Cognitive impairment associated with schizophrenia (CIAS) remains one of the more daunting challenges to treating this often-debilitating mental health condition. And while the standard pharmacological treatment protocol includes antipsychotic medications designed to target dopamine pathways, they aren’t a panacea. And they typically fail to alleviate the frustrating cognitive symptoms that hold patients back.
It’s this lingering disconnect that’s driven researchers to pursue other approaches to treatment. And it’s what’s led them to investigate N-methyl-D-aspartate receptors (NMDARs).
The NMDAR Hypofunction Hypothesis
The NMDAR hypofunction model suggests that impaired NMDAR signaling plays a fundamental role in schizophrenia’s pathophysiology. Researchers subsequently uncovered evidence to back this up. Supporting studies showed that NMDAR antagonists such as phencyclidine (PCP) and ketamine induce schizophrenia-like symptoms in animals and humans.
Additionally, the discovery of anti-NMDAR encephalitis, an autoimmune disorder marked by severe psychiatric and cognitive symptoms, supported the link between NMDAR hypofunction and psychosis.
Genetic studies also identified variants of NMDA signaling genes as potential schizophrenia risk factors with the data illustrating that these variants (in particular) revealed connections to cognitive impairments.
Additionally, biomarkers such as mismatch negativity (MMN) and auditory steady-state response (ASSR) demonstrate impaired NMDAR-dependent auditory processes in schizophrenia patients. Postmortem studies have also uncovered reduced NMDAR subunit expression in the prefrontal cortex and decreased dendritic spine density in schizophrenia patients.
Emerging Potential Schizophrenia Treatments
To address NMDAR hypofunction, researchers have explored approaches that would target NMDAR coagonist sites. Studies have shown that D-serine supplementation can improve schizophrenia symptoms.
One meta-analysis of 40 randomized controlled trials (RCTs) demonstrated that adjunctive treatment with glycine site NMDAR coagonists, including D-serine and glycine, improved schizophrenia symptoms. Notably, researchers found that serum D-serine levels fell off dramatically in schizophrenia patients, along with improvements in cognitive function tied to elevated D-serine levels.
Despite promising results, D-serine treatments still face some hurdles. For starters, trials have shown that patients require high doses to achieve therapeutic efficacy. Researchers blame it on rapid metabolism by kidney D-amino acid oxidase (DAAO). While researchers noted nephrotoxicity in rats treated with higher doses, human trials haven’t replicated that – aside from a lone participant who’d received 120 mg/kg of D-serine. Overall, lower doses (30 mg/kg or lower) produced modest gains, while higher doses (60 mg/kg and higher) showed greater improvements. Even so, progress has stalled on further clinical trials.
Glycine has shown similarly conflicting outcomes in clinical trials. While some studies reported reduced negative symptoms, others, such as the CONSIST trial, failed to show meaningful improvements.
Indirect Modulation Strategies
Given the challenges with direct D-serine or glycine administration, researchers have explored indirect approaches to boost endogenous levels of these co-agonists. DAAO inhibitors prevent D-serine degradation, while glycine transporter 1 (GlyT1) inhibitors accelerate glycine accumulation.
Sodium benzoate, a low-potency DAAO inhibitor, has shown some promise in improving schizophrenia symptoms in small-scale RCTs. But inconsistent results across multiple trials have hindered sodium benzoate’s clinical adoption. Although sodium benzoate increased D-serine levels in animal models, human trials haven’t matched those results.
Luvadaxistat: A Novel DAAO Inhibitor
Luvadaxistat is an investigational, potent, and selective DAAO inhibitor that’s shown potential in increasing D-serine levels. In phase 1 clinical trials, participants tolerated luvadaxistat well, with nausea and headaches reported as the most common side effects. The drug effectively increased D-serine levels in plasma and cerebrospinal fluid (CSF) and exhibited favorable pharmacokinetics, indicating that once-daily dosing could sustain elevated D-serine levels.
In a phase 2a biomarker study, luvadaxistat treatment showed improvements in MMN and a positive trend in ASSR response, suggesting enhanced NMDAR activity, with the greatest cognitive improvements noted at lower doses (50 mg).
The INTERACT Study and Cognitive Impact
The phase 2 INTERACT study evaluated luvadaxistat’s efficacy in treating negative schizophrenia symptoms. While the study failed to meet its primary endpoint for curbing negative symptoms, it demonstrated notable improvements in cognitive performance at the 50 mg dose. These cognitive gains appeared to be directly proportional to the participants’ adherence. Nevertheless, higher doses (between 125 mg and 500 mg) didn’t produce similar improvements.
And even though luvadaxistat seemed to show promise as a cognitive enhancement, subsequent trials, like the ERUDITE study, failed to back that up, which researchers attributed to inconsistencies in cognitive assessments and participant variables.
GlyT1 Inhibitors: An Alternative Way
GlyT1 inhibitors, like iclepertin, have shown encouraging results in improving cognitive performance. While iclepertin improved cognition in phase 2 trials, it did not demonstrate significant efficacy in curbing negative symptoms.
A subsequent phase 2 study combining iclepertin with computerized cognitive treatment (CCT) failed to show added benefits over placebo combined with CCT.
Moving Forward – Hopefully
While both DAAO and GlyT1 inhibitors aim to enhance NMDAR function, they operate through distinct pathways. D-serine levels more closely correlate to the cortical and hippocampal regions, whereas GlyT1 activity predominantly affects the pons and thalamus. These differences suggest that combination therapies or targeted interventions might offer improved treatment outcomes.
Despite the recent setbacks, the pursuit of NMDAR-targeting treatments still shows potential for addressing CIAS. And researchers remain optimistic that adjusting dosing strategies, better patient selection, and combination therapies might unlock more effective treatment options for schizophrenia patients.
Further Reading
Understanding Neurotransmitters in Schizophrenia Beyond Dopamine
Sulforaphane Added to Antipsychotics for Negative Symptoms of Schizophrenia
