Clozapine for Treatment-Resistant Schizophrenia: National Institute of Clinical Excellence (NICE) Guidance in the Real World

Mortimer, Ann; Singh, Praveen; Shepherd, Charles J; Puthiryackal, Junais

doi:10.3371/csrp.4.1.4

Cited by 78 publications

(68 citation statements)

References 13 publications

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“…Clozapine is known to have a superior efficacy in the treatment of treatment-resistant schizophrenia (Kane et al 1998 ;Lewis et al 2006 ;McEvoy et al 2006 ;Mortimer et al 2010). However, clozapine is also known to induce a higher prevalence of metabolic syndrome (MetS) involving abnormalities in lipid metabolism such as hypertriglyceridaemia and hypercholesterolaemia, resulting in weight gain and hypertension compared to other antipsychotics (Allison et al 1999 ;Casey, 2004 ;Henderson et al 2004 ;Meyer & Koro, 2004).…”

Section: Introductionmentioning

confidence: 95%

The effect of clozapine on the AMPK-ACC-CPT1 pathway in the rat frontal cortex

Kim

et al. 2011

Int. J. Neuropsychopharm.

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Clozapine is an antipsychotic drug that has a greater efficacy than other medications in some contexts, especially for the treatment of treatment-resistant schizophrenia. However, clozapine induces more metabolic side-effects involving abnormality in lipid metabolism compared to other antipsychotics. AMP-activated protein kinase (AMPK) plays a central role in controlling lipid metabolism through modulating the downstream acetyl CoA carboxylase (ACC) and carnitine palmitoyl transferase 1 (CPT1) pathway. In this study, we investigated the effect of a single intraperitoneal injection of clozapine on the AMPK-ACC-CPT1 pathway in the rat frontal cortex, which has been implicated as a target site for this antipsychotic drug. At 2 h after injection, the clinically relevant dose of clozapine had activated AMPK, with increased phosphorylation of AMPKα at Thr(172), and had inactivated ACC, with increased phosphorylation of ACC at Ser(79). In addition, clozapine activated the brain-specific isoform of CPT1, CPT1c, whose activity is inhibited by unphosphorylated ACC, in the rat frontal cortex. Immunohistochemistry and immunofluorescence analysis showed that clozapine induced an increase in number of p-AMPKα (Thr(172))- and p-ACC (Ser(79))-positive cells among the neurons of the rat frontal cortex. Taken together, these results show that clozapine activated the AMPK-ACC-CPT1 pathway in the neurons of the rat frontal cortex. These findings indicate that the antipsychotic agent clozapine affects the lipid regulatory system of neurons in the brain.

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Section: Introductionmentioning

confidence: 95%

The effect of clozapine on the AMPK-ACC-CPT1 pathway in the rat frontal cortex

Kim

et al. 2011

Int. J. Neuropsychopharm.

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“…Around 20-30% of patients with schizophrenia prove to be treatment-resistant, and clozapine has been demonstrated to be the drug of choice to offer those patients (1). Treatment resistance has been defined as failure to respond to two or more antipsychotics (one of which should be an atypical) when given at an adequate dose for at least 6-8 weeks (2,3).…”

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confidence: 99%

Clozapine treatment and discontinuation in Iceland: A national longitudinal study using electronic patient records

Ingimarsson

MacCabe

Jónsdóttir

et al. 2016

Nordic Journal of Psychiatry

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Background: Clozapine is the only drug approved for treatment-resistant schizophrenia. There is evidence that clozapine is underutilized. Aims: To evaluate the initiation and discontinuation of clozapine at Landspitali University Hospital in Iceland and the prevalence of antipsychotic polypharmacy in clozapine-treated patients. Methods: The study is a part of an ongoing longitudinal study of schizophrenia in Iceland. We identified 201 patients on clozapine or who have been on clozapine by using a keyword search in the electronic health records and by reviewing their medical records. Results: Mean age at first treatment with clozapine was 37.8 years. Mean follow-up period on clozapine was 11 years. After 20 years of treatment 71.2% of patients were still on clozapine. After one year of treatment 84.4% of patients were still receiving clozapine treatment. We estimate that 11.4% of patients with schizophrenia in Iceland are taking clozapine and that 16% have been treated with clozapine at some point. Polypharmacy is common, since nearly 2/3, 65.6%, of patients taking clozapine use at least one other antipsychotic and 16.9% are also receiving depot injections. Conclusions: We need to increase the awareness of psychiatrists in Iceland with regard to treatment with clozapine, since only about half of the estimated population of patients with treatment-resistant schizophrenia in Iceland have ever been treated with clozapine. Nearly two thirds of patients who are prescribed clozapine in Iceland remain on it long-term.

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“…Reports indicate that clozapine has antisuicidal effects in patients with schizophrenia or schizoaffective disorder [126] and the treatment reduces suicide risk, attempted suicide and rehospitalisation [127]. However, another study demonstrated no influence of clozapine on suicidal behaviour in treatmentresistant schizophrenia [128]. Further, several case studies have shown that clozapine causes suicidal ideation in patients with treatment-resistant/responsive schizophrenia [129][130][131] or after discontinuation [132].…”

Section: Pharmacological Management Of Suicidal Ideationmentioning

confidence: 98%