A Working Hypothesis Regarding Identical Pathomechanisms between Clinical Efficacy and Adverse Reaction of Clozapine via the Activation of Connexin43

Abstract

Clozapine (CLZ) is an approved antipsychotic agent for the medication of treatment-resistant schizophrenia but is also well known as one of the most toxic antipsychotics. Recently, the World Health Organization’s (WHO) global database (VigiBase) reported the relative lethality of severe adverse reactions of CLZ. Agranulocytosis is the most famous adverse CLZ reaction but is of lesser lethality compared with the other adverse drug reactions of CLZ. Unexpectedly, VigiBase indicated that the prevalence and relative lethality of pneumonia, cardiotoxicity, and seizures associated with CLZ were more serious than that of agranulocytosis. Therefore, haematological monitoring in CLZ patients monitoring system provided success in the prevention of lethal adverse events from CLZ-induced agranulocytosis. Hereafter, psychiatrists must amend the CLZ patients monitoring system to protect patients with treatment-resistant schizophrenia from severe adverse CLZ reactions, such as pneumonia, cardiotoxicity, and seizures, according to the clinical evidence and pathophysiology. In this review, we discuss the mechanisms of clinical efficacy and the adverse reactions of CLZ based on the accumulating pharmacodynamic findings of CLZ, including tripartite synaptic transmission, and we propose suggestions for amending the monitoring and medication of adverse CLZ reactions associated with pneumonia, cardiotoxicity, and seizures.

Astroglial Connexin43 as a Potential Target for a Mood Stabiliser

“…Recent neuropharmacological and psychopharmacological studies emphasised the importance of the modulation of tripartite synaptic transmission for the treatment of various neuropsychiatric disorders [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 ]. Tripartite synaptic transmission has traditionally referred to glutamatergic transmission between neurones and astrocytes, whereas, recently, the conception of tripartite synaptic transmission has been extended to other transmission systems, such as monoaminergic tripartite synaptic transmissions [ 14 ].…”

“…Neuron‒glial crosstalk consists not only of extracellular tripartite synaptic transmission, but also of intracellular pan-neuroglial networks via the gap junction [ 1 , 36 , 37 , 38 ]. Both hemichannel and gap junction provide the numerous astroglial functions, including both physiological and pathological conditions [ 1 ]. The hemichannel and gap junction are constructed by connexin, which is a family of 21 protein isoforms [ 1 , 39 , 40 ].…”

“…Both hemichannel and gap junction provide the numerous astroglial functions, including both physiological and pathological conditions [ 1 ]. The hemichannel and gap junction are constructed by connexin, which is a family of 21 protein isoforms [ 1 , 39 , 40 ]. Six connexin units assemble to form homomeric or heteromeric connexons [ 1 ].…”

“…The hemichannel and gap junction are constructed by connexin, which is a family of 21 protein isoforms [ 1 , 39 , 40 ]. Six connexin units assemble to form homomeric or heteromeric connexons [ 1 ]. Two connexons in two neighbouring cells form a gap junction with an aqueous pore and charged surface walls [ 1 ], whereas a single connexon contributes to a chemical connection between the intra- and extra-cellular spaces as a hemichannel [ 1 ].…”

“…Six connexin units assemble to form homomeric or heteromeric connexons [ 1 ]. Two connexons in two neighbouring cells form a gap junction with an aqueous pore and charged surface walls [ 1 ], whereas a single connexon contributes to a chemical connection between the intra- and extra-cellular spaces as a hemichannel [ 1 ]. The transmembrane pores of the connexon are permeable to ions, metabolites, second messengers, mRNA, and purine signalling mediators up to 1.5 kDa [ 41 ].…”