Treatment of Refractory Schizophrenia With Riluzole

Neuroprotective Treatment of Refractory Schizophrenia With Riluzole 01T-432

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.

Study Overview

• Status: Completed
• Conditions: Schizophrenia; Schizoaffective
• Intervention / Treatment: Drug: Placebo; Drug: Riluzole

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
• Enrollment (Actual): 34
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Connecticut
    • New Haven, Connecticut, United States, 06519
      • Yale Department of Psychiatry

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo	Drug: Placebo; placebo
Experimental: Riluzole	Drug: Riluzole; Other Names: Rilutek

What is the study measuring?

Primary Outcome Measures

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

Collaborators and Investigators

• Sponsor: Yale University
• Collaborators: Stanley Medical Research Institute
• Investigators: Principal Investigator: Zoran Zimolo, MD, Ph.D., Yale University

Study record dates

Study Major Dates

• Study Start: May 1, 2002
• Primary Completion (Actual): August 29, 2006
• Study Completion (Actual): August 29, 2006

Study Registration Dates

• First Submitted: September 8, 2006
• First Submitted That Met QC Criteria: September 8, 2006
• First Posted (Estimate): September 12, 2006

Study Record Updates

• Last Update Posted (Actual): December 9, 2019
• Last Update Submitted That Met QC Criteria: December 6, 2019
• Last Verified: December 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Schizophrenia Spectrum and Other Psychotic Disorders; Schizophrenia; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Excitatory Amino Acid Antagonists; Excitatory Amino Acid Agents; Neuroprotective Agents; Protective Agents; Anticonvulsants; Riluzole
• Other Study ID Numbers: 13175