545. Targeting negative and cognitive symptoms in schizophrenia: discussion of novel preclinical and clinical findings with evenamide

Abstract

Abstract Background The recognition of hippocampal pyramidal neuron hyperexcitability as core pathological feature of schizophrenia has led to the idea that the hippocampus might be a promising target for therapeutic intervention (Lodge and Grace, 2011). However, the mechanism of action (MoA) of currently available antipsychotics (AP) is mainly based on dopamine/serotonin modulation occurring downstream from the hippocampus; this may explain why their efficacy is limited only to positive symptoms, while they have failed to provide meaningful improvements of negative symptoms and cognitive deficits. Moreover, apart from clozapine, available AP have not demonstrated efficacy in benefiting patients with treatment-resistant schizophrenia (TRS), characterized by glutamatergic rather than dopaminergic abnormalities (Demjaha et al., 2014). Evenamide is a voltage-gated sodium channel blocker with higher affinity for the inactivated state of the channels, which reduces neuronal hyperexcitability. Recently published findings in the MAM (methylazoxymethanol acetate, a DNA alkylating agent) neurodevelopmental model of schizophrenia showed that evenamide normalizes hippocampal hyperglutamatergic activity and consequently reduces hyperdopaminergic activity in the ventral tegmental area (VTA) (Uliana et al., 2025). Through this unique MoA, evenamide restores impaired recognition memory and improved social interaction in MAM rats. Aims & Objectives To interpret clinical findings from phase 2/3 trials with evenamide in light of the results obtained with MAM model, and to present new analyses on the effect of evenamide on negative symptoms. Method Study 014/015 was a phase 2, 1-year, randomized, open-label, rater-blinded, international study evaluating the long-term efficacy and safety of three doses of evenamide (7.5/15/30 mg bid) as add-on to AP in patients with TRS (Anand et al., 2024). Study 008A was a phase 2/3, 4-week, international, randomized, double-blind, placebo-controlled trial evaluating the efficacy and safety of evenamide 30 mg bid as add-on in patients with inadequately controlled schizophrenia despite stable treatment with an atypical AP (including clozapine) at a therapeutic concentration as measured through screening plasma levels (Anand et al., 2025). Results Evenamide add-on treatment in Study 008A was associated with significant improvement of positive and negative symptoms (based on PANSS subscales) in patients with inadequate response to AP (Anand et al., 2025). Post-hoc analyses showed that evenamide was associated with an increasing improvement in social functioning and life engagement (assessed on PANSS subdomains) which was significantly greater compared to placebo after 4 weeks. Similarly, an increasing improvement up to 1 year was noted in the long-term open-label study in patients with TRS. Moreover, results in circuit demonstrate that evenamide normalizes hyperdopaminergic firing in the VTA with an effect lasting up to 3 hours after administration, despite the short half-life; this suggests that evenamide may induce a circuit-level neuroplasticity and is consistent with long-lasting benefits observed in the 1-year open-label trial in patients with TRS (Anand et al., 2024). Discussion & Conclusions Through the modulation of hippocampal hyperglutamatergic activity, evenamide acts directly at the site of dysfunction and offers broader effects across the various symptom domains, which are durable in time likely due to neuroplasticity. Therefore, evenamide represents an innovative therapeutic approach, which is expected to make an impact on the quality of life of patients with TRS.