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Clonazepam Effects on Brain Oscillations and Cognition in Schizophrenia (KGB)

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ClinicalTrials.gov Identifier: NCT03061136
Recruitment Status : Withdrawn (Delays in equipment procurement prevented the start of the study in time)
First Posted : February 23, 2017
Last Update Posted : April 5, 2018
Sponsor:
Collaborators:
Stanford University
University of California, Los Angeles
Information provided by (Responsible Party):
Jong Yoon, Palo Alto Veterans Institute for Research

Study Description
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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.

Condition or disease Intervention/treatment Phase
Schizophrenia Schizoaffective Disorder Schizophreniform Disorder Drug: Clonazepam Drug: Placebo Phase 4

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.

Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 0 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Clonazepam Effects on Brain Oscillations and Cognition in Schizophrenia
Study Start Date : October 2016
Actual Primary Completion Date : October 2017
Actual Study Completion Date : October 2017

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Schizophrenia
Drug Information available for: Clonazepam

Arms and Interventions
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Arm Intervention/treatment
Placebo Comparator: Placebo
Placebo administered orally
 Drug: Placebo
Experimental: Clonazepam 0.1mg
0.1mg clonazepam administered orally
 Drug: Clonazepam
Other Name: Klonopin
Experimental: Clonazepam 0.2mg
0.2mg clonazepam administered orally
 Drug: Clonazepam
Other Name: Klonopin
Experimental: Clonazepam 0.3mg
0.3mg clonazepam administered orally
 Drug: Clonazepam
Other Name: Klonopin


Outcome Measures
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Primary Outcome Measures :
  1. EEG Gamma-oscillatory power [ Time Frame: 1 day ]
    Gamma-oscillation power is derived from EEG spectrogram, reflecting underlying brain electrical activity


Secondary Outcome Measures :
  1. EEG derived Auditory steady state power [ Time Frame: 1 day ]
    Auditory steady state power is derived from EEG spectrogram, reflecting underlying brain electrical activity responding to auditory stimulation

  2. Brief Psychiatric Rating Scale (BPRS) [ Time Frame: 1 day ]
    Quantification of level of psychopathology, rater-administered survey

  3. Scale for the Assessment of Negative Symptoms (SANS) [ Time Frame: 1 day ]
    Quantification of level of negative symptoms, rater-administered survey

  4. Scale for the Assessment of Positive Symptoms (SAPS) [ Time Frame: 1 day ]
    Quantification of level of positive symptoms, rater-administered survey

  5. Working memory task accuracy [ Time Frame: 1 day ]
    Subject's behavioral performance on a working memory task


Eligibility Criteria
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Ages Eligible for Study:   18 Years to 55 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

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.
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03061136


Locations
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United States, California
VA Palo Alto Health Care System
Palo Alto, California, United States, 94304
Sponsors and Collaborators
Palo Alto Veterans Institute for Research
Stanford University
University of California, Los Angeles
More Information
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Publications:

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Responsible Party: Jong Yoon, Principal Investigator, Palo Alto Veterans Institute for Research
ClinicalTrials.gov Identifier: NCT03061136    
Other Study ID Numbers: YOJ0004ARC
First Posted: February 23, 2017    Key Record Dates
Last Update Posted: April 5, 2018
Last Verified: April 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Keywords provided by Jong Yoon, Palo Alto Veterans Institute for Research:
Cognition
Gamma oscillations
EEG
 Executive function
Benzodiazepine
GABA
Additional relevant MeSH terms:
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Disease
Schizophrenia
Psychotic Disorders
Pathologic Processes
Schizophrenia Spectrum and Other Psychotic Disorders
Mental Disorders
Clonazepam
 Anticonvulsants
GABA Modulators
GABA Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs