Neuroleptic-induced Acute Dystonia Research Articles

Treatment recommendations for extrapyramidal side effects associated with second-generation antipsychotic use in children and youth

Antipsychotic use in children is increasing. The purpose of the present article was to provide guidance to clinicians on the clinical management of extrapyramidal side effects of second-generation antipsychotics. Published literature, key informant interviews, and discussions with panel members and stakeholder partners were used to identify key clinical areas of guidance and preferences on format for the present recommendations. Draft recommendations were presented to a guideline panel. Members of the guideline panel evaluated the information gathered from the systematic review of the literature and used a nominal group process to reach a consensus on treatment recommendations. A description of the neurological abnormalities commonly seen with antipsychotic medications is provided, as well as recommendations on how to examine and quantify these abnormalities. A stepwise approach to the management of neurological abnormalities is provided. Several different types of extrapyramidal symptoms can be seen secondary to antipsychotic use in children including neuroleptic-induced acute dystonia, neuroleptic-induced akathisia, neuroleptic-induced parkinsonism, neuroleptic-induced tardive dyskinesia, tardive dystonia and tardive akathisia, and withdrawal dyskinesias. The overwhelming majority of evidence on the treatment of antipsychotic-induced movement disorders comes from adult patients with schizophrenia. Given the scarcity of paediatric data, recommendations were made with reference to both the adult and paediatric literature. Given the limitations in the generalizability of data from adult subjects to children, these recommendations should be considered on the basis of expert opinion, rather than evidence based. Clinicians must be aware of the potential of second-generation antipsychotics to induce neurological side effects, and should exercise a high degree of vigilance when prescribing these medications.

A randomised controlled study of risperidone and olanzapine for schizophrenic patients with neuroleptic-induced acute dystonia or parkinsonism

The objective of this study was to compare the effects of risperidone and olanzapine in schizophrenic patients with intolerant extrapyramidal side effects (EPS) on first generation antipsychotics. We conducted an 8-week, rater-blinded, flexible dose study. Seventy patients with schizophrenia, who met the DSM-IV research criteria of having neuroleptic-induced acute dystonia or parkinsonism, were randomly assigned to risperidone or olanzapine group. The primary outcome was a comparison of the incidence of concomitant anticholinergic drugs usage between the groups to manage their acute dystonia and parkinsonism. The average doses of risperidone and olanzapine from baseline to study end point were 1.8-3.5 mg/day and 7.7-11.7 mg/day, respectively. There were no significant differences in demographic data, severity of EPS or psychotic symptoms between the groups at baseline assessment. Patients taking risperidone had significantly higher incidence of using anticholinergic drugs to manage acute dystonia or parkinsonism overall during the study (OR = 5.17, 95%CI = 1.49-17.88, P = 0.013). There was no significant between-group difference in the changing of rating scales of EPS and psychotic symptoms. The results of our study favour olanzapine as a better choice in schizophrenic patients with intolerant EPS. Double-blinded, fixed dose and different ethnical study for EPS-intolerant schizophrenic patients is needed to confirm the results of our study.

Aripiprazole-Induced Acute Dystonia

Back to table of contents Previous article Next article Letters to the EditorFull AccessAripiprazole-Induced Acute DystoniaPUSHPAL DESARKAR M.D., D.P.M.ANUPAM THAKUR M.D.VINOD KUMAR SINHA M.D., D.P.M.,PUSHPAL DESARKAR M.D., D.P.M.Search for more papers by this authorANUPAM THAKUR M.D.Search for more papers by this authorVINOD KUMAR SINHA M.D., D.P.M.Search for more papers by this author,Published Online:1 Jun 2006AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail To the Editor: Aripiprazole, the new-generation atypical antipsychotic that is a dopamine system stabilizer, is known for its low propensity to cause extrapyramidal symptoms (1) . Although several reports of dystonia associated with the use of newer atypical antipsychotics are accumulating, a thorough PubMed search through Nov. 6, 2005, did not reveal a single such case induced by aripiprazole. We report a case of acute dystonia observed during aripiprazole therapy. “Mr. A,” an 18-year-old man with no contributory family, past, or personal history was brought to our community clinic with a 4-week history suggestive of a psychotic manic episode. Treatment was initiated with tablet divalproex, which was increased to 500 mg b.i.d., along with aripiprazole, 15 mg/day. In the next follow up, his parents complained about episodes suggestive of dystonia in the form of torticollis, which started within 3 days of treatment initiation. Mr. A did not receive any other medication in between. Trihexyphenidyl, 2 mg/day, was added to the regimen, and dystonia did not recur. Exact mechanism of neuroleptic-induced acute dystonia is still unclear and possibly attributable to a higher ratio of dopamine-acetylcholine antagonism (2) or postsynaptic dopamine hypersensitivity (3) in the basal ganglia. However, preclinical studies with aripiprazole have shown that the drug’s unique partial agonism at dopamine D 2 and serotonin 5-HT 1A receptors, along with antagonism of 5-HT 2A receptors, actually protects against emergence of extrapyramidal symptoms (1) . In our case report, Mr. A had two known risk factors for dystonia, i.e., being young and male (1) . Additionally, we propose the following neurobiological mechanisms that either alone or in combinations could have resulted in acute dystonia with aripiprazole. First, aripiprazole—unlike clozapine, which does not induce acute dystonia—lacks protective anticholinergic action (1) . This was supported by the fact that, in our case, dystonia resolved with anticholinergic medicines. Second, aripiprazole’s action on the D 3 receptor and antagonism of 5-HT 6 and 5-HT 7 receptors is still unknown (1) and could play a potential role. Third, postsynaptic dopamine hypersensitivity was found in bipolar patients (4) , which may be a significant factor. Fourth, the possibility of complex drug interaction of aripiprazole with divalproex cannot be eliminated. Last, preclinical studies found inhibitory action of aripiprazole on serotonin transporter (1) , which could potentially alter dopamine balance in the basal ganglia region. In short, our case report reveals that even aripiprazole may cause rare dystonia in vulnerable individuals, despite having a favorable receptor profile. However, this side effect is amenable to conventional anticholinergic treatment.Ranchi, India Jharkhan, India

Biperiden hydrochlorate ameliorates dystonia of rats produced by microinjection of sigma ligands into the red nucleus

It has been reported that the imbalance of anticholinergic and antidopaminergic activity of each neuroleptic drug correlates with the capacity to produce neuroleptic-induced acute dystonia (NAD) and the major focus of NAD is thought to be the striatum. Anticholinergic drugs are highly effective on NAD, but they are partially effective on neuroleptic-induced tardive dystonia and their effect on idiopathic dystonia is disappointing. Recently, it has been reported that the unilateral microinjection of sigma (σ) ligands into the red nucleus induces torticollis of rats. This animal model appears to be a model of dystonia, but it is not clear whether it is suitable for NAD in man. To clarify this issue, we investigated the effect of an anticholinergic drug, biperiden hydrochlorate (BH), on this animal model. This study revealed that BH dose-dependently ameliorated dystonia of rats induced by two σ ligands, whether each σ ligand had dopaminergic affinity or not. This animal model of dystonia appears to be a model of NAD in man from the viewpoint of treatment-response. The results also suggest that not only dopaminergic and cholinergic systems but also σ system, and not only the striatum but also the red nucleus, may play an important role in the pathophysiology of NAD.

Cocaine as a risk factor for neuroleptic-induced acute dystonia.

A prospective study was conducted to test the hypothesis that cocaine use is a risk factor for neuroleptic-induced acute dystonia (NIAD). The study sample consisted of a high-risk group for NIAD, males aged 17-45 years who had received high-potency neuroleptics within 24 hours of admission and had not used neuroleptics in the month prior to admission. Patients were excluded if they suffered from a neurodegenerative disorder or were exposed to anticholinergics, benzodiazepines, promethazine, carbamazepine, phenytoin, or levodopa during the study. Twenty-nine patients--9 cocaine users and 20 nonusers--entered the study, which lasted 2 years. Patients were followed for 7 days. Cocaine-using psychiatric patients developed significantly more NIAD than did nonusers (relative risk = 4.4, 95% CI = 1.4 to 13.9). Cocaine use is a major risk factor for NIAD and should be added to the list of well-known risk factors. The authors strongly suggest that cocaine-using psychiatric patients who are started on a regimen of neuroleptics should also be administered an anticholinergic for at least 7 days to prevent NIAD.

The Common Marmoset ( Callithrix jacchus) as a Model for Neuroleptic-Induced Acute Dystonia

To examine whether acute dystonia is induced by neuroleptic treatment, common marmosets were treated with haloperidol orally twice a week over 25 weeks until dystonic behavior was elicited. Movement disorders such as acute dystonia were observed 6 weeks after the initial treatment, and had appeared in all treated animals by 25 weeks. Once these movement disorders were induced, they consistently reappeared after further treatment with haloperidol, and once haloperidol dosing was discontinued, the episodes vanished. Then, various neuroleptic drugs (bromperidol, chlorpromazine, risperidone thioridazine, sulpiride, tiapride, and clozapine) or a nonneuroleptic drug (diazepam) were administered orally instead of haloperidol in the above animals. All the neuroleptic drugs except for clozapine elicited similar abnormal behavior, while diazepam failed to induce any dystonia. An anticholinergic drug, trihexyphenidyl, which is known to reduce acute dystonia in patients, was also given orally to the above haloperidol-sensitized animals, followed by further treatment with haloperidol 30 min later. This clearly suppressed the induction of dystonia by haloperidol. The similarity between these findings for haloperidol-pretreated common marmosets and clinical findings suggests that the present model is useful for predicting the potential of antipsychotics to induce acute dystonia in humans.

Neuroleptic binding to sigma receptors: Possible involvement in neuroleptic-induced acute dystonia

Several antipsychotic drugs, belonging to various chemical classes, were compared for their affinity for the sigma, dopamine-D2, and muscarinic receptors. Many neuroleptic drugs were found to bind with high affinity to sigma 2 receptors, and the binding affinity was clearly different from that observed for dopamine-D2 receptors. The dopaminergic and muscarinic theories for the physiopathology of acute dystonia are not completely satisfactory. Since the sigma receptors were reported to play a role in the control of movement, the high affinity of some neuroleptics for these sites suggests their possible involvement in some side effects, such as drug-induced dystonia. There was a correlation between the clinical incidence of neuroleptic-induced acute dystonia and binding affinity of drugs for the sigma receptor, except for some drugs, with a lower incidence, displaying significant affinity for the cholinergic muscarinic receptor. Therefore, we conclude that the affinity for the sigma receptor might be involved in neuroleptic-induced acute dystonia, but this might be partially corrected by the intrinsic anticholinergic properties of the drug.

Epileptic seizures in patients with acute catatonic syndrome.

Acute catatonic syndrome is a condition that can be caused by a variety of metabolic, neurological, psychiatric, and toxic conditions, including neuroleptic malignant syndrome. Although ictal catatonia as a manifestation of non-convulsive status epilepticus has been described, reference to the occurrence of seizures in patients with acute catatonic syndrome is anecdotal. Twenty nine patients with acute catatonic syndrome were reviewed to identify patients with seizures after the onset of acute catatonic syndrome. Patients were divided into four diagnostic groups: affective (15), schizophrenic (eight), toxic (two), and organic (four). Seizures occurred in four patients (13.8%): two patients with dystonic seizures had viral encephalitis and schizophrenic disorder respectively; one patient with complex partial seizures had viral encephalitis and one patient with absence status had neuroleptic malignant syndrome. The results indicate the value of EEG in detection of epileptic activity in patients with acute catatonic syndrome, both at onset and in the course of such disturbance, particularly to provide a differential diagnosis between pseudo-seizures and neuroleptic-induced acute dystonia.

Bromocriptine Sensitization of Neuroleptic-Induced Acute Dystonia

Bromocriptine Sensitization of Neuroleptic-Induced Acute Dystonia

Efficacy of anticholinergic prophylaxis for neuroleptic-induced acute dystonia.

The authors analyzed data from nine studies comparing the incidence of acute dystonia induced by neuroleptic agents with and without concomitant use of anticholinergic agents. Anticholinergic agents reduced the rate of dystonia by 1.9-fold in all patients treated with different neuroleptics and by 5- to 8-fold in patients treated with high-potency neuroleptics. In addition, the incidence of dystonia and the efficacy of anticholinergic prophylaxis were related inversely to age. These results support the efficacy of anticholinergic agents in preventing neuroleptic-induced dystonia, particularly in young male patients treated with high-potency neuroleptics.

Pargyline reduces/prevents neuroleptic-induced acute dystonia in monkeys.

The neuropharmacologic mechanisms underlying neuroleptic-induced extrapyramidal syndromes (EPS) were studied using a nonhuman primate model. Twenty-six Cebus albifrons monkeys were given weekly challenges of haloperidol (0.025 mg/kg IM), and half of the animals received the monoamine oxidase (MAO) inhibitor pargyline (5 mg/kg PO) daily for 17 consecutive days during the protocol. Pargyline caused no changes in baseline behaviors, but significantly reduced haloperidol-induced acute dystonia (AD) (-67%, P less than 0.002) and parkinsonism (-56%, P less than 0.005). The majority (8 of 13) of the experimental group had complete prevention of neuroleptic-induced EPS during cotreatment with pargyline. Behavioral scores returned to baseline levels after stopping pargyline, and did not show the further sensitization to haloperidol-induced AD that occurred in the control group. The possible mechanisms by which an MAO inhibitor might influence neuroleptic-induced AD were considered. The most likely explanation would appear to involve facilitation of striatal dopamine (DA) neurotransmission by inhibition of intra- and extraneuronal MAO, thus supporting the hypothesis that AD is due to decreased striatal DA function with secondary cholinergic hyperfunction.

Pharmacological Modification of Experimental Tardive Dyskinesia

Cebus apella monkeys subjected to chronic haloperidol administration develop neurologic disturbances very similar to neuroleptic-induced acute dystonia human beings. After varying lengths of time, certain monkeys develop a prolonged dyskinetic syndrome resembling tardive dyskinesia (TD), as seen clinically. Two monkeys with signs of TD were given single intramuscular injections of various compounds with known effects on the catecholaminergic, cholinergic, serotoninergic and GABA-ergic neurotransmittor systems, and their effect on the TD signs were rated. Dopamine receptor blockers as well as cholinergics had an ameliorating effect on the symptoms. Some compounds known to activate the GABA system, including some benzodiazepines and the GABA-transaminase inhibitor amino-oxyacetic acid, also reduced the symptoms, as did the serotonin precursor L-5HTP. Results with serotonin antagonists were equivocal. It is concluded that dopamine receptor blockade, as well as increased activity within the GABA-ergic or cholinergic systems cause alleviation of TD. The findings are in agreement with earlier reports in man and thus seem to validate this primate model.

Intravenous diazepam in the treatment of neuroleptic-induced acute dystonia and akathisia.

Intravenous diazepam in the treatment of neuroleptic-induced acute dystonia and akathisia.