The core dysfunction of schizophrenia is due to an increase in presynaptic synthesis and release of striatal dopamine (DA). However, most currently available treatments for psychosis block postsynaptic dopamine 2 (D2) receptors and do not alter DA synthesis capacity. Moreover, D2 antagonism may induce supersensitivity of D2 postsynaptic receptors that leads to tardive dyskinesia (TD). Vesicular monoamine transporter 2 (VMAT2) inhibitors not only treat TD but do so via by inhibiting the very mechanism underlying the core symptoms of schizophrenia – reducing dopamine synthesis.
Specifically, VMAT2 inhibitors deplete vesicular storage of DA (as well as serotonin, norepinephrine, and histamine) in presynaptic nerve terminals. Due to their mechanism of action, a recent meta-analysis investigated whether VMAT2 inhibitors (tetrabenazine, deutetrabenazine, and valbenazine) improved symptoms of schizophrenia and psychosis (Figure 1). Five studies (N=173) of tetrabenazine versus placebo or active comparator (chlorpromazine or reserpine) were included in the meta-analysis. Tetrabenazine was more effective than placebo for the outcome ‘slight improvement’ (risk ratio [RR] = 1.77, 95% confidence interval [CI] = 1.03, 3.04), but not for the outcome ‘moderate improvement’ (RR = 5.00, 95% CI = 0.27, 93.55). Tetrabenazine was as effective as active comparators on the outcome ‘slight improvement’ (RR = 1.05, 95% CI = 0.60, 1.81). Due to study heterogeneity, the quality of evidence was low. Indeed, most of the included studies were from the 1960s and failed to meet today’s methodological standards.
More recent studies investigating deutetrabenazine and valbenazine were not designed to test their efficacy for schizophrenia per se (rather they have been investigated for TD) and were not included in the meta-analysis. Because of these limitations, the authors conclude that VMAT2 inhibition should be properly studied as a potential target for antipsychotic efficacy.
Reference:
Connolly A et al. Psychopharmacology (Berl) 2024;241(2):225-41. Abstract
