A Comprehensive Pharmacological and Clinical Review of LY2140023 (Pomaglumetad Methionil): A Pioneering Glutamatergic Agent for Schizophrenia

Introduction: The Unmet Need in Schizophrenia and the Dawn of the Glutamate Hypothesis

The Limitations of the Dopamine Hypothesis

For over six decades, the development of antipsychotic pharmacotherapies has been overwhelmingly guided by the dopamine hypothesis of schizophrenia.[1] This paradigm, born from the observation that all effective antipsychotic drugs exhibit antagonist activity at the dopamine D2 receptor, has led to the creation of numerous first- and second-generation agents.[3] While these medications can be effective in mitigating the positive symptoms of the disorder, such as hallucinations and delusions, they leave a profound therapeutic void.[3] The negative symptoms (e.g., apathy, anhedonia, social withdrawal) and the pervasive cognitive deficits that are core features of schizophrenia remain largely refractory to treatment with dopamine-blocking agents.[3] Furthermore, the clinical utility of these drugs is often compromised by a burdensome side-effect profile, including debilitating extrapyramidal symptoms (EPS), metabolic dysregulation leading to significant weight gain and diabetes, and hyperprolactinemia.[3] This reality underscores a critical unmet medical need and points to the limitations of a purely dopaminergic model of schizophrenia pathophysiology.

Emergence of the Glutamate Hypothesis