SCHIZOPHRENIA 1 (Disorder) Clinical Trial
Official title:
Effect of Fluvoxamine Augmentation on Cognitive Function , Aggressive Behavior , Clinical Symptoms and mRNA and Protein Expression in Human Peripheral Mononuclear Blood Cells (PMC) in Medicated Schizophrenia Patients
The purpose of this study is to determine effect of Fluvoxamine augmentation on cognitive function , aggressive behavior , clinical symptoms and mRNA (messenger ribonucleic acid) and protein expression in human peripheral mononuclear blood cells (PMC) in medicated schizophrenia patients
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 . The effect of SSRI augmentation on cognitive
impairments of the illness which do not respond to antipsychotics and are associated with
poor outcome has not been adequately tested .
In a recent study we showed that SSRI augmentation alters expression of gamma-aminobutyric
acid(GABA A) receptor, protein kinase(PKC), brain-derived neurotrophic factor(BDNF) and
related systems in peripheral mononuclear blood cells (PMC)of schizophrenia patients . There
is evidence that these systems are abnormal in schizophrenia patients and are associated
with cognitive and negative symptoms strengthening the likelihood that their modulation by
SSRI augmentation can improve cognitive impairments .
Behavioral disturbance , particularly aggression is another feature of schizophrenia which
is difficult to treat and leads to social and legal complications and poor outcome.
Aggression is associated with serotoninergic dysfunction and there is evidence that SSRI can
modify aggressive behavior including in schizophrenia patients .Thus this study will also
examine the effect of SSRI augmentation on aggressive behavior and other behavioral and
functional measures .
The mechanism of SSRI augmentation is not known and is the focus of research interest.
We have recently shown in laboratory studies that 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 and related systems including GABA-Aβ3 receptor, glutamic acid decarboxylase 67
and PKCβ in selected areas of rat brain and in cultures of cortical neurons. 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 .Using this method in schizophrenia patients treated with SSRI augmentation we
showed that changes in mRNA encoding for GABA A receptor , PKC and related proteins were
associated with clinical improvement indicating that the changes observe in the laboratory
have clinical relevance.
Methods The dose of antipsychotics will be unchanged for at least 2 weeks prior to the study
and will remain steady throughout the study period. 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. Behavior and function , including s will be assessed with appropriate scales Blood
samples will be taken at baseline and at 1, 3 and 6 weeks.At the end of the study protocol
(after 6 weeks) the patients will be given the option to continue receiving the fluvoxamine.
It can be assumed that the included subjects would not have received fluvoxamine if it
weren't for their participation in the study for lack of indication for their primary
diagnosis (see inclusion criteria below). The PMC's will be assayed using microarray, (PCR)
polymerase chain reaction and proteomic techniques. Changes in RNA and protein expression
will be detected and compared with changes in clinical symptoms , cognitive function and
behavioral change . 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.
Subjects 40 chronic schizophrenic or schizoaffective patients (DSM-IVTR)who have persistent
negative symptoms and cognitive impairment despite adequate treatment will participate. The
sample will include patients with a history of aggressive behavior hospitalized in the
forensic wards and as well as patients in regular hospital wards and outpatients settings.
Assessments The diagnosis will determined by a consensus of two senior psychiatrists using
the DSM-IVTR criteria. Physical assessment (which includes a physical examination as well as
measurements of blood pressure and pulse) will be taken from the patient's medical records
prior to the commencement of the study. Background and demographic characteristics, details
of the present illness, medications, general medical history and current laboratory tests
will also be evaluated.
Clinical state and cognitive function will be assessed prior to fluvoxamine treatment and
then during the study period according to the flow sheet below.
Clinical assessment scales will include:
Schedule for the Assessment of Negative Symptoms (SANS); Schedule for the Assessment of
Positive Symptoms (SAPS); Simpson Angus Scale for Extrapyramidal Side Effects; Abnormal
Involuntary Movement Scales (AIMS); Calgary Depression Scale
Cognitive assessment will include:
Mini Mental State Examination, Dot test, Digit Span, Finger Tap Test modified, Wechsler
memory tests. Computerized Cognitive Neuropsychological Battery:Computerized judgment of
line orientation (CJOLO); Penn face memory test (PFMT); Visual object learning test (VOLT);
Abstraction inhibition and working memory task (AIM), Identification of facial emotions
(PEAT); Differentiation of facial emotion (EMDIF).
Behavioral and function assessment Overt aggression Scale GAF (DSM IV TR) Critical Events
Blood tests Approx 50cc of blood will be taken at baseline, prior to start of fluvoxamine
treatment, and 1,3 and 6 weeks after the start of fluvoxamine treatment.
Treatment of blood samples: Blood will be collected into heparinized tubes, kept on ice and
transported to the laboratory. Blood samples will be processed to enable assay of PMC
elements of interest, including chemokine receptors, G protein receptors such as the GABAA
receptor , their regulators such as, PKC GSK3 RGS7 and neurotrophins such as BDNF.
Some of the serum will be frozen for subsequent analyses of antipsychotic drug and
neurohormone concentration. The blood samples will be stored in the molecular
neuropsychiatry laboratory at the Technion Institute of Technology (Haifa) under the
supervision of the principal investigator, Prof. Henry Silver. The samples will be unnamed
and numbered. They will be kept for a maximum of 10 years. The participants will be given
the option to ask for the destruction of the samples at any time.
Flow sheet Week 0 Subject entry Clinical assessment Cognitive Assessment Behavioral
Assessment Blood collection- baseline Start Fluvoxamine Week 1 Blood collection Week 3
Clinical assessment Cognitive assessment Behavioral Assessment Blood collection Week 6
Clinical assessment Cognitive assessment Behavioral Assessment Blood collection
Implementation of the protocol The implementation of the protocol will involve a team of
research clinicians from Sha'ar Menashe Mental Health Center (Hadera) as well as the
Technion Institute of Technology (Haifa) under the direction of the principal investigator,
Prof. Henry Silver. Clinical and cognitive ratings will be each respectively obtained by one
rater in order to eliminate inter-rater bias.
Statistical analysis Statistical analysis of all studied parameters will be done between
repeated measures using analysis of variance (ANOVA) and the t-test. For nonparametric
distributions the Mann Whitney U test and the chi test will be utilized.
Risk/Benefit and Safety Considerations The taking of blood sample is the only invasive
procedure. This is a routine procedure accompanied by minor discomfort. Fluvoxamine
augmentation has been studied extensively and has been used safely in numerous studies. Side
effects of fluvoxamine include nausea and GI disturbance. The side effects will be
determined during the clinical assessments on weeks 0,3 and 6 according to the flow sheet
above using a clinical interview as well as a physical examination when necessary. The side
effects will be documented in the study protocol. Severe adverse events will be monitored by
the treating physicians and reported to the team of research clinicians.
The major advance of this methodology is that it enables the detection of RNA and protein
changes in PMC by assigning each subject as his/her own control, and will enable change in
clinical state to be related to the biochemical changes. Thus, the direct potential benefit
for the participants in this study would be improvement cognitive ,behavioral (including
aggressive ) and clinical symptoms, consequently improving their potential for well being
and rehabilitation while the major potential benefit for society would be the identification
of molecular changes accompanying clinical response to SSRI augmentation as a basis for the
understanding of their pharmacological mechanism of action and consequently opening new
vistas for treatments in the future.
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Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment