Acute Dystonic Reactions Research Articles

Mood alteration following oral and intravenous haloperidol and relationship to drug concentration in normal subjects.

Haloperidol was administered to 12 subjects intravenously (0.125 mg/kg) and to nine subjects orally (0.5 mg/kg). These doses produced sedation in most subjects. A minimal decrease in orthostatic blood pressure was observed. Administration of the Profile of Mood States to these subjects revealed effects on factor 4, vigor-activity, and factor 6, confusion-bewilderment, but many subjects could not complete testing due to excessive sedation. Haloperidol concentrations were obtained during testing and correlated moderately with scores of these subscales. Correlation was also noted between haloperidol concentration and chlorpromazine effect as measured by the Addiction Research Center Inventory. Extrapyramidal reactions, mainly acute dystonic reactions and akathisia, were common. Dystonia occurred in four subjects after intravenous, and three subjects, after oral administration. Akathisia occurred in eight subjects after intravenous, and three subjects after oral administration. Extrapyramidal reactions tended to occur relatively early or relatively late, at times when drug concentrations were far less than peak values.

Neuroleptics, extrapyramidal symptoms, and serum-calcium levels

A prospective study of 34 new admissions to a psychiatric center revealed an 80% incidence of extrapyramidal symptoms among patients receiving only neuroleptic drugs (N = 24) during the first 2 weeks of hospitalization. The occurrence of acute dystonic reactions and parkinsonian symptoms (but not akathisia) in this group was significantly associated with a decrease in serumcalcium levels. The findings suggest the need for (1) prophylactic use of antiparkinsonian drugs during the initial stages of neuroleptic treatment and (2) further research into the possible role of calcium metabolism in the production of extrapyramidal side effects.

Drug-induced acute dystonic reactions in children. Alternatives to diphenhydramine therapy.

Drug-induced acute dystonic reactions in children. Alternatives to diphenhydramine therapy.

Extended therapy for acute dystonic reactions

Dystonic reactions to neuroleptic and antiemetic medications are commonly seen in the outpatient setting. Despite initially successful treatment in the emergency department, symptoms may later recur. We have recently seen several cases of recurrent dystonic reactions; four representative cases are reported. Three of the patients experienced no further dystonic reactions when treated appropriately as outpatients. The fourth patient was lost to follow up. Based on this experience in the pharmacology of the drugs involved in producing and treating dystonic reactions, it is recommended that patients successfully treated in the emergency department for dystonia receive continued outpatient therapy for 48 to 72 hours.

The abrupt withdrawal of antiparkinsonian drugs in mentally handicapped patients.

Long-term antiparkinsonian medication given to 20 mentally handicapped patients also on neuroleptics was abruptly withdrawn. Transient extrapyramidal signs developed in most patients during the following four weeks but in 60 per cent had disappeared by 12 weeks. Reintroduction of medication was necessary in only three patients, who developed acute dystonic reactions within one week of withdrawal.

Dystonic reaction after ketamine abuse

A 20-year-old man developed an acute dystonic reaction following the self-administration of ketamine. The episode resolved upon treatment with diphenhydramine. Dystonia is an unusual toxic effect of ketamine abuse; potential mechanisms for its occurrence in this instance are discussed.

A Monkey Model of Tardive Dyskinesia (TD)

Three Cebus apella monkeys were treated with biweekly injections of fluphenazine enanthate for 1 year. Two distinct motor syndromes were produced. The first consisted of acute dystonic, dyskinetic, parkinsonian, and akathisia-like reactions, which worsened after each injection, were not exacerbated by drug withdrawal, and could be abolished or prevented with benztropine. The second appeared after cessation of neuroleptic treatment and consisted of abnormal movements very similar to those of patients with tardive dyskinesia (TD). This syndrome was abolished completely by reinstitution of fluphenazine treatment. One monkey was given a second and third course of fluphenazine, each course lasting 4 weeks. The second syndrome was seen after but not during each course and remained robust for a longer period after the third than after the first or second courses of treatment. We conclude that the first syndrome is analogous to the early appearing extrapyramidal symptoms of neuroleptic-treated patients and that, according to preliminary evidence, reversible TD may turn into irreversible TD with continued periods of on and off neuroleptic treatment.

Neuroleptic-induced acute dyskinesias in rhesus monkeys.

Rhesus monkeys, previously subjected to twice-weekly injections of various neuroleptics, subsequently respond to acute IM injections of haloperidol with marked bucco-lingual and whole body movement disturbances consisting of mouth opening, protrusion, retraction or curling of the tongue together with writhing movements of the neck, trunk and/or limbs. These phenomena, which closely resemble the acute dyskinetic or dystonic reactions described in patients at the beginning of neuroleptic treatment, were also observed after acute IM injections of other neuroleptics such as fluphenazine, metoclopramide, oxiperomide, sulpiride, sultopride and tiapride. No dyskinesias were observed after chlorpromazine, chlordiazepoxide, clozapine, RMI81582 or thioridazine at doses which otherwise had marked behavioural effects. The dyskinesias induced by haloperidol could be suppressed by prior treatment with the anti-cholinergic scopolamine. These observations, which correlate well with clinical findings, suggest that neuroleptic induced acute dyskinesias in the Rhesus monkey might be a useful model for predicting the liability of new anti-psychotics for inducing acute dyskinetic reactions in man.

Neuroleptic‐induced acute dystonic reactions may be due to enhanced dopamine release on to supersensitive postsynaptic receptors

Oral administration of butaperazine (40 mg per kilogram) to rats increased dopamine turnover, as measured by elevation of striatal and mesolimbic concentrations of homovanillic acid and 3,4-dihydroxyphen-ylacetic acid, for 24 to 48 hours. Initially, this dose of butaperazine inhibited stereotyped behavior in response to subcutaneous administration of apomorphine, but this effect was reversed at 12 hours. Later, animals had normal or exaggerated responses to apomorphine. The data suggest that at the critical 20- to 28-hour period after butaperazine administration, when most human acute dystonic reactions occur, normal or supersensitive cerebral dopamine receptors are exposed to an excessive synaptic release of dopamine. This may be responsible for the drug-induced dystonia.

Neuroleptic-induced acute dystonic reactions may be due to enhanced dopamine release on to supersensitive postsynaptic receptors.

Oral administration of butaperazine (40 mg per kilogram) to rats increased dopamine turnover, as measured by elevation of striatal and mesolimbic concentrations of homovanillic acid and 3,4-dihydroxyphenylacetic acid, for 24 to 48 hours. Initially, this dose of butaperazine inhibited stereotyped behavior in response to subcutaneous administration of apomorphine, but this effect was reversed at 12 hours. Later, animals had normal or exaggerated responses to apomorphine. The data suggest that the critical 20- to 28-hour period after butaperazine administration, when most human acute dystonic reactions occur, normal or supersensitive cerebral dopamine receptors are exposed to an excessive synaptic release of dopamine. This may be responsible for the drug-induced dystonia.

Side effects in preventive maintenance therapy with neuroleptics with special emphasis on tardive dyskinesia.

Neuroleptics induce hypersensitivity reactions, and toxic, systemic and extrapyramidal manifestations. The latter mainly include acute dystonic reactions, other early dyskinesias, akathisia, parkinsonism and TD. These drugs have been implicated for DA antagonism exerted by an adenylate cyclase inhibition. Prolonged blockade of DA receptors is considered as the motivation for a counterbalancing mechanism inducing the DA supersensitivity from which TD results. Recent reports suggest cholinergic and GABA ergic insufficiency as secondary participants. The increasing frequency of TD calls for prevention by modifying treatment practices and searching for effective measures to combat the symptoms.

Street Drug Misrepresentation

To the Editor.— Refering to the letter by Falck and Seal (244:332, 1980) regarding their discovery of street manufactured methaqualone (Quaalude) tablets actually containing phencyclidine hydrochloride (PCP). I recently experienced an example of such deception in street drug trade when a 21-year-old man came to our emergency room with an acute dystonic reaction induced by the ingestion of four 10-mg diazepam (Valium) tablets. The product information material for diazepam mentions increased muscle spasticity as a rare paradoxical reaction to the drug. Based on this information, it was initially assumed that 10-mg diazepam tablets were purchased, and such an adverse reaction was experienced. The dystonia was quickly reversed by the intramuscular administration of diphenhydramine hydrochloride. After further questioning, the patient disclosed that the street dealer advertised his wares as generic Valium. He described the tablets as small blue pills with the number '10' on them. On a hunch, I asked the

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.

The pathophysiology of extrapyramidal side-effects of neuroleptic drugs.

The mechanisms responsible for the production of major extrapyramidal side-effects (parkinsonism, akathisia, acute dystonic reactions, chronic tardive dyskinesias) are reviewed in the light of the complex effects of these drugs on cerebral dopamine systems.

Thiethylperazine (Torecan)-Associated Dystonic Reactions in Children

The phenothiazines are probably the most commonly used medications for the symptomatic relief of nausea and vomiting and may be effective irrespective of the primary cause.1,2 Along with their beneficial effects, these agents carry with them a risk of extrapyramidal side effects which may appear as parkinsonian syndromes, akathisias, acute dystonic reactions, and tardive dyskinesias.3 syptoympttoms commonly associated with acute dysic reactionsns with phenothiazines include oculogyri crisis, torticollis, trismus, facial grimace, protusion of the tongue, hyperreflexia, opisthotonos, and rigidity. The majority of these reactions have been reported in children taking the drugs in therapeutic doses.4-6 We wish to report four cases of acute dystonic reactions occurring in association with thiethylperazine (Torecan), a phenothiazine that has recently experienced increased pediatric usage.

Toxic Reactions From a Haloperidol Overdose in Two Children

REPORTS of toxic reactions to haloperidol have been scant. Hollister and Ayd have commented about the relative safety of a drug overdose; also, Davis and associates have reported an absence of fatalities and life-threatening reactions. An extensive search of the literature showed only nine reported cases of pediatrics drug overdose. In the series of Gaultier and Fahti, 1 five children were reported to have reversible symptoms, including somnalence and extrapyramidal signs. Debray and Galland 2 report four cases with acute dystonic reactions and convulsions. Fourteen unpublished cases of drug overdose have been reported to the McNeil Laboratories (according to a personal communication with J. C. Maerz, MD, Feb 11, 1977). These include 9 instances of impaired consciousness, 7 of extrapyramidal symptoms, and 2 of hypertension; one child had no ill effects. In all cases, recovery was complete and there was no mention of cardiovascular manifestations. In view of the fact

ACUTE DYSTONIA AS AN IDIOSYNCRATIC RESPONSE TO NEUROLEPTICS IN BABOONS

Among 25 baboons, Papio papio, 2 consistently showed acute dystonic reactions, with mouthing, compulsive gnawing and limb and trunk dystonia, following the intravenous administration of neuroleptics and related drugs (haloperidol, 0-6-1-2 mg/kg; pimozide 0-5-2-5 mg/kg; chlorpromazine 5-25 mg/kg; metoclopramide 1-5-1-7 mg/kg; oxyperomide 0-25-1-0 mg/kg). The syndrome was not seen after thioridazine (3-7 mg/kg). The dystonic responses occurred within 1-2 h of drug injection and lasted for 2-24 h. They were abolished for 1-3 h within 1-2 min of the intravenous injection of acetylcholine antagonists (benztropine 0-2 mg/kg; hyoscine 0-02 mg/kg). Pre-treatment with a combination of reserpine (2 mg/kg) and alpha-methylparatyrosine (2 X 200 mg/kg) substantially reduced the dystonic response to haloperidol. A second larger dose of haloperidol (5 mg/kg), given 60-90 min after 0-5 mg/kg) initially reduced the intensity of the dystonic response, but after 29 min induced vomiting and generalized seizures in the idiosyncratic baboons. The hypothesis is advanced that the dystonic responses result from release of dopamine on to a sub-population of receptors in the striatum that are relatively insensitive to blockade by neuroleptics.

TETANY, TETANUS OR DRUG REACTION ?

An 8-year-old child was given perphenazine to prevent vomiting after surgery and developed an acute dystonic reaction; There were features of both tetany and tetanus without any of the classical features of extrapyramidal disturbance. The diagnostic difficulties are discussed. The reaction was treated successfully with i.v. diazepam. The prescribing of anti-emetics after surgery is examined critically with special reference to children.

Pharmacokinetics of red blood cell phenothiazine and clinical effects. Acute dystonic reactions.

Pharmacokinetics of the phenothiazine, butaperazine, were studied in relationship to acute dystonic reactions. Dystonias appeared on falling drug concentrations, more than one half-life after plasma and red blood cell (RBC) peak butaperazine concentrations. Red blood cell butaperazine kinetics differentiated better than did plasma butaperazine levels those subjects in whom dystonias would develop from those in whom they did not. We conclude that RBC phenothiazine levels may more clearly reflect drug concentration at critical brain sites than do simple plasma drug levels. Furthermore, dystonic reactions may be the result of differential sensitivity of two or more receptor systems to receptor blockade by antischizophrenic agents.

Dystonic reactions following neuroleptics: time course and proposed mechanisms.

The occurrence of acute dystonic reactions was studied relative to drug pharmacokinetic parameters following a single dose of the phenothiazine, butaperazine. Dystonias occurred more than one half-life from peak butaperazine levels, 23 to 56 h after drug administration. The authors postulate that the appearance of dystonias on falling plasma concentrations may be due to disruption of dopaminergic-cholinergic balance caused by differential antidopaminergic and anticholinergic potencies of the drug.