Gamma-aminobutyric acid agonists for antipsychotic-induced tardive dyskinesia

Review question.

To determine the effects of gamma-aminobutyric acid (GABA) agonist drugs in the treatment of tardive dyskinesia for people with schizophrenia or similar mental health problems.

Background.

People with schizophrenia often hear voices and see things (hallucinations) and have strange beliefs (delusions). The main treatment of schizophrenia is antipsychotic drugs. 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 antipsychotic drugs, is difficult to treat and can be incurable. GABA agonist drugs have been used to treat tardive dyskinesia but have intense sedative properties and may make mental health or psychotic symptoms worse. GABA agonist drugs include baclofen, progabide, sodium valproate, and tetrahydroisoxazolopyridinol (THIP).

Study characteristics.

The review includes 11 studies investigating the use of GABA agonist drugs compared with placebo. All studies involved small numbers of participants (2 to 80 people) with schizophrenia or other chronic mental illnesses who had also developed antipsychotic-induced tardive dyskinesia.

Key results.

Evidence of the effects of GABA agonist drugs in the treatment of tardive dyskinesia is not conclusive and not convincing. Any possible benefits of GABA agonist drugs are likely to be outweighed by the adverse effects associated with their use.

Quality of the evidence.

Evidence is weak, short term, small scale and poorly reported. It is not possible to recommend these drugs as a treatment for tardive dyskinesia.

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

Authors' conclusions: 

We are uncertain about the evidence of the effects of baclofen, progabide, sodium valproate or tetrahydroisoxazolopyridinol (THIP) for people with antipsychotic-induced TD. Evidence is inconclusive and unconvincing. The quality of data available for main outcomes ranges from very low to low. Any possible benefits are likely to be outweighed by the adverse effects associated with their use.

Read the full abstract...
Background: 

Chronic antipsychotic drug treatment may cause tardive dyskinesia (TD), a long-term movement disorder. Gamma-aminobutyric acid (GABA) agonist drugs, which have intense sedative properties and may exacerbate psychotic symptoms, have been used to treat TD.

Objectives: 

1. Primary objective

The primary objective was to determine whether using non-benzodiazepine GABA agonist drugs for at least six weeks was clinically effective for the treatment of antipsychotic-induced TD in people with schizophrenia, schizoaffective disorder or other chronic mental illnesses.

2. Secondary objectives

The secondary objectives were as follows.

To examine whether any improvement occurred with short periods of intervention (less than six weeks) and, if this did occur, whether this effect was maintained at longer periods of follow-up.

To examine whether there was a differential effect between the various compounds.

To test the hypothesis that GABA agonist drugs are most effective for a younger age group (less than 40 years old).

Search strategy: 

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

Selection criteria: 

We included randomised controlled trials of non-benzodiazepine GABA agonist drugs in people with antipsychotic-induced TD and schizophrenia or other chronic mental illness.

Data collection and analysis: 

Two review authors independently selected and critically appraised studies, extracted and analysed data on an intention-to-treat basis. Where possible and appropriate we calculated risk ratios (RRs) and their 95% confidence intervals (CIs). For continuous data we calculated mean differences (MD). We assumed that people who left early had no improvement. We contacted investigators to obtain missing information. We assessed risk of bias for included studies and created a 'Summary of findings' table using GRADE.

Main results: 

We included 11 studies that randomised 343 people. Overall, the risk of bias in the included studies was unclear, mainly due to poor reporting; allocation concealment was not described, generation of the sequence was not explicit, participants and outcome assessors were not clearly blinded. For some studies we were unsure if data were complete, and data were often poorly or selectively reported.

Data from six trials showed that there may be a clinically important improvement in TD symptoms after GABA agonist treatment compared with placebo at six to eight weeks follow-up (6 RCTs, n = 258, RR 0.83, CI 0.74 to 0.92; low-quality evidence). Data from five studies showed no difference between GABA agonist treatment and placebo for deterioration of TD symptoms (5 RCTs, n = 136, RR 1.90, CI 0.70 to 5.16; very low-quality evidence). Studies reporting adverse events found a significant effect favouring placebo compared with baclofen, sodium valproate or progabide for dizziness/confusion (3 RCTs, n = 62 RR 4.54, CI 1.14 to 18.11; very low-quality evidence) and sedation/drowsiness (4 RCTS, n = 144, RR 2.29, CI 1.08 to 4.86; very low-quality evidence). Studies reporting on akathisia (RR 1.05, CI 0.32 to 3.49, 2 RCTs, 80 participants), ataxia (RR 3.25, CI 0.36 to 29.73, 2 RCTs, 95 participants), nausea/vomiting (RR 2.61, CI 0.79 to 8.67, 2 RCTs, 64 participants), loss of muscle tone (RR 3.00, CI 0.15 to 59.89, 1 RCT, 10 participants), seizures (RR 3.00, CI 0.24 to 37.67, 1 RCT, 2 participants), hypotension (RR 3.04, CI 0.33 to 28.31, 2 RCTs, 119 participants) found no significant difference between GABA drug and placebo (very low-quality evidence). Evidence on mental state also showed no effect between treatment groups (6 RCTS, n = 121, RR 2.65, CI 0.71 to 9.86; very low-quality evidence) as did data for leaving the study early (around 10% in both groups, 6 RCTS, n = 218, RR 1.47, CI 0.69 to 3.15; very low-quality evidence). No study reported on social confidence, social inclusion, social networks, or personalised quality of life, a group of outcomes selected as being of particular importance to patients.

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