Neuropsychological differences between treatment-resistant and treatment-responsive schizophrenia: a meta-analysis

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.

Impaired verbal memory function is related to anterior cingulate glutamate levels in schizophrenia: findings from the STRATA study

“…We found no evidence that the relationship between glutamate and verbal memory differed between good and poor antipsychotic responders. Whilst both worse verbal cognition and higher ACC glutamate may be associated with treatment resistance 66 – 68 , the lack of interaction suggests that there is no qualitative difference in the relationship between glutamate and cognition between antipsychotic response groups, at least within the ranges of antipsychotic response, glutamate, and cognitive function measured in the current study. Alternatively, it is possible that the lack of group difference in the relationship between glutamate and cognition may be due to the relative similarity in cognitive function between good and poor antipsychotic responders in our sample 55 .…”

“…Impaired verbal memory function is also evident in the clinical high-risk phase of psychosis and is more severe in high-risk subjects who later progress to psychosis 64 , 65 . A recent meta-analysis found that verbal memory impairments are more apparent in treatment-resistant compared to treatment-responsive schizophrenia 66 , and prospective investigation suggests this group difference is detectable from the first episode of psychosis 67 . However, cognitive performance did not differ between the good and poor antipsychotic response groups in our cohort 55 .…”

“…However, patient groups did not differ in Glx concentrations and the interaction between group and glutamatergic metabolite concentrations on cognition was not directly investigated. Whether the marked cognitive impairments observed in treatment-resistant schizophrenia 66 represent a distinct or exaggerated pathophysiological mechanism compared to those displaying good treatment response warrants further investigation.…”

Anterior cingulate glutamate metabolites as a predictor of antipsychotic response in first episode psychosis: data from the STRATA collaboration

“…Application would also require further optimization and standardization of 1 H-MRS data acquisition, analysis and testretest reliability across scanner manufacturers. Gains in accuracy could also potentially be achieved by combining glutamate measures with other predictors of response, such as resting state activity [60], brain volumes [9], perfusion [61], striatal dopamine synthesis capacity [62], cognitive performance [63] and clinical or demographic predictors [41,42,64].…”

Treatment-resistant schizophrenia: How far have we traveled?

“…This study even found that the treatment-resistant cases differed from treatment-responsive cases in deficits in the domain of memory and learning and also language function. In general, language and verbal intelligence deficits are not the most differentiating finding in schizophrenia compared with healthy controls; however, the deficit in this domain was the most distinguishing feature between treatment-resistant and treatment-responsive schizophrenia on neuropsychological testing ( 47 ). Neurolinguistic research may be an important area of work even in a globalized world where language and culture are continually adapting to the migration of people.…”