Sodium Oxybate in Schizophrenia With Insomnia

Rationale/Study Hypothesis:

Rationale for study of sodium oxybate is twofold: first, sleep dysfunction is an important
and overlooked aspect of schizophrenia intrinsically linked to cognitive and functional
impairments, and, second, GABAB receptors regulate dopaminergic and glutamatergic systems in
vivo, suggesting that GABAB agonists may be therapeutically beneficial in schizophrenia.

We are aware of three previous trials of GHB in schizophrenia, two of which did not show any
overall benefit in psychopathology. We noted multiple limitations in the controlled trials,
including:

1. requirement of cumbersome dosing patterns (up to six times a day) that could have led
to incomplete compliance,

2. lack of objective measures of subjective sleep or sleep architecture,

3. lack of objective cognitive testing,

4. use of GHB as monotherapy or only in conjunction with only low dose antipsychotics,

5. short trial duration (less than 4 weeks),

6. relatively low overall night-time dose of GHB, and

7. a heterogeneous, small sample.

We propose an open label, proof of concept study evaluating the effect of sodium oxybate on
insomnia in schizophrenia. The primary hypothesis of the study is that patients treated with
sodium oxybate will show improved subjective sleep as measured by the overall Epworth
Sleepiness Scale and the Pittsburgh Sleep Quality Index. Secondarily, we expect superior
reduction in total psychopathology and PANSS factor scales (PANSS), polysomnographic
measures, and neurocognition (MATRICS).

Design and dosage schedule:

We plan to enroll eight hospitalized patients with diagnostic & statistical manual text
revision (DSM-IV-TR) schizophrenia and insomnia related to schizophrenia. The study will
include: a one-week evaluation period, which will include tapering of any hypnotics,
baseline diagnostic, psychopathology, neurocognitive, electrophysiological and
polysomnographic measurements. Patients will then begin a four-week trial of adjunctive
sodium oxybate, with a three-week taper of sodium oxybate to follow. Hypnotic/sodium oxybate
taper may be extended or abbreviated, depending on clinical judgment.

Patients entering the study will be permitted to receive both typical and atypical
antipsychotics. Treating psychiatrists will be encouraged to maintain fixed doses of all
psychotropic medication throughout the study.

Other than haloperidol and benztropine prn (up to 10 mg/day of haloperidol), the
prescription of a new psychotropic will not be permitted. After the second week of study
medication, any subject requiring more than 4 doses of haloperidol in one week will be
considered to have relapsed, and will be withdrawn from the study.

Inclusion Criteria:

- Patients aged 18-45 with a DSM-IV diagnosis of schizophrenia and insomnia related to
schizophrenia, confirmed by a structured interview (SCID).

Exclusion Criteria:

- Lack of capacity to give informed consent (capacity is determined by a licensed
member of the treatment team).

- Unstable medical illness.

- Diagnosis of restless leg syndrome, a seizure disorder, uncontrolled hypertension,
unstable cardiac illness, or obstructive sleep apnea.

- Pregnancy or lack of adequate birth control.

- History of substance dependence disorder.

- Current treatment with valproic acid.

- Succinic semialdehyde dehydrogenase deficiency (SSADH).

- Persistent need for treatment with benzodiazepines, barbiturates, opiates or other
sedative hypnotics.