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\begin{document}

\title{Establishing therapeutic plasma clozapine concentrations in older people}



\author[1]{Lauren Evans}%
\author[1]{Jonathan Rogers}%
\author[2]{Graham Blackman}%
\author[3]{Amelia Jewell}%
\author[3]{Pampa Chakravarti}%
\author[4]{Suzanne Reeves}%
\affil[1]{University College London Faculty of Brain Sciences}%
\affil[2]{University of Oxford}%
\affil[3]{South London and Maudsley NHS Foundation Trust}%
\affil[4]{University College London}%


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  \date{May 23, 2024}


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\begin{abstract}
Aims: There is no specific guidance on optimal clozapine plasma
concentrations in older people. This study aimed to test the hypothesis
that therapeutic plasma clozapine concentrations would be lower in
patients with an onset of psychosis after 60 years, compared to those
with an earlier onset of schizophrenia (EOS) and to investigate the
relationship between pharmacokinetic indices and side effects. Methods:
Data were extracted from anonymised healthcare records for clozapine
treated patients aged over 55 years. Median plasma clozapine and
norclozapine concentrations (Cclozapine, Cnorclozapine) were compared
across diagnostic groups. Mixed-effects models were used to investigate
the relationship between pharmacokinetic biomarkers and side effects.
Results: Of the 481 patients (4519 samples, median 6 per person), 430
(89.4\%) were diagnosed with EOS. Cclozapine and Cnorclozapine in those
with Parkinson's disease psychosis (0.17mgL-1, 0.08mgL-1) were lower
than those with EOS (0.41mgL-1, 0.19mgL-1), dementia-related psychosis
(0.40mgL-1, 0.24mgL-1) and very late-onset schizophrenia-like psychosis
(0.42mgL-1, 0.17mgL-1). Cclozapine was associated with higher corrected
QT interval (QTc), whilst Cclozapine and Cnorclozapine were associated
with higher neutrophil counts and body mass index, but not with clinical
thresholds for neutropenia, obesity, QTc prolongation, or with sedation.
Conclusions: Our findings suggest that, compared to EOS, therapeutic
plasma clozapine concentrations are lower in Parkinson's disease
psychosis but not in other forms of later onset psychosis.
Interpretation was limited by the relatively young age of the sample and
the small number of samples associated with side effects. Prospective
studies are needed to further explore optimal dosing specifically in
older people.%
\end{abstract}%



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\verb`Clozapine Elderly Manuscript for Submission.docx`  available at \url{https://authorea.com/users/660845/articles/664177-establishing-therapeutic-plasma-clozapine-concentrations-in-older-people}

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