Clozapine and all‐cause mortality in treatment‐resistant schizophrenia: a historical cohort study

Cho, Jaelim; Hayes, Richard D.; Jewell, Amelia; Kadra, Giouliana; Shetty, Hitesh; MacCabe, James H.; Downs, Johnny

doi:10.1111/acps.12989

Cited by 59 publications

(64 citation statements)

References 43 publications

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“…Although CLZ can interact with genetic factors to evoke rare but potentially fatal complications such as agranulocytosis and neutropenia 42 , CLZ is currently one of the most commonly used atypical antipsychotic drugs for treatment-resistant schizophrenia 10 . As CLZ readily crosses the blood-brain barrier, it can be used reliably to activate DREADD receptors in a variety of chemogenetic experiments, replacing CNO.…”

Section: Discussionmentioning

confidence: 99%

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Optimizing clozapine for chemogenetic neuromodulation of somatosensory cortex

Cho

Ryu

Lee

et al. 2020

Sci Rep

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clozapine (cLZ) has been proposed as an agonist for Designer Receptors exclusively Activated by Designer Drugs (DREADDs), to replace Clozapine-N-oxide (CNO); however, there are no reliable guidelines for the use of cLZ for chemogenetic neuromodulation. We titrated the optimal dose of cLZ required to evoke changes in neural activity whilst avoiding off-target effects. We also performed [ 18 f] fluoro-deoxy-glucose micro positron emission tomography (fDG-micropet) scans to determine the global effect of CLZ-induced hM3D(Gq) DREADD activation in the rat brain. Our results show that low doses of CLZ (0.1 and 0.01 mg/kg) successfully induced neural responses without off-target effects. CLZ at 1 mg/kg evoked a stronger and longer-lasting neural response but produced off-target effects, observed as changes in locomotor behavior and FDG-microPET imaging. Unexpectedly, FDG-microPET imaging failed to demonstrate an increase in regional glucose metabolism in the stimulated cortex during CLZ chemogenetic neuromodulation. Therefore, caution should be used when interpreting FDGpet images in the context of cortical chemogenetic activation.

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Section: Discussionmentioning

confidence: 99%

“…CLZ is an atypical antipsychotic drug, most commonly used in patients with treatment-resistant schizophrenia 10 . CLZ has been suggested for use in chemogenetic neuromodulation, in place of CNO, because it readily crosses the blood-brain barrier 4,7 .…”

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confidence: 99%

Optimizing clozapine for chemogenetic neuromodulation of somatosensory cortex

Cho

Ryu

Lee

et al. 2020

Sci Rep

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“…Regarding clozapine, in a meta-analysis of 24 studies with long-term follow-up of treatment, Vermeulen et al [114] found long-term, crude mortality rate ratios were significantly lower in patients continuously treated with clozapine compared to patients treated with other antipsychotics (mortality rate ratio = 0.56). Online supplementary Box S4 [112][113][114][115][116] describes two additional studies published after the meta-analysis, also showing lower mortality in clozapine patients [115,116]…”

Section: Baseline Risk Of Poor Outcomes From Trs Without Treatmentmentioning

confidence: 99%

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

Leon

Ruan

Schoretsanitis

et al. 2020

Psychother Psychosom

114

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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“…Tertiary care programs for TRS should include individually tailored psychosocial rehabilitation, as well as personalised and evidence-based medication management, to achieve flexible and effective care. 9 Clozapine is the only recommended antipsychotic treatment for TRS and is the most effective agent for reducing symptoms, 10 hospital use, 11 suicide rates, 12,13 aggressive behaviour, 14 violent crime 15 and substance misuse. 16 However, the management of clozapine therapy for patients with severe and chronic behavioural problems requires carefully developed strategies and close monitoring of adverse effects, which can be challenging in a primary or secondary care setting.…”

Section: Tertiary Services For Complex Trsmentioning

confidence: 99%

Real-world effectiveness of admissions to a tertiary treatment-resistant psychosis service: 2-year mirror-image study

et al. 2020

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Background Treatment-resistant schizophrenia is a major disabling illness which often proves challenging to manage in a secondary care setting. The National Psychosis Unit (NPU) is a specialised tertiary in-patient facility that provides evidence-based, personalised, multidisciplinary interventions for complex treatment-resistant psychosis, in order to reduce the risk of readmission and long-term care costs. Aims This study aimed to assess the long-term effectiveness of treatment at the NPU by considering naturalistic outcome measures. Method Using a mirror image design, we compared the numbers of psychiatric and general hospital admissions, in-patient days, acuity of placement, number of psychotropic medications and dose of antipsychotic medication prescribed before and following NPU admission. Data were obtained from the Clinical Records Interactive Search system, an anonymised database sourced from the South London and Maudsley NHS Trust electronic records, and by means of anonymous linkage to the Hospital Episode Statistics system. Results Compared with the 2 years before NPU admission, patients had fewer mental health admissions (1.65 ± 1.44 v. 0.87 ± 0.99, z = 5.594, P < 0.0001) and less mental health bed usage (335.31 ± 272.67 v. 199.42 ± 261.96, z = 5.195 P < 0.0001) after NPU admission. Total in-patient days in physical health hospitals and total number of in-patient days were also significantly reduced (16.51 ± 85.77 v. 2.83 ± 17.38, z = 2.046, P = 0.0408; 351.82 ± 269.09 v. 202.25 ± 261.05, z = 5.621, P < 0.0001). The reduction in level of support required after treatment at the NPU was statistically significant (z = −8.099, P < 0.0001). Conclusions This study demonstrates the long-term effectiveness of a tertiary service specialising in treatment-resistant psychosis.

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Clozapine and all‐cause mortality in treatment‐resistant schizophrenia: a historical cohort study

Cited by 59 publications

References 43 publications

Optimizing clozapine for chemogenetic neuromodulation of somatosensory cortex

Optimizing clozapine for chemogenetic neuromodulation of somatosensory cortex

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

Real-world effectiveness of admissions to a tertiary treatment-resistant psychosis service: 2-year mirror-image study

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