Effect of Fluvoxamine Augmentation on Cognitive Function , Aggressive Behavior , Clinical Symptoms and mRNA and Protein Expression in Human Peripheral Mononuclear Blood Cells (PMC) in Medicated Schizophrenia Patients

Clinical studies have shown that adding selective serotonin reuptake inhibitor (SSRI) antidepressants to antipsychotics can improve negative symptoms of schizophrenia in patients unresponsive to antipsychotics alone . The effect of SSRI augmentation on cognitive impairments of the illness which do not respond to antipsychotics and are associated with poor outcome has not been adequately tested .

In a recent study we showed that SSRI augmentation alters expression of gamma-aminobutyric acid(GABA A) receptor, protein kinase(PKC), brain-derived neurotrophic factor(BDNF) and related systems in peripheral mononuclear blood cells (PMC)of schizophrenia patients . There is evidence that these systems are abnormal in schizophrenia patients and are associated with cognitive and negative symptoms strengthening the likelihood that their modulation by SSRI augmentation can improve cognitive impairments .

Behavioral disturbance , particularly aggression is another feature of schizophrenia which is difficult to treat and leads to social and legal complications and poor outcome. Aggression is associated with serotoninergic dysfunction and there is evidence that SSRI can modify aggressive behavior including in schizophrenia patients .Thus this study will also examine the effect of SSRI augmentation on aggressive behavior and other behavioral and functional measures .

The mechanism of SSRI augmentation is not known and is the focus of research interest.

We have recently shown in laboratory studies that combined treatment of SSRI antidepressant and antipsychotic drug resulted in biochemical changes, different from the effects of the individual medications. Changes unique to the combined treatment were found in GABAergic components and related systems including GABA-Aβ3 receptor, glutamic acid decarboxylase 67 and PKCβ in selected areas of rat brain and in cultures of cortical neurons. Studies of drug mechanisms in humans have utilized blood products and PMC which are readily accessible and may reflect molecular processes in the central nervous system (CNS) of schizophrenic patients .Using this method in schizophrenia patients treated with SSRI augmentation we showed that changes in mRNA encoding for GABA A receptor , PKC and related proteins were associated with clinical improvement indicating that the changes observe in the laboratory have clinical relevance.