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

Schizophrenia Clinical Trial

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT00645580
• Other study ID #: 1-3-08
• Status: Active, not recruiting
• Phase: N/A
• First received: March 23, 2008
• Last updated: February 18, 2009
• Start date: April 2008
• Est. completion date: April 2009

Study information

• Verified date: March 2008
• Source: Sha’ar Menashe Mental Health Center
• Contact: n/a
• Is FDA regulated: No
• Health authority: Israel: Israeli Health Ministry Pharmaceutical Administration
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 15
• Est. completion date: April 2009
• Est. primary completion date: April 2009
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 65 Years

Eligibility

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

Study Design

Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Schizophrenia

Intervention

Drug:
• Fluvoxamine
Fluvoxamine 100mg/day PO for 6 weeks.

Locations

Country	Name	City	State
Israel	Sha'ar Menashe Mental Health Center	Mobile Post Hefer

Sponsors (1)

Lead Sponsor	Collaborator
Sha’ar Menashe Mental Health Center

Country where clinical trial is conducted

Israel, 

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* Note: There are 32 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Schedule for the Assessment of Negative Symptoms (SANS)		0 weeks, 3 weeks, 6 weeks	No
Secondary	Schedule for the Assessment of Positive Symptoms (SAPS)		0 weeks, 3 weeks, 6 weeks	No
Secondary	Simpson Angus Scale for Extrapyramidal Side Effects (SA)		0 weeks, 3 weeks, 6 weeks	No
Secondary	Abnormal Involuntary Movement Scales (AIMS)		0 weeks, 3 weeks, 6 weeks	No
Secondary	Calgary Depression Scale		0 weeks, 3 weeks, 6 weeks	No
Secondary	Mini Mental State Examination		0 weeks, 3 weeks, 6 weeks	No
Secondary	Dot test (Keefe et al., 1997)		0 weeks, 3 weeks, 6 weeks	No
Secondary	Digit Span (Wechsler, 1998)		0 weeks, 3 weeks, 6 weeks	No
Secondary	Finger Tap Test (Reitan and Davison, 1974)		0 weeks, 3 weeks, 6 weeks	No
Secondary	Wechsler memory tests (Wechsler, 1998)		0 weeks, 3 weeks, 6 weeks	No
Secondary	Computerized Cognitive Neuropsychological Battery (Silver et al 2003)		0 weeks, 3 weeks, 6 weeks	No