Abstract
Antipsychotic treatment resistance affects up to a third of individuals with schizophrenia. Of those affected, 70-84% are reported to be treatment resistant from the outset. This raises the possibility that the neurobiological mechanisms of treatment resistance emerge before the onset of psychosis and have a neurodevelopmental origin. Neuropsychological investigations can offer important insights into the nature, origin and pathophysiology of treatment-resistant schizophrenia (TRS), but methodological limitations in a still emergent field of research have obscured the neuropsychological discriminability of TRS. We report on the first systematic review and meta-analysis to investigate neuropsychological differences between TRS patients and treatment-responsive controls across 17 published studies (1864 participants). Five meta-analyses were performed in relation to (1) executive function, (2) general cognitive function, (3) attention, working memory and processing speed, (4) verbal memory and learning, and (5) visual-spatial memory and learning. Small-to-moderate effect sizes emerged for all domains. Similarly to previous comparisons between unselected, drug-naïve and first-episode schizophrenia samples v. healthy controls in the literature, the largest effect size was observed in verbal memory and learning [dl = -0.53; 95% confidence interval (CI) -0.29 to -0.76; z = 4.42; p < 0.001]. A sub-analysis of language-related functions, extracted from across the primary domains, yielded a comparable effect size (dl = -0.53, 95% CI -0.82 to -0.23; z = 3.45; p < 0.001). Manipulating our sampling strategy to include or exclude samples selected for clozapine response did not affect the pattern of findings. Our findings are discussed in relation to possible aetiological contributions to TRS.
Highlights
Up to a third of individuals with schizophrenia show resistance to antipsychotic treatment (Elkis & Buckley, 2016; Lally, Gaughran, Timms, & Curran, 2016b; Mørup, Kymes, & Oudin Åström, 2020; Stokes et al, 2020), i.e. they do not respond adequately to two or more trials of antipsychotic medication, each lasting 4–6 weeks, at doses in at least the mid-point of the licensed therapeutic range (NICE guidelines; National Institute for Health and Care Excellence, 2014)
Integrated with earlier research, our findings offer new insights into possible aetiological contributions to treatment-resistant schizophrenia (TRS), but they need to be viewed in the light of some limitations: Even though the largest effects sizes for verbal memory and learning and for languagerelated functions were moderate, distinguishable from the remaining effect sizes, there was substantial overlap in 95% confidence interval (CI)
Patients with TRS show wide-ranging deficits of small to moderate effect sizes compared to treatment responders, which are most salient in verbal memory and learning and in language functions
Summary
Evidence of glutamatergic rather than dopaminergic abnormalities in TRS (Demjaha et al, 2014; Gillespie, Samanaite, Mill, Egerton, & MacCabe, 2017; Goldstein, Anderson, Pillai, Kydd, & Russell, 2015; Mouchlianitis et al, 2016) raises the possibility that the disorder is categorically distinct from treatment-responsive schizophrenia (Gillespie et al, 2017) Running counter to this possibility, clozapine surpasses other antipsychotics in improving total and positive symptoms in both TRS and treatment-responsive patients (Mizuno, McCutcheon, Brugger, & Howes, 2020), supporting arguments against an illness subtype that responds to clozapine (Mizuno et al, 2020). Some of the strongest predictors of poor therapeutic response in schizophrenia are the same as the defining features of what has been termed ‘neurodevelopmental’ schizophrenia: male sex, younger age at disease onset, poor premorbid adjustment, and longer duration of untreated illness (Carbon & Correll, 2014; Murray, O’Callaghan, Castle, & Lewis, 1992)
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