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Found in the National Library of Medicine:

CNS Drugs. 2022; 36(7): 659–679.

Published online 2022 Jun 27. doi: 10.1007/s40263-022-00932-2

PMCID: PMC9243911

PMID: 35759211

A Guideline and Checklist for Initiating and Managing Clozapine Treatment in Patients with Treatment-Resistant Schizophrenia

C. U. Correll,1,2,3 Ofer Agid,4 Benedicto Crespo-Facorro,5 Andrea de Bartolomeis,6 Andrea Fagiolini,7 Niko Seppälä,8 and Oliver D. Howes 9

Author information Article notes Copyright and License information PMC Disclaimer

This article has been corrected. See CNS Drugs. 2022 August 17; 36(9): 1015.

Abstract

Treatment-resistant schizophrenia (TRS) will affect about one in three patients with schizophrenia. Clozapine is the only treatment approved for TRS, and patients should be treated as soon as possible to improve their chances of achieving remission. Despite its effectiveness, concern over side effects, monitoring requirements, and inexperience with prescribing often result in long delays that can expose patients to unnecessary risks and compromise their chances of achieving favorable long-term outcomes. We critically reviewed the literature on clozapine use in TRS, focusing on guidelines, systematic reviews, and algorithms to identify strategies for improving clozapine safety and tolerability. Based on this, we have provided an overview of strategies to support early initiation of clozapine in patients with TRS based on the latest evidence and our clinical experience, and have summarized the key elements in a practical, evidence-based checklist for identifying and managing patients with TRS, with the aim of increasing confidence in prescribing and monitoring clozapine therapy.

Key Points

Early and sustained treatment with clozapine represents the best available strategy for achieving and maintaining remission in patients with treatment-resistant schizophrenia.Common side effects including sialorrhea, constipation and weight gain may result in poor adherence to treatment, while the existence of rare severe adverse events and the associated monitoring burden may result in delays in starting therapy.Strategies for optimizing treatment and managing side effects are summarized and a checklist is provided.

Introduction

Schizophrenia is a serious mental illness involving positive and negative symptoms, as well as cognitive impairment [1]. It has a median incidence of 287 (uncertainty interval 246–331)/100,000 [2] and median standardized mortality ratio of 2.6 [3]. Therapies targeting postsynaptic dopamine receptors are not effective in all cases, especially regarding negative symptoms and in patients with treatment-resistant schizophrenia (TRS). TRS is defined as patients who do not respond sufficiently to sequential trials of at least two different antipsychotics administered at appropriate doses, duration, and with adequate adherence from the patient [4–7].

TRS is a major clinical challenge that can occur early in the treatment pathway or develop later in patients who respond initially to antipsychotic treatment [8–10]. Several lines of evidence indicate that it has a different neurobiology to schizophrenia that responds to dopamine D2 receptor blockers [11, 12]. It has been hypothesized that TRS could represent a neurobiologically distinct sub-type of schizophrenia [13, 14]. Some data point to a sub-type of schizophrenia associated with TRS characterized by unaltered dopamine function [15–17], and glutamate dysregulation [18–20], which would explain why these patients do not respond to dopamine D2 blockers [21]. TRS occurs in 20–50% of patients with schizophrenia [22–24], including in community settings [25]. It is associated with higher disease burden [26, 27] and poorer outcomes [28], especially involving persistent positive symptoms despite adherence with treatment [29].

Clozapine is the only drug approved for TRS by regulators in North America, Europe, and many other jurisdictions. It is a tricyclic dibenzodiazepine derivative that interacts with multiple neuroreceptors, including dopamine, serotonin and muscarinic receptors [30, 31]. Its low affinity for D2 dopamine receptors may explain its relative lack of extrapyramidal side effects [30], whilst its actions to modulate glutamate levels may contribute to its superior efficacy in TRS [32]. Clozapine is more effective than other antipsychotics for TRS [33], and it reduces rates of hospital readmission and all-cause mortality [34–36]. A systematic review and meta-analysis of long-term studies (median follow-up 5.4 years) revealed that continuous clozapine treatment was associated with a significantly lower all-cause mortality rate compared to other antipsychotics (mortality rate ratio = 0.56, 95% confidence interval (CI) = 0.36–0.85, P = 0.007) [37], which may be due to reduced suicidality [38].

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Found in UpToDate, Wolters Kluwer, The whole article is excellent. Find the complete article at UpToDate

Schizophrenia in adults: Guidelines for prescribing clozapine

CONTRAINDICATIONS AND PRECAUTIONS NeutropeniaDuffy-null associated neutrophil count (DANC) Cardiac disease Seizures Other conditions PHARMACOLOGYPharmacodynamics Pharmacokinetics ADMINISTRATIONPretreatment assessment Dose titration and plasma levels Maintenance dosing Re-initiation after interruption MONITORING Neutrophil countRequired bloodwork and COVID-19 CardiovascularMyocarditis QTc prolongation Metabolic Gastrointestinal ADVERSE EFFECTS

Neutropenia/agranulocytosis Myocarditis/cardiomyopathy QTc interval prolongation Pulmonary embolism Weight gain Insulin resistance and diabetes mellitus Seizures Excessive salivation Urinary incontinence Gastrointestinal hypomotility Sedation Teratogenic and neonatal risks Mortality risk Movement disorders TablesCauses of long QT syndrome AUTHORS:Oliver Freudenreich, MDJoseph McEvoy, MD

SECTION EDITOR:Stephen Marder, MD

DEPUTY EDITOR:Michael Friedman, MDContributor DisclosuresAll topics are updated as new evidence becomes available and our peer review process is complete.Literature review current through: Apr 2024.This topic last updated: May 22, 2023

CONTRAINDICATIONS AND PRECAUTIONS:

Neutropenia —Duffy-null associated neutrophil count (DANC) — Lower neutrophil thresholds were established for starting and treating clozapine in patients with confirmed DANC, a cause of neutropenia not associated with recurrent or severe infection that is most often seen in individuals of African descent and Sephardic Jews [3]. Treatment can be instituted and continued in patients with an ANC of at least 1000/microL. Collaboration with hematology is recommended to manage moderate or severe neutropenia in this patient group. (See "Approach to the adult with unexplained neutropenia", section on 'Normal variants

The recommended dosage at the start is 12.5 mg once or twice a day, on the first day, followed by daily incrementation of 25/50 mg a day, up to a dose of 250/450 mg/day, varying with consideration for several factors including gender, race, and smoking status

**Dell’Osso, L.; Bonelli, C.; Nardi, B.; Giovannoni, F.; Pronestì, C.; Cremone, I.M.; Amatori, G.; Pini, S.; Carpita, B. Rethinking Clozapine: Lights and Shadows of a Revolutionary Drug. Brain Sci. 2024, 14, 103. https://doi.org/10.3390/ brainsci14010103