Genome-wide association analysis of treatment resistant schizophrenia for variant discovery and polygenic assessment.

BACKGROUND: Treatment resistant schizophrenia (TRS) is broadly defined as inadequate response to adequate treatment and is associated with a substantial increase in disease burden. Clozapine is the only approved treatment for TRS, showing superior clinical effect on overall symptomatology compared to other drugs, and is the prototype of atypical antipsychotics. Risperidone, another atypical antipsychotic with a more distinctive dopamine 2 antagonism, is commonly used in treatment of schizophrenia. Here, we conducted a genome-wide association study on patients treated with clozapine (TRS) vs. risperidone (non-TRS) and investigated whether single variants and/or polygenic risk score for schizophrenia are associated with TRS status. We hypothesized that patients who are treated with clozapine and risperidone might exhibit distinct neurobiological phenotypes that match pharmacological profiles of these drugs and can be explained by genetic differences. The study population (n = 1286) was recruited from a routine therapeutic drug monitoring (TDM) service between 2005 and 2022. History of a detectable serum concentration of clozapine and risperidone (without TDM history of clozapine) defined the TRS (n = 478) and non-TRS (n = 808) group, respectively. RESULTS: We identified a suggestive association between TRS and a common variant within the LINC00523 gene with a significance just below the genome-wide threshold (rs79229764 C > T, OR = 4.89; p = 1.8 × 10-7). Polygenic risk score for schizophrenia was significantly associated with TRS (OR = 1.4, p = 2.1 × 10-6). In a large post-mortem brain sample from schizophrenia donors (n = 214; CommonMind Consortium), gene expression analysis indicated that the rs79229764 variant allele might be involved in the regulation of GPR88 and PUDP, which plays a role in striatal neurotransmission and intellectual disability, respectively. CONCLUSIONS: We report a suggestive genetic association at the rs79229764 locus with TRS and show that genetic liability for schizophrenia is positively associated with TRS. These results suggest a candidate locus for future follow-up studies to elucidate the molecular underpinnings of TRS. Our findings further demonstrate the value of both single variant and polygenic association analyses for TRS prediction.

Elevated intrinsic cortical curvature in treatment-resistant schizophrenia: Evidence of structural deformation in functional connectivity areas and comparison with alternate indices of structure.

BACKGROUND: Research suggests structural and connectivity abnormalities in patients with treatment-resistant schizophrenia (TRS) compared to first-line responders and healthy-controls. However, measures of these abnormalities are often influenced by external factors like nicotine and antipsychotics, limiting their clinical utility. Intrinsic-cortical-curvature (ICC) presents a millimetre-scale measure of brain gyrification, highly sensitive to schizophrenia differences, and associated with TRS-like traits in early stages of the disorder. Despite this evidence, ICC in TRS remains unexplored. This study investigates ICC as a marker for treatment resistance in TRS, alongside structural indices for comparison. METHODS: We assessed ICC in anterior cingulate, dorsolateral prefrontal, temporal, and parietal cortices of 38 first-line responders, 30 clozapine-resistant TRS, 37 clozapine-responsive TRS, and 52 healthy-controls. For comparative purposes, Fold and Curvature indices were also analyzed. RESULTS: Adjusting for age, sex, nicotine-use, and chlorpromazine equivalence, principal findings indicate ICC elevations in the left hemisphere dorsolateral prefrontal (p < 0.001, η2partial = 0.142) and temporal cortices (LH p = 0.007, η2partial = 0.060; RH p = 0.011, η2partial = 0.076) of both TRS groups, and left anterior cingulate cortex of clozapine-resistant TRS (p = 0.026, η2partial = 0.065), compared to healthy-controls. Elevations that correlated with reduced cognition (p = 0.001) and negative symptomology (p < 0.034) in clozapine-resistant TRS. Fold and Curvature indices only detected group differences in the right parietal cortex, showing interactions with age, sex, and nicotine use. ICC showed interactions with age. CONCLUSION: ICC elevations were found among patients with TRS, and correlated with symptom severity. ICCs relative independence from sex, nicotine-use, and antipsychotics, may support ICC's potential as a viable marker for TRS, though age interactions should be considered.

Treatment-resistant schizophrenia: Addressing white matter integrity, intracortical glutamate levels, clinical and cognitive profiles between early- and adult-onset patients.

BACKGROUND: Treatment-resistance in schizophrenia is 30-40%. Its neurobiology remains unclear; to explore it, we conducted a combined spectrometry/tractography/cognitive battery and psychopathological rating study on patients with treatment-resistant schizophrenia (TRS), dividing the sample into early-onset (N = 21) and adult-onset TRS (N = 20). Previous studies did not differentiate between early- (onset 13-18 years) and adult-onset (>18 years at formal diagnosis of schizophrenia) TRS. METHODS: We evaluated cross-sectionally 41 TRS patients (26 male and 15 female) and 20 matched healthy controls (HCs) with psychopathological and cognitive testing prior to participating in brain imaging scanning using magnetic resonance spectroscopy and diffusion tensor imaging to determine the relationship between their symptoms and their glutamate levels and white matter integrity. RESULTS: TRS patients scored lower than HCs on all cognitive domains; early-onset patients performed better than adult-onset patients only on the Symbol Coding domain. TRS correlated with symptom severity, especially negative symptoms. Glutamate levels and glutamate/creatine were increased in anterior cingulate cortex. Diffusion tensor imaging showed low fractional anisotropy in TRS patients in specific white matter tracts compared to HCs (bilateral anterior thalamic radiation, cortico-spinal tract, forceps minor, inferior fronto-occipital fasciculus, inferior longitudinal fasciculus, superior longitudinal fasciculus, and right uncinate fasciculus). CONCLUSIONS: We identified specific magnetic resonance spectroscopy and diffusion tensor imaging alterations in TRS patients. Adult-onset TRS differed little from early-onset TRS on most measures; this points to alterations being present since the outset of schizophrenia and may constitute a biological signature of treatment-resistance.

N-methyl-D-aspartate Receptor Antibody and White Matter Deficits in Schizophrenia Treatment-Resistance.

Insufficient or lack of response to antipsychotic medications in some patients with schizophrenia is a major challenge in psychiatry, but the underlying mechanisms remain unclear. Two seemingly unrelated observations, cerebral white matter and N-methyl-D-aspartate receptor (NMDAR) hypofunction, have been linked to treatment-resistant schizophrenia (TRS). As NMDARs are critical to axonal myelination and signal transduction, we hypothesized that NMDAR antibody (Ab), when present in schizophrenia, may impair NMDAR functions and white matter microstructures, contributing to TRS. In this study, 50 patients with TRS, 45 patients with nontreatment-resistant schizophrenia (NTRS), 53 patients with schizophrenia at treatment initiation schizophrenia (TIS), and 90 healthy controls were enrolled. Serum NMDAR Ab levels and white matter diffusion tensor imaging fractional anisotropy (FA) were assessed. The white matter specificity effects by NMDAR Ab were assessed by comparing with effects on cortical and subcortical gray matter. Serum NMDAR Ab levels of the TRS were significantly higher than those of the NTRS (P = .035). In patients with TRS, higher NMDAR Ab levels were significantly associated with reduced whole-brain average FA (r = -.37; P = .026), with the strongest effect at the genu of corpus callosum (r = -.50; P = .0021, significant after correction for multiple comparisons). Conversely, there was no significant correlation between whole-brain or regional cortical thickness or any subcortical gray matter structural volume and NMDAR Ab levels in TRS. Our finding highlights a potential NMDAR mechanism on white matter microstructure impairment in schizophrenia that may contribute to their treatment resistance to antipsychotic medications.