Neuroleptic-induced Movement Disorders Research Articles

Handedness as a risk factor for neuroleptic-induced movement disorders

Tardive dyskinesia (TD) is one of the most serious consequences of exposure to antipsychotic medication. Despite extensive research, there remains disagreement over its etiology and risk factors. Likewise little is known about:tOe risk factors for akathisia and drug-induced~parkinsonism (DIP). There is conflicting evidence on the role of handedness as a risk factor. McCreadie et al (1982), in a survey of all schizophrenic inpatients and outpatients in a discrete geographical area, found an excess of non-right-handedness (NRH) in dyskinetic, Feighner-positive subjects. Joseph (1990) reported similar findings in 48 consecutive outpatients with a variety of diagnoses. Ban et al (1989), however, in a study on 43 inpatient schizophrenics, reported dextrals to be at greater risk of developing TD. As the literature is inconclusive a further study is warranted. We have also sought to extend the investigation to include akathisia and DIP.

Neuroleptic use, parkinsonian symptoms, tardive dyskinesia, and associated factors in child and adolescent psychiatric patients

The authors' goal was to determine the prevalence of and risk factors for neuroleptic-induced movement disorders in a group of psychiatrically hospitalized children and adolescents. They evaluated the presence or absence of parkinsonism, tardive dyskinesia, and akathisia in 104 children and adolescents who were in residence in or admitted over a 6-month period to a state-operated child psychiatric center. They applied a standardized, structured assessment procedure used in research on adult and geriatric psychiatric patients and the mentally retarded. The prevalence of parkinsonism among the 61 subjects at risk was 34% and was significantly associated with longer neuroleptic treatment periods immediately before evaluation. The prevalence of treatment-emergent tardive dyskinesia among the 41 subjects at risk was 12% and showed no association with quantitative neuroleptic treatment variables. However, patients with tardive dyskinesia were significantly more likely to have a family history of mental illness and significantly less likely to have a history of assaultive behavior. A pattern of complex pharmacological responses for parkinsonism and tardive dyskinesia, some of which are not typical of those most commonly reported in adults, was seen in this group of young patients. The study data highlight the acute sensitivity of the neuroleptic-treated child and adolescent to the development of parkinsonism, the possible role of certain patient characteristics in the vulnerability to develop tardive dyskinesia, and the possibility that neuroleptic-induced side effects experienced by children and adolescents differ in some ways from those experienced by adults. The data further strongly support the need for systematic monitoring of neuroleptic-treated child and adolescent patients for a full range of side effects.

Instrumental Evidence That Age Increases Motor Instability in Neuroleptic-treated Patients

Fine control of isometric finger flexion force was measured to evaluate motor instability in 40 schizophrenic/schizoaffective patients exposed to neuroleptics and 43 age-comparable normal controls without prior neuroleptic exposure. All the subjects were free of idiopathic or neuroleptic-induced movement disorders. Older neuroleptic-treated patients exhibited significantly greater instability of isometric force compared with older controls, younger patients, or younger controls. Our study indicated that advanced age and neuroleptic exposure contributed to significantly greater motor instability than would be expected by advanced age or neuroleptic exposure alone. These findings are discussed as they pertain to potential mechanisms underlying neuroleptic-induced extrapyramidal side effects.

Patterns of manual dominance in patients with neuroleptic-induced movement disorders

To explore the association between patterns of manual dominance and extrapyramidal symptoms we examined 32 chronic schizophrenic inpatients at Camarillo State Hospital for signs of tardive dyskinesia (TD) and neuroleptic-induced parkinsonism (NIP) using clinical rating scales (Abnormal Involuntary Movement Scale and Columbia Unified Parkinsons Disease Rating Scale) and specialized electromechanical instruments. Manual dominance was assessed using an eight-item hand preference demonstration test. Patients were divided into dextral (consistent use of right hand) and nondextral (any use of the left hand) groups. Dextrals showed a higher prevalence of TD than nondextrals on clinical rating measures (p < 0.01). Orofacial ultrasound measures of TD revealed a similar association between TD and handedness. The two handedness groups did not differ on either the clinical or electromechanical measures of NIP. Interestingly, 28 of the 32 patients showed greater left than right facial movement. It is hypothesized that patients with more standard patterns of manual dominance may be at higher risk for TD than those with atypical patterns.

Risk Factors for Neuroleptic-Induced Movement Disorders

Chronic neuroleptic therapy may be associated with the development of diverse movement disorders including Tardive dyskinesia (TD), Parkinsonism, dystonia, and akathisia in a subset of schizophrenic patients. It is presently unknown why only a proportion of neuroleptic-treated patients develop these movement disorders. In the following communication, we present a series of studies which demonstrate that the development of these movement disorders may be facilitated by certain risk factors including disturbances in pineal melatonin functions, diabetes mellitus, cognitive deficits, suicidal behavior, and disturbances in the functions of the choroid plexus. Recognition of these biological factors may prove useful in: (a) further understanding of the pathophysiology of these disorders, and (b) identifying patients at risk for these movement disorders.

Intermittent versus continuous neuroleptic treatment in a rat model

The treatment schedule for neuroleptic therapy is of relevance when evaluating the development of side-effects. Seventy-five rats were treated discontinuously or continuously with the predominantly dopamine D 2 receptor blocker haloperidol or the combined dopamine D 1/D 2 receptor blocker zuclopenthixol for 15 weeks. During and after treatment, a broad spectrum of behavioural parameters including vacuous chewing movements and tongue protrusions were observed. Discontinuous neuroteptic treatment as opposed to continuous neuroleptic treatment produced a significant long-lasting increase in oral activity. The changes were most pronounced in haloperidol-treated rats. The differences observed may have methodological implications for animal models of neuroleptic-induced movement disorders. Our finding are consistent with the hypothesis that pharmacological sensitization to the dyskinetic side-effects of neuroleptics develops when the drug effect is allowed to wear off between repeated administration.

The association of pineal calcification with drug-induced dystonic movements

There is evidence that reduced melatonin secretion is associated with the pathophysiology of neuroleptic-induced movement disorders including tardive dyskinesia and Parkinsonism. It has been recently reported that pinealectomized rats developed increased incidence and severity of spontaneous chewing movements compared to normal controls. Increased chewing movements in rats has been suggested to reflect acute drug-induced dystonias in humans. To investigate the relationship between melatonin secretion and the pathophysiology of neuroleptic-induced dystonic movements, the presence and size of pineal calcification (PC) on CT scan was studied in relation to the severity of dystonic movements in 34 neuroleptic-treated chronic schizophrenic patients. The incidence of pathologically enlarged PC (greater than 1 cm in diameter) in the schizophrenic patients was 8-9 times greater than the incidence reported in the literature among nonpsychiatric patients. In addition, there were significant differences (p less than .0001) between the severity of dystonic movements in patients with no PC and those with pathologically enlarged PC, and between the severity of the dystonic movements in patients with PC of less than 1 cm and those with PC of greater than 1 cm diameter. These findings indicate an association between the pathophysiology of neuroleptic-induced dystonic movements and the presence of enlarged PCs and suggest that disturbances of melatonin secretion is associated with the emergence of neuroleptic-induced dystonic movements in schizophrenic patients. Further studies using direct measurements of plasma melatonin levels are required more precisely to confirm the association between pineal melatonin secretion and the pathophysiology of drug-induced dystonic movement disorders.

Management of neuroleptic-induced movement disorders: effects of physician training

Residents given a specialized 4-hour course in managing extrapyramidal syndromes prescribed significantly lower neuroleptic doses and were more skilled at diagnosis of extrapyramidal syndromes than residents given standard psychopharmacology training. The results suggest that focused training in extrapyramidal syndromes should be part of residency curricula.

Increased Incidence and Severity of Neuroleptic-Induced Movement Disorder in Pinealectomized Rats

The effects of prior pinealectomy on neuroleptic-induced perioral movements were examined in male Sprague-Dawley rats. Treatment with haloperidol resulted in significantly more severe movement disorder in pinealectomized rats than in unoperated control rats. Subsequent administration of melatonin (4 mg, i.p.) was associated with a nonsignificant reduction of the severity of movements in the pinealectomized rats within one hour. We conclude that pinealectomy facilitates the onset of neuroleptic-induced perioral movements, and suggest that impaired melatonin secretion may be implicated in the pathophysiology of tardive dyskinesia in humans.

Clinical nonrecognition of neuroleptic-induced movement disorders: a cautionary study.

Extrapyramidal side effects are a major limitation in the use of neuroleptics, and tardive dyskinesia is a special public health problem. Accurate clinical diagnosis of extrapyramidal syndromes is necessary for effective management. The authors compared clinicians' recognition of the major extrapyramidal syndromes in 48 psychotic inpatients with independent blind diagnoses by clinical researchers using standardized ratings. The major finding was a high rate of clinical underrecognition of all major extrapyramidal syndromes, especially tardive dyskinesia. The authors discuss the clinical predictors of nonrecognition of extrapyramidal side effects and recommend improved training in their detection.

Risks of neuroleptic drugs in children.

We surveyed members of the Child Neurology Society to examine their attitudes about use of neuroleptic drugs in children and their experiences with neuroleptic-induced movement disorders. Sixty percent of the membership responded to our questionnaire. Of these responders, over 99% agreed that there were clinical indications for neuroleptics in children, but their criteria varied. Only a minority of the responders routinely incorporated drug holidays in the therapeutic plans of children treated with neuroleptics. The majority had not had clinical experience with patients who developed chronic movement disorders associated with neuroleptic treatment, but 35% (140/410) had encountered patients whose symptoms they considered typical of tardive dyskinesia. However, some of these patients did not meet strict criteria for diagnosis of this movement disorder. The results suggest that neuroleptic-induced movement disorders occur with significant frequency in children and that more detailed prospective studies of the risks and benefits of these drugs in children are warranted.

Tardive dyskinesia and anticholinergic drugs

The evidence from the literature does not support the notion that psychotropic drugs with central anticholinergic properties (antiparkinsonian drugs, neuroleptics, antidepressants) constitute a risk factor in tardive dyskinesia. Antiparkinsonian drugs tend to produce reversible increases in the severity of dyskinetic movements and can be used as pharmacological probes in the assessment of neuroleptic-induced movement disorders.

Tardive dyskinesia and anticholinergic drugs.

The evidence from the literature does not support the notion that psychotropic drugs with central anticholinergic properties (antiparkinsonian drugs, neuroleptics, antidepressants) constitute a risk factor in tardive dyskinesia. Antiparkinsonian drugs tend to produce reversible increases in the severity of dyskinetic movements and can be used as pharmacological probes in the assessment of neuroleptic-induced movement disorders.

Changing epidemiology of tardive dyskinesia: an overview.

Dyskinesia is found significantly more often among neuroleptic-treated psychiatric patients than among non-neuroleptic-treated patients. The epidemiology of tardive dyskinesia is changing; its reported prevalence among neuroleptic-treated psychiatric inpatients has been progressively rising and has reached 25% during the past five years. The prevalence of persistent tardive dyskinesia that may be attributable to neuroleptics is about 13%. Tardive dyskinesia is not restricted to old, brain-damaged inpatients but also occurs with a noticeable frequency among younger patients, including outpatients, treated neuroleptics. Yet neuroleptics are the most effective available treatment for schizophrenia; hence, any drastic curtailment of their use in the treatment of chronic schizophrenic patients may not be justified. Cautious use of these drugs, along with intensified research on tardive dyskinesia is warranted.

Dopamine, acetylcholine, and GABA effects in acute dystonia in primates.

Neurological side effects associated with neuroleptic drugs result from a complex interaction of multiple neurotransmitters. To clarify the etiology of neuroleptic-induced acute dystonic reactions, monkeys (Cercopithecus aethiops) were treated with haloperidol at doses sufficient to evoke dystonia, and the effects of agents that influenced dopaminergic, cholinergic, or GABAergic neurotransmitters were evaluated. Apomorphine, a dopamine (DA) agonist, and biperiden, an acetylcholine (ACh) antagonist, decreased acute dystonia, whereas alpha-methyl-p-tyrosine (AMPT), an inhibitor of DA synthesis, and physostigmine, an ACh agonist, agonist, increased the symptoms. Muscimol, a GABA agonist, increased the dystonias in a dose-dependent way, and GABA inhibition with picrotoxin also aggravated dystonia, complicated by systemic intoxication and seizures. The reciprocal interaction between DA and ACh influences is consistent with clinical findings and animal models of dyskinesias. Dystonia may also be modulated by GABAergic substrates, but the results suggest complex interactions among DA, ACh, and GABA neurotransmission. Symptoms involving the orofacial, limb, and trunk regions, and purposeless overactivity are discussed in comparison with acute and tardive neuroleptic-induced movement disorders.

Tardive dyskinesia and other drug-induced movement disorders among handicapped children and youth.

Neuroleptic drugs are used in substantial numbers of mentally retarded children and youth. Many children are treated for very long periods of time, often with the sole purpose of suppressing undesirable behavior. Neuroleptic drugs can exert untoward effects upon many biological systems, and movement disorders or dyskinesias are among the most important consequences of neuroleptic use. The literature concerned with tardive dyskinesias, the most serious of these movement disorders, is examined. A brief discussion of neuroleptic-induced movement disorders, as well as of withdrawal emergent symptoms and acute extrapyramidal effects, is presented. Studying abnormal drug-induced movements in a population already prone to abnormal movements (e.g., stereotypies) even without drugs is extremely difficult but vital to establishing proper guidelines for neuroleptic use.

A survey of tardive dyskinesia in psychiatric outpatients

The authors found a high prevalence--43.4% of tardive dyskinesia in a sample of psychiatric outpatients, a population previously thought to be at nominal risk for development of this syndrome. There was no significant relationship between the presence of dyskinesia and age, sex, years of neuroleptic use, or various organic factors. The effects of dentures and of drug combinations are discussed, and it is noted that structured scales of dyskinesia and videotope recordings are important tools in diagnosing and following the course of dyskinesia.