Low-dose cariprazine for clozapine-induced constipation and sialorrhea?

Clozapine, a well-known antipsychotic used for treatment-resistant schizophrenia, has been linked to serious life-threatening adverse effects, including chronic gastrointestinal hypomotility which can lead to paralytic ileus and sialorrhea, which, if severe, can cause aspiration pneumonia. This can be very disturbing for patients and cannot only affect the overall day-to-day activities and social interactions, but can increase the medication drop-out causing more harm to the patients in general. From the perspective of clozapine-induced constipation, the mechanism is thought to be a combination of histaminergic, cholinergic and serotoninergic 5HT-3 antagonism. Although the pathophysiology of clozapine-induced sialorrhea remains unclear some key mechanisms have been eluded: muscarinic M4 agonism, alpha-2 adrenergic antagonism, decreased laryngeal peristaltic movements and reduction on swallowing reflex. Cariprazine is a potent D3/D2 partial agonist who demonstrated negligible affinity for alpha-2 and cholinergic muscarinic receptors. We aim to present two of our inpatients who presented with positive symptoms of schizophrenia and with severe sialorrhea and constipation as an adverse effect from long term clozapine use. Both of them had been taken a medium dose of clozapine previous to admission (350 milligrams per day, respectively 300 milligrams/day) at which we decided to add low dose of cariprazine. They benefitted from the unique binding profile of cariprazine not only by reducing the positive symptoms (at 6, respectively 3 milligrams/day) , but by decreasing the rates of hypersalivation and constipation. For monitoring sialorrhea we used The Toronto Nocturnal Hypersalivation Rating Scale at the admission of the patients in the hospital and after two weeks of add-on treatment with cariprazine and for constipation we used the chart file of each patient who monitors daily the frequency of bowel movement. Improvements have been shown within the first days of adding 1,5 milligrams per day of cariprazine with a range in frequency for sialorrhea from severe to minimal in one patient and from severe to absent in another. We also noted that patients reported to have bowel movement every day after we associated low-dose cariprazine. Empirically, it appears that cariprazine as an add-on treatment for schizophrenic patients who had partial response to clozapine have been also efficacious in reducing hypersalivation and gastrointestinal hypomotility. As the mechanism of action of both sialorrhea and chronic constipation is not yet fully eluded, but appears to have in common the action on muscarinic cholinergic receptors, we raise the question of whether the higher affinity of cariprazine for dopaminergic D3 receptors than for the D2 receptors is responsible for the improvements. Further research needs to be done in order to establish the mechanism of action and the minimal dose of cariprazine as an adjuvant treatment only for the adverse effects induced by long-term use of clozapine, as it’s hard to say from our point of view since it was used by us in the first place to improve the positive symptoms.

References

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