A growing body of schizophrenia research has helped fuel a treatment breakthrough. It represents nothing less than a new generation of therapy that centers on the role of D-serine.
Multiple studies point to D-serine as a crucial modulator for N-methyl-D-aspartate (NMDA) receptors, which are essential for cognitive function. The evidence ties lower D-serine levels to schizophrenia. And that suggests that boosting D-serine concentrations could, in turn, boost cognitive and behavioral symptoms.Two important enzymes regulate D-serine levels:
- Serine racemase, which synthesizes D-serine, and
- D-amino acid oxidase (DAAO), which breaks it down.
Researchers believe that elevated DAAO activity – common in schizophrenia patients – tamps down D-serine levels. As a result, researchers have started exploring ways to rein in that activity to stabilize D-serine levels and tweak NMDA receptor functions. At least two promising new treatments have already cropped up.
Luvadaxistat
Luvadaxistat – a potent DAAO inhibitor – has emerged as one of the more promising drugs still in development.
In a phase 2a clinical trial involving nearly three dozen schizophrenia patients, researchers tested luvadaxistat at 50 mg and 500 mg doses over an eight-day period. The study failed to show any notable boost in cerebellar-related learning through eyeblink conditioning. Even so, it did reveal encouraging evidence that the lower 50 mg dose improved cognitive biomarkers linked to NMDA receptor function. Specifically, participants at that dose showed improved mismatch negativity (MMN). They also exhibited a positive trend in auditory steady-state response (ASSR), both indicators of improved brain function.
It’s worth noting that the 500 mg dose didn’t produce the same beneficial effects. And that hints at a non-linear, inverted-U dose response, which lines up with other previous studies indicating that excessive D-serine elevation could overcorrect deficiencies, potentially diminishing the drug’s efficacy.
A related phase 2 study (INTERACT) revealed that 12 weeks of treatment with luvadaxistat 50 mg improved cognitive performance, reinforcing the notion that moderate DAAO inhibition might offer the best results.
Even though the trial’s small sample size demands cautious interpretation, the results highlight the potential of MMN and ASSR to serve as crucial biomarkers to help in NMDA receptor function in schizophrenia treatments. These biomarkers could be instrumental in guiding future drug development efforts. It could also help other researchers fine-tune the dosage and forecast cognitive improvements.
The research underscores the importance of exploring innovative approaches to schizophrenia treatment. Its particularly important in addressing the underlying NMDA receptor dysfunction that increasingly appears to contribute to cognitive impairments. And although luvadaxistat failed to significantly curb the emergence of negative symptoms, its ability to shore up cognitive performance still holds promise.
The study’s authors insist that further research is critical if we want to confirm these findings. It’s also necessary to understand the mechanics behind the inverted-U response and explore the long-term impact of luvadaxistat.
The ongoing investigation into D-serine modulation and DAAO inhibition offers a promising path for transforming our approach to schizophrenia treatment and dramatically improving the lives of those affected.
Ω-NaBen
New research from manufacturer SyneuRx has shown the potential of Ω-NaBen, a newly developed crystalline form of sodium benzoate, as an effective schizophrenia treatment alternative. The study, published in CNS & Neurological Disorders – Drug Targets, highlights the drug’s improved pharmaceutical properties and therapeutic benefits.
Ω-NaBen has demonstrated the ability to address all three major symptom domains of schizophrenia — positive, negative, and cognitive. Researchers also found that Ω-NaBen boasts enhanced aqueous solubility, which improves its bioavailability and strengthens its antipsychotic effects.
It’s worth pointing out that the compound shows robust crystal stability independently – and in combination with – clozapine, the standard last-resort schizophrenia treatment.
Similar drugs have shown promise in improving cognitive function and schizophrenia symptoms by enhancing NMDA receptor-mediated neurotransmission. But their effectiveness has been hampered by low bioavailability, requiring impractically high doses. Ω-NaBen gets around this by offering dramatically improved absorption and therapeutic efficacy.
Researchers are in the middle of a multi-center clinical trial to study Ω-NaBen as an add-on therapy.
“Ω-NaBen exemplifies an effective strategy for patients taking clozapine as a last-line treatment, extending the frontier of schizophrenia care,” UCLA Professor Dr. Guochuan Emil Tsai, MD, PhD, said in a press release.
