טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
Ph.D Thesis
Ph.D StudentChertkow Yael
SubjectThe Effects of Typical and Atypical Antipsychotics alone
and in Combination with SSRI Antidepressant on
Gene and Protein Expression and their
Relationship to Clinical...
DepartmentDepartment of Medicine
Supervisors Professor Henry Silver
Professor Emeritus Moussa Youdim


Abstract

_ Clinical studies in schizophrenia patients have shown that adding a selective serotonin reuptake inhibitor (SSRI) to antipsychotics can ameliorate negative symptoms that frequently resist standard treatments. It has been proposed that this combined treatment produces a ‘net effect’, different from that of the individual drugs and possibly common to that of the atypical antipsychotic, clozapine, which also ameliorates negative symptoms. Studies were conducted in laboratory and clinical settings. Rats received a daily intraperitoneal injection with haloperidol (1mg/kg), fluvoxamine (11mg/kg), clozapine (11mg/kg), haloperidol (1mg/kg) plus fluvoxamine (11mg/kg), or vehicle for 30 days. cDNA arrays were used to screen a broad range of genes in the frontal cortex. Several genes were also determined at the protein level by Western-blotting technique. Expression changes, specific to the combined treatment, were found in proteins involved in GABA system, including glutamic acid decarboxylase (GAD67) and protein kinase Cb (PKCb). The latter showed a similar trend following clozapine treatment. Also investigated were the effects of the drugs on monoamine metabolism at 1.5hr and 24hrs after the last drug injections. The combined treatment induced distinctive changes in cerebellar and striatal dopamine metabolism. 1.5h after last dose, antipsychotic treatments increased dopamine turnover in the striatum and frontal cortex and reduced striatal tyrosine hydroxylase activity, whereas at 24h, both dopamine turnover and tyrosine hydroxylase activity were reduced. It was concluded that in chronically-modified system, the immediate response of dopamine metabolism to antipsychotic drug challenge is similar to drug naive animals, but it does not depend on tyrosine hydroxylase activity. The unique effects of haoperidol-fluvoxamine treatment were not caused by pharmacokinetic interactions between the drugs since their concentrations in the brain and serum were similar when given individually or combined. the effects of fluvoxamine augmentation on gene expression was also studied in peripheral mononuclear cells of schizophrenic individuals. Gene expression profiles of patients treated with antipsychotics were determined before and at 3 and 6 weeks after addition of fluvoxamine. The main findings were a reduction in the mRNA levels of the chemokine receptors interleukin 8 (IL8R) and chemokine receptor1 (CCR1) after treatment. This occurred in parallel with improvement in negative symptoms. The present study supports the main hypothesis that SSRI-antipsychotic combination induces unique biochemical and behavioral effects, different from that of the individual drugs and may provide some insight into the molecular pathways underlying the therapeutic effects of antipsychotic treatment in schizophrenia.