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AZD8529, a positive allosteric modulator at the mGluR2 receptor, does not improve symptoms in schizophrenia: A proof
Robert E Litman1, Mark A Smith2, James J Doherty3
1CBH Health, LLC, 9210 Corporate Blvd., Suite 110, Rockville, MD, United States; Georgetown University, 3700 O St. NW, Washington, DC 20057, United States.
Introduction:
Activation of metabotropic glutamate (mGluR2/3) receptors has been proposed as an alternative mechanism to dopaminergic-based antipsychotics to correct glutamatergic deficits hypothesized to underlie schizophrenia symptoms. This study investigates the efficacy and safety of AZD8529, a selective positive allosteric modulator (PAM) at the mGlu2 receptor, in symptomatic patients with schizophrenia.
Methods:
Patients were randomized to receive AZD8529 40 mg, risperidone 4 mg, or placebo as monotherapy. Treatment lasted for 28 days, and clinical efficacy was assessed using Positive and Negative Syndrome Scale (PANSS) and Clinical Global Impression (CGI) scores.
Results:
There were no significant differences between patients treated with AZD8529 versus placebo in change from baseline to endpoint in PANSS total, negative and positive symptom subscale, or CGI-S scores. In contrast, risperidone demonstrated significant efficacy relative to placebo.
Conclusion:
These results do not support a role for the mGluR-2 PAM AZD8529 as an antipsychotic and indicate that positive modulation of mGluR type 2 receptors alone is not sufficient for antipsychotic effects in acutely ill schizophrenia patients.
Insights
AZD8529, a drug targeting metabotropic glutamate 2 (mGluR2) receptors, did not show antipsychotic efficacy in schizophrenia patients. This suggests positive modulation of mGluR2 alone is insufficient for treating schizophrenia symptoms.
Area of Science:
- Neuroscience
- Psychiatry
- Pharmacology
Background:
- Schizophrenia is associated with glutamatergic deficits, leading to interest in targeting metabotropic glutamate (mGluR2/3) receptors as an alternative to dopaminergic antipsychotics.
- Metabotropic glutamate receptor 2 (mGluR2) positive allosteric modulators (PAMs) are being investigated for their potential antipsychotic effects.
Purpose of the Study:
- To evaluate the efficacy and safety of AZD8529, a selective mGluR2 PAM, as a monotherapy in patients with schizophrenia.
- To determine if positive modulation of mGluR2 receptors can yield antipsychotic effects.
Main Methods:
- A 28-day randomized, controlled trial involving patients with schizophrenia.
- Participants received monotherapy with AZD8529 (40 mg), risperidone (4 mg), or placebo.
- Clinical efficacy was assessed using the Positive and Negative Syndrome Scale (PANSS) and Clinical Global Impression (CGI) scores.
Main Results:
- AZD8529 did not demonstrate significant differences compared to placebo in reducing overall, positive, or negative schizophrenia symptoms (PANSS scores) or in global impression (CGI-S).
- Risperidone, an established antipsychotic, showed significant efficacy compared to placebo.
- No significant differences were observed between AZD8529 and placebo for any efficacy measures.
Conclusions:
- The findings do not support the use of AZD8529 as an antipsychotic medication.
- Positive modulation of mGluR type 2 receptors alone is insufficient to achieve antipsychotic effects in acutely ill schizophrenia patients.
- Further research may be needed to explore combination therapies or different targets for schizophrenia treatment.
