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.

Keywords: adverse drug reaction; clozapine; connexin; protein kinase B; schizophrenia.

Figure 1

Effects of clozapine (CLZ), aripiprazole (APZ), and memantine (MEM) on glutamatergic transmission in the thalamocortical pathway from the mediodorsal thalamic nucleus (MDTN) to the frontal cortex. Glutamatergic neurons in the MDTN receive GABAergic inhibition from the reticular thalamic nucleus (RTN). Glutamatergic neurons in the MDTN also receive inhibitory and excitatory tripartite synaptic transmission via group II metabotropic glutamate receptors (II-mGluR) and glutamate/α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPAR), respectively. Astrocytes release L-glutamate through the transporter (system Xc-), hemichannel, and exocytosis mechanisms. Astrocytes also release D-serine via an activated astroglial exocytosis mechanism. The combination of astroglial-released L-glutamate and D-serine enhances the glutamate/N-methyl-D-aspartate receptor (NMDAR). L-glutamate output through system Xc- activates II-mGluR and III-mGluR in the thalamus and frontal cortex. The output of L-glutamate through the hemichannel activates AMPAR in the thalamus.

Figure 2

The life cycle of connexin43 (Cx43). Cx43 synthesis is regulated by several transcriptional factors (Sp1, activator protein 1 complex, cyclic AMP, and the Wnt pathway) and epigenetic processes (histone modifications, DNA methylation, and microRNA species). Synthesized six Cx43 fold oligomerise to form a connexon in the endoplasmic reticulum (ER) and trans-Golgi network. Trafficked connexons to the plasma membrane become hemichannels as functional connexons, and dock with connexons on neighbouring cells to form gap-junctions. The trafficking process of connexons is regulated by various signalling systems, including phosphorylation, acetylation, nitrosylation, sumoylation, and ubiquitination. CLZ likely activates connexon trafficking via enhanced ubiquitylation via the phosphorylation of protein kinase B (pPKB). Both hemichannels and gap-junctions are low open probabilities during the resting stage; however, the elevation of extracellular potassium ions, the removal of extracellular calcium ions, or the depolarization activation of the hemichannel/gap-junction leading to the persistent opening of Cx43 containing channels. The internalisation of the gap-junction generates the connexosome (also known as an annular gap-junction). The connexosome is degraded by autophagy via the formation of an autophagosome or endocytic pathway. The Cx43 turn-over is very fast in the brain, and the half-life is several hours.

Figure 3

The proposed hypothesis of the pathomechanisms of clinical efficacy and severe adverse reactions of CLZ. Electroencephalogram (EEG).