Efficacy and tolerability of antipsychotic polypharmacy for schizophrenia spectrum disorders. A systematic review and meta-analysis of individual patient data.

BACKGROUND: Antipsychotic polypharmacy (APP) is frequently prescribed for schizophrenia-spectrum disorders. Despite the inconsistent findings on efficacy, APP may be beneficial for subgroups of psychotic patients. This meta-analysis of individual patient data investigated moderators of efficacy and tolerability of APP in adult patients with schizophrenia-spectrum disorders. DESIGN: We searched PubMed, EMBASE, and the Cochrane Central Register of Randomized Trials until September 1, 2022, for randomized controlled trials comparing APP with antipsychotic monotherapy. We estimated the effects with a one-stage approach for patient-level moderators and a two-stage approach for study-level moderators, using (generalized) linear mixed-effects models. Primary outcome was treatment response, defined as a reduction of 25 % or more in the Positive and Negative Syndrome Scale (PANSS) score. Secondary outcomes were study discontinuation, and changes from baseline on the PANSS total score, its positive and negative symptom subscale scores, the Clinical Global Impressions Scale (CGI), and adverse effects. RESULTS: We obtained individual patient data from 10 studies (602 patients; 31 % of all possible patients) and included 599 patients in our analysis. A higher baseline PANSS total score increased the chance of a response to APP (OR = 1.41, 95 % CI 1.02; 1.94, p = 0.037 per 10-point increase in baseline PANSS total), mainly driven by baseline positive symptoms. The same applied to changes on the PANSS positive symptom subscale and the CGI severity scale. Extrapyramidal side effects increased significantly where first and second-generation antipsychotics were co-prescribed. Study discontinuation was comparable between both treatment arms. CONCLUSIONS: APP was effective in severely psychotic patients with high baseline PANSS total scores and predominantly positive symptoms. This effect must be weighed against potential adverse effects.

Neurocognitive performance and cognitive biases in young adults with schizotypal traits.

Recent research suggests that neurocognitive deficits in patients with schizophrenia may increase the risk of developing cognitive biases. As such, we set out to determine this predictive relationship as it pertains to the development of a first-episode psychosis. We hypothesized that poorer performance in processing speed would be associated with jumping to conclusions and an externalizing bias. Poorer performance in working memory would be associated with belief inflexibility and jumping to conclusions, and poorer performance in attention would be associated with attention to threat. We hypothesized that all cognitive biases would be associated with subsyndromal positive symptoms, and schizotypal traits would moderate these relationships. Undergraduate students (N = 130) completed the Schizotypal Personality Questionnaire, DAVOS Assessment of Cognitive Biases, Community Assessment of Psychic Experiences, and a computerized neuropsychological assessment battery. Processing speed had a small effect on externalizing bias, which in turn affected subsyndromal positive symptoms. There was no moderating effect of schizotypal traits on externalizing bias, but it was significantly associated with subsyndromal positive symptoms. Only the externalizing bias was associated with subsyndromal positive symptomatology, which might be explained by a restricted range and reduced variance in performance as a result of using a university student sample. This is one of few studies that sought to explain the mechanism responsible for the development of subsyndromal positive symptoms in a healthy sample using self-report measures.

Effect of personality traits, psychological resilience and life adversities on lifetime violence trajectories: A novel classification model in schizophrenia.

The risk of violence is higher in schizophrenia spectrum disorders (SSD) compared to the general population and it is a pressing and understudied issue. Several dispositional and environmental factors have been previously correlated with violence, however, there has been little success in assessing their ability to predict violence patterns across the life span. This study aims to assess violence prediction based on personality traits, psychological resilience, and life-course adversities in a non-forensic population of SSD patients. In a sample of 231 patients with SSD, we assessed violence using the Brown-Goodwin History of Lifetime Aggression Scale and conducted cross-sectional assessments of possible predictors such as childhood trauma, personality traits and resilience scores. We then utilized a logistic regression classification algorithm to predict different violence trajectories based on the proposed risk factors. Our model significantly predicted individuals with violence in both childhood and adulthood, as well as childhood-only violence (p < 0.001). However, the model did not show significance for adult-only violence (p = 0.604). In all given trajectories, female sex appeared to be protective against violence, while stressful life events appeared to contribute to it. These results suggest that distinct factors can better inform risk assessment of lifespan violence patterns for personalized interventions in SSD.

Clozapine treatment and astrocyte activity in treatment resistant schizophrenia: A proton magnetic resonance spectroscopy study.

Clozapine is the only antipsychotic approved for treating treatment-resistant schizophrenia (TRS), characterized by persistent positive symptoms despite adequate antipsychotic treatment. Unfortunately, clozapine demonstrates clinical efficacy in only ~30-60 % of patients with TRS (clozapine-responders; ClzR+), while the remaining ~40-70 % are left with no pharmacological recourse for improvement (clozapine-resistant; ClzR-). Mechanism(s) underlying clozapine's superior efficacy remain unclear. However, in vitro evidence suggests clozapine may mitigate glutamatergic dysregulations observed in TRS, by modulating astrocyte activity in ClzR+, but not ClzR-. A factor that if proven correct, may help the assessment of treatment response and development of more effective antipsychotics. To explore the presence of clozapine-astrocyte interaction and clinical improvement, we used 3 T proton-magnetic resonance spectroscopy to quantify levels of myo-Inositol, surrogate biomarker of astrocyte activity, in regions related to schizophrenia neurobiology: Dorsal-anterior-cingulate-cortex (dACC), left-dorsolateral-prefrontal-cortex (left-DLPFC), and left-striatum (left-striatum) of 157 participants (ClzR- = 30; ClzR+ = 37; responders = 38; controls = 52). Clozapine treatment was assessed using clozapine to norclozapine plasma levels, 11-12 h after last clozapine dose. Measures for symptom severity (i.e., Positive and Negative Symptoms Scale) and cognition (i.e., Mini-Mental State Examination) were also recorded. Higher levels of myo-Inositol were observed in TRS groups versus responders and controls (dACC (p < 0.001); left-striatum (p = 0.036); left-DLPFC (p = 0.023)). In ClzR+, but not ClzR-, clozapine to norclozapine ratios were positively associated with myo-Inositol levels (dACC (p = 0.004); left-DLPFC (p < 0.001)), and lower positive symptom severity (p < 0.001). Our results support growing in vitro evidence of clozapine-astrocyte interaction in clozapine-responders. Further research may determine the viability of clozapine-astrocyte interactions as an early marker of clozapine response.

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.

Analysis of schizophrenia-associated genetic markers in the HLA region as risk factors for tardive dyskinesia.

OBJECTIVES: The pathology of Tardive Dyskinesia (TD) has yet to be fully understood, but there have been proposed hypotheses for the cause of this condition. Our team previously reported a possible association of TD with the Complement Component C4 gene in the HLA region. In this study, we explored the HLA region further by examining two previously identified schizophrenia-associated HLA-region single-nucleotide polymorphisms (SNPs), namely rs13194504 and rs210133. METHODS: The SNPs rs13194504 and rs210133 were tested for association with the occurrence and severity of TD in a sample of 172 schizophrenia patients who were recruited for four studies from three different clinical sites in Canada and USA. RESULTS: The rs13194504 AA genotype was associated with decreased severity for TD as measured by Abnormal Involuntary Movement Scale (AIMS) scores (p = 0.047) but not for TD occurrence. SNP rs210133 was not significantly associated with either TD occurrence or AIMS scores. CONCLUSION: Our findings suggest that the rs13194504 AA genotype may play a role in TD severity, while SNP rs210133 may not have a major role in the risk or severity of TD.

Assessing past suicidal behaviour in schizophrenia spectrum disorders using the Columbia-Suicide Severity Rating Scale and the Beck Scale for Suicide Ideation: Analysis across the life-span.

Assessing the number of past suicide attempts is vital in clinical and research settings, as it is a significant variable in assessing suicide risk. This study sought to compare the accuracy of the C-SSRS and the BSS in reporting past suicide attempts in schizophrenia spectrum disorders . Six hundred participants were recruited from the Centre for Addiction and Mental Health in Toronto, and completed the BSS and C-SSRS. A medical chart review was performed to determine the number of past suicide attempts. In addition, receiver operating characteristic curves were generated to compare the accuracy of both tests under various stratifications. Based on our findings, there were no significant differences (P = 0.8977) between the BSS and CSSRS in detecting a history of past suicide attempts. The BSS exhibited a sensitivity of 0.847 and a specificity of 0.841, while the C-SSRS had a slightly lower sensitivity of 0.795 and a slightly higher specificity of 0.889. Additionally, repeating the analysis to determine the accuracy of detecting multiple past suicide attempts, the BSS demonstrated a sensitivity of 0.704 and a specificity of 0.959, whereas the C-SSRS had a sensitivity of 0.787 and a specificity of 0.927. We further contrasted the two scales, stratified by different demographic variables such as age and sex. The accuracy of both tools, which is defined as the ability to identify true positive cases while minimizing false positives, increased as age increased, but these differences were not statistically significant. Therefore, both tools show a high level of accuracy in reporting past suicide attempt history and should be utilized to fit the specific needs of the research or clinical teams. These findings can inform clinical practice and future research, highlighting the importance of selecting assessment tools that fit the population's needs and context.

Safety of BEN guidelines in clozapine treatment: A Canadian perspective.

OBJECTIVE: Unidentified benign ethnic neutropenia (BEN) has been recognized as a factor contributing to clozapine underutilization and discontinuation. Guidelines were implemented to accommodate BEN in Canada, and our main objective was to evaluate clozapine's safety in a sample of Canadian psychiatric patients with BEN. METHOD: A retrospective chart review was conducted at the Centre for Addiction and Mental Health, Toronto, Canada. Through the clozapine clinic registry, participants were identified who (i) received clozapine using the approved BEN guidelines for hematological monitoring, and (ii) had at least one complete blood count pre- and post-clozapine initiation. RESULTS: Our sample population was comprised of 41 BEN patients who were African-Caribbean (49 %), African (34 %), African-North American (12 %), Middle Eastern (2 %), and Indian-Caribbean (2 %). There was a significant reduction in hematological alerts for these patients while monitored under BEN guidelines (p < 0.001). The mean within-patient ANC value was not significantly different one year after clozapine initiation compared to the pre-clozapine baseline (p = 0.069). None of the patients discontinued clozapine for hematological reasons. CONCLUSIONS: Findings demonstrated that patients monitored under the modified hematological guidelines for BEN can be safely treated with clozapine. These findings have important clinical ramifications as increased implementation of BEN guidelines may allow for broader use of clozapine.