Schizoaffective Disorder, Schizophrenia, Schizophreniform Disorder
Conditions
Keywords
Cognition, Gamma oscillations, EEG, Executive function, Benzodiazepine, GABA
Brief summary
Cognitive deficits are some of the most prominent and disabling symptoms of schizophrenia. Evidence suggests that schizophrenia involves alterations to the functioning of a neural system under the control of a brain chemical called GABA. The present project will compare the effects of low-dose clonazepam (at a sub-sedating dose) to placebo, for effects on GABA- modulated brain activity measured by EEG, and associated cognitive processes in people who have schizophrenia.
Detailed description
Schizophrenia is a common, disabling mental illness with a considerable public health impact. Cognitive dysfunction (e.g in attention, memory, etc.) is an enduring feature of the illness, a strong predictor of functional outcome, and presently has no established treatment. Therefore, advances in treatment of cognition in schizophrenia are likely to alleviate a significant health burden. Deficits in executive control functions, such as those measurable on task-switching paradigms, are among the most important cognitive deficits in schizophrenia, and arise from disturbances in distributed neural networks operated by the prefrontal cortex. An important phenomenon that underpins cortical information processing are oscillations in brain activity that can be measured both with intracranial electrical recordings and at the scalp with EEG. These networks and their cortical oscillatory signatures are also strongly modulated by cortical interneurons that use gamma-amino butyric acid (GABA) as a neurotransmitter. Post-mortem evidence suggests that GABAergic neurons are altered in schizophrenia. Furthermore, studies in animals, using optogenetic manipulations that are restricted to a subset of cortical GABA neurons, also suggest that GABA neurons can be selectively modulated to improve PFC-dependent cognition in animal models of schizophrenia. This includes experiments that involve administration of sub-sedating doses of clonazepam, a representative FDA-approved medication from the benzodiazepine class. Therefore, this neurochemical system represents a novel set of candidate treatment targets that are both implicated in the pathophysiology of schizophrenia and the potential remediation of associated cognitive dysfunction.
Interventions
DRUGClonazepam
DRUGPlacebo
Sponsors
Stanford University
University of California, Los Angeles
Palo Alto Veterans Institute for Research
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
* Subjects will be included if they are adults (18-55 years old) who currently meet criteria for schizophrenia, schizophreniform disorder or schizoaffective disorder from the DSM-IV (295.X). * Healthy control subjects: 18-55 years of age.
Exclusion criteria
* All subjects will be excluded if they have a history of any substance-related disorder (by DSM-IV, other than cannabis abuse) in the prior 6 months, or repeated positive urine drug screens for other illicit substances. They will also be excluded if they are clinically-unstable, have significant baseline or emergent suicide risk (by Columbia Suicide Severity Risk Scale), estimated IQ \< 70, or EEG contraindications. Subjects must also have no major medical or neurological illness, or significant head trauma. * Active pregnancy or lactation will also be considered contraindications for treatment with clonazepam, and as criteria for exclusion. Excluded medications: * Prospective subjects will be excluded if they are currently in treatment with benzodiazepines, anticonvulsants, and medications such as zolpidem and baclofen, each of which directly affect GABA neurons or may be associated with changes in GABA system function. * Known allergy/sensitivity or any hypersensitivity to components of study drug(s) or their formulation, or sensitivity/hypersensitivity to clonazepam will be criteria for exclusion. * Healthy controls must be free of a diagnosis of a chronic or recurrent Axis I (or certain Axis II) psychiatric disorder and will be excluded if they have a first degree relative with a psychotic disorder. * Education, parental education, ethnicity, handedness, and native language will be used as exclusionary factors as necessary to maintain balanced groups. This information is collected during the telephone screen to ensure group balance.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| EEG Gamma-oscillatory power | 1 day | Gamma-oscillation power is derived from EEG spectrogram, reflecting underlying brain electrical activity |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| EEG derived Auditory steady state power | 1 day | Auditory steady state power is derived from EEG spectrogram, reflecting underlying brain electrical activity responding to auditory stimulation |
| Brief Psychiatric Rating Scale (BPRS) | 1 day | Quantification of level of psychopathology, rater-administered survey |
| Scale for the Assessment of Negative Symptoms (SANS) | 1 day | Quantification of level of negative symptoms, rater-administered survey |
| Scale for the Assessment of Positive Symptoms (SAPS) | 1 day | Quantification of level of positive symptoms, rater-administered survey |
| Working memory task accuracy | 1 day | Subject's behavioral performance on a working memory task |
Countries
United States
Outcome results
None listed