Summary
All currently marketed antipsychotic medications for treating schizophrenia rely on mechanisms of action which target dopamine and serotonin receptors. Although these medications reduce delusions and hallucinations without inducing symptoms of Parkinson's Disease or other abnormal muscle movements, they are not effective in relieving the cognitive impairment and social withdrawal which are the most disabling features of the illness and have other dangerous effects on weight, glucose control, cholesterol and lipids. Lilly Pharmaceutical has developed LY2140023 which acts by modulating the activity of certain receptors for glutamate, and in an early trial has demonstrated superiority to placebo in reducing delusions, hallucinations, cognitive impairment, and social withdrawal without causing neurological side effects or dangerous metabolic effects.
Analysis
Current second generation antipsychotic medications include risperdal (Janseen), zyprexa (Lilly), Seroquel (Astra-Zeneca), Geodon (Pfizer) and Abilify (Otsuka and Bristol-Myers Squib). These represent a multi-billion dollar market. In addition, new drugs are in late stage development by Solvay and Vanda Pharmaceuticals. These drugs share very similar mechanisms of action, and have failed to demonstrate significant activity in reducing cognitive impairment and negative symptoms. This is a crucial deficiency since these impairments account for the poor functional outcomes achieved by current treatments. In addition, only Geodon and Abilify have favorable side- effect profiles. Futhermore, all of these drugs will likely be effected when risperdal is available as a generic within the next year.
LY2140023 represents a totally novel approach, modulating metabotropic glutamate receptors. Previous attempts to target other glutamate receptors have proven dangerous because of seizure risk, but Lilly's drug targets a different glutamate receptor. Glutamate has been an attractive target because glutamate- blockers such as phencyclidine (PCP) and ketamine. Indeed chronic PCP use also results in cognitive and negative symptoms resembling those observed in schizophrenic patients.
Larger trials are in progress. If Lilly successfully brings this drug to market, it will represent a paradigm change in the pharmacologic treatment of schizophrenia.
