Treatment of Refractory Schizophrenia With Riluzole

• ClinicalTrials.gov Identifier: NCT00375050
• Recruitment Status: Completed
• First Posted: September 12, 2006
• Last Update Posted: December 9, 2019
• Sponsor: Yale University
• Collaborator: Stanley Medical Research Institute
• Information provided by (Responsible Party): Yale University

Tracking Information

• First Submitted Date: September 8, 2006
• First Posted Date: September 12, 2006
• Last Update Posted Date: December 9, 2019
• Study Start Date: May 2002
• Actual Primary Completion Date: August 29, 2006 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: May 23, 2017)

• PANSS (Positive and Negative Syndrome Scale) [ Time Frame: 12 weeks ]
• SANS (Scale for the Assessment of Negative Symptoms) [ Time Frame: 12 weeks ]
• CGI- Clinical Global Impression Scale [ Time Frame: 12 weeks ]
• Calgary Depression Scale: To assess mood symptoms in psychotic patients [ Time Frame: 12 weeks ]
• Neuropsychological tests: [ Time Frame: 12 weeks ]
• Computerized Working Memory Task [ Time Frame: 12 weeks ]
• Verbal Fluency [ Time Frame: 12 weeks ]
• HVLT-Hopkins Verbal Learning Test [ Time Frame: 12 weeks ]
• DSST-Digit Symbol Substitution Test [ Time Frame: 12 weeks ]
• Continuous performance test [ Time Frame: 12 weeks ]
• CANTAB- Cambridge Neuropsychological Test Automated Battery [ Time Frame: 12 weeks ]
• AIMS (abnormal involuntary movement scale), EPS (extrapyramidal symptom) assessment, Barnes akathisia scale, Simpson Angus scale [ Time Frame: 12 weeks ]

Original Primary Outcome Measures (submitted: September 8, 2006)

• PANSS (Positive and Negative Syndrome Scale)
• SANS (Scale for the Assessment of Negative Symptoms)
• CGI- Clinical Global Impression Scale
• Calgary Depression Scale: To assess mood symptoms in psychotic patients
• Neuropsychological tests:
• Computerized Working Memory Task
• Verbal Fluency
• HVLT-Hopkins Verbal Learning Test
• DSST-Digit Symbol Substitution Test
• Continuous performance test
• CANTAB- Cambridge Neuropsychological Test Automated Battery
• AIMS (abnormal involuntary movement scale), EPS (extrapyramidal symptom) assessment, Barnes akathisia scale, Simpson Angus scale

• Current Secondary Outcome Measures: Not Provided
• Original Secondary Outcome Measures: Not Provided
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Treatment of Refractory Schizophrenia With Riluzole
• Official Title: Neuroprotective Treatment of Refractory Schizophrenia With Riluzole 01T-432
• Brief Summary: The proposed study would evaluate the benefits of riluzole add-on treatment to patients with schizophrenia who are already receiving medications, but still experience symptoms. Neuroprotective medication riluzole is currently approved for treatment of amyotrophic lateral sclerosis (Lou Gehrig's disease), a severe neurological illness. Due to its unique mechanism of action, riluzole, if effective in helping the symptoms of schizophrenia, would open novel directions in treatment of schizophrenia.

Detailed Description

Schizophrenia is perhaps one of the most debilitating illnesses. Over the past years there has been limited improvement in the efficacy of the medications used to treat this disorder. In particular, the currently available antipsychotic drugs have small efficacy against negative symptoms and cognitive impairment associated with schizophrenia. This is critical considering that both negative symptoms and cognitive deficits contribute significantly to social and vocational impairment in schizophrenic patients. Furthermore, current treatment can not always provide satisfactory control of positive symptoms. While various extracellular neurotransmitter systems (dopamine, 5HT, GABA, etc. ) have been explored as targets for antipsychotic treatment, a substantial body of evidence suggests that neurodegenerative intracellular processes might be responsible for some of the symptoms of schizophrenia, resulting in cytopathic effects or inadequate cellular functioning. Some of these processes may be triggered by excitotoxic influence of neurotransmitters (i.e. glutamate). As many neuroleptic agents currently in use have some neuroprotective properties it is possible to speculate that medications with primarily neuroprotective mode of action might be of additional help in treatment of schizophrenia.

Huntington's disease patients who in its advanced form exhibit some symptoms similar to that of psychotic illness, have, in a recent small (n=9) open label study with a neuroprotective drug riluzole, shown a temporary improvement in not only motor function, but also cognitive, and behavioral functioning (Seppi 2001).

Based on all of the above, it seems possible to expect improvement in symptoms of schizophrenia with neuroprotective agents such as riluzole.

Riluzole is the only effective medication approved for use in ALS (amyotrophic lateral sclerosis, Lou Gehrig's disease) which is one of the most severe and rapidly progressing neurodegenerative illnesses that affects motor neurons in the brain and spinal cord. A subset of ALS is inherited and involves more than 70 different mutations in the antioxidant enzyme superoxide dismutase (SOD) thereby contributing to reduced antioxidative defense against oxidative injury. This results in increased reactive oxygen species level in several organs/tissues while the bulk of symptomatology is related to degeneration in the subset of CNS neurons. Although riluzole is effective in both humans and the transgenic mouse model of familial ALS where it slows decrease in motor power, its exact neuroprotective mechanism of action is not known. Various studies suggest that riluzole might exert some of its beneficial effect by inhibition of glutamate release, inhibition of voltage-gated Na+ channels, but also intracellularly by inhibiting of protein kinase C (PKC), enzyme that was linked to oxidative neuronal injury. Although riluzole is generally well tolerated, side effects can occur and are mostly related to gastrointestinal problems, hepatotoxicity and asthenia.

This 14 week study would evaluate the benefits of riluzole add-on treatment to patients with schizophrenia on neuroleptics with refractory symptoms.

• Study Type: Interventional
• Study Phase: Not Applicable
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Care Provider); Primary Purpose: Treatment

Condition

• Schizophrenia
• Schizoaffective

Intervention

• Drug: Riluzole
  Other Name: Rilutek
• Drug: Placebo
  placebo

Study Arms

• Experimental: Riluzole
  Intervention: Drug: Riluzole
• Placebo Comparator: Placebo
  Intervention: Drug: Placebo

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: December 6, 2019): 34
• Original Enrollment (submitted: September 8, 2006): 30
• Actual Study Completion Date: August 29, 2006
• Actual Primary Completion Date: August 29, 2006 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Men or women with a diagnosis of schizophrenia or schizoaffective disorder as defined by DSM- IV criteria.
• Age between 18 and 65. Special attention will be placed on selective enrolling of patients 18-25 to assess that they have been exposed to adequate medication trials (minimum two medications) for sufficient length of time.
• During the 3 months prior to study entry, the patient must not have been an inpatient in a hospital for longer than 4 weeks (cumulative hospitalizations) due to worsening of psychiatric illness (although could have been participating in an inpatient research protocol).
• Patients able to comprehend and satisfactorily comply with the protocol requirements;
• Patients with a PANSS total score of 60 or higher and a score of 4 (moderate) or higher on two or more of the following PANSS items: delusions, hallucinatory behavior, conceptual disorganization or suspiciousness.
• CGI scale rating of at least mildly ill, but not greater than severely ill.
• For women only: The patient must be non-pregnant, non-lactating, or has undergone tubal ligation, bilateral oophorectomy or hysterectomy; or the patient must be at least one year post menopausal; or the patient a) has negative urine or serum pregnancy test (Beta HCG) and b) agrees to reliably practice contraception throughout the study.

Exclusion Criteria:

• Primary psychiatric diagnosis other than schizophrenia or schizoaffective disorder.
• Patients who have had psychosurgery
• Recent (< 3 weeks) change in antipsychotic regimen
• Presence of clinically significant somatic disease that requires frequent changes in medications or that could be aggravated by taking riluzole (i.e. severe liver illness)
• Currently receiving treatment with potentially hepatotoxic drugs (e.g. allopurinol, methyldopa, sulfasalazine)
• HIV positive, as assessed by blood testing (in part to avoid subjects with possible brain HIV infection and to avoid rare complications of rarely occurring riluzole induced neutropenia)
• Patients who pose immediate or significant enough risk for suicide or harm for others as assessed by the study MD.
• Pregnant or nursing women, or women of childbearing potential who do not use adequate contraception or who are judged to be unreliable in their use of contraception (because there is not enough experience with riluzole use in nursing or pregnant women)

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 65 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT00375050
• Other Study ID Numbers: 13175
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Yale University
• Original Responsible Party: Not Provided
• Current Study Sponsor: Yale University
• Original Study Sponsor: Same as current
• Collaborators: Stanley Medical Research Institute

Investigators

• Principal Investigator: Zoran Zimolo, MD, Ph.D.; Yale University

• PRS Account: Yale University
• Verification Date: December 2019