Abstract
The second-generation antipsychotic drugs are widely used in the field of psychiatry, for an expanding number of different conditions. While their clinical efficacy remains indispensable, many of the drugs can cause severe metabolic side-effects, resulting in an increased risk of developing cardiometabolic disorders. The physiological basis of these side-effects remains an ongoing area of investigation. In the present study, we examined the potential role of peripheral catecholamines in antipsychotic-induced glucose intolerance. Adult female rats were acutely treated with either the first-generation antipsychotic drug haloperidol (0.1, 0.5 or 1 mg/kg) or the second-generation drugs risperidone (0.25, 1.0 or 2.5 mg/kg), olanzapine (1.5, 7.5 or 15 mg/kg) or clozapine (2, 10 or 20 mg/kg) or vehicle. Fasting glucose levels were measured and then animals were subjected to the intraperitoneal glucose tolerance test. Levels of peripheral norepinephrine, epinephrine and dopamine were concurrently measured in the same animals 75, 105 and 135 min after drug treatment. All antipsychotics caused glucose intolerance, with strongest effects by clozapine > olanzapine > risperidone > haloperidol. Plasma catecholamines were also increased by drug treatment, with greatest effects for norepinephrine and epinephrine caused by clozapine > risperidone > olanzapine > haloperidol. Importantly, there were strong and statistically significant associations between norepinephrine/epinephrine levels and glucose intolerance for all drugs. These findings confirm that increases in peripheral catecholamines co-occur in animals that exhibit antipsychotic-induced glucose intolerance, and these effects are strongly associated with each other, providing further evidence for elevated catecholamines as a substrate for antipsychotic metabolic side-effects.
Highlights
The antipsychotic drugs remain the most effective form of pharmacotherapy for schizophrenia spectrum disorders
These metabolic side-effects result in increased risk for developing cardiometabolic disorders with chronic use (Newcomer, 2007; Kessing et al, 2010; Deng, 2013; Tse et al, 2014; Bozymski et al, 2018; Kim et al, 2018; Yuen et al, 2018; Tumiel et al, 2019), which is a particular concern as many idiopathic psychotic disorders require lifelong treatment with these medications (Lindenmayer and Khan, 2004)
Preclinical rodent models are especially helpful in advancing our understanding of the biochemical pathways involved, as they provide the opportunity for invasive experimental procedures, direct experimental control, and are not prone to the multifactorial causes of metabolic dysregulation observed in antipsychotictreated patients, which include diet, exercise and nonprescribed substance use (Laursen et al, 2012; Marteene et al, 2019)
Summary
The antipsychotic drugs remain the most effective form of pharmacotherapy for schizophrenia spectrum disorders. A wide number of non-dopaminergic receptors and other physiological substrates are posited to play key roles in the metabolic side-effects of the second-generation antipsychotics, including both central and peripheral mechanisms (De Hert et al, 2011; Reynolds and McGowan, 2017; Bush et al, 2018; Kowalchuk et al, 2019; Marteene et al, 2019) In this regard, preclinical rodent models are especially helpful in advancing our understanding of the biochemical pathways involved, as they provide the opportunity for invasive experimental procedures, direct experimental control, and are not prone to the multifactorial causes of metabolic dysregulation observed in antipsychotictreated patients, which include diet, exercise and nonprescribed substance use (Laursen et al, 2012; Marteene et al, 2019)
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