Spatiotemporal Mapping Techniques Show Clozapine Impairs Neurogenic and Myogenic Patterns of Activity in the Colon of the Rabbit in a Dose-Dependent Manner

Abstract

Background: Clozapine, an antipsychotic used in treatment-resistant schizophrenia, has adverse gastrointestinal effects with significant associated morbidity and mortality. However, its effects on defined patterns of colonic contractile activity have not been assessed.Method: We used novel radial and longitudinal spatiotemporal mapping techniques, combined with and monitoring of ambient lumen pressure, in ex vivo preparations of triply and of singly haustrated portions of rabbit colon. We identified the contractile patterns of mass peristalses, fast phasic, and ripple contractions and directly qualified the effects of clozapine, at concentrations of 10 μmol/L, 20 μmol/L, and 30 μmol/L, and of norclozapine, the main metabolite of clozapine, on contractile patterns. The effects of carbachol, serotonin and naloxone on clozapine-exposed preparations were also determined. Tetradotoxin was used to distinguish neurogenic from myogenic contractions.Results: At 10 μmol/L, clozapine temporarily abolished the longitudinal contractile components of mass peristalsis, which on return were significantly reduced in number and amplitude, as was maximal mass peristaltic pressure. These effects were reversed by carbachol (1 μmol/L) and to some extent by serotonin (15 μmol/L). At 10 μmol/L, myogenic ripple contractions were not affected. At 20 μmol/L, clozapine had a similar but more marked effect on mass peristalses with both longitudinal and radial components and corresponding maximal pressure greatly reduced. At 30 μmol/L, clozapine suppressed the radial and longitudinal components of mass peristalses for over 30 min, as well as ripple contractions. Similar dose-related effects were observed on addition of clozapine to the mid colon. At 20 μmol/L, norclozapine had opposite effects to those of clozapine, causing an increase in the frequency of mass peristalsis with slight increases in basal tone. These slightly augmented contractions were abolished on addition of clozapine. Concentrations of norclozapine below 20 μmol/L had no discernible effects.Conclusion: Clozapine, but not norclozapine, has potent effects on the motility of the rabbit colon, inhibiting neurogenic contractions at lower concentrations and myogenic contractions at higher concentrations. This is the likely mechanism for the serious and life-threatening gastrointestinal complications seen in human clozapine-users. These effects appear to be mediated by cholinergic and serotonergic mechanisms. Spatiotemporal mapping is useful in directly assessing the effects of pharmaceuticals on particular patterns of gastrointestinal motility.

Safety of antipsychotics for the treatment of schizophrenia: a focus on the adverse effects of clozapine

“…103 It has been demonstrated that clozapine, but not norclozapine, has potent effects on the motility of the colon of a rabbit, thus inhibiting neurogenic contractions at lower concentrations and myogenic contractions at higher concentrations. 104 These effects may be mediated by cholinergic and serotonergic receptors, presumably via M1–M3 and 5HT-3 and 5HT-7 receptors. Moreover, de Alvarenga and colleagues 105 showed that clozapine significantly reduced the frequency of cycles of contractions of zebrafish larvae gastrointestinal tracts through anticholinergic action.…”

Clozapine-Induced Gastrointestinal Hypomotility: A 22-Year Bi-National Pharmacovigilance Study of Serious or Fatal ‘Slow Gut’ Reactions, and Comparison with International Drug Safety Advice

“…CIGH is defined as an acquired state of delayed transit through the gastrointestinal tract (i.e. transit time >2 standard deviations [SD] above the mean), colloquially known as clozapine-related ‘slow gut’, resulting from the drug’s pharmacological actions on the enteric nervous system [ 7 ]. In vitro, clozapine is shown to have potent effects on the mammalian colon, inhibiting neurogenic and, at higher concentrations, myogenic contractions, profoundly disrupting gastrointestinal motility [ 7 ].…”

“…transit time >2 standard deviations [SD] above the mean), colloquially known as clozapine-related ‘slow gut’, resulting from the drug’s pharmacological actions on the enteric nervous system [ 7 ]. In vitro, clozapine is shown to have potent effects on the mammalian colon, inhibiting neurogenic and, at higher concentrations, myogenic contractions, profoundly disrupting gastrointestinal motility [ 7 ]. These effects can be reversed by carbachol and to some extent by serotonin, suggesting both anticholinergic and anti-serotonergic mechanisms [ 7 ].…”

“…In vitro, clozapine is shown to have potent effects on the mammalian colon, inhibiting neurogenic and, at higher concentrations, myogenic contractions, profoundly disrupting gastrointestinal motility [ 7 ]. These effects can be reversed by carbachol and to some extent by serotonin, suggesting both anticholinergic and anti-serotonergic mechanisms [ 7 ].…”

Profile of Clozapine Therapy: a Cross Sectional Piloting in a Tertiary Care Setting of Bangladesh

“…The common adverse effects of clozapine are sedation, hypersalivation, constipation, hypotension, hypertension, tachycardia, weight gain, fever, seizure, nocturnal enuresis, neutropenia/agranulocytosis, gastroesophageal reflux disease (GERD) [6][7][8][9][10][11][12]. The uncommon or unusual adverse effects are agranulocytosis/neutropenia, colitis, delirium, eosinophilia, heat stroke, hepatic failure, interstitial nephritis, ocular pigmentation, pancreatitis, parotid gland swelling, pericardial effusion, pneumonia, reflux esophagitis, stuttering, vasculitis and thrombocytopenia [6,[13][14][15][16][17]. Serious haematological and cardiovascular adverse effects are agranulocytosis, thromboembolism, cardiomyopathy and myocarditis [6,[18][19][20][21][22].…”