Treatment of Refractory Schizophrenia With Riluzole

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.

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)