patients were decreased atbaseline and 1, 2, and 4 hr post-load (p < 0.005). Pretreat-ment with tetrahydrobiopterin (7.5 mg/kg) normalizedphenylalanine and tyrosine profiles in two adult patients.In the children with DRD, phenylalanine-to-tyrosineratios were slightly elevated at baseline. Following phe-nylalanine loading, the phenylalanine profiles were simi-lar to those seen in the adult patients, but there was noelevation in plasma tyrosine. Baseline biopterin levelswere lower in the children with DRD than in the adultpatients or the controls, and there was no increase in biop-terin post-load. In both the children and adults with DRD,neopterin concentrations did not differ from control val-ues at baseline or after phenylalanine load. These resultsare consistent with decreased liver phenylalanine hydrox-ylase activity due to defective synthesis of tetrahydro-biopterin in patients with DRD. The findings show that aphenylalanine load may be useful in the diagnosis of thisdisorder.

NEUROLEPTIC MALIGNANT SYNDROME

Among the complications of neuroleptic chemotherapy,the most serious and potentially fatal complication ismalignant syndrome, which is characterized by extremehyperthermia; “lead pipe” skeletal muscle rigidity causingdyspnea, dysphagia, and rhabdomyolysis; autonomicinstability; fluctuating consciousness; leukocytosis; andelevated creatine phosphokinase (see References 3, 4, and221 through 232).

Neuroleptic malignant syndrome, which is sometimesassociated with abrupt withdrawal of anticholinergicagents,233 may occur without muscular rigidity.234 Further-more, an acute imbalance of sodium in the central ner-vous system has been proposed to play a role in the



pathophysiology of neuroleptic malignant syndrome,235

and dehydration and hot weather are additional factors forthe development of neuroleptic malignant syndrome.236

Neuroleptic malignant syndrome associated with dysar-thric disorders has been reported.237 Pure akinesia is asyndrome characterized by akinesia without rigidity,tremor, and supranuclear gaze palsy. Yoshikawa et al.238

reported a patient with pure akinesia-manifested in neuro-leptic malignant syndrome. Clozapine, an atypical neuro-leptic, was initially reported not to cause neurolepticmalignant syndrome. As a matter of fact, chronic schizo-phrenic patients should be considered for clozapine treat-ment.239 However, it is evident that clozapinemonotherapy may cause neuroleptic malignant syn-drome.240,241 Moreover, withdrawal from clozapine hascaused catatonia.242

Neuroleptic malignant syndrome, as the most seriousbut the rarest and least known of the complications ofneuroleptic chemotherapy,243 is viewed as a triad of fever,movement disorder, and altered mentation.226 Pulmonaryabnormalities, including tachypnea, dyspnea, stridor, andpulmonary edema, are probably secondary complicationsresulting from movement disorder, alteration in the func-tions of the autonomic nervous system (tachycardia, dia-phoresis, and labile blood pressure), and changes inmental status (stupor, lethargy, and coma).

In 115 cases of neuroleptic malignant syndrome stud-ied by Addonizio et al.,228 the primary psychiatric diag-noses, in descending order of occurrence, consisted ofschizophrenia (44%), bipolar mania (26%), major depres-sion (10%), schizoaffective disorder (6%), atypical psy-chosis (3%), alcohol abuse (3%), bipolar depression(2%), mental retardation (2%), organic mental syndrome(1%), Alzheimer’s disease (1%), and sedative abuse (1%).Among these 115, there were 72 men (63%) and 43women (37%). Furthermore, greater than 50% of thecases were patients 40 years or younger. Unlike the morefamiliar neuroleptic-induced movement disorders, whichoccur in 15 to 50% of patients, neuroleptic malignant syn-drome is relatively rare, and the annual incidence of thesyndrome has been reported to be 0.15%,244 0.4 to1.4%,223,245–247 or 2.4%.227,247 Among the 115 casesreported by Addonizio et al.228 and 52 cases analyzed byKurlan et al.,227 the incidence of neuroleptic malignantsyndrome seems to be considerably higher with haloperi-dol than with any other neuroleptic.

DIFFERENTIAL DIAGNOSIS OF NEUROLEPTIC MALIGNANT SYNDROME

Many diseases and toxic reactions mimic the cardinalfeatures of neuroleptic malignant syndrome, namely fever,muscular rigidity, changes in mental status, and autonomicdysfunction. Therefore, care must be taken to differentiateneuroleptic malignant syndrome from malignant hyper-

thermia, lethal catatonia, heat stroke, central anticholin-ergic toxicity, central nervous system infection, severedystonic reaction, drug- and food-related allergic reac-tions, electrolyte imbalance, thyrotoxicosis, strychninepoisoning, 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 theincidence or severity of neuroleptic malignant syndromeare dehydration,249 exhaustion,250 pre-existing organicbrain syndrome,251 external heat load,252 large dosage andrapid dose titration of neuroleptics,253 excessive sympa-thetic discharge,254,255 concurrent lithium therapy, andabrupt discontinuation of antiparkinsonian agents.

COMPLICATIONS OF NEUROLEPTIC MALIGNANT SYNDROME

In addition to respiratory failure, acute renal failure, andcardiovascular collapse, which occur frequently in inade-quately treated or untreated patients with neurolepticmalignant syndrome, other serious complications haveoccurred, even in patients treated well with dantrolene anddopamine-enhancing substances. The reported complica-tions are myocardial infarction,256 periarticular ossifica-tion,257 peripheral neuropathy,258 respiratory distress syn-drome and disseminated intravascular coagulation,259 andnecrotizing enterocolitis.260 The cluster of aforementionedsymptoms occurred in 52 patients who received neurolep-tics for schizophrenia (24), for affective disorder (13), forother psychiatric disorders (13), for preinduction anesthe-sia (1), and for withdrawal from sedative-hypnotic drugs(1). Receiving more than one neuroleptic significantlyincreases the incidence of neuroleptic malignant syn-drome. Furthermore, it is generally believed that the inci-dence of malignant syndrome is higher with high-potencyneuroleptics than low-potency ones.

THE PATHOGENESIS OF NEUROLEPTIC MALIGNANT SYNDROME—THE ROLE OF DOPAMINE

Although the pathogenesis of neuroleptic malignant syn-drome is not entirely clear, a blockade of dopaminergicreceptors in the corpus striatum is thought to cause mus-cular contraction and rigidity-generating heat, and ablockade of dopaminergic receptors in the hypothalamusis thought to lead to impaired heat dissipation. Therefore,the excess heat production along with a lack of heat dis-sipation produces pronounced hyperthermia, which is thehallmark of the syndrome. Furthermore, a blockade ofdopamine receptors in the spinal cord is thought to beresponsible for dysautonomia. The involvement of dopam-



ine in the genesis of malignant syndrome is further sup-ported by the observation that, in addition to neuroleptics,which block dopamine receptors, dopamine-depletingagents such as reserpine, dopamine storage blockingagents such as tetrabenazine, and dopamine synthesisinhibitors such as α-methylparatyrosine might also pro-duce neuroleptic malignant syndrome. The rapid (4-hr)reversal of hyperthermia of neuroleptic malignant syn-drome by L-dopa/carbidopa also indicates that an alter-ation in the metabolism or function of dopamine and/orits receptors may be responsible for the hyperthermia.Because dopamine plays a role in central thermoregulationin mammals261–263 and, because neuroleptics block dopam-ine receptor sites, the hyperthermia associated with neu-roleptic malignant syndrome might result from a blockadeof dopamine target sites within the preoptic-anterior hypo-thalamus.264,265 A stereotaxic injection of dopamine intothe preoptic-anterior hypothalamus causes a reduction incore temperature, and this effect is blocked by haloperi-dol.262 Histidylproline diketopiperazine [cyclo(His-Pro)],an endogenously occurring cyclic dipeptide, shares certainproperties with dopamine in that it causes hypothermiaand is found in preoptic-anterior hypothalamus and instriatum.266

In addition to hyperthermia, the parkinsonism(98%) and alteration in mental status (8 to 27%) seen inpatients with neuroleptic malignant syndrome mayresult from blockade of dopaminergic receptors in thenigrostriatal system and from disruption of dopaminer-gic function in the mesocortical system.264 The gradual(1 to 5 days) disappearance of parkinsonism seen inpatients with neuroleptic malignant syndrome and theresumption of normal physiological functions aftertreatment with L-dopa/carbidopa support this conten-tion. In addition to Sinemet, other dopamine-function-enhancing drugs, such as bromocriptine98,267–276 andamantadine277–282 have shown efficacy in treating neuro-leptic malignant syndrome.

TREATMENT OF NEUROLEPTIC MALIGNANT SYNDROME

GENERAL TREATMENTS

The most important factor in treatment of neurolepticmalignant syndrome is the early recognition of the incip-ient syndrome and prompt discontinuation of neurolepticmedication.283 Allsop and Twigley284 described a psy-chotic patient who developed neuroleptic malignant syn-drome after administration of fluphenthixol. Because thetreatment with dantrolene sodium was instituted too late,the patient died after massive intestinal hemorrhage, intra-abdominal sepsis, and disseminated intravascular coagu-lation. In addition to blocking dopamine receptors in thehypothalamus, basal ganglia, and spinal cord, neuroleptics

cause excessive release of calcium from the sarcoplasmicreticulum in peripheral muscle fibers, resulting in exag-gerated muscular contraction and in enhanced thermogen-esis.223 Dantrolene or other muscle relaxants are useful285

when used in conjunction with dopamine-enhancing sub-stances. Furthermore, every attempt should be made toreduce morbidity and to avert mortality, which are relatedto the development of cardiac problems, pneumonia, pul-monary embolus, and renal failure, secondary to myoglo-binuria.286 Airway intubation and other supportive caremight be required in some patients. Lack of fluid intakealong with diaphoresis may result in dehydration requiringfluid supplementation. Furthermore, vigorous fluid ther-apy is needed to combat myoglobinuria. Although dialysismay improve renal failure, neuroleptic agents are proteinbound and are not removed readily by dialysis. In treatingneuroleptic malignant syndrome, it should be recalled thatsignificant variations might occur in patients. For exam-ple, it is generally presumed that neuroleptic malignantsyndrome lasts for 5 to 10 days after discontinuation oforal neuroleptic.287 However, if the syndrome is causedby a long-acting neuroleptic, such as fluphenazine enan-thate, a more prolonged and severe case may be antici-pated.281 Patients who are receiving neuroleptics and suf-fer from heat stroke may present with fever, rigidity, andelevated creatine kinase. However, their skin is dry, andtheir blood pressure is low or normal.288,289 Neurolepticmalignant syndrome may occur in a milder form after theadministration of weaker dopamine-depleting substancessuch as reserpine, and later develop fully in the samepatient after the administration of a potent dopaminereceptor blocking agent such as haloperidol.290 Finally,neuroleptic malignant syndrome may be superimposedupon tardive dyskinesia,291 making both diagnosis andtreatment difficult.

SPECIFIC TREATMENTS

In neuroleptic malignant syndrome, central dopaminergicreceptors are blocked, and altered levels of dopaminemetabolites such as 3,4-dihydroxyphenylacetic acid andhomovanillic acid have been found postmortem.292 There-fore, the treatment of choice is to reverse the hypodopam-inergic state by administration of L-dopa/carbidopa, bro-mocriptine, or amantadine.

L-DOPA/CARBIDOPA

L-dopa/carbidopa (Sinemet 25:100) is often effective inreversing hyperthermia and making the patient afebrile inhours. Treatment, however, may need to be continued forseveral days.226 Harris et al.293 reported a patient in whommalignant 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 102after the administration of dantrolene. Twenty-four hoursafter carbidopa-L-dopa (25:100) treatment was started, thetemperature dropped to 100. When subsequent carbidopa-L-dopa was inadvertently not given, the temperatureincreased, despite continuous treatment with dant-rolene.293 Hirschorn and Greenberg294 reported a case ofL-dopa-induced myoclonus combined with L-dopa with-drawal-induced neuroleptic malignant syndrome, whichwas successfully treated with L-dopa/carbidopa alongwith 2 mg/day of methysergide (a serotonin receptorantagonist). It has been suggested that prolonged L-dopatherapy may result in deregulation of serotonergic trans-mission producing myoclonus.295

BROMOCRIPTINE

In 1983, several investigators269,272,274,276 explored the ben-eficial effects of bromocriptine in reversing neurolepticmalignant syndrome. The recommended initial dose is 5.0to 7.5 mg three times daily.296 If the syndrome has pro-gressed to the point at which the patient is unable toswallow the orally available bromocriptine, it is necessaryto produce muscular relaxation by dantrolene (3 mg/kgfour times daily). However, it should be stated that thehyperthermia in malignant syndrome does not respond tomuscle relaxation alone.297 Because dantrolene producesa rare but potentially fatal idiosyncratic hepatocellularinjury, bromocriptine may be administered by a nasogas-tric tube in patients in whom a pre-existing liver diseasemay preclude the use of dantrolene.

Dhib-Jalbut et al.269 reported that the amount of bro-mocriptine mesylate to be given to a patient depends onbody temperature, autonomic and extrapyramidal signs,and symptoms. Therefore, in treating five patients withmalignant syndrome, they used 7.5 to 45.0 mg/day inthree divided doses for 10 days. In all five patients, signif-icant improvement in vital signs and reduction in creatinekinase was noted within 24 to 72 hr after initiation of bro-mocriptine treatment. Resolution of confusion and mut-ism was noted within 24 to 48 hr, and resolution ofextrapyramidal rigidity occurred within 1 week. In twopatients, early discontinuation of bromocriptine resultedin a relapse of neuroleptic malignant syndrome, whichresponded to reinstitution of the drug.269

DANTROLENE SODIUM (DANTRIUM)

Dantrolene, a nitrophenylamino hydantoin derivative, is aunique skeletal muscle relaxant in that, unlike competitiveneuromuscular blocking agents (e.g., D-tubocurarine),depolarizing blocking agents (e.g., succinylcholine anddecamethonium), and agents enhancing or mimickingGABAergic transmission (e.g., diazepam and baclofen),dantrolene exerts its effects by direct action on excitation-contraction coupling and by reducing the amount of cal-

cium released from sarcoplasmic reticulum.298 Dantrolene,which depresses the central nervous system, does notaffect neuromuscular transmission, nor does it change theelectric properties of skeletal muscle membranes.299

Although the hepatotoxicity of dantrolene precludes itswidespread and chronic usage, it has proven beneficial intreating patients with spasticity associated with stroke,cerebral palsy, spinal cord injury, and multiple sclerosis.Furthermore, it is effective in reducing the muscular rigid-ity associated with malignant hyperthermia300,301 and inneuroleptic malignant syndrome.285,302 In malignant hyper-thermia, a dose of 2.4 mg/kg is given by intravenousinfusion for prophylaxis or initial treatment of hyperther-mia.300 Britt301 recommended that dantrolene should beadministered at a rate of 1 mg/kg/min while monitoringelectroencephalogram and until heart rate and temperaturebegin to fall and muscle stiffness starts to subside. Ifnecessary, treatment may be repeated every minute, or amaintenance infusion of 1 to 2 mg/kg per 3 to 4 hoursinitiated until all evidence of hyperthermia has disap-peared. Similar to L-dopa or bromocriptine, dantrolenesodium may produce rapid reversal of neuroleptic malig-nant syndrome.246,248,272,296,303–306 The initial usual recom-mended dose of dantrolene, which may vary dependingon the severity of the problem and the perceived need ofthe patient, to be decided by the attending physician (seeReference 307), is between 0.8 and 2.5 mg/kg given intra-venously every 6 hr308 or between 0.25 and 3.0 mg givenintravenously every 6 hr.272,304 When symptoms abate andthe patient is able to swallow, oral doses in the range of100 to 200 mg/day may be substituted.305 Rapid resolutionof symptoms (within 24 hr) is possible if treatment isbegun early,309 although the usual course of treatment is5 to 10 days.248

AMANTADINE

Although universal agreement on its efficacy does notexist, amantadine has been tried in the management ofneuroleptic malignant syndrome.272,277–281

ANTICHOLINERGIC AGENTS

Anticholinergic drugs such as benztropine (Cogentin) areusually ineffective in treating the rigidity of neurolepticmalignant syndrome and do not affect or may even aggra-vate the associated hyperthermia.310 However, Schrehlaand Herjanic311 reported a schizoaffective patient whodeveloped neuroleptic malignant syndrome and did notrespond 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 GABAergicfunction, have produced transient relief of symp-



toms.222,214,264,306,312,313 Benzodiazepine derivatives havealso been recommended to control “agitated” patientswhile being treated for neuroleptic malignant syn-drome.248,296

NEUROLEPTIC-INDUCED PARKINSONISM

The cardinal features of Parkinson’s disease are tremor atrest, rigidity, akinesia, and postural abnormalities. A smallnumber of patients, however, might display only akinesiawithout rigidity or tremor.314–317 Drug-induced parkin-sonism is common but under-recognized.318 A majority ofpatients initially diagnosed as having Parkinson’s diseasewere subsequently shown to have drug-induced syn-drome.319,320 By far the most frequent causes of drug-induced parkinsonism are neuroleptics that block dopam-ine receptors in nigrostriatal dopaminergic pathways. Fur-thermore, there is a direct relationship between thepotency of neuroleptics as antipsychotics and the inci-dence of parkinsonism. The more potent agents, such ashaloperidol, produce more frequent pseudoparkinsonismthan the less potent agents such as chlorpromazine.

INCIDENCE OF PARKINSONISM

Although the severity of neuroleptic-induced parkin-sonism varies with class of drug, potency of drug, dosagelevel, and the length of treatment, the factors enhancingone’s susceptibility to develop parkinsonism are notknown.96,97,321 Some patients do not develop parkin-sonism, even after taking potent neuroleptics for a longperiod of time, whereas others experience severe and dis-abling symptoms after a few doses of relatively weakneuroleptics. Neuroleptic-induced parkinsonism is revers-ible and disappears after discontinuation or lowering ofdrug dosage.

TREATMENT OF PARKINSONISM

Neuroleptic-induced parkinsonism is best treated byreducing doses of neuroleptic and by adding an anticho-linergic agent such as benztropine or trihexyphenidyl.Anticholinergic drugs should not be used prophylactically,because the incidence of tardive dyskinesia is far higherin patients who receive neuroleptics and an anticholinergicdrug given prophylactically to prevent parkinsonism. L-dopa is contraindicated, because it might aggravate theunderlying psychiatric problem for which neuroleptictreatment was initiated. In animal models of Parkinson’sdisease, glutamate receptor antagonists diminishlevodopa-associated motor fluctuations and dyskinesia.322

ANTITREMOR EFFECTS OF CLOZAPINE

Tremor at rest is a classic symptom of Parkinson’s diseasethat causes significant disability and distress for the

patient and is generally only weakly responsive to con-ventional treatment such as anticholinergic or amanta-dine. Jansen323 reported that clozapine (18 mg/day)improved tremor.

PARKINSONISM, SCHIZOPHRENIA, AND DOPAMINE

The coexistence of Parkinson’s disease and schizophreniais of theoretical interest and of therapeutic importance.Parkinson’s disease is known to be a striatal dopaminedeficiency syndrome. On the other hand, schizophrenicpatients are thought to suffer from a dopaminergic hyper-activity state.324–329 Clozapine along with L-dopa/carbi-dopa may be used in the management of patients withParkinson’s disease who also suffer from schizophre-nia,330–331 or in patients with L-dopa-induced psychosis.332

Moreover, clozapine therapy may allow an increase inantiparkinson therapy leading to further amelioration ofparkinsonism.333 Clozapine has also been advocated to beof value in treating resistant schizophrenics334 and in aparanoid subgroup of schizophrenics.335

NEUROLEPTIC-INDUCED TARDIVE DYSKINESIA

Persistent dyskinesia, which was initially described in1956,336,337 also became known as reversible and irrevers-ible drug-related dyskinesia.338 This neuroleptic-inducedmovement disorder is characterized by abnormal involun-tary movements frequently involving the facial, buccal,and masticatory muscles and extending often to the upperand lower extremities, including the neck, trunk, fingers,and toes. The typical abnormal facial movements includeopening and protrusion and retrieval of the tongue andclosing of the mouth, chewing, licking, sucking, pucker-ing, smacking, panting, and grimacing. Abnormal move-ments associated with the disorder, which might involveany part of the body, can be ataxic, myoclonic, dystonic,dyskinetic, or choreiform in nature. The neuroleptic-induced dyskinesias, which have been reported and stud-ied extensively in adult patients,339–341 occur also in chil-dren.342

Steen et al.343 believe that autosomal inheritance oftwo polymorphic Ser 9 Gly alleles (2-2 genotype), but nothomozygosity for the wild-type allele (1-1 genotype), is asusceptibility factor for the development of tardive dyski-nesia.

DRUGS AND CONDITIONS CAUSING DYSKINESIA

In addition to neuroleptics339,340–342 dyskinesias have beenreported to occur after exposure to antidepressants,344,345

anxiolytic agents,346 anticonvulsants,156 antihistamin-ics,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 inas-much as the incidence of tardive dyskinesia is higheramong smokers. However, because smoking induces theactivity of the hepatic microsomal enzymes and enhancesthe metabolism of neuroleptics, it necessitates the use ofhigher-than-ordinary doses of neuroleptics for patients.352

The reported higher incidence of tardive dyskinesia insmokers taking neuroleptics might be due to higher dosesof neuroleptics themselves. In addition to drug-inducedmovement disorders, dyskinesias have been reported totake place occasionally in infantile autism, in Huntington’schorea, in some elderly individuals, and in some patientswith mental retardation.353 As a matter of fact, a positivecorrelation between cognitive impairment and tardive dys-kinesia has been suggested.354

HETEROGENEITY OF TARDIVE DYSKINESIA

Tardive dyskinesia, a late-developing side effect syndromearising as a consequence of chronic neuroleptic treatment,is pharmacologically heterogenous, and this heterogeneityis seen between individual patients (and groups ofpatients) as well as within body areas of individual patients(and groups of patients) as well as within body areas ofindividual patients.355 For example, tardive dyskinesiamost often involves the oral-lingual-facial regions but canaffect all other body areas as well. The symptoms oftardive dyskinesia are most commonly choreoathetoid innature but can have dystonic as well as other features (e.g.,tics, akathisia, myoclonus). Symptoms of tardive dyski-nesia vary widely in severity, but the majority of cases aremild. In addition, the syndrome varies in its duration withsymptoms being transient in some patients, whereas, inothers, they persist and in some cases may be irreversible.Although disturbances in dopamine and acetylcholineseem to be involved in these disorders, they do not in allcases exist in functionally opposite relationships. Theobserved pharmacologic heterogeneity in tardive dyskine-sia response reflects the limitations of the dopamine/ace-tylcholine model of tardive dyskinesia, which oversimpli-fies the neuroanatomy of the basal ganglia (Figure 46.1)and the pathophysiology of tardive dyskinesia. The chem-ical and anatomical complexity of this region suggests thatother neurotransmitter systems such as glutamate356 andneuronal circuits within and extending from the basal gan-glia might be disturbed in the pathogenesis (Figure 46.2).Consistent with these views is the observation thatalthough trihexyphenidyl is effective in the treatment ofneuroleptic-induced parkinsonism, a subpopulation ofpatients with tardive dyskinesia also shows improvementafter anticholinergic treatment.357

TARDIVE DYSKINESIA AND DIABETES

Diabetic patients have been shown to exhibit a greaterincidence of tardive dyskinesia.358 Hyperglycemia sup-

presses the basal firing of dopamine-containing neu-rons,359 and insulin reduces the severity of symptoms intardive dyskinesia.360

L-DOPA-INDUCED DYSKINESIA

L-dopa-induced dyskinesias are a heterogeneous phenom-enon, which might be difficult to explain on the basis ofa single pathological mechanism. For example, Luquin etal.361 classified L-dopa-induced dyskinesias into “on” dys-kinesias, “diphasic dyskinesia,’” and “off” periods. Cho-rea, myoclonus, and dystonic movements occurred duringthe “on” period. Dystonic postures, particularly affectingthe feet, were mainly present in the “off” period, but afew patients had a diphasic presentation. Repetitive ste-reotyped movements of the lower limbs always corre-sponded to diphasic dyskinesia. Moreover, Luquin et al.361

have shown that dopamine agonists enhanced “on” dys-kinesias and markedly reduced or abolished “off” perioddystonia and diphasic dyskinesia. Dopamine receptorantagonists reduced all types of L-dopa-induced dyskine-sia but also aggravated parkinsonism. These data indicatethat L-dopa-induced dyskinesias in Parkinson’s disease isa heterogeneous phenomenon difficult to explain on thebasis of a single pathophysiological mechanism.361

TARDIVE OCULOGYRIC CRISIS

The syndrome of oculogyric crisis was originallydescribed in association with epidemic encephalitislethargica.362 Oculogyric crisis is now most commonlyseen as a side effect of neuroleptic medication.363 It isrecognized as a form of acute dystonia involving primarilythe ocular muscles, although retrocollis, blepharospasm,contraction of the frontalis, jaw opening, and other move-ments might be associated with it. The importance of thesyndrome lies in the fact that it is common, being reportedin 10% to more than 60% of patients recently treated withneuroleptic medication, and very distressing to the patientand onlookers. It usually occurs within a few days ofstarting the drug or increasing its dose, with one reportsuggesting that 90% of patients experienced it in the first4 days of drug treatment. Sachdev364 reported on sixpatients with chronically recurring oculogyric crisis; threeof the patients developed tardive side effects, and in onepatient the episodes persisted for some months after ces-sation of neuroleptic.

TARDIVE DYSKINESIA AND TYPE II SCHIZOPHRENIA

Davis et al.365 found a significant association betweentardive dyskinesia, cognitive impairment, some negativesymptoms, and formal thought disorders. These associa-tions were independent of other illnesses and treatmentvariables. The severity of tardive dyskinesia correlatedsignificantly with that of cognitive impairment.



MECHANISMS OF NEUROLEPTIC-INDUCED DYSKINESIA

Long-term administration of neuroleptics and other drugscauses tardive dyskinesia, which closely resembles L-dopa-induced dyskinesias and is brought about throughcomplex mechanisms that are ill defined. It is generallybelieved that its pathogenesis involves blockade of dopam-ine receptor sites and that its pathophysiology results froma hypersensitivity of dopamine receptors (see Reference366). This hypothesis, however, is not universallyaccepted, for the reasons presented in Table 46.7. Theaforementioned studies, when examined collectively, indi-cate that the hypothesis proposing dopaminergic hyperac-tivity cannot explain completely the etiology of schizo-phrenia and/or the pathogenesis of tardive dyskinesia,hence making treatment difficult.

γ-AMINOBUTYRIC ACID IN THE PATHOGENESIS OF TARDIVE DYSKINESIA

GABA has been shown to interact with nigrostriataldopaminergic neurons.367–370 Defective GABAergic trans-mission has been advanced as a possible etiologic factorin the pathogenesis of tardive dyskinesia.371,372 There is areduction in the concentration of GABA in the cerebral

spinal fluid of patients with tardive dyskinesia, andGABA-mimetic drugs improve dyskinetic symptoms.Moreover, it has been suggested that diminished neuralactivity in efferent GABAergic tracts from the substantianigra pars reticulata to the thalamus underlies tardive dys-kinesia in human beings (Figures 46.1 and 46.3). Therepeated administration of neuroleptics reduces the activ-ity of glutamic acid decarboxylase only in substantia nigraof animals developing dyskinesia.373,374 Therefore, one ofthe recent therapeutic regimens advocates the administra-tion of substances that functionally enhance GABAergictransmission, such as diazepam, or of agents that act asGABA receptor agonists, such as muscimol. GABA-related pharmacological treatment is based on the obser-vation in experimental animals that the GABAergic effer-ent tract in the striatum constitutes a segment of the stri-atonigral feedback loop (Figure 46.3) with the ability tomodulate the activity of dopaminergic cells in the substan-tia nigra.375–378 Based on this concept, it has been shownthat muscimol,379 a GABA receptor agonist, and γ-acety-lenic-GABA380 or γ-vinyl-GABA,195 substances that ele-vate the concentration of GABA by inhibiting GABA-transaminase, were effective in alleviating the severity oftardive dyskinesia. Singh et al.381 have shown that diaz-epam significantly improved tardive dyskinesia and that

TABLE 46.7The 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 reserpine-like properties.406–409 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 Parkinson’s 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 Parkinson’s 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. D1 receptor blockade improves L-dopa-induced dyskinesia but worsens parkinsonism in MPTP monkeys.



some of the improvement persisted after discontinuationof the administration of diazepam. Studies by Sandyk382

have shown that baclofen and clonazepam were effectivein the treatment of neuroleptic-induced akathisia. Theseobservations suggest, but do not confirm, a direct linkbetween dopaminergic transmission, GABAergrc trans-mission, the pathogenesis of neuroleptic-induced dyski-nesia, and the treatment of the dyskinesia with diazepamor GABA-mimetic agents.

An attempt has been made to demonstrate this associ-ation by studying the effects of treatment with diazepamalone, with haloperidol alone, and with haloperidol incombination with diazepam on the activity of glutamicacid decarboxylase and on the metabolism of dopamineand serotonin in discrete regions of the rat brain at the endof treatment with drugs and in brains of animals allowedto undergo a drug-free “holiday.”386 During a 3-day with-drawal period, after daily administration of 3 mg/kg ofhaloperidol (i.p.) for 3 weeks, the activity of glutamicacid decarboxylase in the striatum increased from 72.6 ±7.8 to 92.6 ± 10.2 nmol 14CO2/mg/protein/hr, and the con-centration of dopamine in the striatum increased from7.87 ± 0.23 to 8.86 ± 0.38 µg/g wet tissue. Diazepam (5mg/kg, i.p.), given during the withdrawal period fromhaloperidol, was able to nullify the enhancement in theconcentration of dopamine but not in the activity ofglutamic acid decarboxylase in the striatum. The resultsof these studies were interpreted to indicate that thereported beneficial effects of diazepam and GABA-mimetic agents in ameliorating the symptoms of tardivedyskinesia might occur through a mechanism that doesnot necessarily link transmission involving both dopam-ine and GABA.383 In another study, Mithani et al.384 haveshown that neuroleptic-induced chewing movements anddecreases in nigral glutamic acid decarboxylase activitywere not causally related.

DOPAMINE, PEPTIDES, SCHIZOPHRENIA, AND NEUROLEPTICS

The metabolism of neuropeptides including opioids, neu-rotensin, metenkephalin, substance P, and cholecystokininin the spinal fluids of control and neuroleptic-treatedschizophrenic patients has been reviewed.385–394 The lackof detailed knowledge describing the exact nature of theinteraction between dopamine and these neuropeptidesmilitates against a comprehensive discussion of theirinvolvement either in the pathogenesis of schizophreniaor 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 thepathogenesis of schizophrenia has been reviewed.395 CCK,

a 33-amino acid peptide, originally characterized in theporcine gastrointestinal tract, was first detected in the ver-tebrate central nervous system by Vanderhaeghen et al.396

In the brain, the majority of CCK-gastrin-like peptidesexist as the sulfated form of CCK octapeptide(CCK8S).397–400 CCK8S may serve as a neurotransmitteror a neuromodulator, influencing, among other functions,dopaminergic transmission.

The coexistence of dopamine and CCK8S in a sub-population of mesolimbic dopaminergic neurons has beendemonstrated,411,412 suggesting that this peptide mightmodulate dopamine function. This observation is of inter-est in view of the suggested hyperactive dopaminergictransmission in schizophrenia; the beneficial antipsy-chotic effect of neuroleptics, which allegedly block thehyperactive dopamine receptors; and, as discussed previ-ously, of neuroleptic-induced tardive dyskinesia, postu-lated to result from denervation supersensitivity ofdopaminergic neurons in the striatum.413,414 Other evi-dence pointing to a dopamine-CCK-linked transmissionare the observations that CCK elevates the density ofbrain D2 receptors415 and that intrastriatally injected CCKis able to stimulate dopamine-mediated transmission.416

In an attempt to study further the possibility of dopamine-CCK cotransmission, Hama and Ebadi417 determined theCCK binding sites in the mouse brain. By using a synap-tosomal fraction isolated from the mouse cerebral cortexand [propionyl-3H]CCK8-sulfate ([3H]CCK8S) as aligand, a single binding site for [3H]CCK8S with a KD

value of 1.04 nM and a Bmax value of 42.9 fmol/mg/pro-tein was identified. The competitive inhibition of[3H]CCK8S binding by related peptides produced anorder of potency of CCK8-sulfated (IC50 = 5.4 nM) >CCK8-unsulfated (IC50 = 40 nM) > CCK4 (IC50 =125 nM). The regional distribution of [3H]CCK8S bind-ing in the mouse brain was highest in the olfactory bulb(34.3 ± 5.6 fmol/mg/protein) > cerebral cortex> cerebel-lum> olfactory tubercle> striatum> pons-medulla> mid-brain> hippocampus> hypothalamus (12.4 ± 2.1fmol/mg/protein).417

CCK peptides share certain properties with neurolep-tics in that they induce catalepsy, antagonize conditionedavoidance behavior, antagonize stereotyped behavior,induce hypothermia, induce ptosis, and antagonize certainactions of amphetamine. In addition, ceruletide, CCK8, orCCK33 may produce rapid, effective, and persistentantipsychotic effects, especially in some neuroleptic-resistant patients.414

The aforementioned data led neuroscientists to studythe effects of acute or chronic administration of neurolep-tics, including haloperidol, on the concentrations of CCKand its receptor sites. The results of these studies providedinteresting but inconclusive observations. The variedeffects of haloperidol on the concentration of CCK418–420

might depend on the varied mammalian species studied,



the areas of brain examined, the nature of the experimentsconducted, and especially the ligand used to determineeither the content or the density of receptor sites for theoctapeptide. Indeed, a study by Zetler421 has shown thatCCK-like peptides with neuroleptic activity were able toantagonize stereotyped behaviors caused by dopaminer-gic receptor agonists, but the mechanism of action of thepeptides was not due to a simple clear-cut neuroleptic-likeblockade of postsynaptic dopamine receptors. The coex-istence of CCK peptides in the nigrostriatal and mesolim-bic dopaminergic systems might modulate the synthesis,storage, and/or functions of dopamine and provide addi-tional insight into the efficacy of neuroleptics and the psy-chopathology of schizophrenia. However, the nonuniformdistribution of CCK8S receptors in the central nervoussystem signifies a broader function for the octapeptidethan once anticipated, deserving further in-depth investi-gation.416

NEUROLEPTIC-OPIOID INTERACTION

Experimental evidence suggests close interaction betweenneuroleptic therapy and the endogenous opioid peptides140

(see Table 46.8). The experimental evidence and clinicalfindings strongly support the contention that a modifica-tion in the metabolism and/or action of dopamine-opioidand dopamine-CCK transmission in part might have bothbeneficial and harmful effects with regard to the neuro-leptic-induced movement disorders.

TREATMENT OF TARDIVE DYSKINESIA

BUSPIRONE IN L-DOPA-INDUCED DYSKINESIAS

Buspirone is an azaspirodecandeione drug with an anxi-olytic efficacy comparable to that of the benzodiazepines,but without any sedative, muscle relaxant, or anticonvul-sant effects.422,423 Unlike the benzodiazepines, buspironedoes not interact with GABA-benzodiazepine chloridechannel complex, is thought to exert its neuropharmaco-logical properties as an agonist for serotonin 5-HT1A

receptor subtype, and blocks presynaptic dopamine D2

receptors.424 By stimulating 5-HT1A autoreceptors locatedon raphe neurons, buspirone inhibits the firing of seroton-ergic neurons, leading to a decrease of serotonin transmis-sion in the brain. Moreover, it interacts directly with 5-HT1A postsynaptic receptors in the hippocampus, an actionthat has been invoked to explain, at least in part, its anx-iolytic effects.425 Bonifati et al.425 reported that buspirone(10 mg orally twice a day) for 3 weeks significantly less-ened the severity of the L-dopa-induced dyskinesia with-out worsening parkinsonism. Buspirone in relatively largedoses of 180 mg/day (the recommended dosage of bus-pirone in anxiety is 20 to 60 mg/day) has been shown tobe effective in the treatment of tardive dyskinesia.

Improvement was also observed in neuroleptic-inducedparkinsonism and akathisia. Although the dosages admin-istered were considerably higher than those used in thetreatment of anxiety, drug side effects were reported to bemild.426 Although dyskinetic movements may improvewith reduction in anxiety,427 Moss et al.426 believed thatthe observed antidyskinetic effect associated with bus-pirone treatment occurred independently of buspirone’seffects on anxiety.

VITAMIN E AND DYSKINESIA

Vitamin E (1200 mg daily) for 1 month significantly ame-liorated the severity of tardive dyskinesia.428 Moreover,Dannon et al.429 treated 16 patients with tardive dyskinesiawith vitamin E in an open trial of on-off-on design. Abnor-mal involuntary movement scale (AIMS) ratings were per-formed in every phase of the study. The patients exhibiteda significant reduction in their mean AIMS scores duringvitamin E treatment. Thus, this finding may suggest apossible role for vitamin E in the treatment of tardivedyskinesia.

TABLE 46.8Experimental 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.430–434

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

Opioids might participate in the pathogenesis of neuroleptic-induced akathisia.437,438

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.



AMANTADINE IN TARDIVE DYSKINESIA

Angus et al.442 reported that amantadine, initially100 mg/day during the first week and then 300 mg/dayduring the third week, produced an improvement in dys-kinesia without exacerbation of psychosis even with pro-longed administration.

CLOZAPINE IN AXIAL TARDIVE DYSTONIA

Functionally disabling tardive dystonia is a well recog-nized subtype of tardive dyskinesia for which treatmentis often ineffective.159,443–445 Trugman et al.446 reported apatient with severe axial tardive dystonia who showedimprovement for 4 years after treatment with the atypicalantipsychotic drug clozapine (625 mg/day). Clozapine dif-fers from conventional neuroleptics in that it has higheraffinity for dopamine D1 and lower affinity for dopamineD2 receptors than do conventional antipsychotics, whichare relatively selective dopamine D2 antagonists.

CHOLECYSTOKININ IN TARDIVE DYSKINESIA

CCK is known to modulate the nigrostriatal and mesolim-bic dopamine neuronal system.2,416 Kojima et al.447 in adouble-blind, placebo-controlled, and matched-pairsstudy, reported on the effectiveness of ceruletide(0.8 µg/kg/week), an analog of CCK, in suppressing thesymptoms of neuroleptic-induced tardive dyskinesia. Glo-bal evaluation of the severity of tardive dyskinesia symp-toms over the 8-week study period revealed a significantimprovement with ceruletide as compared with placebo.Analysis of the therapeutic response to ceruletide over thecourse of treatment revealed a slow but long-lastingimprovement of tardive dyskinesia symptoms. Sideeffects, which were mild and transient, consisted mainlyof nausea and epigastric discomfort. The incidence of sideeffects did not differ between the ceruletide- and placebo-treated groups. Ceruletide appears to be a novel and prac-tical treatment that can substantially alleviate the symp-toms of dyskinesia.

RISPERIDONE AND TARDIVE DYSKINESIA

Risperidone is a novel benzisoxazole derivative that ischaracterized as a potent central serotonin receptor antag-onist with less potent dopamine D2 receptor antagonistproperties.448,449 The incidence of tardive dyskinesia withrisperidone is low. In all studies to date, no cases of tardivedyskinesia have been conclusively attributed to risperi-done. For example, in a Canadian multicenter, double-blind clinical trial of risperidone, 135 hospitalized chronicschizophrenic patients were randomly assigned to one ofsix 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 signif-

icantly (P < 0.05) lower dyskinetic scores than thosereceiving placebo, whereas in haloperidol- and placebo-treated patients, no significant differences for dyskineticsymptoms were noted.450

The efficacy of risperidone versus haloperidol andamitriptyline in the treatment of patients with a combinedpsychotic and depressive syndrome has been studied.451

In a multicenter, double-blind, parallel group trial, theefficacy of risperidone was compared with a combinationof haloperidol and amitriptyline over 6 weeks in patientswith coexisting psychotic and depressive symptoms witheither a schizoaffective disorder, depressive type, a majordepression with psychotic features, or a nonresidualschizophrenia with major depressive symptoms accordingto DSM-III-R criteria. A total of 123 patients (62 risperi-done; 61 haloperidol and amitriptyline) were included;the mean daily dosage at endpoint was 6.9 mg risperidoneversus 9 mg haloperidol combined with 180 mg amitrip-tyline. Efficacy results for those 98 patients (47 risperi-done; 51 haloperidol/amitriptyline) who completed atleast 3 weeks of double-blind treatment revealed, in bothtreatment groups, large reductions in the Positive andNegative Syndrome Scale-derived Brief Psychiatric Rat-ing Scale (risperidone 37%; haloperidol/amitriptyline51%) and the Bech-Rafaelsen Melancholia Scale totalscores (risperidone 51%; haloperidol/amitriptyline 70%).The reductions in the Brief Psychiatric Rating Scale andthe Bech-Rafaelsen Melancholia Scale scores in the totalgroup were significantly larger in the haloperidol/amitrip-tyline group than in the risperidone group (P < 0.01),mostly because of significant differences in the subgroupof patients suffering from depression with psychotic fea-tures, whereas treatment differences in the other diagnos-tic subgroups were not significant.

The incidence of extrapyramidal side effects asassessed by the Extrapyramidal Symptom Rating Scalewas slightly higher under risperidone (37%) than underhaloperidol/amitriptyline (31%). Adverse events werereported by 66% of risperidone and 75% of haloperi-dol/amitriptyline patients. The results of this trial suggestthat the therapeutic effect of haloperidol/amitriptyline issuperior to risperidone in the total group of patients withcombined psychotic and depressive symptoms. However,subgroup differences have to be considered.451 Risperi-done also causes neuroleptic malignant syndrome.452–454

CONCLUSIONS

A variety of neurological syndromes, involving particu-larly the extrapyramidal motor system, occur followingthe use of many drugs, but especially with almost allantipsychotic drugs. These drug-induced movement dis-orders are particularly prominent during treatment withthe high-potency agents (tricyclic piperazines and buty-rophenones). There is less likelihood of acute extrapyra-



midal side effects with clozapine, thioridazine, or lowdoses of risperidone.

Six varieties of neurological syndromes are character-istic of antipsychotic drugs. Four of these (acute dystonia,akathisia, parkinsonism, and the rare neuroleptic malig-nant syndrome) usually appear soon after administrationof the drug, and two (rare perioral tremor and tardive dys-kinesias or dystonias) are late-appearing syndromes thatoccur following prolonged treatment.

The pharmacodynamics of drug-induced movementsare ill defined, and treatments are often unsatisfactory.

ACKNOWLEDGMENTS

The author gratefully acknowledges, appreciates, andadmires the unique, dedicated, and excellent secretarialskills of Mrs. Dani Stramer. The studies cited in this paperhave been supported by a grant from USPHS no.NS34566.

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Neuroleptic-Induced Movement Disorders