Impact of patient-specific factors on clozapine metabolism in individuals with treatment-resistant schizophrenia or schizoaffective disorder.

BACKGROUND: There is high inter-individual variability in clozapine metabolism due to genetic and non-genetic differences. Patient-specific factors such as smoking, inflammation indicated by elevated C-reactive protein (CRP), and certain concurrent medications have a significant influence on clozapine metabolism. AIM: To assess which patient-specific factors best explain variability in clozapine metabolism estimated by clozapine concentration to dose (C/D) ratios. METHODS: A retrospective cohort analysis using electronic medical data was conducted on 172 inpatients at the BC Psychosis Program. Patients with normal renal and liver function were included if they were on clozapine and had at least one steady-state plasma concentration. The degree of influence of each factor on the variability of clozapine metabolism in the entire cohort and subgroups stratified by fluvoxamine use was evaluated using multiple linear regression analysis of C/D ratios. RESULTS: Model fit testing showed that the entire cohort model accounts for 52.7% of C/D ratio variability, while the no fluvoxamine and fluvoxamine models accounted for 40.8% and 43.8%. In the entire cohort (n = 172), fluvoxamine use explained the highest variance, and C/D ratios were higher by 30.6% on average. The second strongest predictor was elevated CRP > 10 mg/L, and C/D ratios were higher by 22.9% on average. Subsequently, obesity, nonsmoker status, and female sex explained a significant but modest proportion of variance. Among participants on fluvoxamine (n = 58), only fluvoxamine dose was associated with an increase, and for every 25 mg increase in dose, C/D ratios increased by 5% on average. CONCLUSION: In a clinical population, this study replicated the relationship between reduced rate of clozapine metabolism and the use of fluvoxamine, elevated CRP, obesity, nonsmoking status, and female sex; and the magnitude of the effects were large enough to be clinically relevant.

Virtual twins for model-informed precision dosing of clozapine in patients with treatment-resistant schizophrenia.

Model-informed precision dosing using virtual twins (MIPD-VTs) is an emerging strategy to predict target drug concentrations in clinical practice. Using a high virtualization MIPD-VT approach (Simcyp version 21), we predicted the steady-state clozapine concentration and clozapine dosage range to achieve a target concentration of 350 to 600 ng/mL in hospitalized patients with treatment-resistant schizophrenia (N = 11). We confirmed that high virtualization MIPD-VT can reasonably predict clozapine concentrations in individual patients with a coefficient of determination (R2 ) ranging between 0.29 and 0.60. Importantly, our approach predicted the final dosage range to achieve the desired target clozapine concentrations in 73% of patients. In two thirds of patients treated with fluvoxamine augmentation, steady-state clozapine concentrations were overpredicted two to four-fold. This work supports the application of a high virtualization MIPD-VT approach to inform the titration of clozapine doses in clinical practice. However, refinement is required to improve the prediction of pharmacokinetic drug-drug interactions, particularly with fluvoxamine augmentation.

Association of clozapine treatment and rate of methamphetamine or amphetamine relapses and abstinence among individuals with concurrent schizophrenia spectrum and amphetamine use disorder: A retrospective cohort study.

BACKGROUND: Preliminary evidence suggest clozapine is associated with more favorable impact on concurrent substance use disorder related outcomes in patients with concurrent schizophrenia spectrum disorders (SSD). At the same time, there is a dearth of evidence with regards to clozapine outcomes in the context of concurrent methamphetamine or amphetamine use disorder (MAUD). AIMS: To examine whether clozapine use decreases rate of methamphetamine or amphetamine (MA) relapses and increases the likelihood of maintaining abstinence from any MA use. METHODS: A descriptive-analytic retrospective cohort study was conducted on individuals with SSD-MAUD in an inpatient provincial treatment and rehabilitation center for concurrent disorders. Antipsychotic exposure was categorized as "on clozapine" or "on other antipsychotic(s)." Data were collected using electronic health records. Logistic regression was used to examine association of clozapine treatment with likelihood of complete abstinence from MA use for the duration of antipsychotic exposure. Negative binomial regression was used to examine association of clozapine treatment with rate of MA relapses for the duration of antipsychotic exposure. RESULTS: The majority of the 87 included patients were male. Ethnicity was diverse, with the largest groups self-identifying as Indigenous and European. Clozapine use was both associated with increased likelihood of maintaining abstinence from MA use (adjusted odds ratio (aOR) = 3.05, 95% confidence intervals (CI) = 1.15-8.1, p = 0.025), and decreased rate of MA relapses (aRR = 0.45, 95% CI = 0.25-0.82, p = 0.009) for the duration of antipsychotic exposure. Co-prescription of psychostimulants was associated with increased rate of MA relapses (aRR = 2.43, 95% CI = 1.16-5.10, p = 0.019). CONCLUSION(S): In this study, clozapine use compared with other antipsychotics in SSD was associated with improved outcomes related to severe concurrent MAUD. Co-prescription of psychostimulant medications was associated with a poor outcome.

Effects of clozapine treatment on the improvement of substance use disorders other than nicotine in individuals with schizophrenia spectrum disorders: A systematic review and meta-analysis.

BACKGROUND: Antipsychotic medications are the mainstay of treatment for schizophrenia and are associated with a reduction in psychiatric hospitalization and overall mortality. Some evidence suggest that antipsychotic medications might have a varying effect on the improvement of comorbid substance use disorders (SUDs), with clozapine showing more favorable outcomes. AIM: We systematically reviewed all available evidence on effects of clozapine on the improvement of SUDs other than nicotine. METHODS: Electronic searches of MEDLINE, Embase, PsycINFO, and CINHAL were conducted up to March 1, 2022. Studies of any methodological design involving two concepts: (1) clozapine and (2) SUD terms (excluding nicotine) were included. For SUD outcomes with three or more comparative studies with available raw data meta-analysis was performed. SUD outcomes not meeting criteria for meta-analysis were described qualitatively. Risk of bias was examined using "Downs and Black," and "Q-Coh" instruments. RESULTS: The majority of individuals in the included 31 studies were male and of European ancestry. Abstinence was the most common outcome. Most of the studies were of low-to-moderate quality, and none of the studies met all the quality criteria. Pooled findings from four observational studies in samples of patients with predominantly comorbid alcohol use disorder showed that clozapine treatment is associated with significantly higher odds of remaining abstinent. In addition clozapine was associated with decreased odds of psychiatric hospitalization in all but one observational study. CONCLUSIONS: Our systematic review and meta-analysis builds upon previous reviews, and it suggests the association of clozapine treatment with significantly higher odds of remaining abstinent from substance use and decreased likelihood of psychiatric hospitalization, compared with continuing treatment with other antipsychotic medications. Still, the validity of this association needs greater exploration and providing recommendations for the utility of clozapine in individuals without treatment-resistant psychosis and comorbid SUDs would be premature.

Repeated subcutaneous racemic ketamine in treatment-resistant depression: case series.

Interest in the use of parenteral ketamine has been increasing over the last 2 decades for the management of treatment-resistant depression (TRD). While intravenous (IV) ketamine has been the most common parenteral route of administration, subcutaneous (SC) and intramuscular options have been described. We developed a clinical treatment protocol for the use of repeated SC racemic ketamine (maximum six treatments, twice per week) in an inpatient psychiatric care setting with inclusion/exclusion criteria, dosing schedule, and description of treatment, assessment, and monitoring procedures. Results from the first 10 consecutive patients demonstrated the effectiveness of SC racemic ketamine in relieving symptoms of TRD as measured by the Montgomery-Åsberg Depression Rating Scale (MADRS) and Quick Inventory of Depressive Symptomatology, Self-Report (QIDS-SR 16 ). Response (≥50% reduction in scores from baseline to endpoint) was achieved in 8/10 cases on the MADRS and 6/10 on the QIDS-SR 16 . Remission was achieved in 8/10 (based on MADRS ≤10) and 5/10 (based on QIDS-SR 16 ≤6). Patients tolerated the treatments well with only transient blood pressure changes and dissociative side effects. Repeated SC ketamine treatments could be a safe, feasible, and effective alternative to IV ketamine infusions for patients with TRD.

Risk Evaluation for Antipsychotic Agents Used in Elderly Inpatients (REPAIR).

BACKGROUND: Antipsychotics have been approved for the treatment of certain psychiatric illnesses. However, these medications are also frequently used off label, and recent studies have suggested a concerning potential increase in the risk of death when used by elderly patients with dementia. Most of the available literature focusing on off-label use of antipsychotics comes from long-term care facilities; there is a lack of quantitative data for elderly patients in the acute care setting. This study was designed to examine this scenario and to identify potential quality improvement opportunities to minimize harm. OBJECTIVES: The primary objectives were to determine the prevalence of hospital-initiated off-label use of antipsychotics for elderly inpatients and to determine the plan for these drugs upon discharge. The secondary objectives included identifying the most common diagnosis and the most common agent used. METHODS: A retrospective cohort study was performed with a convenience sample. Patients included in the analysis were elderly adults (≥ 65 years) who had been admitted to either of 2 medical units at a community hospital between September 1 and November 8, 2014. Descriptive statistics were used to examine prevalence patterns for the off-label use of antipsychotics. RESULTS: A total of 250 patients were included in the analysis. Forty-five patients (18%, 95% confidence interval [CI] 13.7%-23.2%) received a hospital-initiated antipsychotic for off-label use during the admission. For 27 (60%, 95% CI 45.5%-73.0%) of these 45 patients, the off-label therapy was discontinued upon discharge or death, and for 13 (29%, 95% CI 17.7%-43.4%), the agent was continued upon discharge without a plan in place. The most frequent diagnosis was delirium, and the agent most frequently used was haloperidol. CONCLUSIONS: Off-label antipsychotic therapy was initiated for almost 1 in every 5 elderly patients receiving care in 2 medical units at a community hospital. These findings suggest a need to monitor and reassess the off-label use of these agents, especially at the time of discharge.

CONTEXTE: Les antipsychotiques ont été approuvés pour le traitement de certains troubles psychiatriques. Or, ces médicaments sont aussi fréquemment utilisés en dérogation des directives de l'étiquette et des études récentes ont supposé une potentielle augmentation préoccupante du risque de décès lorsqu'ils sont employés pour traiter des patients âgés atteints de démence. La majeure partie de la littérature portant sur l'emploi non conforme d'antipsychotiques provient de centres d'hébergement et de soins de longue durée. Or, on constate un manque de données quantitatives sur les patients âgés dans les milieux de soins de courte durée. La présente étude a été conçue pour examiner ce scénario et découvrir de potentielles occasions d'amélioration de la qualité en vue de réduire au minimum les risques de préjudice. OBJECTIFS: Les objectifs principaux étaient de déterminer la prévalence de l'emploi non conforme d'antipsychotiques amorcé à l'hôpital chez les patients aînés et de déterminer le plan relatif à la prescription de ces médicaments au moment du congé. Les objectifs secondaires incluaient de déterminer quels étaient le diagnostic le plus fréquent et le médicament le plus utilisé. MÉTHODES: Une étude de cohorte rétrospective a été menée à l'aide d'un échantillon de commodité. Les patients retenus pour l'analyse étaient des personnes âgées (de 65 ans et plus) ayant été admises à l'une des deux unités médicales dans un hôpital communautaire entre le 1er septembre et le 8 novembre 2014. Des statistiques descriptives ont été employées pour analyser les modèles de prévalence en ce qui concerne l'emploi non conforme d'antipsychotiques. RÉSULTATS: Au total, 250 patients ont été retenus pour l'analyse. Pendant l'hospitalisation, un antipsychotique a été amorcé hors conformité chez 45 patients (18 %, intervalle de confiance [IC] de 95 % de 13,7 % à 23,2 %). Pour 27 (60 %, IC de 95 % de 45,5 % à 73,0 %) de ces 45 patients, le traitement non conforme a été arrêté au moment du congé et, pour 13 autres (29 %, IC de 95 % de 17,7 %­43,4 %), le traitement a été poursuivi au congé sans mise en place d'un plan. Le diagnostic motivant le plus souvent l'emploi non conforme de ces médicaments était le délire et le médicament le plus employé était l'halopéridol. CONCLUSIONS: Le traitement non conforme par antipsychotique a été amorcé pendant le séjour à l'hôpital pour près d'un patient âgé sur cinq qui recevait des soins dans l'une des deux unités médicales d'un hôpital communautaire. Ces résultats laissent croire qu'une surveillance de l'emploi non conforme de ces médicaments et qu'une réévaluation d'un tel traitement sont nécessaires, particulièrement au moment du congé.

Characterization of Venous Thromboembolism Risk in Medical Inpatients Using Different Clinical Risk Assessment Models.

BACKGROUND: Symptomatic venous thromboembolism (VTE) occurs in about 1% of patients within 3 months after admission to a medical unit. Recent evidence for thromboprophylaxis in an unselected medical inpatient population has suggested only a modest net benefit. Consequently, guidelines recommend careful risk stratification to guide thromboprophylaxis. OBJECTIVES: To compare candidacy for thromboprophylaxis according to 4 risk stratification models: a regional preprinted order (PPO) set used in the study institution, the Padua Prediction Score, and the IMPROVE predictive and associative risk assessment models. METHODS: A retrospective review of health records was undertaken for patients with no contraindication to pharmacologic thromboprophylaxis who were admitted to the internal medicine service of a teaching hospital between April and July 2013. RESULTS: Of the 298 patients in the study cohort, 238 (80.0%) received pharmacologic thromboprophylaxis on admission, ordered according to the regional PPO. However, according to the Padua and the IMPROVE predictive risk assessment models, only 64 (21.5%) and 21 (7.0%) of the patients, respectively, were eligible for thromboprophylaxis at the time of admission. On the basis of risk factors identified during the subsequent hospital stay, 54 (18.1%) of the patients were eligible for thromboprophylaxis according to the IMPROVE associative model. Chance-corrected agreement between the PPO and the published risk assessment models was generally poor, with kappa coefficients of 0.109 for the PPO compared with the Padua Prediction Score and 0.013 for the PPO compared with the IMPROVE predictive model. CONCLUSIONS: These data suggest that quantitative models such as the Padua Prediction Score and the IMPROVE models identify more patients at low risk of venous thromboembolism than do in-hospital qualitative risk assessment models. Adoption of these guideline-based risk assessment models for predicting thromboembolic risk in medical inpatients could reduce the use of pharmacologic thromboprophylaxis from 80% to as low as 7%. Further external prognostic validation of risk assessment models and impact analysis studies may show improvements in safety and resource utilization.

La thromboembolie veineuse symptomatique se produit chez environ 1 % des patients dans les trois mois suivant leur admission à un service médical. Des données récentes portant sur la thromboprophylaxie chez une population non sélectionnée de patients hospitalisés ne suggéraient qu'un modeste avantage. Par conséquent, les lignes directrices recommandent une stratification du risque rigoureuse pour guider l'emploi d'une thromboprophylaxie.