**1. Introduction**

Epstein–Barr virus (EBV) is a member of the *Herpesviridae* family and causes infectious mononucleosis. EBV was the first virus discovered to cause cancer in humans. EBV is associated with Burkitt lymphoma, Hodgkin lymphoma, gastric carcinoma, nasopharyngeal carcinoma, and post-transplant lymphoproliferative disorder. After infection with EBV, the virus maintains a lifelong latent infection within the host. The expression of a few viral genes during the latent phase allows the virus to persist. The viral life cycle alternates between two phases: the latent and the lytic phases. During the lytic phase the virus replicates and spreads among cells and hosts.

The lytic phase of the virus can be triggered in latently infected cultured cells by various inducing agents [1]. Sodium butyrate (NaB), a short-chain fatty acid that inhibits histone deacetylases, promotes the reactivation of the lytic cycle (Figure 1) [2]. Although quite different in chemical structure from butyrate, the DNA methyltransferase inhibitors 5-azacytidine and 5-aza-2'-deoxycytidine (dAzaC), and the protein kinase C agonist 12-*O*-tetradecanoylphorbol-13-acetate (TPA) also induce the EBV lytic cycle [3]. Molecules with diverse structures inhibit reactivation of the EBV lytic cycle by these inducing agents. Some inhibitors are structurally similar to butyrate. Valproate (valproic acid, VPA) and valpromide (VPM) prevent the virus from reactivating into the lytic cycle in Burkitt lymphoma cells [4,5]. VPA and VPM are used clinically as anticonvulsant and mood-stabilizing drugs.

**Figure 1.** Structures of drugs tested for effects on Epstein-Barr virus (EBV) lytic reactivation: sodium butyrate (NaB), 5-aza-2'-deoxycytidine (dAzaC), 12-*O*-tetradecanoylphorbol-13-acetate (TPA), clozapine, clozapine-N-oxide, and N-desmethylclozapine.

To determine if there is any commonality between the effects of VPA in neurological and psychological conditions and in blocking EBV reactivation, we investigated other drugs used to treat neurological conditions for effects on the EBV lytic cycle. Clozapine, a member of the dibenzodiazepine class, is used in the treatment of schizophrenia and bipolar disorder (Figure 1). Clozapine (ClozarilTM) was the first atypical, or second-generation, antipsychotic drug developed [6]. It is therapeutically effective at treating schizophrenic patients who are resistant to typical antipsychotic drugs [7]. We demonstrate here that clozapine and one of its metabolites inhibit the induction of EBV lytic cycle gene expression.
