Sodium Oxybate in Schizophrenia With Insomnia
Condition: Schizophrenia; Insomnia Related to Schizophrenia (307.42)
MeSH terms: Sleep Initiation and Maintenance Disorders; Schizophrenia
Study type: Interventional
Phase: Phase 2

Summary: 
      The present protocol proposes study of the recently approved compound sodium oxybate (Xyrem),
      a gamma-aminobutyric acid type b (GABAB) and a g-hydroxybutyric acid (GHB) receptor agonist,
      for the study of persistent symptoms of schizophrenia. Sodium oxybate is a central nervous
      system depressant currently approved for treatment of narcolepsy associated with cataplexy
      and excessive daytime sleepiness. In addition to evaluating effects on sodium oxybate on
      persistent symptoms and neurocognitive deficits in schizophrenia, the study will test the
      hypothesis that this medication may be particularly effective in combating Insomnia Related
      to Schizophrenia, and in normalizing symptomatic and polysomnographic manifestations of
      sleep-related brain dysfunction in schizophrenia.
    

Detailed description: 
      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.
    

Intervention name(s): Sodium Oxybate
Intervention type(s): Drug
Intervention description(s): Patients will undergo a one-week evaluation period, which will include a taper and discontinuation of any currently prescribed sedative/hypnotics, as well as baseline diagnostic, psychopathology, neurocognitive and polysomnographic measurements (see below for details). Hypnotic taper may be extended or abbreviated, depending on clinical judgment. Patients will then begin a 4-week trial of adjunctive Xyrem (sodium oxybate). Patients will begin at 4.5 g/night (in divided doses of 2.25 g, with 1st dose at bedtime and then 2nd dose four hours later). Dosage will increase by 1.5 g/day every week, until a dose of 9 g nightly is reached, or a patient cannot tolerate further dose escalations. Medication will be administered in divided dosage for the duration of the study. A three-week taper (by 3 g/day weekly) of sodium oxybate will follow the four-week trial of sodium oxybate.
Other intervention name(s): Xyrem
Intervention MeSH terms: Sodium Oxybate
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Schizophrenia; Sleep Architecture; Sodium Oxybate; Insomnia; Cognition