Association With Hospitalization and All-Cause Discontinuation Among Patients With Schizophrenia on Clozapine vs Other Oral Second-Generation Antipsychotics

Masuda, Takahiro; Misawa, Fuminari; Takase, Masayuki; Kane, John M.; Correll, Christoph U.

doi:10.1001/jamapsychiatry.2019.1702

Cited by 263 publications

(100 citation statements)

References 71 publications

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“…These results have been replicated with claims data in the United States, which found a 22% reduction in the risk of hospitalization during periods following clozapine initiation (HR = 0.78, 95% CI = 0.69-0.88) (22). Similarly, a meta-analysis of cohort studies comparing clozapine treatment to non-clozapine second-generation antipsychotics found greater symptom reduction for clozapine (Hedges g, 0.22, 95% CI = 0.01-0.43), as well as lower hospitalization risk (relative risk [RR] = 0.82, 95% CI = 0.73-0.92) and all-cause discontinuation (RR = 0.73,95% CI = 0.64-0.84) (26). In addition to reductions in hospitalization, data from a cohort of 2370 individuals with TRS showed that individuals receiving clozapine treatment had almost half the mortality rate than individuals not receiving clozapine (HR = 1.88, 95% CI = 1.16-3.05) (27).…”

Section: Clozapine Eligibilitymentioning

confidence: 99%

How and when to use clozapine

Rubio

Kane

2019

Acta Psychiatr Scand

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Objective Clozapine is the only approved strategy for treatment‐resistant schizophrenia, although it is highly underutilized. We aim to generate practical and actionable evidence‐based recommendations for the use of this drug considering prescription barriers. Method Narrative review. Results A consistent body of evidence supports the efficacy of clozapine reducing morbidity and mortality in schizophrenia. The main obstacles to its use are the lack of experience by prescribers and perceived treatment burden. Systematic screening of eligibility, utilization of available resources for consultation, developing a professional network with other stakeholders, as well as optimizing how clozapine is presented to patients is discussed. Furthermore, specific evidence‐based recommendations for initiation, maintenance, and safety monitoring with clozapine are provided. Conclusion Clozapine prescription is one of the areas in psychiatry with the greatest mismatch between efficacy and utilization in clinical practice. Although multiple barriers to the use of clozapine exist, some of these may be overcome by updates of routine clinical practice.

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Section: Clozapine Eligibilitymentioning

confidence: 99%

How and when to use clozapine

Rubio

Kane

2019

Acta Psychiatr Scand

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“…Nev-ertheless, our study represents the largest study on a broad variety of clinically highly relevant outcomes among a severely-ill cohort of patients treated with clozapine. Furthermore, our study contributes to the discussion of clozapine's cardiovascular safety [66] with regard to its efficacy in terms of a risk-benefit evaluation. Given the presumed shared underlying neurobiology of schizophrenia and nicotine use [67][68][69], our smoking clozapine patients might define an ultra-treatment-resistant subgroup with an early onset of the disease requiring further research.…”

Section: Discussionmentioning

confidence: 92%

Effects of Smoking Status on Remission and Metabolic and Cognitive Outcomes in Schizophrenia Patients Treated with Clozapine

et al. 2020

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Background Even though clozapine is the recommended last-resort antipsychotic, many patients fail to respond and show treatment-refractory psychotic symptoms. Smoking has been suggested as a possible risk factor for poor clozapine response, hampering remission and negatively impacting somatic outcomes. Methods Our aim was to test whether smoking status is associated with remission rates and other symptomatic and somatic outcomes. We therefore assessed remission rates according to The Remission in Schizophrenia Working Group (RSWG) criteria, and metabolic and cognitive outcomes among patients with schizophrenia-spectrum disorders treated with clozapine for at least 6 months. For analyses, we grouped our cohort into 3 groups according to clozapine treatment duration (6 months, 2 years, 5 years). Results One hundred five patients were included in our analyses and grouped according to their clozapine treatment duration. In the 6-months analyses, patients who smoked were significantly more likely to be younger of age (p=0.002) despite on average shorter duration of clozapine treatment (p=0.041) and significantly more likely to be treated with mood-stabilizing co-medication (p=0.030) compared to nonsmokers. Remission rates (p=0.490), as well as a set of metabolic and cognitive variables did not differ between the 2 groups. A related pattern could be observed for the 2- and 5-years analyses. Conclusions Smoking behavior among clozapine-treated schizophrenia patients might delineate a cohort with an earlier onset of the disease. Nevertheless, most findings comparing disease-specific and clinical outcomes among smokers and nonsmokers were negative. Further research is needed to identify strategies to overcome insufficient remission rates in this patient group.

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“…Clozapine is one of the antipsychotics most strongly associated with weight gain, hyperglycemia, and hyperlipidemia [208,209]. In a systematic review of cohort studies, clozapine was also associated with higher cardiometabolic-related risk outcomes [128]. As described before, clozapine is associated with longer survival [114]; it appears that its positive effects may outweigh its metabolic risks.…”

Section: Other Potentially Lethal Clozapine Adrsmentioning

confidence: 91%

“…If one takes a more comprehensive view of what is important in clinical practice [126], and considers effectiveness based on two systematic reviews of naturalistic cohort studies [127,128], clozapine was superior to other antipsychotics in decreasing discontinuation and decreasing hospitalization.…”

Section: Effectivenessmentioning

confidence: 99%

“…The importance of well-being during pharmacotherapy is receiving more and more attention [129] and is particularly relevant in explaining the high adherence of some patients to clozapine, demonstrated by the lower discontinuation rates in cohort studies [127,128]. Clozapine positive effects on well-being in some patients may be influenced by clozapine effects on extrapyramidal symptoms [130][131][132][133][134][135][136][137][138][139][140][141][142], hostility [143,144] and the "awakening" phenomenon [145][146][147] (online suppl.…”

Section: Clozapine and Well-beingmentioning

confidence: 99%

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A Rational Use of Clozapine Based on Adverse Drug Reactions, Pharmacokinetics, and Clinical Pharmacopsychology

Leon

Ruan

Schoretsanitis

et al. 2020

Psychother Psychosom

121

113

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Using Richardson and Davidson's model and the sciences of pharmacokinetics and clinical pharmacopsychology, this article reviewed the: (1) poor life expectancy associated with treatment-resistant schizophrenia (TRS), which may be improved in patients who adhere to clozapine; (2) findings that clozapine is the best treatment for TRS (according to efficacy, effectiveness and well-being); and (3) potential for clozapine to cause vulnerabilities, including potentially lethal adverse drug reactions such as agranulocytosis, pneumonia, and myocarditis. Rational use requires: (1) modification of the clozapine package insert worldwide to include lower doses for Asians and to avoid the lethality associated with pneumonia, (2) the use of clozapine levels for personalizing dosing, and (3) the use of slow and personalized titration. This may make clozapine as safe as possible and contribute to increased life expectancy and well-being. In the absence of data on COVID-19 in clozapine patients, clozapine possibly impairs immunological mechanisms and may increase pneumonia risk in infected patients. Psychiatrists should call their clozapine patients and families and explain to them that if the patient develops fever or flu-like symptoms, the psychiatrist should be called and should consider halving the clozapine dose. If the patient is hospitalized with pneumonia, the treating physician needs to assess for symptoms of clozapine intoxication since halving the dose may not be enough for all patients; consider decreasing it to one-third or even stopping it. Once the signs of inflammation and fever have disappeared, the clozapine dose can be slowly increased to the prior dosage level. 46, 48, 52-67] describes the important pharmacokinetic variables for clozapine clearance. Higher clozapine C/D ratios, indicating lower clearance, are associated with females, non-smokers, Asians, genetic poor metabolizers, inhibitors, obesity, inflammation, and possibly with renal impairment and pregnancy. Lower clozapine C/D ratios indicate lack of adherence or higher clearance associated with males, smokers, non-Asians, and inducers.Two prior TDM review articles [68,69] are summarized in online supplementary Box S3 [31, 44, 50, 51, 55, 58-61, 63, 65, 68-91] which also describe our extensive experience with thousands of inpatient clozapine TDMs under standard conditions (trough and steady-state levels) in the US [44] and China [45,65]. Many of these inpatients were followed for months and/or years after changes in important pharmacokinetic variables [31, 44, 50, 58-61, 63, 65, 74, 79, 86-91].Published review articles [92][93][94] usually insist on the wide variability of clozapine TDM among individuals and the difficulty of interpreting a single clozapine level, but they fail to pay attention to findings from these two sciences: pharmacokinetics and clinical pharmacopsychology, which help in interpreting variability in clozapine levels. In inpatients, repeated measures allow the calculation of average clozapine clearance in an individual through a...

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Association With Hospitalization and All-Cause Discontinuation Among Patients With Schizophrenia on Clozapine vs Other Oral Second-Generation Antipsychotics

Cited by 263 publications

References 71 publications

How and when to use clozapine

How and when to use clozapine

Effects of Smoking Status on Remission and Metabolic and Cognitive Outcomes in Schizophrenia Patients Treated with Clozapine

A Rational Use of Clozapine Based on Adverse Drug Reactions, Pharmacokinetics, and Clinical Pharmacopsychology

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