Prevalence of treatment resistance and clozapine use in early intervention services

Stokes, Imogen; Griffiths, Siân Lowri; Jones, Rowena; Everard, Linda; Jones, Peter; Fowler, David; Hodgekins, Joanne; Amos, Tim; Freemantle, Nick; Sharma, Vimal; Marshall, Max; Singh, Swaran P.; Birchwood, Max; Upthegrove, Rachel

doi:10.1192/bjo.2020.89

Cited by 32 publications

(46 citation statements)

References 44 publications

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“…Up to a third of individuals with schizophrenia show resistance to antipsychotic treatment (Elkis & Buckley, 2016; Lally, Gaughran, Timms, & Curran, 2016b; Mørup, Kymes, & Oudin Åström, 2020; Stokes et al, 2020), i.e. they do not respond adequately to two or more trials of antipsychotic medication, each lasting 4–6 weeks, at doses in at least the mid-point of the licensed therapeutic range (NICE guidelines; National Institute for Health and Care Excellence, 2014).…”

Section: Introductionmentioning

confidence: 99%

Neuropsychological differences between treatment-resistant and treatment-responsive schizophrenia: a meta-analysis

et al. 2021

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Antipsychotic treatment resistance affects up to a third of individuals with schizophrenia. Of those affected, 70–84% are reported to be treatment resistant from the outset. This raises the possibility that the neurobiological mechanisms of treatment resistance emerge before the onset of psychosis and have a neurodevelopmental origin. Neuropsychological investigations can offer important insights into the nature, origin and pathophysiology of treatment-resistant schizophrenia (TRS), but methodological limitations in a still emergent field of research have obscured the neuropsychological discriminability of TRS. We report on the first systematic review and meta-analysis to investigate neuropsychological differences between TRS patients and treatment-responsive controls across 17 published studies (1864 participants). Five meta-analyses were performed in relation to (1) executive function, (2) general cognitive function, (3) attention, working memory and processing speed, (4) verbal memory and learning, and (5) visual−spatial memory and learning. Small-to-moderate effect sizes emerged for all domains. Similarly to previous comparisons between unselected, drug-naïve and first-episode schizophrenia samples v. healthy controls in the literature, the largest effect size was observed in verbal memory and learning [dl = −0.53; 95% confidence interval (CI) −0.29 to −0.76; z = 4.42; p < 0.001]. A sub-analysis of language-related functions, extracted from across the primary domains, yielded a comparable effect size (dl = −0.53, 95% CI −0.82 to −0.23; z = 3.45; p < 0.001). Manipulating our sampling strategy to include or exclude samples selected for clozapine response did not affect the pattern of findings. Our findings are discussed in relation to possible aetiological contributions to TRS.

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Section: Introductionmentioning

confidence: 99%

Neuropsychological differences between treatment-resistant and treatment-responsive schizophrenia: a meta-analysis

et al. 2021

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“…Nevertheless, clozapine prescribing appears suboptimal, with at least a third of eligible patients at any given time not prescribed clozapine. Stokes et al (2020), 22 using data from the UK National Evaluation of the Development and Impact of Early Intervention Services study, showed slightly lower clozapine eligibility across EIP services (7.7%), and lower prescribing rates (2.4%) over a 12-month study period, highlighting the persistent underuse of clozapine and more commonly seen polypharmacy practice in this patient population. Important barriers to clozapine prescribing in an EIP service include tolerability, the need for good adherence, patient willingness and the requirement for regular blood monitoring.…”

Section: Discussionmentioning

confidence: 99%

“…10,11 Clozapine has long been recognised as underutilised, with its use in eligible early psychosis patients ranging from 2.4-16.3%. [19][20][21][22] Clozapine, although superior in efficacy compared with other antipsychotic medicines and effective in treatment-refractory schizophrenia patients, 23,24 also poses a challenge in terms of its potential side-effect profile, with the need for close monitoring and adherence to ensure safe prescribing. 25 Side-effects range from early and mostly benign (such as fever, sedation and tachycardia), to more serious, including haematological (neutropenia), cardiovascular (cardiomyopathy and myocarditis), neurological and metabolic.…”

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confidence: 99%

COVID‐19 and clozapine use in an early intervention for psychosis service

Jafry

Kelbrick

2022

Prog Neurol Psychiatry

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“…In clinical practice, switching to clozapine is highly recommended for the treatment of TRS patients [ 17 , 18 ]. However, the risk of metabolic adverse events, especially diabetes, among TRS patients is of increasing concern [ 19 – 22 ]. To date, few investigations have assessed clozapine-induced MetS in TRS patients.…”

Section: Side Effects Of Antipsychotic Drugsmentioning

confidence: 99%

Mechanistic/mammalian target of rapamycin and side effects of antipsychotics: insights into mechanisms and implications for therapy

Zhuo

Hou

et al. 2022

Transl Psychiatry

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Antipsychotic pharmacotherapy has been widely recommended as the standard of care for the treatment of acute schizophrenia and psychotic symptoms of other psychiatric disorders. However, there are growing concerns regarding antipsychotic-induced side effects, including weight gain, metabolic syndrome (MetS), and extrapyramidal motor disorders, which not only decrease patient compliance, but also predispose to diabetes and cardiovascular diseases. To date, most studies and reviews on the mechanisms of antipsychotic-induced metabolic side effects have focused on central nervous system mediation of appetite and food intake. However, disturbance in glucose and lipid metabolism, and hepatic steatosis induced by antipsychotic drugs might precede weight gain and MetS. Recent studies have demonstrated that the mechanistic/mammalian target of rapamycin (mTOR) pathway plays a critical regulatory role in the pathophysiology of antipsychotic drug-induced disorders of hepatic glucose and lipid metabolism. Furthermore, antipsychotic drugs promote striatal mTOR pathway activation that contributes to extrapyramidal motor side effects. Although recent findings have advanced the understanding of the role of the mTOR pathway in antipsychotic-induced side effects, few reviews have been conducted on this emerging topic. In this review, we synthesize key findings by focusing on the roles of the hepatic and striatal mTOR pathways in the pathogenesis of metabolic and extrapyramidal side effects, respectively. We further discuss the potential therapeutic benefits of normalizing excessive mTOR pathway activation with mTOR specific inhibitors. A deeper understanding of pathogenesis may inform future intervention strategies using the pharmacological or genetic inhibitors of mTOR to prevent and manage antipsychotic-induced side effects.

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Prevalence of treatment resistance and clozapine use in early intervention services

Cited by 32 publications

References 44 publications

Neuropsychological differences between treatment-resistant and treatment-responsive schizophrenia: a meta-analysis

Neuropsychological differences between treatment-resistant and treatment-responsive schizophrenia: a meta-analysis

COVID‐19 and clozapine use in an early intervention for psychosis service

Mechanistic/mammalian target of rapamycin and side effects of antipsychotics: insights into mechanisms and implications for therapy

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