Tardive dyskinesia (TD) remains a troublesome adverse effect of conventional antipsychotic (neuroleptic) medication. It has been proposed that TD could have a component of central cholinergic deficiency. Cholinergic drugs have been used to treat TD.
To determine the effects of cholinergic drugs (arecoline, choline, deanol, lecithin, meclofenoxate, physostigmine, RS 86, tacrine, metoxytacrine, galantamine, ipidacrine, donepezil, rivastigmine, eptastigmine, metrifonate, xanomeline, cevimeline) for treating antipsychotic-induced TD in people with schizophrenia or other chronic mental illness.
An electronic search of the Cochrane Schizophrenia Group’s Study-Based Register of Trials (16 July 2015 and April 2017) was undertaken. This register is assembled by extensive searches for randomised controlled trials in many electronic databases, registers of trials, conference proceedings and dissertations. References of all identified studies were searched for further trial citations.
We included reports identified by the search if they were of controlled trials involving people with antipsychotic-induced TD and chronic mental illness, who had been randomly allocated to either a cholinergic agent or to a placebo or no intervention. Two review authors independently assessed the methodological quality of the trials.
Data collection and analysis
Two review authors extracted data and, where possible, estimated risk ratios (RR) or mean differences (MD), with 95% confidence intervals (CI). We analysed data on an intention-to-treat basis, with the assumption that people who left early had no improvement. We assessed risk of bias and created a ‘Summary of findings’ table using GRADE.
We included 14 studies investigating the use of cholinergic drugs compared with placebo published between 1976 and 2014. All studies involved small numbers of participants (five to 60 people). Three studies that investigated the new cholinergic Alzheimer drugs for the treatment of TD are new to this update. 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, studies were not clearly blinded, we are unsure if data are incomplete, and data were often poorly or selectively reported.
We are uncertain about the effect of new or old cholinergic drugs on no clinically important improvement in TD symptoms when compared with placebo; the quality of evidence was very low (RR 0.89, 95% CI 0.65 to 1.23; 27 people, 4 RCTs). Eight trials found that cholinergic drugs may make little or no difference to deterioration of TD symptoms (low-quality evidence, RR 1.11, 95% CI 0.55 to 2.24; 147 people). Again, due to very low-quality evidence, we are uncertain about the effects on mental state (RR 0.50, 95% CI 0.10 to 2.61; 77 people, 5 RCTs), adverse events (RR 0.56, 95% CI 0.15 to 2.14; 106 people, 4 RCTs), and leaving the study early (RR 1.09,95% CI 0.56 to 2.10; 288 people 12 RCTs). No study reported on social confidence, social inclusion, social networks, or personalised quality of life.
TD remains a major public health problem. The clinical effects of both older cholinergic drugs and new cholinergic agents, now used for treating Alzheimer’s disease, are unclear, as too few, too small studies leave many questions unanswered. Cholinergic drugs should remain of interest to researchers and currently have little place in routine clinical work. However, with the advent of new cholinergic agents now used for treating Alzheimer’s disease, scope exists for more informative trials. If these new cholinergic agents are to be investigated for treating people with TD, their effects should be demonstrated in large well-designed, conducted and reported randomised trials.
Plain language summary
Cholinergic medication for antipsychotic-induced tardive dyskinesia
Are cholinergic drugs useful for treating the unpleasant side-effect – tardive dyskinesia – in people with schizophrenia or other similar mental health problems who are taking antipsychotics.
People with schizophrenia often hear voices and see things (hallucinations) and have strange beliefs (delusions). These symptoms are usually treated with 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 of antipsychotic drugs, is difficult to treat and can be incurable. It has been proposed that tardive dyskinesia could be due to cholinergic deficiency. Older cholinergic drugs, such as deanol, lecithin and meclofenoxate, have been used to treat tardive dyskinesia. New cholinergic drugs, such as donepezil, galantamine and rivastigmine, have been developed for the treatment of Alzheimer’s disease and may also be promising in the treatment for tardive dyskinesia.
We searched for trials in July 2015 and April 2017, using the Cochrane Schizophrenia Group’s register of trials. The review includes 14 studies investigating the use of cholinergic drugs compared with placebo. All studies randomised small numbers of participants (five to 60 people) with schizophrenia or other chronic mental illnesses who had also developed antipsychotic-induced tardive dyskinesia.
We found the effects of both older and newer cholinergic drugs to be unclear as too few and too small studies are available and do not yield great evidence and leave many questions unanswered.
Quality of the evidence.
The available evidence is weak, limited, and small scale. It is not possible to recommend these drugs as a treatment for tardive dyskinesia based on our findings. To fully investigate whether the use of cholinergic drugs have any positive effects for people with tardive dyskinesia, there would have to be well-designed, larger, longer-term studies, particularly on new cholinergic drugs currently being used for treating Alzheimer’s disease.
Ben Gray, Senior Peer Researcher, McPin Foundation.