Considerations of HLA, Renal Failure, Valproic Acid Use, and Current Treatment Guidelines in Clozapine-Induced Agranulocytosis.

Clozapine, the choice atypical antipsychotic for refractory schizophrenia, schizoaffective disorder, and bipolar disorder, has been shown to reduce positive and negative symptoms of schizophrenia. Clozapine, though beneficial in reducing the need for hospitalization, rehabilitation, and health care costs, is known as a drug of last resort due to its potential adverse event of clozapine-induced agranulocytosis, which holds a case fatality rate between 4.2 and 16%. Herein, we describe a female patient with longstanding schizoaffective disorder and chronic kidney disease who suffered from clozapine-induced agranulocytosis after failing two other atypical antipsychotics. Retrospective considerations of this case and management highlight risk factors such as HLA status, renal failure, and concurrent valproic acid use which presently do not have official screening, guidelines, or restrictions in place when prescribing clozapine. Additionally, there are no specific clozapine-induced agranulocytosis management recommendations such as G-CSF/filgrastim dose, timing of bone marrow aspirate and biopsy, and use of concomitant valproate. We propose that further comprehensive official screening, monitoring, and guidelines in the prescribing of clozapine, and further guidelines in the treatment of clozapine induced agranulocytosis, could increase the cost-effectiveness of clozapine treatment, and decrease the incidence, and morbidity of this feared adverse event.

ArgBP2gamma interacts with Akt and p21-activated kinase-1 and promotes cell survival.

Akt/protein kinase B is a major cell survival pathway through phosphorylation of proapoptotic proteins Bad and Bax and of additional apoptotic pathways linked to Forkhead proteins glycogen synthase kinase-3beta and ASK1. To further explore the mechanism by which Akt regulates cell survival, we identified an Akt interaction protein by yeast two-hybrid screening. It is highly homologous to ARG-binding protein 2 (ArgBP2) with splicing exon 8 of the coding region of the ArgBP2. As two splicing isoforms (ArgBP2alpha and -beta) of ArgBP2 have been identified (Wang, B., Golemis, E. A., and Kruh, G. D. (1997) J. Biol. Chem. 272, 17542-17550), it was named ArgBP2gamma. ArgBP2gamma contains four Akt phosphorylation consensus sites, a SoHo motif, and three Src homology (SH) 3 domains and binds to C-terminal proline-rich motifs of Akt through its first and second SH3 domains. It also interacts with p21-activated protein kinase (PAK1) via its first and third SH3 domains, indicating the SH3 domains of ArgBP2gamma as docking sites for Akt and PAK1. Akt phosphorylates ArgBP2gamma in vitro and in vivo. Expression of ArgBP2gamma induces PAK1 activity and overrides apoptosis induced by ectopic expression of Bad or DNA damage. Nonphosphorylatable ArgBP2gamma-4A and SH3 domain-truncated mutant ArgBP2gamma inhibit Akt-induced PAK1 activation and reduce Akt and PAK1 phosphorylation of Bad and antiapoptotic function. These data indicate that ArgBP2gamma is a physiological substrate of Akt, functions as an adaptor for Akt and PAK1, and plays a role in Akt/PAK1 cell survival pathway.