ORCID Profile
0000-0002-7147-6167
Current Organisation
UNSW Sydney
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Publisher: Springer Science and Business Media LLC
Date: 22-09-2021
DOI: 10.1038/S41398-021-01613-2
Abstract: A recent increase in the literature regarding the evidence base for clozapine has made it increasingly difficult for clinicians to judge “best evidence” for clozapine use. As such, we aimed at elucidating the state-of-the-art for clozapine with regard to efficacy, effectiveness, tolerability, and management of clozapine and clozapine-related adverse events in neuropsychiatric disorders. We conducted a systematic PRISMA-conforming quantitative meta-review of available meta-analytic evidence regarding clozapine use. Primary outcome effect sizes were extracted and transformed into relative risk ratios (RR) and standardized mean differences (SMD). The methodological quality of meta-analyses was assessed using the AMSTAR-2 checklist. Of the 112 meta-analyses included in our review, 61 (54.5%) had an overall high methodological quality according to AMSTAR-2 . Clozapine appears to have superior effects on positive, negative, and overall symptoms and relapse rates in schizophrenia (treatment-resistant and non-treatment-resistant subpopulations) compared to first-generation antipsychotics (FGAs) and to pooled FGAs/second-generation antipsychotics (SGAs) in treatment-resistant schizophrenia (TRS). Despite an unfavorable metabolic and hematological adverse-event profile compared to other antipsychotics, hospitalization, mortality and all-cause discontinuation (ACD) rates of clozapine surprisingly show a pattern of superiority. Our meta-review outlines the superior overall efficacy of clozapine compared to FGAs and most other SGAs in schizophrenia and suggests beneficial efficacy outcomes in bipolar disorder and Parkinson’s disease psychosis (PDP). More clinical studies and subsequent meta-analyses are needed beyond the application of clozapine in schizophrenia-spectrum disorders and future studies should be directed into multidimensional clozapine side-effect management to foster evidence and to inform future guidelines.
Publisher: Institute of Electrical and Electronics Engineers (IEEE)
Date: 07-2021
Publisher: Wiley
Date: 27-09-2020
DOI: 10.1111/ACPS.13228
Publisher: Elsevier BV
Date: 09-2019
Publisher: Wiley
Date: 25-08-2021
DOI: 10.1111/ACPS.13361
Abstract: Clozapine levels may be a more useful predictor of therapeutic response than the dose, given the variability in clozapine metabolism between in iduals. We therefore systematically reviewed and meta‐analysed the impact of clozapine levels on response and/or relapse to provide guidance on optimal clozapine levels. We systematically searched PubMed, PsycInfo and Embase for studies exploring clozapine levels and response and/or relapse. Our primary meta‐analysis was rates of response above and below clozapine level thresholds of 350 ng/ml and 600 ng/ml. Secondary analyses were undertaken of mean clozapine levels, dose and concentration/dose (C/D) ratio and response and/or relapse. A meta‐regression by study duration was conducted. Twenty studies met inclusion criteria. Clozapine levels above 350 ng/ml were associated with statistically significantly higher rates of response (OR 2.27 95% CI 1.40–3.67, p 0.001), but not above 600 ng/ml (OR 1.40 95% CI 0.85–2.31, p = 0.19). Higher mean clozapine levels were associated with better rates of response (SMD 0.24, 95% CI 0.00–0.49, p = 0.05), and lower rates of relapse (SMD −0.72, 95% CI −1.26 to −0.19, p = 0.008). By contrast, neither clozapine dose nor C/D ratio was associated with differing rates of response. Similarly, study duration did not affect outcome. Our findings are in keeping with current guidelines that recommend targeting clozapine levels above 350 ng/ml before augmentation is considered. As some clozapine associated ADRs are dose dependent, levels above 600 ng/ml may have an unfavourable risk‐benefit ratio.
Publisher: SAGE Publications
Date: 30-01-2019
Abstract: Treatment options for clozapine resistance are erse whereas, in contrast, the evidence for augmentation or combination strategies is sparse. We aimed to extract levels of evidence from available data and extrapolate recommendations for clinical practice. We conducted a systematic literature search in the PubMed/MEDLINE database and in the Cochrane database. Included meta-analyses were assessed using Scottish Intercollegiate Guidelines Network criteria, with symptom improvement as the endpoint, in order to develop a recommendation grade for each clinical strategy identified. Our search identified 21 meta-analyses of clozapine combination or augmentation strategies. No strategies met Grade A criteria. Strategies meeting Grade B included combinations with first- or second-generation antipsychotics, augmentation with electroconvulsive therapy for persistent positive symptoms, and combination with certain antidepressants (fluoxetine, duloxetine, citalopram) for persistent negative symptoms. Augmentation strategies with mood-stabilisers, anticonvulsants, glutamatergics, repetitive transcranial magnetic stimulation, transcranial direct current stimulation or cognitive behavioural therapy met Grades C–D criteria only. More high-quality clinical trials are needed to evaluate the efficacy of add-on treatments for symptom improvement in patients with clozapine resistance. Applying definitions of clozapine resistance would improve the reporting of future clinical trials. Augmentation with second-generation antipsychotics and first-generation antipsychotics can be beneficial, but the supporting evidence is from low-quality studies. Electroconvulsive therapy may be effective for clozapine-resistant positive symptoms.
Publisher: Springer Science and Business Media LLC
Date: 07-04-2022
DOI: 10.1038/S41398-022-01884-3
Abstract: Clozapine is the most effective antipsychotic for patients with treatment-resistant schizophrenia. However, response is highly variable and possible genetic underpinnings of this variability remain unknown. Here, we performed polygenic risk score (PRS) analyses to estimate the amount of variance in symptom severity among clozapine-treated patients explained by PRSs (R2) and examined the association between symptom severity and genotype-predicted CYP1A2, CYP2D6, and CYP2C19 enzyme activity. Genome-wide association (GWA) analyses were performed to explore loci associated with symptom severity. A multicenter cohort of 804 patients (after quality control N = 684) with schizophrenia spectrum disorder treated with clozapine were cross-sectionally assessed using the Positive and Negative Syndrome Scale and/or the Clinical Global Impression-Severity (CGI-S) scale. GWA and PRS regression analyses were conducted. Genotype-predicted CYP1A2, CYP2D6, and CYP2C19 enzyme activities were calculated. Schizophrenia-PRS was most significantly and positively associated with low symptom severity ( p = 1.03 × 10 −3 R2 = 1.85). Cross-disorder-PRS was also positively associated with lower CGI-S score ( p = 0.01 R2 = 0.81). Compared to the lowest tertile, patients in the highest schizophrenia-PRS tertile had 1.94 times ( p = 6.84×10 −4 ) increased probability of low symptom severity. Higher genotype-predicted CYP2C19 enzyme activity was independently associated with lower symptom severity ( p = 8.44×10 −3 ). While no locus surpassed the genome-wide significance threshold, rs1923778 within NFIB showed a suggestive association ( p = 3.78×10 −7 ) with symptom severity. We show that high schizophrenia-PRS and genotype-predicted CYP2C19 enzyme activity are independently associated with lower symptom severity among in iduals treated with clozapine. Our findings open avenues for future pharmacogenomic projects investigating the potential of PRS and genotype-predicted CYP - activity in schizophrenia.
No related grants have been discovered for Elias Wagner.