Potential New Approach To Treat Cognitive Impairments In Schizophrenia

Schizophrenia is considered one of the most devastating of the major psychiatric disorders, which has three distinct facets, often referred to as "positive" (hallucinations, delusions), "negative" (blunted emotions, reduced capacity for pleasure), and "cognitive" (impairments in attention, memory, and problem-solving) symptoms. The cognitive impairments associated with schizophrenia are the aspect of this disorder most strongly associated with the inability to function in the workplace.

The medications currently approved to treat schizophrenia block a subclass of dopamine receptors (dopamine D2 receptors). They have limited efficacy in treating the negative and cognitive symptoms of this disorder and they are frequently associated with significant side effects. "Hence, there is an acute need to develop alternative treatments for schizophrenia that have fewer side effects and are more effective in treating cognitive and negative symptoms of the disorder," according to the authors of this study, scheduled for publication in Biological Psychiatry on October 1st.

"Multidisciplinary work has led to the emergence of the glutamate system as a promising therapeutic target for [the] treatment of schizophrenia," says Bita Moghaddam, Ph.D., the corresponding author on the study.

Abnormal function of brain circuits that utilize glutamate as a chemical messenger, particularly in brain regions including the prefrontal cortex and hippocampus, has been implicated in the cognitive deficits associated with schizophrenia. The glutamate-related circuit dysfunction associated with schizophrenia may be modeled, to a meaningful extent, by blocking the NMDA subtype of glutamate receptor.

The authors now report that by administering 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide or CDPPB, a drug that stimulates another type of glutamate receptor, the metabotropic glutamate 5 receptor (mGluR5), they can normalize abnormalities in prefrontal cortical function produced by blocking the NMDA glutamate receptor. In other words, CDPPB appears to "treat" an abnormality in brain function that may resemble aspects of schizophrenia.

Dr. Moghaddam comments, "This work is significant because it shows that in an awake behaving mammal (as opposed to in tissue cultures or similar preparation), activation of these receptors has a normalizing effect on the spontaneous activity of prefrontal cortex neurons." John H. Krystal, M.D., Editor of Biological Psychiatry and affiliated with both Yale University School of Medicine and the VA Connecticut Healthcare System, adds, "These exciting new data provide important new evidence supporting the testing of mGluR5 stimulating medications for the treatment of schizophrenia, particularly cognitive deficits associated with impairments in the function of the prefrontal cortex.

It would be very interesting to know whether this class of medication reduces the transient impairments in cognitive function associated with the administration of NMDA receptor blockers to humans." Although the authors acknowledge that much more research is needed to evaluate the clinical impact of this treatment approach, this study indicates a "promising therapeutic potential" that could ultimately result in making improved treatments available to patients struggling with this illness.

The article is "Positive Allosteric Modulation of Metabotropic Glutamate 5 (mGlu5) Receptors Reverses N-Methyl-D-Aspartate Antagonist-Induced Alteration of Neuronal Firing in Prefrontal Cortex" by Lucas Lecourtier, Houman Homayoun, Gilles Tamagnan and Bita Moghaddam. Drs. Lecourtier, Homayoun, and Moghaddam are affiliated with the Department of Neuroscience at University of Pittsburgh in Pittsburgh, Pennsylvania. Dr. Tamagnan is with the Institute for Neurodegenerative Disorders in New Haven, Connecticut. The article appears in Biological Psychiatry, Volume 62, Issue 7 (October 1, 2007), published by Elsevier.