Clinical trial NCT00594256: Sodium Oxybate in Schizophrenia With Insomnia
Official title: Open Label, Pilot Study of Adjunctive Xyrem (Sodium Oxybate) for the Treatment of Schizophrenia and Associated Sleep Disturbances
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Schizophrenia
Insomnia Related to Schizophrenia (307.42)
Keywords: Schizophrenia
Sleep Architecture
Sodium Oxybate
Insomnia
Cognition
Lead sponsor: Nathan Kline Institute for Psychiatric Research
Sponsor class: OTHER
Collaborators: name: Jazz Pharmaceuticals
First posted: 2008-01-15
Enrollment: 8
Sex: ALL
Minimum age (years): 18
Maximum age (years): 45
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Pittsburgh Sleep Quality Index
timeFrame: 1 month
measure: Epworth Sleepiness Scale
timeFrame: 1 month
Secondary outcomes:
measure: Positive and Negative Syndrome Scale (PANSS) Negative Factor
timeFrame: 1 month
measure: MATRICS Neurocognitive Battery Composite
timeFrame: 1 month
measure: Slow Wave Sleep Minutes
timeFrame: 1 month
Other outcomes:
Locations:
city: Orangeburg
country: United States
facility: Nathan Kline Insitute for Psychiatric Research
state: New York
Study officials:
affiliation: Nathan Kline Institute for Psychiatric Research
name: Daniel C Javitt, MD PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Kantrowitz JT, Oakman E, Bickel S, Citrome L, Spielman A, Silipo G, Battaglia J, Javitt DC. The importance of a good night's sleep: an open-label trial of the sodium salt of gamma-hydroxybutyric acid in insomnia associated with schizophrenia. Schizophr Res. 2010 Jul;120(1-3):225-6. doi: 10.1016/j.schres.2010.03.035. No abstract available.