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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT00645580
Recruitment Status : Unknown
Verified March 2008 by Sha’ar Menashe Mental Health Center.
Recruitment status was:  Active, not recruiting
First Posted : March 27, 2008
Last Update Posted : February 19, 2009
Information provided by:
Sha’ar Menashe Mental Health Center

Brief 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.

Condition or disease Intervention/treatment Phase
Schizophrenia Drug: Fluvoxamine Not Applicable

Detailed Description:

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 (Silver and Nassar, 1992; Spina et al., 1994; Goff et al., 1995). However, the effect of SSRI augmentation on cognitive impairments of the illness has not been adequately tested.

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

We have recently shown that in animals, 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 (GABA-Aβ3 receptor, glutamic acid decarboxylase 67 and PKCβ (Chertkow et al., 2005)) and changes unique to the combined treatment were found in selected areas of rat brain.

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 (Kronfol and Remick, 2000; Avissar et al., 2001; Ilani et al., 2001; Rothermundt et al., 2001). In a recent study (Chertkow et al., 2007) which examined the gene expression profile of PMC's from antipsychotic-treated patients before the addition of the SSRI fluvoxamine, we found that mRNA expression of chemokine receptors, IL8RA and CCR1, and of RGS7 was significantly down-regulated following fluvoxamine augmentation. Additionally, the clinical assessments showed improvement in negative symptoms following the combined treatment. These findings suggested that gene expression changes in PMC's may be useful in investigating the mechanism of drug action in schizophrenia.

In this study we will examine RNA and protein expression in the course of fluvoxamine augmentation treatment. 15 chronic schizophrenic patients who have persistent negative symptoms and cognitive impairment despite adequate treatment will participate. Fluvoxamine 100mg/day will be added to the treatment regimen and continued for 6 weeks. Clinical state will be assessed using validated rating scales and cognitive performance will be assessed with a cognitive test battery. Blood samples will be taken at baseline and at 1, 3 and 6 weeks. The PMC's will be assayed using microarray, RT PCR and proteomic techniques. Changes in RNA and protein expression will be detected and compared with changes in clinical symptoms and cognitive function. Identification of biochemical changes related to augmentation treated and their relation to symptomatic and cognitive changes will be the major potential benefit of the study.

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 15 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Alterations in mRNA and Protein Expression in Human Peripheral Mononuclear Blood Cells (PMC) of Schizophrenia Patients Treated With Fluvoxamine Augmentation of Antipsychotics: Relationship to Clinical Symptoms and Cognitive Function
Study Start Date : April 2008
Estimated Primary Completion Date : April 2009
Estimated Study Completion Date : April 2009

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Schizophrenia

Arm Intervention/treatment
Experimental: A Drug: Fluvoxamine
Fluvoxamine 100mg/day PO for 6 weeks.
Other Names:
  • Favoxil
  • Luvox
  • Dumyrox
  • Fevarin
  • Faverin

Primary Outcome Measures :
  1. Schedule for the Assessment of Negative Symptoms (SANS) [ Time Frame: 0 weeks, 3 weeks, 6 weeks ]

Secondary Outcome Measures :
  1. Schedule for the Assessment of Positive Symptoms (SAPS) [ Time Frame: 0 weeks, 3 weeks, 6 weeks ]
  2. Simpson Angus Scale for Extrapyramidal Side Effects (SA) [ Time Frame: 0 weeks, 3 weeks, 6 weeks ]
  3. Abnormal Involuntary Movement Scales (AIMS) [ Time Frame: 0 weeks, 3 weeks, 6 weeks ]
  4. Calgary Depression Scale [ Time Frame: 0 weeks, 3 weeks, 6 weeks ]
  5. Mini Mental State Examination [ Time Frame: 0 weeks, 3 weeks, 6 weeks ]
  6. Dot test (Keefe et al., 1997) [ Time Frame: 0 weeks, 3 weeks, 6 weeks ]
  7. Digit Span (Wechsler, 1998) [ Time Frame: 0 weeks, 3 weeks, 6 weeks ]
  8. Finger Tap Test (Reitan and Davison, 1974) [ Time Frame: 0 weeks, 3 weeks, 6 weeks ]
  9. Wechsler memory tests (Wechsler, 1998) [ Time Frame: 0 weeks, 3 weeks, 6 weeks ]
  10. Computerized Cognitive Neuropsychological Battery (Silver et al 2003) [ Time Frame: 0 weeks, 3 weeks, 6 weeks ]

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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Age 18-65
  • A diagnosis of schizophrenia (DSM-IVTR)
  • Antipsychotic dose unchanged for at least 2 weeks prior to study
  • SANS score>= 3 on at least one of the global measures of affective blunting, alogia or avolition.
  • Knowledge of Hebrew

Exclusion Criteria:

  • Dementia or other serious neurological disorders
  • History of alcohol or drug use
  • Patients with a legal guardian
  • Patients involuntarily hospitalized by order of the district psychiatrist
  • Use of antidepressants within 1 month of the study
  • Renal or hepatic disorder
  • Patients with upper GI bleeds
  • Patients with SIADH syndrome
  • Pregnant woman

Criteria for the cessation of the study after initial commencement:

  • Severe adverse events (including but not only GI, cardiovascular, neurologic, hematologic or urologic severe adverse events)
  • Emergent suicidality
  • Emergence of hypomanic or manic symptoms
  • If the subject requests to stop

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT00645580

Sha'ar Menashe Mental Health Center
Mobile Post Hefer, Israel, 37806
Sponsors and Collaborators
Sha’ar Menashe Mental Health Center
Principal Investigator: Henry Silver, PhD Sha'ar Menshae Mental Health Center

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
Reitan RM, Davison LA. Clinical Neuropsychology: Current Status and Applications. New York, New York: 1974, Hemisphere
Andreasen NC. Scale for the Assessment of Positive Symptoms (SAPS). 1983, Iowa City. The University of Iowa
Wechsler D. Wechsler Adult Intelligence Scale Manual. New York, New York: Guilford Press, 1998; pp. 95-188

Responsible Party: Prof. Henry Silver, Sha'ar Menashe Mental Health Center Identifier: NCT00645580     History of Changes
Other Study ID Numbers: 1-3-08
First Posted: March 27, 2008    Key Record Dates
Last Update Posted: February 19, 2009
Last Verified: March 2008

Additional relevant MeSH terms:
Schizophrenia Spectrum and Other Psychotic Disorders
Mental Disorders
Anti-Anxiety Agents
Tranquilizing Agents
Central Nervous System Depressants
Physiological Effects of Drugs
Psychotropic Drugs
Serotonin Uptake Inhibitors
Neurotransmitter Uptake Inhibitors
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action
Neurotransmitter Agents
Serotonin Agents
Antidepressive Agents, Second-Generation
Antidepressive Agents
Cytochrome P-450 CYP1A2 Inhibitors
Cytochrome P-450 Enzyme Inhibitors
Enzyme Inhibitors
Cytochrome P-450 CYP2C19 Inhibitors