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

• ClinicalTrials.gov Identifier: NCT03061136
• Recruitment Status: Withdrawn
• First Posted: February 23, 2017
• Last Update Posted: April 5, 2018
• Sponsor: Palo Alto Veterans Institute for Research
• Collaborators: Stanford University; University of California, Los Angeles
• Information provided by (Responsible Party): Jong Yoon, Palo Alto Veterans Institute for Research

Tracking Information

• First Submitted Date: February 15, 2017
• First Posted Date: February 23, 2017
• Last Update Posted Date: April 5, 2018
• Study Start Date: October 2016
• Actual Primary Completion Date: October 2017 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: February 17, 2017)

EEG Gamma-oscillatory power [ Time Frame: 1 day ]

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

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: February 17, 2017)

• 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
• Brief Psychiatric Rating Scale (BPRS) [ Time Frame: 1 day ]
  Quantification of level of psychopathology, rater-administered survey
• Scale for the Assessment of Negative Symptoms (SANS) [ Time Frame: 1 day ]
  Quantification of level of negative symptoms, rater-administered survey
• Scale for the Assessment of Positive Symptoms (SAPS) [ Time Frame: 1 day ]
  Quantification of level of positive symptoms, rater-administered survey
• Working memory task accuracy [ Time Frame: 1 day ]
  Subject's behavioral performance on a working memory task

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Clonazepam Effects on Brain Oscillations and Cognition in Schizophrenia
• Official Title: Clonazepam Effects on Brain Oscillations and Cognition in Schizophrenia
• 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.

• Study Type: Interventional
• Study Phase: Phase 4
• Study Design: Allocation: Randomized; Intervention Model: Crossover Assignment; Masking: Triple (Participant, Investigator, Outcomes Assessor); Primary Purpose: Treatment

Condition

• Schizophrenia
• Schizoaffective Disorder
• Schizophreniform Disorder

Intervention

• Drug: Clonazepam
  Other Name: Klonopin
• Drug: Placebo

Study Arms

• Placebo Comparator: Placebo
  Placebo administered orally
  Intervention: Drug: Placebo
• Experimental: Clonazepam 0.1mg
  0.1mg clonazepam administered orally
  Intervention: Drug: Clonazepam
• Experimental: Clonazepam 0.2mg
  0.2mg clonazepam administered orally
  Intervention: Drug: Clonazepam
• Experimental: Clonazepam 0.3mg
  0.3mg clonazepam administered orally
  Intervention: Drug: Clonazepam

Publications *

• 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.
• 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.
• 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.
• 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.
• 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.

Recruitment Information

• Recruitment Status: Withdrawn
• Actual Enrollment (submitted: August 28, 2017): 0
• Original Estimated Enrollment (submitted: February 17, 2017): 24
• Actual Study Completion Date: October 2017
• Actual Primary Completion Date: October 2017 (Final data collection date for primary outcome measure)

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 55 Years (Adult)
• Accepts Healthy Volunteers: Yes
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT03061136
• Other Study ID Numbers: YOJ0004ARC
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Jong Yoon, Palo Alto Veterans Institute for Research
• Original Responsible Party: Palo Alto Veterans Institute for Research
• Current Study Sponsor: Palo Alto Veterans Institute for Research
• Original Study Sponsor: Same as current

Collaborators

• Stanford University
• University of California, Los Angeles

• Investigators: Not Provided
• PRS Account: Palo Alto Veterans Institute for Research
• Verification Date: April 2018