Background: Despite their efficacy in improving positive symptoms, first- and second-generation antipsychotics (FGAs and SGAs) fail to provide benefit to a large portion of patients with schizophrenia. Evenamide, uniquely acting at the site of dysfunction, normalizes hippocampal glutamatergic aberrant activity and reduces downstream hyperdopaminergic state, potentially alleviating also negative and cognitive symptoms, and providing benefit to patients with treatment-resistant schizophrenia (TRS) or inadequate response to antipsychotics (APs).
Objectives: Evaluate the clinical benefits of glutamate modulation through evenamide as an add-on treatment to FGAs and SGAs in patients with TRS or inadequate response to APs.
Design: Post-hoc analyses of results from two phase II/III clinical trials with evenamide add-on to antipsychotic treatment.
Methods: Data from Study 014/015, an open-label, 1-year trial in patients with TRS, was analyzed to assess the proportion of patients no longer meeting the baseline severity criteria for TRS (modified Intent-to-Treat (mITT) population; Observed Cases (OC)) and the proportion of patients in the mITT population achieving remission. Data from Study 008A, a randomized, double-blind, placebo-controlled, 4-week trial in patients with schizophrenia not adequately benefiting from SGA (including clozapine), was analyzed to assess patients' response according to the number of previously failed AP attempts (ITT population; mixed model repeated measures (MMRM) linear regression model). The effect of evenamide on social functioning and life engagement was evaluated in both studies (mITT population) using an MMRM linear regression model for Study 008A and an OC analysis for Study 014/015.
Results: Patients with TRS receiving evenamide add-on for 1-year improved to such an extent that 55% of them no longer satisfied baseline TRS severity criteria, and approximately one-fourth achieved remission according to literature criteria (27.6% Lieberman et al., 1993; 25.0% Andreasen et al., 2005). In Study 008A, irrespective of the number of failed APs, a statistically significant drug-placebo difference was observed in patients with a single failed attempt (-4.9, p = 0.0122) and in those with 2 or more failed attempts (-2.36, p = 0.0311). Moreover, add-on treatment with evenamide in Study 014/015 was associated with a progressive improvement on the PANSS subdomains of social functioning and life engagement. In Study 008A as well, evenamide resulted in a greater effect, compared to placebo, on the same subdomains.
Conclusion: Add-on treatment with evenamide to APs (including clozapine) was associated with clinically meaningful and progressive long-term benefits across numerous post-hoc analyses including improvements on patient's daily life and functioning.
Keywords: evenamide; glutamate modulation; inadequate response; treatment-resistant schizophrenia.
Evenamide, a new drug under development, may help people with schizophrenia who do not respond to standard treatments, improving symptoms and daily functioning Many standard medications for schizophrenia, called antipsychotics, help reduce “positive” symptoms (like hearing voices or having unusual thoughts), but they do not benefit everyone. Some patients still have issues with thinking, emotions, and one third of them do not gain any benefit from treatment, a condition called treatment-resistant schizophrenia (TRS). What is evenamide Evenamide is a novel drug under development that works differently from other antipsychotics. It helps normalize the neurotransmitter glutamate in a brain area called ‘hippocampus’ which in turn rebalances the levels of another key substance, dopamine. Because of this, evenamide might help not just the “positive” symptoms but also the “negative” ones (low motivation or flat mood). What was studied Researchers looked at two main clinical trials: 1. A one-year study in people with TRS, where they added evenamide to the regular antipsychotics patients were already using. They checked how many patients improved so much that they could not being defined TRS anymore, and how many achieved remission. 2. A four-week, placebo-controlled trial in patients who did not respond adequately to antipsychotics. Researchers looked at how previous failed treatments affected response to evenamide added to their standard of care. Researchers also looked at the effects of evenamide on patients’ social involvement and wellbeing. What was found 1. In the one-year study, more than half of patients improved to the point that they no longer met criteria for TRS, and about one-fourth achieved remission. 2. In the four-week study, patients given evenamide improved more than those on placebo irrespective of how many failed prior treatments patients had gone through. In both studies, meaningful gains in social functioning and wellbeing in patients taking evenamide were observed. Take-home message These results suggest that evenamide may deliver long-term benefits, enhancing the wellbeing and social involvement.
© The Author(s), 2026.