Antipsychotic medication-mediated cognitive change in schizophrenia and polygenic score for cognitive ability
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SUBMITTER: Blackman R
PROVIDER: S-EPMC8602047 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:ImportanceSchizophrenia is a clinically heterogeneous disorder. It is currently unclear how variability in symptom dimensions and cognitive ability is associated with genetic liability for schizophrenia.ObjectiveTo determine whether phenotypic dimensions within schizophrenia are associated with genetic liability to schizophrenia, other neuropsychiatric disorders, and intelligence.Design, setting, and participantsIn a genetic association study, 3 cross-sectional samples of 1220 individuals with a diagnosis of schizophrenia were recruited from community, inpatient, and voluntary sector mental health services across the UK. Confirmatory factor analysis was used to create phenotypic dimensions from lifetime ratings of the Scale for the Assessment of Positive Symptoms, Scale for the Assessment of Negative Symptoms, and the MATRICS Consensus Cognitive Battery. Analyses of polygenic risk scores (PRSs) were used to assess whether genetic liability to schizophrenia, other neuropsychiatric disorders, and intelligence were associated with these phenotypic dimensions. Data collection for the cross-sectional studies occurred between 1993 and 2016. Data analysis for this study occurred between January 2019 and March 2021.Main outcomes and measuresOutcome measures included phenotypic dimensions defined from confirmatory factor analysis relating to positive symptoms, negative symptoms of diminished expressivity, negative symptoms of motivation and pleasure, disorganized symptoms, and current cognitive ability. Exposure measures included PRSs for schizophrenia, bipolar disorder, major depression, attention-deficit/hyperactivity disorder, autism spectrum disorder, and intelligence.ResultsOf the 1220 study participants, 817 were men (67.0%). Participants' mean (SD) age at interview was 43.10 (12.74) years. Schizophrenia PRS was associated with increased disorganized symptom dimension scores in both a 5-factor model (β = 0.14; 95% CI, 0.07-0.22; P = 2.80 × 10-4) and a 3-factor model across all samples (β = 0.10; 95% CI, 0.05-0.15; P = 2.80 × 10-4). Current cognitive ability was associated with genetic liability to schizophrenia (β = -0.11; 95% CI, -0.19 to -0.04; P = 1.63 × 10-3) and intelligence (β = 0.23; 95% CI, 0.16-0.30; P = 1.52 × 10-10). After controlling for estimated premorbid IQ, current cognitive performance was associated with schizophrenia PRS (β = -0.08; 95% CI, -0.14 to -0.02; P = 8.50 × 10-3) but not intelligence PRS.Conclusions and relevanceThe findings of this study suggest that genetic liability for schizophrenia is associated with higher disorganized dimension scores but not other symptom dimensions. Cognitive performance in schizophrenia appears to reflect distinct contributions from genetic liabilities to both intelligence and schizophrenia.
| S-EPMC8340009 | biostudies-literature
Project description:ObjectivePharmacogenomic studies of antipsychotics have typically examined effects of individual polymorphisms. By contrast, polygenic risk scores (PRSs) derived from genome-wide association studies (GWAS) can quantify the influence of thousands of common alleles of small effect in a single measure. The authors examined whether PRSs for schizophrenia were predictive of antipsychotic efficacy in four independent cohorts of patients with first-episode psychosis (total N=510).MethodAll study subjects received initial treatment with antipsychotic medication for first-episode psychosis, and all were genotyped on standard single-nucleotide polymorphism (SNP) arrays imputed to the 1000 Genomes Project reference panel. PRS was computed based on the results of the large-scale schizophrenia GWAS reported by the Psychiatric Genomics Consortium. Symptoms were measured by using total symptom rating scales at baseline and at week 12 or at the last follow-up visit before dropout.ResultsIn the discovery cohort, higher PRS significantly predicted higher symptom scores at the 12-week follow-up (controlling for baseline symptoms, sex, age, and ethnicity). The PRS threshold set at a p value <0.01 gave the strongest result in the discovery cohort and was used to replicate the findings in the other three cohorts. Higher PRS significantly predicted greater posttreatment symptoms in the combined replication analysis and was individually significant in two of the three replication cohorts. Across the four cohorts, PRS was significantly predictive of adjusted 12-week symptom scores (pooled partial r=0.18; 3.24% of variance explained). Patients with low PRS were more likely to be treatment responders than patients with high PRS (odds ratio=1.91 in the two Caucasian samples).ConclusionsPatients with higher PRS for schizophrenia tended to have less improvement with antipsychotic drug treatment. PRS burden may have potential utility as a prognostic biomarker.
| S-EPMC6461047 | biostudies-literature
Project description:BACKGROUND:Long-term treatment with antipsychotic medications in early episode schizophrenia spectrum disorders is common, but both short and long-term effects on the illness are unclear. There have been numerous suggestions that people with early episodes of schizophrenia appear to respond differently than those with multiple prior episodes. The number of episodes may moderate response to drug treatment. OBJECTIVES:To assess the effects of antipsychotic medication treatment on people with early episode schizophrenia spectrum disorders. SEARCH STRATEGY:We searched the Cochrane Schizophrenia Group register (July 2007) as well as references of included studies. We contacted authors of studies for further data. SELECTION CRITERIA:Studies with a majority of first and second episode schizophrenia spectrum disorders comparing initial antipsychotic medication treatment with placebo, milieu, or psychosocial treatment. DATA COLLECTION AND ANALYSIS:Working independently, we critically appraised records from 681studies, of which five studies met inclusion criteria. John Rathbone from the Schizophrenia Group supported us with the data extraction. We calculated risk ratios (RR) and their 95% confidence intervals (CI) where possible. For continuous data, we calculated mean difference (MD). We calculated numbers needed to treat/harm (NNT/NNH) where appropriate. MAIN RESULTS:Five studies with a combined N = 998 met inclusion criteria. Four studies (N = 724) provided leaving the study early data and results suggested that individuals treated with a typical antipsychotic medication are less likely to leave the study early than those treated with placebo (Chlorpromazine: 3 RCTs N = 353, RR 0.4 CI 0.3 to 0.5, NNT 3.2, Fluphenaxine: 1 RCT N = 240, RR 0.5 CI 0.3 to 0.8, NNT 5; Thioridazine: 1 RCT N = 236, RR 0.44 CI 0.3 to 0.7, NNT 4.3, Trifulperazine: 1 RCT N = 94, RR 0.96 CI 0.3 to 3.6). Two studies (Cole 1964; May 1976) contributed data to assessment of side effects and present a general pattern of more frequent side effects among individuals treated with typical antipsychotic medications compared to placebo. Rappaport 1978 suggested a higher rehospitalisation rate for those receiving chlorpromazine compared to placebo (N = 80, RR 2.29 CI 1.3 to 4.0, NNH 2.9). However, a higher attrition in the placebo group is likely to have introduced a survivor bias into this comparison, as this difference becomes non-significant in a sensitivity analysis on intent-to-treat participants (N = 127, RR 1.69 CI 0.9 to 3.0). One study (May 1976) contributes data to a comparison of trifluoperazine to psychotherapy on long-term health in favour of the trifluoperazine group (N = 92, MD 5.8 CI 1.6 to 0.0); however, data from this study are also likely to contain biases due to selection and attrition. One study (Mosher 1995) contributes data to a comparison of typical antipsychotic medication to psychosocial treatment on six-week outcome measures of global psychopathology (N = 89, MD 0.01 CI -0.6 to 0.6) and global improvement (N = 89, MD -0.03 CI -0.5 to 0.4), indicating no between-group differences. On the whole, there is very little useable data in the few studies meeting inclusion criteria. AUTHORS' CONCLUSIONS:With only a few studies meeting inclusion criteria, and with limited useable data in these studies, it is not possible to arrive at definitive conclusions. The preliminary pattern of evidence suggests that people with early episode schizophrenia treated with typical antipsychotic medications are less likely to leave the study early, but more likely to experience medication-related side effects. Data are too sparse to assess the effects of antipsychotic medication on outcomes in early episode schizophrenia.
| S-EPMC4105695 | biostudies-other
Project description:ObjectiveDifferent cognitive development histories in schizophrenia may reflect variation across dimensions of genetic influence. The authors derived and characterized cognitive development trajectory subgroups within a schizophrenia sample and profiled the subgroups across polygenic scores (PGSs) for schizophrenia, cognition, educational attainment, and attention deficit hyperactivity disorder (ADHD).MethodsDemographic, clinical, and genetic data were collected at the National Institute of Mental Health from 540 schizophrenia patients, 247 unaffected siblings, and 844 control subjects. Cognitive trajectory subgroups were derived through cluster analysis using estimates of premorbid and current IQ. PGSs were generated using standard methods. Associations were tested using general linear models and logistic regression.ResultsCluster analyses identified three cognitive trajectory subgroups in the schizophrenia group: preadolescent cognitive impairment (19%), adolescent disruption of cognitive development (44%), and cognitively stable adolescent development (37%). Together, the four PGSs significantly predicted 7.9% of the variance in subgroup membership. Subgroup characteristics converged with genetic patterns. Cognitively stable individuals had the best adult clinical outcomes and differed from control subjects only in schizophrenia PGSs. Those with adolescent disruption of cognitive development showed the most severe symptoms after diagnosis and were cognitively impaired. This subgroup had the highest schizophrenia PGSs and had disadvantageous cognitive PGSs relative to control subjects and cognitively stable individuals. Individuals showing preadolescent impairment in cognitive and academic performance and poor adult outcome exhibited a generalized PGS disadvantage relative to control subjects and were the only subgroup to differ significantly in education and ADHD PGSs.ConclusionsSubgroups derived from patterns of premorbid and current IQ showed different premorbid and clinical characteristics, which converged with broad genetic profiles. Simultaneous analysis of multiple PGSs may contribute to useful clinical stratification in schizophrenia.
| S-EPMC9627722 | biostudies-literature
Project description:Cognitive impairments are considered core features in schizophrenia and other psychotic disorders. Cognitive impairments are, to a lesser degree, also documented in healthy first-degree relatives. Although recent studies have shown (negative) genetic correlations between schizophrenia and general cognitive ability, the association between polygenic risk for schizophrenia and individual cognitive phenotypes remains unclear. We here investigated the association between a polygenic score for schizophrenia (SCZPGS) and six well-defined cognitive domains, in addition to a composite measure of cognitive ability and a measure of premorbid intellectual ability in 731 participants with a psychotic disorder and 851 healthy controls. We also investigated the association between a PGS for general cognitive ability (COGPGS) and the same cognitive domains in the same sample. We found no significant associations between the SCZPGS and any cognitive phenotypes, in either patients with a psychotic disorder or healthy controls. For COGPGS we observed stronger associations with cognitive phenotypes in healthy controls than in participants with psychotic disorders. In healthy controls, the association between COGPGS (at the p value threshold of ≥0.01) and working memory remained significant after Bonferroni correction (β = 0.12, p = 8.6 × 10-5). Altogether, the lack of associations between SCZPGS and COGPGS with cognitive performance in participants with psychotic disorders suggests that either environmental factors or unassessed genetic factors play a role in the development of cognitive impairments in psychotic disorders. Working memory should be further studied as an important cognitive phenotype.
| S-EPMC7705731 | biostudies-literature
Project description:BackgroundProgressive brain volume loss in schizophrenia has been reported in previous studies but its cause and regional distribution remains unclear. We investigated progressive regional brain reductions in schizophrenia and correlations with potential mediators.MethodParticipants were drawn from the Northern Finland Birth Cohort 1966. A total of 33 schizophrenia individuals and 71 controls were MRI scanned at baseline (mean age=34.7, SD=0.77) and at follow-up (mean age=43.4, SD=0.44). Regional brain change differences and associations with clinical mediators were examined using FSL voxelwise SIENA.ResultsSchizophrenia cases exhibited greater progressive brain reductions than controls, mainly in the frontal and temporal lobes. The degree of periventricular brain volume reductions were predicted by antipsychotic medication exposure at the fourth ventricular edge and by the number of days in hospital between the scans (a proxy measure of relapse duration) at the thalamic ventricular border. Decline in social and occupational functioning was associated with right supramarginal gyrus reduction.ConclusionOur findings are consistent with the possibility that antipsychotic medication exposure and time spent in relapse partially explain progressive brain reductions in schizophrenia. However, residual confounding could also account for the findings and caution must be applied before drawing causal inferences from associations demonstrated in observational studies of modest size. Less progressive brain volume loss in schizophrenia may indicate better preserved social and occupational functions.
| S-EPMC4604250 | biostudies-literature
Project description:Treatment-resistant schizophrenia (TRS) affects around one-third of individuals with schizophrenia. Although a number of sociodemographic and clinical predictors of TRS have been identified, data on the genetic risk of TRS are sparse. We aimed to investigate the association between a polygenic risk score for schizophrenia and treatment resistance in patients with schizophrenia. We conducted a nationwide, population-based follow-up study among all Danish individuals born after 1981 and with an incident diagnosis of schizophrenia between 1999 and 2007. Based on genome-wide data polygenic risk scores for schizophrenia were calculated in 862 individuals with schizophrenia. TRS was defined as either clozapine initiation or at least 2 periods of different antipsychotic monotherapies and still being hospitalized. We estimated hazard rate ratios (HRs) for TRS in relation to the polygenic risk score while adjusting for population stratification, age, sex, geographical area at birth, clinical treatment setting, psychiatric comorbidity, and calendar year. Among the 862 individuals with schizophrenia, 181 (21.0%) met criteria for TRS during 4674 person-years of follow-up. We found no significant association between the polygenic risk score and TRS, adjusted HR = 1.13 (95% CI: 0.95-1.35). Based on these results, the use of the polygenic risk score for schizophrenia to identify individuals with TRS is at present inadequate to be of clinical utility at the individual patient level. Future research should include larger genetic samples in combination with non-genetic markers. Moreover, a TRS-specific developed polygenic risk score would be of great interest towards early prediction of TRS.
| S-EPMC5581885 | biostudies-literature
Project description:Standard-of-care biological treatment of schizophrenia remains dependent upon antipsychotic medications, which demonstrate D2 receptor affinity and elicit variable, partial clinical responses via neural mechanisms that are not entirely understood. In the striatum, where D2 receptors are abundant, antipsychotic medications may affect neural function in studies of animals, healthy volunteers, and patients, yet the relevance of this to pharmacotherapeutic actions remains unresolved. In this same brain region, some individuals with schizophrenia may demonstrate phenotypes consistent with exaggerated dopaminergic signaling, including alterations in dopamine synthesis capacity; however, the hypothesis that dopamine system characteristics underlie variance in medication-induced regional blood flow changes has not been directly tested. We therefore studied a cohort of 30 individuals with schizophrenia using longitudinal, multi-session [15O]-water and [18F]-FDOPA positron emission tomography to determine striatal blood flow during active atypical antipsychotic medication treatment and after at least 3 weeks of placebo treatment, along with presynaptic dopamine synthesis capacity (ie, DOPA decarboxylase activity). Regional striatal blood flow was significantly higher during active treatment than during the placebo condition. Furthermore, medication-related increases in ventral striatal blood flow were associated with more robust amelioration of excited factor symptoms during active medication and with higher dopamine synthesis capacity. These data indicate that atypical medications enact measureable physiological alterations in limbic striatal circuitry that vary as a function of dopaminergic tone and may have relevance to aspects of therapeutic responses.
| S-EPMC5603816 | biostudies-other
Project description:Language disturbances are key aberrations in schizophrenia. Little is known about the influence of antipsychotic medication on these symptoms. Using computational language methods, this study evaluated the impact of high versus low dopamine D2 receptor (D2R) occupancy antipsychotics on language disturbances in 41 patients with schizophrenia, relative to 40 healthy controls. Patients with high versus low D2R occupancy antipsychotics differed by total number of words and type-token ratio, suggesting medication effects. Both patient groups differed from the healthy controls on percentage of time speaking and clauses per utterance, suggesting illness effects. Overall, more severe negative language disturbances (i.e. slower articulation rate, increased pausing, and shorter utterances) were seen in the patients that used high D2R occupancy antipsychotics, while less prominent disturbances were seen in low D2R occupancy patients. Language analyses successfully predicted drug type (sensitivity = 80.0%, specificity = 76.5%). Several language disturbances were more related to drug type and dose, than to other psychotic symptoms, suggesting that language disturbances may be aggravated by high D2R antipsychotics. This negative impact of high D2R occupancy drugs may have clinical implications, as impaired language production predicts functional outcome and degrades the quality of life.
| S-EPMC7477551 | biostudies-literature
Project description:OBJECTIVE: Previous research has shown that a better therapeutic relationship (TR) predicts more positive attitudes towards antipsychotic medication, but did not address whether it is also linked with actual adherence. This study investigated whether the TR is associated with adherence to antipsychotics in patients with schizophrenia. METHODS: 134 clinicians and 507 of their patients with schizophrenia or a related psychotic disorder participated in a European multi-centre study. A logistic regression model examined how the TR as rated by patients and by clinicians is associated with medication adherence, adjusting for clinician clustering and symptom severity. RESULTS: Patient and clinician ratings of the TR were weakly inter-correlated (r(s) = 0.13, p = 0.004), but each was independently linked with better adherence. After adjusting for patient rated TR and symptom severity, each unit increase in clinician rated TR was associated with an increase of the odds ratio of good compliance by 65.9% (95% CI: 34.6% to 104.5%). After adjusting for clinician rated TR and symptom severity, for each unit increase in patient rated TR the odds ratio of good compliance was increased by 20.8% (95% CI: 4.4% to 39.8%). CONCLUSIONS: A better TR is associated with better adherence to medication among patients with schizophrenia. Patients' and clinicians' perspectives of the TR are both important, but may reflect distinct aspects.
| S-EPMC3338634 | biostudies-other