Treatment for Antipsychotic-Induced Tardive Dyskinesia: New Insights

Tardive dyskinesia (TD), the involuntary athetoid or choreiform movements, generally of the tongue, lower face and jaw, and extremities, is a long-term adverse effect of antipsychotic medication. It is highly prevalent in patients with schizophrenia and has been associated with poorer quality of life.¹ Two vesicular monoamine transporter-2 inhibitors, valbenazine and deutetrabenazine, have been FDA-approved for the treatment of TD.

A previous meta-analysis of 3 studies suggested that clozapine was associated with a reduction of TD.²Mentzel and colleagues³ undertook a meta-analysis of the effect of switching to clozapine monotherapy on the severity of TD in patients with schizophrenia.

Mentzel and colleagues systematically searched Embase, MEDLINE, and PsychINFO. The meta-analysis included studies in English or Dutch of patients with schizophrenia who were switched to clozapine monotherapy and assessed for TD on a rating scale at least once before and after the switch. Studies of patients with established TD as well as studies that assessed TD as a secondary outcome were included.

The primary outcome was the standardized mean change in TD total score before and after starting clozapine (negative values indicate a decrease in TD symptoms). Data were analyzed using random effects models. Subanalyses were performed for (1) studies with TD as an inclusion criterion, (2) days between baseline and follow-up, (3) age, and (4) baseline severity of psychopathology.

The researchers identified 283 articles, of which 17 met the inclusion criteria: 4 studies looked at switching to clozapine for clinically significant TD; the other 13 studies looked at TD as a secondary outcome. The AIMS (Abnormal Involuntary Movement Scale) was used to assess TD in 14 of the studies.

TD decreased significantly following the switch to clozapine in patients with clinical TD. There was a non-significant trend for a reduction in TD severity following a switch to clozapine in patients with subclinical TD. Statistical significance was seen after 3 outlying studies were excluded. Between-study heterogeneity was significant for these estimates.

In studies that used the AIMS (first 7 items), the mean reduction following switch to clozapine was 3 points in all studies and 11 points in studies of patients with clinical TD. There was no evidence of publication bias. Adjustment for the time between pre- and post-clozapine assessments did not reduce heterogeneity.

The researchers concluded that switching to clozapine was associated with a reduction in the severity of TD symptoms, with stronger effects in patients with clinically-significant TD at baseline. An important limitation is the small cumulative sample size (n=4 studies and n=48 patients) with clinical TD. Mentzel and colleagues suggest that in addition to treatment-resistant psychopathology (moderate-to-severe), TD warrants additional consideration as a potential indication for switching patients with schizophrenia to clozapine.