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

Primary Purpose

Schizophrenia, Schizoaffective Disorder, Schizophreniform Disorder

Status

Withdrawn

Phase

Phase 4

Locations

United States

Study Type

Interventional

Intervention

Clonazepam

Placebo

About this trial

This is an interventional treatment trial for Schizophrenia focused on measuring Cognition, Gamma oscillations, EEG, Executive function, Benzodiazepine, GABA

Eligibility Criteria

18 Years - 55 Years (Adult)All SexesAccepts Healthy Volunteers

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.

Sites / Locations

VA Palo Alto Health Care System

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Placebo Comparator

Experimental

Arm Label

Placebo

Clonazepam 0.1mg

Clonazepam 0.2mg

Clonazepam 0.3mg

Arm Description

Placebo administered orally

0.1mg clonazepam administered orally

0.2mg clonazepam administered orally

0.3mg clonazepam administered orally

Outcomes

Primary Outcome Measures

EEG Gamma-oscillatory power

Gamma-oscillation power is derived from EEG spectrogram, reflecting underlying brain electrical activity

Secondary Outcome Measures

EEG derived Auditory steady state power

Auditory steady state power is derived from EEG spectrogram, reflecting underlying brain electrical activity responding to auditory stimulation

Brief Psychiatric Rating Scale (BPRS)

Quantification of level of psychopathology, rater-administered survey

Scale for the Assessment of Negative Symptoms (SANS)

Quantification of level of negative symptoms, rater-administered survey

Scale for the Assessment of Positive Symptoms (SAPS)

Quantification of level of positive symptoms, rater-administered survey

Working memory task accuracy

Subject's behavioral performance on a working memory task

Full Information

NCT ID

NCT03061136

First Posted

February 15, 2017

Last Updated

April 3, 2018

Sponsor

Palo Alto Veterans Institute for Research

Collaborators

Stanford University, University of California, Los Angeles

1. Study Identification

Unique Protocol Identification Number

NCT03061136

Brief Title

Clonazepam Effects on Brain Oscillations and Cognition in Schizophrenia

Acronym

KGB

Official Title

Clonazepam Effects on Brain Oscillations and Cognition in Schizophrenia

Study Type

Interventional

2. Study Status

Record Verification Date

April 2018

Overall Recruitment Status

Withdrawn

Why Stopped

Delays in equipment procurement prevented the start of the study in time

Study Start Date

October 2016 (undefined)

Primary Completion Date

October 2017 (Actual)

Study Completion Date

October 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Palo Alto Veterans Institute for Research

Collaborators

Stanford University, University of California, Los Angeles

4. Oversight

Data Monitoring Committee

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Schizophrenia, Schizoaffective Disorder, Schizophreniform Disorder

Keywords

Cognition, Gamma oscillations, EEG, Executive function, Benzodiazepine, GABA

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 4

Interventional Study Model

Crossover Assignment

Masking

ParticipantInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

0 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Placebo

Arm Type

Placebo Comparator

Arm Description

Placebo administered orally

Arm Title

Clonazepam 0.1mg

Arm Type

Experimental

Arm Description

0.1mg clonazepam administered orally

Arm Title

Clonazepam 0.2mg

Arm Type

Experimental

Arm Description

0.2mg clonazepam administered orally

Arm Title

Clonazepam 0.3mg

Arm Type

Experimental

Arm Description

0.3mg clonazepam administered orally

Intervention Type

Drug

Intervention Name(s)

Clonazepam

Other Intervention Name(s)

Klonopin

Intervention Type

Drug

Intervention Name(s)

Placebo

Primary Outcome Measure Information:

Title

EEG Gamma-oscillatory power

Description

Gamma-oscillation power is derived from EEG spectrogram, reflecting underlying brain electrical activity

Time Frame

1 day

Secondary Outcome Measure Information:

Title

EEG derived Auditory steady state power

Description

Auditory steady state power is derived from EEG spectrogram, reflecting underlying brain electrical activity responding to auditory stimulation

Time Frame

1 day

Title

Brief Psychiatric Rating Scale (BPRS)

Description

Quantification of level of psychopathology, rater-administered survey

Time Frame

1 day

Title

Scale for the Assessment of Negative Symptoms (SANS)

Description

Quantification of level of negative symptoms, rater-administered survey

Time Frame

1 day

Title

Scale for the Assessment of Positive Symptoms (SAPS)

Description

Quantification of level of positive symptoms, rater-administered survey

Time Frame

1 day

Title

Working memory task accuracy

Description

Subject's behavioral performance on a working memory task

Time Frame

1 day

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

55 Years

Accepts Healthy Volunteers

Eligibility 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.

Facility Information:

Facility Name

VA Palo Alto Health Care System

City

Palo Alto

State/Province

California

ZIP/Postal Code

94304

Country

United States

12. IPD Sharing Statement

Plan to Share IPD

Citations:

PubMed Identifier

16122570

Citation

Bowie CR, Harvey PD. Cognition in schizophrenia: impairments, determinants, and functional importance. Psychiatr Clin North Am. 2005 Sep;28(3):613-33, 626. doi: 10.1016/j.psc.2005.05.004.

Results Reference

background

PubMed Identifier

22178120

Citation

Minzenberg MJ, Carter CS. Developing treatments for impaired cognition in schizophrenia. Trends Cogn Sci. 2012 Jan;16(1):35-42. doi: 10.1016/j.tics.2011.11.017. Epub 2011 Dec 16.

Results Reference

background

PubMed Identifier

20844478

Citation

Lesh TA, Niendam TA, Minzenberg MJ, Carter CS. Cognitive control deficits in schizophrenia: mechanisms and meaning. Neuropsychopharmacology. 2011 Jan;36(1):316-38. doi: 10.1038/npp.2010.156. Epub 2010 Sep 15.

Results Reference

background

PubMed Identifier

19652121

Citation

Minzenberg MJ, Laird AR, Thelen S, Carter CS, Glahn DC. Meta-analysis of 41 functional neuroimaging studies of executive function in schizophrenia. Arch Gen Psychiatry. 2009 Aug;66(8):811-22. doi: 10.1001/archgenpsychiatry.2009.91.

Results Reference

background

PubMed Identifier

25754826

Citation

Cho KK, Hoch R, Lee AT, Patel T, Rubenstein JL, Sohal VS. Gamma rhythms link prefrontal interneuron dysfunction with cognitive inflexibility in Dlx5/6(+/-) mice. Neuron. 2015 Mar 18;85(6):1332-43. doi: 10.1016/j.neuron.2015.02.019. Epub 2015 Mar 5.

Results Reference

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Clonazepam Effects on Brain Oscillations and Cognition in Schizophrenia

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