SchizophreniaNCT00645580
Genetic Expression in Schizophrenics Treated With SSRI Augmentation: Relationship to Clinical and Cognitive Function
A study testing Fluvoxamine in people with Schizophrenia, run by Sha'ar Menashe Mental Health Center at 1 site in Israel.
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). Read more about this study
- Who is it for?
- Ages 18 to 65 years
- Conditions the study is for
- Schizophrenia
- What is being tested?
- Fluvoxamine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 15 participants
- Where
- 1 siteIsrael
- Study dates
- Apr 2008to Apr 2009
- Phase
- Interventional
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 65 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Who cannot join
- 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
Show all 14Show fewer
- 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
Trial locations and contacts
1 site in 1 country.
About this study
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
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.
Read the 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.
- Conditions
- Schizophrenia
- Being tested
- Fluvoxamine
- Medical subject headings
- Schizophrenia
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
FluvoxamineDrug
Also called Favoxil, Luvox, Dumyrox, Fevarin
Fluvoxamine 100mg/day PO for 6 weeks.
| Study group | Role | What they receive |
|---|---|---|
| A | Experimental | Not described Receives: Drug: Fluvoxamine |
What is being measured
The primary outcome is the main question the study is designed to answer.
Schedule for the Assessment of Negative Symptoms (SANS)
Measured: 0 weeks, 3 weeks, 6 weeks
Secondary outcomes (10)
Schedule for the Assessment of Positive Symptoms (SAPS)
Measured: 0 weeks, 3 weeks, 6 weeks
Simpson Angus Scale for Extrapyramidal Side Effects (SA)
Measured: 0 weeks, 3 weeks, 6 weeks
Abnormal Involuntary Movement Scales (AIMS)
Measured: 0 weeks, 3 weeks, 6 weeks
Calgary Depression Scale
Measured: 0 weeks, 3 weeks, 6 weeks
Mini Mental State Examination
Measured: 0 weeks, 3 weeks, 6 weeks
Dot test (Keefe et al., 1997)
Measured: 0 weeks, 3 weeks, 6 weeks
Digit Span (Wechsler, 1998)
Measured: 0 weeks, 3 weeks, 6 weeks
Finger Tap Test (Reitan and Davison, 1974)
Measured: 0 weeks, 3 weeks, 6 weeks
Wechsler memory tests (Wechsler, 1998)
Measured: 0 weeks, 3 weeks, 6 weeks
Computerized Cognitive Neuropsychological Battery (Silver et al 2003)
Measured: 0 weeks, 3 weeks, 6 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted27 Mar 2008 (estimated)
- Study startApr 2008
- Primary completionApr 2009 (estimated)
- Study completionApr 2009 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (32)Papers the sponsor has linked to this study.
- Other trials for SchizophreniaStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 15 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Sha'ar Menashe Mental Health Center
- Sponsor type
- University, hospital or other
- Investigators
- Henry Silver, PhD, Principal investigator, Sha'ar Menshae Mental Health Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00645580
- Sponsor's protocol ID
- 1-3-08
- Status last verified
- Mar 2008
- First submitted
- 23 Mar 2008
- Last updated
- 19 Feb 2009
- Results posted
- No
- Data monitoring committee
- No
Publications
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.
PubMed 2089097Addington 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.
PubMed 2278986Andreasen 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.
PubMed 2695141Avissar 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.
PubMed 12043849Chalifour 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.
PubMed 7513971Chertkow 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.
PubMed 15967061Chertkow 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.
PubMed 17576515Chertkow 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.
PubMed 17662512Debouck C, Goodfellow PN. DNA microarrays in drug discovery and development. Nat Genet. 1999 Jan;21(1 Suppl):48-50. doi: 10.1038/4475.
PubMed 9915501de 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.
PubMed 9447592DeRisi 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.
PubMed 9381177Duman 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.
PubMed 10560024Folstein 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.
PubMed 1202204Goff 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.
PubMed 7604142Guy 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
Study at a glance
From the registry record, last updated by the sponsor on 19 Feb 2009. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT00645580
- Acronym / sponsor ID
- 1-3-08
- Conditions
- Schizophrenia
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 15 participants (estimated)
- Lead sponsor
- Sha'ar Menashe Mental Health CenterUniversity, hospital or other
- Study start
- Apr 2008
- Primary completion
- Apr 2009 (estimated)
- Study completion
- Apr 2009 (estimated)
- First posted
- 27 Mar 2008 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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 design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| A | Experimental | Drug: Fluvoxamine |
Who may qualify
- Ages
- 18 to 65 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (5 listed)
- 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
Key exclusion criteria (14 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| FluvoxamineAlso: Favoxil, Luvox, Dumyrox, FevarinFluvoxamine 100mg/day PO for 6 weeks. | Drug | A |
Primary outcome
Schedule for the Assessment of Negative Symptoms (SANS)
Time frame: 0 weeks, 3 weeks, 6 weeks
10 secondary outcomes
Schedule for the Assessment of Positive Symptoms (SAPS)
Time frame: 0 weeks, 3 weeks, 6 weeks
Simpson Angus Scale for Extrapyramidal Side Effects (SA)
Time frame: 0 weeks, 3 weeks, 6 weeks
Abnormal Involuntary Movement Scales (AIMS)
Time frame: 0 weeks, 3 weeks, 6 weeks
Calgary Depression Scale
Time frame: 0 weeks, 3 weeks, 6 weeks
Mini Mental State Examination
Time frame: 0 weeks, 3 weeks, 6 weeks
Dot test (Keefe et al., 1997)
Time frame: 0 weeks, 3 weeks, 6 weeks
Digit Span (Wechsler, 1998)
Time frame: 0 weeks, 3 weeks, 6 weeks
Finger Tap Test (Reitan and Davison, 1974)
Time frame: 0 weeks, 3 weeks, 6 weeks
Wechsler memory tests (Wechsler, 1998)
Time frame: 0 weeks, 3 weeks, 6 weeks
Computerized Cognitive Neuropsychological Battery (Silver et al 2003)
Time frame: 0 weeks, 3 weeks, 6 weeks
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 19 Feb 2009.
- Background: PubMed 2089097Ackenheil 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: PubMed 2278986Addington 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: PubMed 2695141Andreasen 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: PubMed 12043849Avissar 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: PubMed 7513971Chalifour 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: PubMed 15967061Chertkow 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: PubMed 17576515Chertkow 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: PubMed 17662512Chertkow 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: PubMed 9915501Debouck C, Goodfellow PN. DNA microarrays in drug discovery and development. Nat Genet. 1999 Jan;21(1 Suppl):48-50. doi: 10.1038/4475.
- Background: PubMed 9447592de 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: PubMed 9381177DeRisi 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: PubMed 10560024Duman 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.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Henry Silver, PhD principal investigator
Sha'ar Menshae Mental Health Center
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Fluvoxamine in people with Schizophrenia, run by Sha'ar Menashe Mental Health Center at 1 site in Israel.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 5 inclusion and 14 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 19 Feb 2009. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Israel. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Schedule for the Assessment of Negative Symptoms (SANS) (time frame: 0 weeks, 3 weeks, 6 weeks). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00645580, which also lists 32 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 19 Feb 2009.