Tardive dyskinesia risk with first‐ and second‐generation antipsychotics in comparative randomized controlled trials: a meta‐analysis

Abstract

Tardive dyskinesia (TD) risk with D2/serotonin receptor antagonists or D2 receptor partial agonists (second-generation antipsychotics, SGAs) is considered significantly lower than with D2 antagonists (first-generation antipsychotics, FGAs). As some reports questioned this notion, we meta-analyzed randomized controlled studies (RCTs) to estimate the risk ratio (RR) and annualized rate ratio (RaR) of TD comparing SGAs vs. FGAs and SGAs vs. SGAs. Additionally, we calculated raw and annualized pooled TD rates for each antipsychotic. Data from 57 head-to-head RCTs, including 32 FGA and 86 SGA arms, were meta-analyzed, yielding 32 FGA-SGA pairs and 35 SGA-SGA pairs. The annualized TD incidence across FGA arms was 6.5% (95% CI: 5.3-7.8%) vs. 2.6% (95% CI: 2.0-3.1%) across SGA arms. TD risk and annualized rates were lower with SGAs vs. FGAs (RR=0.47, 95% CI: 0.39-0.57, p<0.0001, k=28; RaR=0.35, 95% CI: 0.28-0.45, p<0.0001, number-needed-to-treat, NNT=20). Meta-regression showed no FGA dose effect on FGA-SGA comparisons (Z=-1.03, p=0.30). FGA-SGA TD RaRs differed by SGA comparator (Q=21.8, df=7, p=0.003), with a significant advantage of olanzapine and aripiprazole over other non-clozapine SGAs in exploratory pairwise comparisons. SGA-SGA comparisons confirmed the olanzapine advantage vs. non-clozapine SGAs (RaR=0.66, 95% CI: 0.49-0.88, p=0.006, k=17, NNT=100). This meta-analysis confirms a clinically meaningfully lower TD risk with SGAs vs. FGAs, which is not driven by high dose FGA comparators, and documents significant differences with respect to this risk between individual SGAs.

Adjunctive metformin for antipsychotic-induced dyslipidemia: a meta-analysis of randomized, double-blind, placebo-controlled trials

“…Outcomes: the primary outcome was LDL-C (mg/dL); the secondary outcomes were total cholesterol (mg/dL), triglyceride (mg/dL), HDL-C (mg/dL), body weight (kg), body mass index (BMI, kg/m 2 ), waist circumference (cm), waist-to-hip rate, leptin (ug/L), glycated hemoglobin A1c (HbA1c, %), fast insulin (mIU/L) and homeostasis model assessment of insulin resistance (HOMA-IR), fasting glucose (mmol/L), blood pressure including diastolic and systolic blood pressure (mmHg), adverse drug reactions (ADRs), and discontinuation due to any reason. Study: following other meta-analyses 39,40 , only published double-blind RCTs that examined the efficacy and safety of metformin for dyslipidemia with available data were included. Studies without data of blood lipid were excluded [41][42][43] .…”

20‐year follow‐up study of physical morbidity and mortality in relationship to antipsychotic treatment in a nationwide cohort of 62,250 patients with schizophrenia (FIN20)

“…Antipsychotics are effective in preventing relapses in schizophrenia, according to both randomized controlled trials (RCTs) and observational studies representing real‐world patients with long follow‐up periods. However, antipsychotic use is associated with the risk of serious adverse events, such as tardive dyskinesia. In addition, adverse effects of antipsychotic drugs on physical health are numerous.…”

How do we select an antipsychotic for those with schizophrenia?

“…Quality of life measures between SGAs and FGAs present conflicting results, and although SGAs are less likely to precipitate EPS and TD than FGAs, the risk has not been eliminated [7,8]. In comparison to FGAs, a metaanalysis of 57 studies showed that SGAs reduce the annualized incidence of TD to one-third [9]. The problem may lie in the classification system of FGAs and SGAs, implying that each class is homogenous.…”