Reappraising the variability of effects of antipsychotic medication in schizophrenia: a meta‐analysis

Abstract

It is common experience for practising psychiatrists that individuals with schizophrenia vary markedly in their symptomatic response to antipsychotic medication. What is not clear, however, is whether this variation reflects variability of medication‐specific effects (also called “treatment effect heterogeneity”), as opposed to variability of non‐specific effects such as natural symptom fluctuation or placebo response. Previous meta‐analyses found no evidence of treatment effect heterogeneity, suggesting that a “one size fits all” approach may be appropriate and that efforts at developing personalized treatment strategies for schizophrenia are unlikely to succeed. Recent advances indicate, however, that earlier approaches may have been unable to accurately quantify treatment effect heterogeneity due to their neglect of a key parameter: the correlation between placebo response and medication‐specific effects. In the present paper, we address this shortcoming by using individual patient data and study‐level data to estimate that correlation and quantitatively characterize antipsychotic treatment effect heterogeneity in schizophrenia. Individual patient data (on 384 individuals who were administered antipsychotic treatment and 88 who received placebo) were obtained from the Yale University Open Data Access (YODA) database. Study‐level data were obtained from a meta‐analysis of 66 clinical trials including 17,202 patients. Both individual patient and study‐level analyses yielded a negative correlation between placebo response and treatment effect for the total score on the Positive and Negative Syndrome Scale (PANSS) (ρ=–0.32, p=0.002 and ρ=–0.39, p<0.001, respectively). Using the most conservative of these estimates, a meta‐analysis of treatment effect heterogeneity provided evidence of a marked variability in antipsychotic‐specific effects between individuals with schizophrenia, with the top quartile of patients experiencing beneficial treatment effects of 17.7 points or more on the PANSS total score, while the bottom quartile presented a detrimental effect of treatment relative to placebo. This evidence of clinically meaningful treatment effect heterogeneity suggests that efforts to personalize antipsychotic treatment of schizophrenia have potential for success.

Timing of antipsychotics and benzodiazepine initiation during a first episode of psychosis impacts clinical outcomes: Electronic health record cohort study

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Arrestin-3 agonism at D3 dopamine receptors defines a subclass of second generation antipsychotics that promotes drug tolerance

“…In 2017, roughly 11 million adults, or 4.2% of the adult population, in the United States had a diagnosis of SMI, including bipolar disorder, major depressive disorder, schizophrenia, and schizoaffective disorder (Cohen and Gorrindo, 2020). Recently, several meta-analyses sought to elucidate which antipsychotic drugs most benefit patients (Huhn et al, 2019; McCutcheon et al, 2022). Most people living with SMI rotate through a number of drug treatments and protocols before finding an effective strategy through a protracted and stochastic process.…”

Data Driven Taxonomy for Antipsychotic Medication: A New Classification System

“…There are large interindividual differences in antipsychotic response and many patients switch antipsychotics multiple times before finding one that is both well tolerated and effective. (11)(12)(13) There is currently no grouping of antipsychotics to guide clinicians and patients in their choice of initial or subsequent drug. For patients whose psychotic symptoms have not improved adequately with first-line treatment or who are experiencing side-effects, clinical guidelines recommend switching to a different antipsychotic but give little guidance on which drug to select.…”