A Focused Review of the Metabolic Side-Effects of Clozapine

Abstract

The second generation antipsychotic drug clozapine represents the most effective pharmacotherapy for treatment-resistant psychosis. It is also associated with low rates of extrapyramidal symptoms and hyperprolactinemia compared to other antipsychotic drugs. However, clozapine tends to be underutilized in clinical practice due to a number of disabling and serious side-effects. These are characterized by a constellation of metabolic side-effects which include dysregulation of glucose, insulin, plasma lipids and body fat. Many patients treated with clozapine go on to develop metabolic syndrome at a higher rate than the general population, which predisposes them for Type 2 diabetes mellitus and cardiovascular disease. Treatments for the metabolic side-effects of clozapine vary in their efficacy. There is also a lack of knowledge about the underlying physiology of how clozapine exerts its metabolic effects in humans. In the current review, we focus on key studies which describe how clozapine affects each of the main symptoms of the metabolic syndrome, and cover some of the treatment options. The clinical data are then discussed in the context of preclinical studies that have been conducted to identify the key biological substrates involved, in order to provide a better integrated overview. Suggestions are provided about key areas for future research to better understand how clozapine causes metabolic dysregulation.

Clozapine resistant schizophrenia: Newer avenues of management

“…Many of the side effects encountered with clozapine are dose-dependent including sedation, tachycardia, hypersalivation, enuresis, constipation, delirium, obsessive-compulsive symptoms, seizures, and orthostatic hypotension[ 81 , 120 , 138 ] Among all antipsychotics, the prevalence of metabolic dysfunction or metabolic syndrome is the highest for clozapine and olanzapine[ 81 , 126 , 127 , 132 , 139 ]. Whether metabolic side effects are also dose-dependent is not clear[ 81 , 138 ].…”

“…However, systematic reviews and meta-analyses have indicated a dose-outcome association between clozapine and metabolic side effects, particularly with lipid levels and weight gain[ 140 , 141 ]. Risk factors for metabolic syndrome include higher baseline weight or body mass index, gender, non-White, possibly Asian ethnicity, and several genetic and peptide markers[ 126 , 127 , 136 , 139 , 142 ]. Somewhat paradoxically, metabolic disturbances are also associated with a reduction in symptoms[ 126 , 127 ].…”

Clozapine Worsens Glucose Intolerance, Nonalcoholic Fatty Liver Disease, Kidney Damage, and Retinal Injury and Increases Renal Reactive Oxygen Species Production and Chromium Loss in Obese Mice

“…One study discovered a genetic overlap between the pathogenesis of schizophrenia and the mechanism of clozapine as an antipsychotic, indicating that if the mechanism of clozapine could be understood, valid therapeutic targets could be identified, and perhaps, schizophrenia's complex pathophysiology could be elucidated [3]. Researchers, however, reported associations between clozapine and adverse metabolic events-such as elevated cholesterol, blood glucose concentration, triglyceride levels, and body weight-and these events negatively influence medication compliance and health [4,5].…”

Antipsychotic Drug-Induced Increases in Peripheral Catecholamines are Associated With Glucose Intolerance

“…These findings therefore provide additional evidence that peripheral catecholamines may play a key role in the acute metabolic effects of antipsychotic drugs. The metabolic side-effects of antipsychotic drugs in clinical populations are now well established ( Allison et al, 1999 ; McEvoy et al, 2005 ; Newcomer, 2007 ; Kessing et al, 2010 ; Mitchell et al, 2013 ; Kim et al, 2017 ; Tumiel et al, 2019 ; Yuen et al, 2021a ), and animal studies have faithfully modelled these many of these effects, using comparable techniques that are commonly used in humans, including the GTT ( Monzillo and Hamdy, 2003 ). We and many other research groups ( Smith et al, 2008 ; Muller et al, 2010 ; Boyda et al, 2013a ; Boyda et al, 2014 ; Evers et al, 2017 ; Lord et al, 2017 ; Stefanidis et al, 2017 ; Oxenkrug and Summergrad, 2020 ; Sylvester et al, 2020 ; Shamshoum et al, 2021 ) routinely observe that antipsychotics generate acute glucose intolerance of an equivalent magnitude to that noted in human studies ( Albaugh et al, 2011 ) without a change in factors such as food intake or obesity, indicating a direct effect of the drugs on glucose dysregulation.…”