Genetic Expression in Schizophrenics Treated With SSRI Augmentation: Relationship to Clinical and Cognitive Function

Summary

In our study we aim to examine the effect of SSRI augmentation on negative symptoms and cognitive function in schizophrenia patients as well as to examine the effect of SSRI augmentation on the RNA and protein products in peripheral mononuclear cells (PMC). Finally, we aim to relate changes in PMC elements to changes in clinical symptoms and cognitive function. Our study hypotheses are that SSRI augmentation of anti-psychotic treatment in schizophrenia patients will improve negative symptoms as well as cognitive symptoms and that this improvement will be related to biochemical changes identifiable in PMC elements.

Timeline

Start

2008-04

Primary completion

2009-04

Completion

2009-04

Publications

• Background Ackenheil M. The mechanism of action of antidepressants revised. J Neural Transm Suppl. 1990;32:29-37. doi: 10.1007/978-3-7091-9113-2_3.
• Background Addington D, Addington J, Schissel B. A depression rating scale for schizophrenics. Schizophr Res. 1990 Jul-Aug;3(4):247-51. doi: 10.1016/0920-9964(90)90005-r.
• Background Andreasen NC. The Scale for the Assessment of Negative Symptoms (SANS): conceptual and theoretical foundations. Br J Psychiatry Suppl. 1989 Nov;(7):49-58. No abstract available.
• Background Avissar S, Roitman G, Schreiber G. Differential effects of the antipsychotics haloperidol and clozapine on G protein measures in mononuclear leukocytes of patients with schizophrenia. Cell Mol Neurobiol. 2001 Dec;21(6):799-811. doi: 10.1023/a:1015164423918.
• Background Chalifour LE, Fahmy R, Holder EL, Hutchinson EW, Osterland CK, Schipper HM, Wang E. A method for analysis of gene expression patterns. Anal Biochem. 1994 Feb 1;216(2):299-304. doi: 10.1006/abio.1994.1045.
• Background Chertkow Y, Weinreb O, Youdim MB, Silver H. The effect of chronic co-administration of fluvoxamine and haloperidol compared to clozapine on the GABA system in the rat frontal cortex. Int J Neuropsychopharmacol. 2006 Jun;9(3):287-96. doi: 10.1017/S1461145705005626. Epub 2005 Jun 21.
• Background Chertkow Y, Weinreb O, Youdim MB, Silver H. Dopamine and serotonin metabolism in response to chronic administration of fluvoxamine and haloperidol combined treatment. J Neural Transm (Vienna). 2007;114(11):1443-54. doi: 10.1007/s00702-007-0753-1. Epub 2007 Jun 18.
• Background Chertkow Y, Weinreb O, Youdim MB, Silver H. Gene expression changes in peripheral mononuclear cells from schizophrenic patients treated with a combination of antipsychotic with fluvoxamine. Prog Neuropsychopharmacol Biol Psychiatry. 2007 Oct 1;31(7):1356-62. doi: 10.1016/j.pnpbp.2007.04.016. Epub 2007 Apr 29.
• Background Debouck C, Goodfellow PN. DNA microarrays in drug discovery and development. Nat Genet. 1999 Jan;21(1 Suppl):48-50. doi: 10.1038/4475.
• Background de Saizieu A, Certa U, Warrington J, Gray C, Keck W, Mous J. Bacterial transcript imaging by hybridization of total RNA to oligonucleotide arrays. Nat Biotechnol. 1998 Jan;16(1):45-8. doi: 10.1038/nbt0198-45.
• Background DeRisi JL, Iyer VR, Brown PO. Exploring the metabolic and genetic control of gene expression on a genomic scale. Science. 1997 Oct 24;278(5338):680-6. doi: 10.1126/science.278.5338.680.
• Background Duman RS, Malberg J, Thome J. Neural plasticity to stress and antidepressant treatment. Biol Psychiatry. 1999 Nov 1;46(9):1181-91. doi: 10.1016/s0006-3223(99)00177-8.
• Background Folstein MF, Folstein SE, McHugh PR. "Mini-mental state". A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res. 1975 Nov;12(3):189-98. doi: 10.1016/0022-3956(75)90026-6. No abstract available.
• Background Goff DC, Midha KK, Sarid-Segal O, Hubbard JW, Amico E. A placebo-controlled trial of fluoxetine added to neuroleptic in patients with schizophrenia. Psychopharmacology (Berl). 1995 Feb;117(4):417-23. doi: 10.1007/BF02246213.
• Background Guy W (ed). National Institute of Mental Health. Abnormal Involuntary Movement Scale (AIMS). Early Clinical Drug Evaluation Unit Assessment Manual. Rockville, Maryland: US Department of Health and Human Services, 1976; pp. 534-537
• Background Ilani T, Ben-Shachar D, Strous RD, Mazor M, Sheinkman A, Kotler M, Fuchs S. A peripheral marker for schizophrenia: Increased levels of D3 dopamine receptor mRNA in blood lymphocytes. Proc Natl Acad Sci U S A. 2001 Jan 16;98(2):625-8. doi: 10.1073/pnas.98.2.625. Epub 2001 Jan 9.
• Background Keefe RS, Lees-Roitman SE, Dupre RL. Performance of patients with schizophrenia on a pen and paper visuospatial working memory task with short delay. Schizophr Res. 1997 Jul 25;26(1):9-14. doi: 10.1016/S0920-9964(97)00037-6.
• Background Kronfol Z, Remick DG. Cytokines and the brain: implications for clinical psychiatry. Am J Psychiatry. 2000 May;157(5):683-94. doi: 10.1176/appi.ajp.157.5.683.
• Background Lesch KP, Aulakh CS, Wolozin BL, Tolliver TJ, Hill JL, Murphy DL. Regional brain expression of serotonin transporter mRNA and its regulation by reuptake inhibiting antidepressants. Brain Res Mol Brain Res. 1993 Jan;17(1-2):31-5. doi: 10.1016/0169-328x(93)90069-2.
• Background Lesch KP, Manji HK. Signal-transducing G proteins and antidepressant drugs: evidence for modulation of alpha subunit gene expression in rat brain. Biol Psychiatry. 1992 Oct 1;32(7):549-79. doi: 10.1016/0006-3223(92)90070-g.
• Background Peiffer A, Veilleux S, Barden N. Antidepressant and other centrally acting drugs regulate glucocorticoid receptor messenger RNA levels in rat brain. Psychoneuroendocrinology. 1991;16(6):505-15. doi: 10.1016/0306-4530(91)90034-q.
• Background Pepin MC, Pothier F, Barden N. Antidepressant drug action in a transgenic mouse model of the endocrine changes seen in depression. Mol Pharmacol. 1992 Dec;42(6):991-5.
• Background Reitan RM, Davison LA. Clinical Neuropsychology: Current Status and Applications. New York, New York: 1974, Hemisphere
• Background Andreasen NC. Scale for the Assessment of Positive Symptoms (SAPS). 1983, Iowa City. The University of Iowa
• Background Rothermundt M, Arolt V, Bayer TA. Review of immunological and immunopathological findings in schizophrenia. Brain Behav Immun. 2001 Dec;15(4):319-39. doi: 10.1006/brbi.2001.0648.
• Background Silver H, Nassar A. Fluvoxamine improves negative symptoms in treated chronic schizophrenia: an add-on double-blind, placebo-controlled study. Biol Psychiatry. 1992 Apr 1;31(7):698-704. doi: 10.1016/0006-3223(92)90279-9. No abstract available.
• Background Silver H, Shmugliakov N. Augmentation with fluvoxamine but not maprotiline improves negative symptoms in treated schizophrenia: evidence for a specific serotonergic effect from a double-blind study. J Clin Psychopharmacol. 1998 Jun;18(3):208-11. doi: 10.1097/00004714-199806000-00005.
• Background Silver H, Feldman P, Bilker W, Gur RC. Working memory deficit as a core neuropsychological dysfunction in schizophrenia. Am J Psychiatry. 2003 Oct;160(10):1809-16. doi: 10.1176/appi.ajp.160.10.1809.
• Background Simpson GM, Angus JW. A rating scale for extrapyramidal side effects. Acta Psychiatr Scand Suppl. 1970;212:11-9. doi: 10.1111/j.1600-0447.1970.tb02066.x. No abstract available.
• Background Spina E, De Domenico P, Ruello C, Longobardo N, Gitto C, Ancione M, Di Rosa AE, Caputi AP. Adjunctive fluoxetine in the treatment of negative symptoms in chronic schizophrenic patients. Int Clin Psychopharmacol. 1994 Winter;9(4):281-5. doi: 10.1097/00004850-199400940-00007.
• Background Toth M, Shenk T. Antagonist-mediated down-regulation of 5-hydroxytryptamine type 2 receptor gene expression: modulation of transcription. Mol Pharmacol. 1994 Jun;45(6):1095-100.
• Background Wechsler D. Wechsler Adult Intelligence Scale Manual. New York, New York: Guilford Press, 1998; pp. 95-188

Drugs

Indications