title: SSRI augmentation of antipsychotic alters expression of GABA(A) receptor and related genes in PMC of schizophrenia patients.
abstract: Clinical studies have shown that negative symptoms of schizophrenia unresponsive to antipsychotic given alone can improve after augmentation with SSRI antidepressant. Laboratory investigations into the mechanism of this synergism showed that co-administration of SSRI and antipsychotic produces changes in GABA(A) receptor and related systems, which differ from the effects of each drug alone. To examine the clinical relevance of these findings, the current study examined the effects of SSRI augmentation treatment on GABA(A) receptor and related systems in schizophrenia patients. Schizophrenia patients with high levels of negative symptoms unresponsive to antipsychotic treatment received add-on fluvoxamine (100 mg/d). Blood was taken before and 1, 3 and 6 wk after adding fluvoxamine and peripheral mononuclear cells (PMC) isolated. RNA encoding for GABA(A)β3, 5-HT2A, and 5-HT7 receptors, PKCβ2, and brain-derived neurotrophic factor (BDNF) was assayed with real-time RT-PCR. Plasma BDNF protein was assayed using ELISA. Clinical symptoms were assessed with validated rating scales. We found significant increase in mRNA encoding for GABA(A)β3 and 5-HT2A, 5-HT7 receptors and BDNF and a reduction in PKCβ2 mRNA. Plasma BDNF protein concentrations were increased. There were significant correlations among the genes. Clinical symptoms improved significantly. mRNA expression of PKCβ2, 5-HT2A and 5-HT7 showed significant associations with clinical symptoms. Combined SSRI+antipsychotic treatment is associated with changes in GABA(A) receptor and in related signalling systems in patients. These changes may be part of the mechanism of clinically effective drug action and may prove to be biomarkers of pharmacological response.
authors.affiliation: Molecular Neuropsychiatry Unit, Sha'ar Menashe Brain Behavior Laboratory, Sha'ar Menashe Mental Health Center, and Rappaport Faculty of Medicine, Technion Israel Institute of Technology, Haifa, Israel. mdsilver@tx.technion.ac.il
authors.forename: Henry
authors.initials: H
authors.lastname: Silver
authors.forename: Ehud
authors.initials: E
authors.lastname: Susser
authors.forename: Lena
authors.initials: L
authors.lastname: Danovich
authors.forename: Warren
authors.initials: W
authors.lastname: Bilker
authors.forename: Moussa
authors.initials: M
authors.lastname: Youdim
authors.forename: Vladimir
authors.initials: V
authors.lastname: Goldin
authors.forename: Orly
authors.initials: O
authors.lastname: Weinreb
mesh_terms: D000928:Antidepressive Agents / Q000627:therapeutic use; D018687:Antidepressive Agents, Second-Generation / Q000627:therapeutic use; D014150:Antipsychotic Agents / Q000627:therapeutic use*; D054316:Biomarkers, Pharmacological; D019208:Brain-Derived Neurotrophic Factor / Q000097:blood / Q000502:physiology; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005260:Female; D016666:Fluvoxamine / Q000627:therapeutic use*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000502:physiology; D008297:Male; D011493:Protein Kinase C / Q000097:blood / Q000502:physiology; D064546:Protein Kinase C beta; D011569:Psychiatric Status Rating Scales; D012333:RNA, Messenger / Q000097:blood; D044402:Receptor, Serotonin, 5-HT2A / Q000097:blood / Q000502:physiology; D011963:Receptors, GABA-A / Q000235:genetics* / Q000378:metabolism; D012559:Schizophrenia / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D017367:Selective Serotonin Reuptake Inhibitors / Q000627:therapeutic use*
chemical_list: D000928:Antidepressive Agents; D018687:Antidepressive Agents, Second-Generation; D014150:Antipsychotic Agents; D054316:Biomarkers, Pharmacological; D019208:Brain-Derived Neurotrophic Factor; D016666:Fluvoxamine; D011493:Protein Kinase C; D064546:Protein Kinase C beta; D012333:RNA, Messenger; D044402:Receptor, Serotonin, 5-HT2A; D011963:Receptors, GABA-A; D017367:Selective Serotonin Reuptake Inhibitors