Dear Sir,

In a recent Cochrane Systematic Review,Reference Wang, Xia, Helfer, Li and Leucht ¹ valproate had only a flimsy evidence-base in the pharmacotherapy of schizophrenia driven largely by open trials. It addressed chiefly aggressive and affective domains as “add-on” to ongoing antipsychotic treatment.Reference Strassnig, Nascimento and Deckler ² This might be through downstreaming of signal transduction. Moreover, it makes better sense when combined with clozapine especially to safeguard against the latter’s epileptogenicity at higher doses, typically above 600 mg/d, by virtue of inhibiting repetitive firing and voltage-gated Na/K-channel blockade.Reference Davis, Ryan and Adinoff ³ Valproate-clozapine pharmacokinetic interactions should be borne in mind where previous studies have showed no effect, mild inhibition, or induction of clozapine metabolism.Reference Diaz, Eap and Ansermot ⁴ Moreover, dynamic interactions including myelosuppression, oversedation and confusion, and metabolic derangement have been reported in literature.Reference Roerig ⁵

Nonetheless, mechanistically, valproate is GABA potentiator. GABA deficiency is well established in the neurobiology of schizophrenia. So, correcting this deficit might enhance dopaminergic blockade in the mesolimbic pathway, and attenuate serotonergic input in mesocortical pathway.Reference Naguy ⁶ Moreover, as an allosteric enhancer of GABA_A inhibition, valproate might rectify a fundamental neurobiological underpinning in catatonic syndrome. Kruger and BraunigReference Kruger and Braunig ⁷ have reported on a successful intravenous valproate treatment of severe catatonia. Furthermore, valproate possesses dopaminergic blockade activity, and ergo, the use in Sydenham’s choreaReference Cardoso ⁸ and the reported extrapyramidal syndromes.Reference Sasso, Delsoldato, Negrotti and Mancia ⁹ More interestingly, valproate is histone deacetylase inhibitor. The increased acetylated histone content has been demonstrated to prevent methionine-induced releen promoter hypermethylation and normalize schizophrenia-like behaviors in mice.Reference Tremolizzo, Doueiri and Dong ¹⁰ All these pharmacodynamic actions (Table 1) would converge to translate clinically into putative antipsychotic properties of valproate.

Table 1. Mechanisms of Action of Valproate.

Valproate, in addition, has been shown to be neuro-protective. It also induces the anti-apoptotic Bcl-2. It has anti-glutamate actions, and hence protects against glutamate excitotoxicity,Reference Vajda ¹¹ typically seen with neuro-progression in treatment-resistant schizophrenia.Reference Naguy and Alamiri ¹²

Quo Vadis? Valproate use in schizophrenia, despite the evidence, is multi-folded transcending anti-aggressivity and thymoleptic actions to bona fide antipsychotic actions and ultimately neuroprotective actions. It is rather an art than science!