SchizophreniaPhase 4KGBNCT03061136
Clonazepam Effects on Brain Oscillations and Cognition in Schizophrenia
A Phase 4 study testing Clonazepam in people with Schizophrenia and Schizoaffective Disorder, run by Palo Alto Veterans Institute for Research at 1 site in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 55 yearsHealthy volunteers can take part
- Conditions the study is for
- Schizophrenia, Schizoaffective Disorder, Schizophreniform Disorder
- What is being tested?
- Clonazepam
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 0 participants
- Where
- 1 siteUnited States
- Study dates
- Oct 2016to Oct 2017
- Phase
- Phase 4
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 55 years
- All sexes
- Healthy volunteers accepted
- Adult
Who may be able to join
- 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.
Who cannot join
- 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.
Trial locations and contacts
1 site in 1 country.
United States1 site
VA Palo Alto Health Care System
Palo Alto, California, 94304
About this study
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.
Read the 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.
- Being tested
- Clonazepam, Placebo
- Keywords
- Cognition, Gamma oscillations, EEG, Executive function, Benzodiazepine, GABA
- Medical subject headings
- Schizophrenia, Psychotic Disorders
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
ClonazepamDrug
Also called Klonopin
PlaceboDrug
| Study group | Role | What they receive |
|---|---|---|
| Placebo | Placebo comparator | Placebo administered orally Receives: Drug: Placebo |
| Clonazepam 0.1mg | Experimental | 0.1mg clonazepam administered orally Receives: Drug: Clonazepam |
| Clonazepam 0.2mg | Experimental | 0.2mg clonazepam administered orally Receives: Drug: Clonazepam |
| Clonazepam 0.3mg | Experimental | 0.3mg clonazepam administered orally Receives: Drug: Clonazepam |
What is being measured
The primary outcome is the main question the study is designed to answer.
EEG Gamma-oscillatory power
Gamma-oscillation power is derived from EEG spectrogram, reflecting underlying brain electrical activity
Measured: 1 day
Secondary outcomes (5)
EEG derived Auditory steady state power
Auditory steady state power is derived from EEG spectrogram, reflecting underlying brain electrical activity responding to auditory stimulation
Measured: 1 day
Brief Psychiatric Rating Scale (BPRS)
Quantification of level of psychopathology, rater-administered survey
Measured: 1 day
Scale for the Assessment of Negative Symptoms (SANS)
Quantification of level of negative symptoms, rater-administered survey
Measured: 1 day
Scale for the Assessment of Positive Symptoms (SAPS)
Quantification of level of positive symptoms, rater-administered survey
Measured: 1 day
Working memory task accuracy
Subject's behavioral performance on a working memory task
Measured: 1 day
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted23 Feb 2017
- Study startOct 2016
- Primary completionOct 2017
- Study completionOct 2017
Why it stopped: Delays in equipment procurement prevented the start of the study in time
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (5)Papers the sponsor has linked to this study.
- Other trials for SchizophreniaStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Triple blind
- Who is masked
- Participant, Investigator, Outcomes assessor
- Enrolment
- 0 participants (actual)
Sponsor and investigators
- Lead sponsor
- Palo Alto Veterans Institute for Research
- Sponsor type
- University, hospital or other
- Collaborators
- Stanford University, University of California, Los Angeles
- Responsible party
- Principal investigator, Jong Yoon, Palo Alto Veterans Institute for Research
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03061136
- Sponsor's protocol ID
- YOJ0004ARC
- Acronym
- KGB
- Status last verified
- Apr 2018
- First submitted
- 15 Feb 2017
- Last updated
- 5 Apr 2018
- Results posted
- No
- Data monitoring committee
- No
- Individual data sharing
- No
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.
PubMed 16122570Minzenberg 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.
PubMed 22178120Lesh 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.
PubMed 20844478Minzenberg 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.
PubMed 19652121Cho 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.
PubMed 25754826
Study at a glance
From the registry record, last updated by the sponsor on 5 Apr 2018. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Clonazepam Effects on Brain Oscillations and Cognition in Schizophrenia
- ClinicalTrials.gov ID
- NCT03061136
- Acronym / sponsor ID
- KGB / YOJ0004ARC
- Keywords
- Cognition, Gamma oscillations, EEG, Executive function, Benzodiazepine, GABA
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- WithdrawnReason stopped: Delays in equipment procurement prevented the start of the study in time
- Enrolment
- 0 participants (actual)
- Lead sponsor
- Palo Alto Veterans Institute for ResearchUniversity, hospital or other
- Collaborators
- Stanford University, University of California, Los Angeles
- Study start
- Oct 2016
- Primary completion
- Oct 2017 (actual)
- Study completion
- Oct 2017 (actual)
- First posted
- 23 Feb 2017 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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 design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Triple blind (participant, investigator, outcomes assessor)
- Number of arms
- 4
| Arm | Type | Receives |
|---|---|---|
| Placebo | Placebo comparator | Drug: PlaceboPlacebo administered orally |
| Clonazepam 0.1mg | Experimental | Drug: Clonazepam0.1mg clonazepam administered orally |
| Clonazepam 0.2mg | Experimental | Drug: Clonazepam0.2mg clonazepam administered orally |
| Clonazepam 0.3mg | Experimental | Drug: Clonazepam0.3mg clonazepam administered orally |
Who may qualify
- Ages
- 18 to 55 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (2 listed)
- 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.
Key exclusion criteria (7 listed)
- 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.
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| ClonazepamAlso: Klonopin | Drug | Clonazepam 0.1mg, Clonazepam 0.2mg, Clonazepam 0.3mg |
| Placebo | Drug | Placebo |
Primary outcome
EEG Gamma-oscillatory power
Time frame: 1 day
Gamma-oscillation power is derived from EEG spectrogram, reflecting underlying brain electrical activity
5 secondary outcomes
EEG derived Auditory steady state power
Time frame: 1 day
Brief Psychiatric Rating Scale (BPRS)
Time frame: 1 day
Scale for the Assessment of Negative Symptoms (SANS)
Time frame: 1 day
Scale for the Assessment of Positive Symptoms (SAPS)
Time frame: 1 day
Working memory task accuracy
Time frame: 1 day
Results and safety
The study was withdrawn before enrolling participants, so there are no results.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 5 Apr 2018.
- Background: PubMed 16122570Bowie 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.
- Background: PubMed 22178120Minzenberg 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.
- Background: PubMed 20844478Lesh 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.
- Background: PubMed 19652121Minzenberg 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.
- Background: PubMed 25754826Cho 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.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
The record lists no contact. Use the official record to reach the sponsor.
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Clonazepam in people with Schizophrenia and Schizoaffective Disorder, run by Palo Alto Veterans Institute for Research at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 2 inclusion and 7 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: withdrawn, as of the sponsor's last update on 5 Apr 2018. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study was withdrawn before enrolling participants, so there are no results.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
EEG Gamma-oscillatory power (time frame: 1 day). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03061136, which also lists 5 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 5 Apr 2018.