Miscellaneous treatments for antipsychotic-induced tardive dyskinesia

What is the aim of this review?

The aim of this Cochrane Review was to find out if drugs, supplements, surgical interventions, electroconvulsive therapy, or mind-body therapies not covered in other Cochrane reviews of tardive dyskinesia can improve tardive dyskinesia. We collected and analysed all relevant randomised controlled trials to answer this question.

Key messages

The drug valbenazine and extract of the herb Ginkgo biloba probably improves symptoms of tardive dyskinesia. But we still need more high-quality studies to confirm these findings that were taken from only one study per intervention.

What was studied in the review?

Antipsychotic drugs are used to treat chronic mental illnesses such as schizophrenia by controlling, for instance, abnormal perceptions (hallucinations), disordered thinking and fixed false beliefs (delusions). Tardive dyskinesia is a disfiguring and disabling disorder of abnormal, repetitive and involuntary movements, and it is often caused by antipsychotic drugs. More than 20% of people who rely on antipsychotic drugs to control their mental illness have developed tardive dyskinesia. Many different interventions have been studied for easing the symptoms of tardive dyskinesia. Several Cochrane reviews have summarised the effects of the many treatments used to manage these involuntary movements. This review focusses on 'miscellaneous', a group of other non-connected, interventions not covered in the other Cochrane reviews on tardive dyskinesia.

What are the main results of the review?

We found 31 studies that reported on 24 different interventions to improve tardive dyskinesia in 1278 people who take antipsychotic medication for their chronic mental illnesses. Unfortunately most studies followed up on participants for a short time (most were three to six weeks) and included few participants (the average number of participants was 41 per study).

• Valbenazine probably reduces symptoms of tardive dyskinesia to a clinically important extent compared with placebo (moderate-certainty evidence). However, this evidence is based on only one study in the USA with 92 participants; we are awaiting results from recently completed and ongoing trials to confirm these results.

• Extract of Ginkgo biloba probably reduces symptoms of tardive dyskinesia to a clinically important extent compared with placebo (moderate-certainty evidence). However, this evidence is based on only one study in China with 157 participants; we are awaiting results from recently completed and ongoing trials to confirm these results.

• Evidence for the remaining interventions was of low- to very low-certainty evidence and we consider the results for these other interventions to be inconclusive.

How up-to-date is this review?

We searched for studies that had been published up to 26 April 2017.

Authors' conclusions: 

This review has found that the use of valbenazine or extract of Ginkgo biloba may be effective in relieving the symptoms of tardive dyskinesia. However, since only one RCT has investigated each one of these compounds, we are awaiting results from ongoing trials to confirm these results. Results for the remaining interventions covered in this review must be considered inconclusive and these compounds probably should only be used within the context of a well-designed evaluative study.

Read the full abstract...

Antipsychotic (neuroleptic) medication is used extensively to treat people with chronic mental illnesses. Its use, however, is associated with adverse effects, including movement disorders such as tardive dyskinesia (TD) - a problem often seen as repetitive involuntary movements around the mouth and face. This review, one in a series examining the treatment of TD, covers miscellaneous treatments not covered elsewhere.


To determine whether drugs, hormone-, dietary-, or herb-supplements not covered in other Cochrane reviews on TD treatments, surgical interventions, electroconvulsive therapy, and mind-body therapies were effective and safe for people with antipsychotic-induced TD.

Search strategy: 

We searched the Cochrane Schizophrenia Group’s Study-Based Register of Trials including trial registers (16 July 2015 and 26 April 2017), inspected references of all identified studies for further trials and contacted authors of trials for additional information.

Selection criteria: 

We included reports if they were randomised controlled trials (RCTs) dealing with people with antipsychotic-induced TD and schizophrenia or other chronic mental illnesses who remained on their antipsychotic medication and had been randomly allocated to the interventions listed above versus placebo, no intervention, or any other intervention.

Data collection and analysis: 

We independently extracted data from these trials and we estimated risk ratios (RR) or mean differences (MD), with 95% confidence intervals (CIs). We assumed that people who left early had no improvement. We assessed risk of bias and created 'Summary of findings' tables using GRADE.

Main results: 

We included 31 RCTs of 24 interventions with 1278 participants; 22 of these trials were newly included in this 2017 update. Five trials are awaiting classification and seven trials are ongoing. All participants were adults with chronic psychiatric disorders, mostly schizophrenia, and antipsychotic-induced TD. Studies were primarily of short (three to six6 weeks) duration with small samples size (10 to 157 participants), and most (61%) were published more than 20 years ago. The overall risk of bias in these studies was unclear, mainly due to poor reporting of allocation concealment, generation of the sequence, and blinding.

Nineteen of the 31 included studies reported on the primary outcome 'No clinically important improvement in TD symptoms'. Two studies found moderate-quality evidence of a benefit of the intervention compared with placebo: valbenazine (RR 0.63, 95% CI 0.46 to 0.86, 1 RCT, n = 92) and extract of Ginkgo biloba (RR 0.88, 95% CI 0.81 to 0.96, 1 RCT, n = 157), respectively. However, due to small sample sizes we cannot be certain of these effects.

We consider the results for the remaining interventions to be inconclusive: Low- to very low-quality evidence of a benefit was found for buspirone (RR 0.53, 95% CI 0.33 to 0.84, 1 RCT, n = 42), dihydrogenated ergot alkaloids (RR 0.45, 95% CI 0.21 to 0.97, 1 RCT, n = 28), hypnosis or relaxation, (RR 0.45, 95% CI 0.21 to 0.94, 1 study, n = 15), pemoline (RR 0.48, 95% CI 0.29 to 0.77, 1 RCT, n = 46), promethazine (RR 0.24, 95% CI 0.11 to 0.55, 1 RCT, n = 34), insulin (RR 0.52, 95% CI 0.29 to 0.96, 1 RCT, n = 20), branched chain amino acids (RR 0.79, 95% CI 0.63 to 1.00, 1 RCT, n = 52), and isocarboxazid (RR 0.24, 95% CI 0.08 to 0.71, 1 RCT, n = 20). There was low- to very low-certainty evidence of no difference between intervention and placebo or no treatment for the following interventions: melatonin (RR 0.89, 95% CI 0.71 to 1.12, 2 RCTs, n = 32), lithium (RR 1.59, 95% CI 0.79 to 3.23, 1 RCT, n = 11), ritanserin (RR 1.00, 95% CI 0.70 to 1.43, 1 RCT, n = 10), selegiline (RR 1.37, 95% CI 0.96 to 1.94, 1 RCT, n = 33), oestrogen (RR 1.18, 95% CI 0.76 to 1.83, 1 RCT, n = 12), and gamma-linolenic acid (RR 1.00, 95% CI 0.69 to 1.45, 1 RCT, n = 16).

None of the included studies reported on the other primary outcome, 'no clinically significant extrapyramidal adverse effects'.