Calcium channel blockers for antipsychotic-induced tardive dyskinesia

Review question

Are a group of medicines called calcium channel blockers (diltiazem, nifedipine, nimodipine, verapamil, flunarizine) useful for the treatment of an unpleasant side effect, tardive dyskinesia, in people with schizophrenia or similar mental health problems?

Background

People with schizophrenia often hear voices and see things (hallucinations) and have strange beliefs (delusions). These symptoms are usually treated with antipsychotic medicines. However, these drugs can have debilitating side effects. Tardive dyskinesia is an involuntary movement that causes the face, mouth, tongue and jaw to convulse, spasm and grimace. It is caused by long-term or high-dose of antipsychotic medicines, is difficult to treat and can be incurable. A group of medicines called calcium channel blockers (diltiazem, nifedipine, nimodipine, verapamil, flunarizine) have been used as experimental treatments for tardive dyskinesia.

Study characteristics

We searched for clinical trials (up to April 2017) using Cochrane Schizophrenia's specialised register of trials. The review includes three small, short trials published in the 1990s. The trials randomised 47 people with schizophrenia or other chronic mental illnesses who had also developed tardive dyskinesia because they were taking antipsychotic medicines. The treatments the participants received were the calcium channel blockers, flunarizine, nifedipine or diltiazem hydrochloride or placebo (dummy treatment).

Key results

A small set of very low quality data were available from three small and poorly reported trials. Currently, it is uncertain whether calcium channel blockers are helpful in the treatment of tardive dyskinesia that is caused by taking antipsychotic medicines. Therefore, the use of calcium channel blockers for this purpose remains experimental.

Quality of the evidence

Evidence was limited and small scale. It is not possible to recommend these drugs as a treatment for antipsychotic-induced tardive dyskinesia. To fully investigate whether calcium channel blockers have any positive effects, there would have to be more well-designed, conducted and reported clinical trials.

This plain language summary was adapted by the review authors from a summary originally written by Ben Gray, Senior Peer Researcher, McPin Foundation (mcpin.org/).

Authors' conclusions: 

Available evidence from randomised controlled trials is extremely limited and very low quality, conclusions cannot be drawn. The effects of calcium channel blockers for antipsychotic-induced tardive dyskinesia are unknown. Their use is experimental and should only be given in the context of well-designed randomised trials.

Read the full abstract...
Background: 

Schizophrenia and related disorders affect a sizable proportion of any population. Antipsychotic medications are the primary treatment for these disorders. Antipsychotic medications are associated with a variety of adverse effects including tardive dyskinesia. Dyskinesia is a disfiguring movement disorder of the orofacial region that can be tardive (having a slow or belated onset). Tardive dyskinesia is difficult to treat, despite experimentation with several treatments. Calcium channel blockers (diltiazem, nifedipine, nimodipine, verapamil, flunarizine) have been among these experimental treatments.

Objectives: 

To determine the effects of calcium channel blocker drugs (diltiazem, nifedipine, nimodipine, verapamil) for treatment of neuroleptic-induced tardive dyskinesia in people with schizophrenia, schizoaffective disorder or other chronic mental illnesses.

Search strategy: 

We searched the Cochrane Schizophrenia Group Trials Register (July 2015 and April 2017), inspected references of all identified studies for further trials and contacted authors of trials for additional information.

Selection criteria: 

We selected randomised controlled trials comparing calcium channel blockers with placebo, no intervention or any other intervention for people with both tardive dyskinesia and schizophrenia or serious mental illness who remained on their antipsychotic medication.

Data collection and analysis: 

We independently extracted data and estimated risk ratios of dichotomous data or mean differences (MD) of continuous data, with 95% confidence intervals (CI). We assumed that people who left the trials early had no improvement. We also created a 'Summary of findings' table using GRADE.

Main results: 

Previous versions of this review included no trials. From the 2015 search, we identified three cross-over trials that could be included. The 2017 search found no new studies relevant to this review. The included trials randomised 47 inpatients with chronic mental illnesses in the USA and China. Trials were published in the 1990s and were of short duration (six to 10 weeks). Overall, the risk of bias was unclear, mainly due to poor reporting; allocation concealment was not described, generation of the sequence was not explicit, studies were not clearly blinded, and attrition and outcome data were not fully reported. Findings were sparse, no study reported on the primary outcome 'no clinically important improvement in tardive dyskinesia symptoms,' but two small studies (37 participants) found no difference on the tardive dyskinesia symptoms scale Abnormal Involuntary Movement Scale (AIMS) scores between diltiazem or flunarizine and placebo after three to four weeks' treatment (MD -0.71, 95% CI -2.68 to 1.26, very low quality evidence). Only one study randomising 20 participants reported on adverse events, and reported that there were no adverse events with flunarizine or with placebo (very low quality evidence). One study with 18 participants reported no events of deterioration in mental state with diltiazem or with placebo (very low quality evidence). No studies reported on acceptability of treatment or on social confidence, social inclusion, social networks or personalised quality of life outcomes designated important to patients.

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