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Endocannabinoid Control of Microglia Activation as a New Therapeutic Target in the Treatment of Schizophrenia (CANGLIA)

Primary Purpose

Schizophrenia

Status
Completed
Phase
Not Applicable
Locations
Netherlands
Study Type
Interventional
Intervention
Placebo
Cannabidiol
Sponsored by
UMC Utrecht
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional basic science trial for Schizophrenia focused on measuring Schizophrenia, Cannabidiol, Magnetic Resonance Spectroscopy (1H-MRS), Microglia

Eligibility Criteria

16 Years - 40 Years (Child, Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • A DSM-IV diagnosis of 295.x (schizophrenia, schizophreniform disorder or schizoaffective disorder) or 298.9 (psychosis NOS). Diagnosis must be confirmed in writing by the treating psychiatrist.
  • Age 16 - 40
  • Onset of first psychosis no longer than five years ago
  • Written informed consent of the subject

Exclusion Criteria:

  • Any clinically significant medical condition that may influence the results of the trial or affect the ability to take part in a trial
  • Routine laboratory screening values considered an impediment for participation by a medical doctor (see Appendix 1)
  • Positive urine test on any drug of abuse, except cannabis
  • Treatment with more than one antipsychotic agent or with an unstable dose of one type of antipsychotic medication in the month prior to study inclusion
  • Use of glucocorticosteroids or non-steroidal anti-inflammatory drugs (NSAIDs) within two weeks prior to study inclusion
  • Use of co-medication other than antipsychotics that has a clinically relevant interaction with the cytochrome P450 (CYP) 2C19 or CYP3A classes of liver enzymes within two weeks prior to study inclusion (because CBD may be an inhibitor of these classes of liver enzymes; see paragraph 6.3)
  • Intake of investigational drug within one month prior to study inclusion
  • Daily use of alcohol or drugs of abuse (including cannabis) in the three months prior to study inclusion
  • Any current or previous neurological disorder, including epilepsy
  • History of head injury resulting in unconsciousness lasting at least 1 hour
  • IQ < 70, as measured with Dutch version of the National Adult Reading Test (DART)
  • Breastfeeding, pregnancy or attempting to conceive
  • MRI contraindications, e.g. claustrophobia or metal objects in or around the body

Sites / Locations

  • University Medical Center Utrecht

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Cannabidiol

Placebo

Arm Description

Patients will be treated with 600mg CBD daily for 4 weeks (28 days)

Patients will be treated with placebo daily for 4 weeks (28 days)

Outcomes

Primary Outcome Measures

the concentration of prefrontal metabolites as measured with 1H-MRS
the concentration of prefrontal metabolites as measured with 1H-MRS, with the level of myo-inositol being regarded as a marker of glia function

Secondary Outcome Measures

Tolerability associated with CBD treatment
Number of treatment-related adverse events as assessed by the study physician
Psychotic symptoms
Measured with the Positive and Negative Syndrome Scale (PANSS)
Depressive symptoms
Measured with the Hamilton Depression Rating Scale (HAM-D)
Anxiety
Measured with the State-Trait Anxiety Inventory (STAI)
Clinical impression
Measured with the Clinical Global Impressions Scale (CGI)
Psychosocial functioning
Measured with the Global Assessment of Functioning scale (GAF)
Social and Occupational functioning
Measured with the Social and Occupational Functional Assessment Scale (SOFAS)
Role functioning
Measured with the Global Functioning Role (GF:R) scale
Social functioning
Measured with the Global Functioning Social (GF:S) scale
Cognitive function
Measured with the Brief Assessment of Cognition in Schizophrenia (BACS)
CBD plasma concentrations
Blood cytokine concentrations
Examples of cytokines that could be assessed in the current study include but are not restricted to interferon-γ, interleukin (IL)-1α, IL-1RA, IL-6, IL-10, IL-12, IL-15, tumour necrosis factor-α, and S100B
Haematological blood parameters
Platelet activation and platelet aggregate formation are measured
MRI measures
Brain structure and function

Full Information

First Posted
September 21, 2016
Last Updated
March 26, 2020
Sponsor
UMC Utrecht
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1. Study Identification

Unique Protocol Identification Number
NCT02932605
Brief Title
Endocannabinoid Control of Microglia Activation as a New Therapeutic Target in the Treatment of Schizophrenia
Acronym
CANGLIA
Official Title
Endocannabinoid Control of Microglia Activation as a New Therapeutic Target in the Treatment of Schizophrenia
Study Type
Interventional

2. Study Status

Record Verification Date
March 2020
Overall Recruitment Status
Completed
Study Start Date
November 3, 2017 (Actual)
Primary Completion Date
January 31, 2020 (Actual)
Study Completion Date
January 31, 2020 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
UMC Utrecht

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
The main objective of this study is to compare microglia activation as measured with proton Magnetic Resonance Spectroscopy (1H-MRS) between recent-onset schizophrenia patients who are randomised to CBD and those randomised to placebo.
Detailed Description
Schizophrenia is a chronic and severe mental disorder with an urgent need for new and more effective treatments. A promising novel pharmacological target in this respect is the endocannabinoid system. In particular the cannabinoid compound cannabidiol (CBD) displays a highly favourable profile for development as a new antipsychotic agent. Increasing evidence indicates a significant role for neuroinflammation in the pathophysiology of schizophrenia, especially for activation of resident macrophages of the brain: microglia. Interestingly, converging preclinical evidence suggests that microglia activation is under control of the endocannabinoid system. However, how manipulation of the endocannabinoid system affects microglia activation in humans has not been established, but it is presumably related to clinical improvement of schizophrenia patients. In this project, we propose to study endocannabinoid control of microglia activation as a new therapeutic target in the treatment of schizophrenia. Using a placebo-controlled, randomised, double-blind design, we will investigate this in a group of 36 recent-onset schizophrenia patients after four weeks of daily CBD treatment, in addition to their regular antipsychotic medication. First, we will examine if CBD treatment attenuates microglia activation and levels of peripheral inflammatory markers. In vivo microglia activation is assessed before and after treatment using 1H-MRS, with the level of myo-inositol being regarded as a marker of glia function. Second, we will determine if reduced microglia activation and levels of inflammatory markers relate to improvement of symptomatology and cognitive function. Third, we will assess how microglia activation and levels of inflammatory markers before treatment predict the clinical response to CBD.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Schizophrenia
Keywords
Schizophrenia, Cannabidiol, Magnetic Resonance Spectroscopy (1H-MRS), Microglia

7. Study Design

Primary Purpose
Basic Science
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
32 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Cannabidiol
Arm Type
Experimental
Arm Description
Patients will be treated with 600mg CBD daily for 4 weeks (28 days)
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Patients will be treated with placebo daily for 4 weeks (28 days)
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Placebo
Intervention Type
Drug
Intervention Name(s)
Cannabidiol
Intervention Description
Cannabidiol
Primary Outcome Measure Information:
Title
the concentration of prefrontal metabolites as measured with 1H-MRS
Description
the concentration of prefrontal metabolites as measured with 1H-MRS, with the level of myo-inositol being regarded as a marker of glia function
Time Frame
4 weeks
Secondary Outcome Measure Information:
Title
Tolerability associated with CBD treatment
Description
Number of treatment-related adverse events as assessed by the study physician
Time Frame
4 weeks
Title
Psychotic symptoms
Description
Measured with the Positive and Negative Syndrome Scale (PANSS)
Time Frame
4 weeks
Title
Depressive symptoms
Description
Measured with the Hamilton Depression Rating Scale (HAM-D)
Time Frame
4 weeks
Title
Anxiety
Description
Measured with the State-Trait Anxiety Inventory (STAI)
Time Frame
4 weeks
Title
Clinical impression
Description
Measured with the Clinical Global Impressions Scale (CGI)
Time Frame
4 weeks
Title
Psychosocial functioning
Description
Measured with the Global Assessment of Functioning scale (GAF)
Time Frame
4 weeks
Title
Social and Occupational functioning
Description
Measured with the Social and Occupational Functional Assessment Scale (SOFAS)
Time Frame
4 weeks
Title
Role functioning
Description
Measured with the Global Functioning Role (GF:R) scale
Time Frame
4 weeks
Title
Social functioning
Description
Measured with the Global Functioning Social (GF:S) scale
Time Frame
4 weeks
Title
Cognitive function
Description
Measured with the Brief Assessment of Cognition in Schizophrenia (BACS)
Time Frame
4 weeks
Title
CBD plasma concentrations
Time Frame
4 weeks
Title
Blood cytokine concentrations
Description
Examples of cytokines that could be assessed in the current study include but are not restricted to interferon-γ, interleukin (IL)-1α, IL-1RA, IL-6, IL-10, IL-12, IL-15, tumour necrosis factor-α, and S100B
Time Frame
4 weeks
Title
Haematological blood parameters
Description
Platelet activation and platelet aggregate formation are measured
Time Frame
4 weeks
Title
MRI measures
Description
Brain structure and function
Time Frame
4 weeks

10. Eligibility

Sex
All
Minimum Age & Unit of Time
16 Years
Maximum Age & Unit of Time
40 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: A DSM-IV diagnosis of 295.x (schizophrenia, schizophreniform disorder or schizoaffective disorder) or 298.9 (psychosis NOS). Diagnosis must be confirmed in writing by the treating psychiatrist. Age 16 - 40 Onset of first psychosis no longer than five years ago Written informed consent of the subject Exclusion Criteria: Any clinically significant medical condition that may influence the results of the trial or affect the ability to take part in a trial Routine laboratory screening values considered an impediment for participation by a medical doctor (see Appendix 1) Positive urine test on any drug of abuse, except cannabis Treatment with more than one antipsychotic agent or with an unstable dose of one type of antipsychotic medication in the month prior to study inclusion Use of glucocorticosteroids or non-steroidal anti-inflammatory drugs (NSAIDs) within two weeks prior to study inclusion Use of co-medication other than antipsychotics that has a clinically relevant interaction with the cytochrome P450 (CYP) 2C19 or CYP3A classes of liver enzymes within two weeks prior to study inclusion (because CBD may be an inhibitor of these classes of liver enzymes; see paragraph 6.3) Intake of investigational drug within one month prior to study inclusion Daily use of alcohol or drugs of abuse (including cannabis) in the three months prior to study inclusion Any current or previous neurological disorder, including epilepsy History of head injury resulting in unconsciousness lasting at least 1 hour IQ < 70, as measured with Dutch version of the National Adult Reading Test (DART) Breastfeeding, pregnancy or attempting to conceive MRI contraindications, e.g. claustrophobia or metal objects in or around the body
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Matthijs Bossong, PhD
Organizational Affiliation
UMC Utrecht
Official's Role
Principal Investigator
Facility Information:
Facility Name
University Medical Center Utrecht
City
Utrecht
Country
Netherlands

12. IPD Sharing Statement

Plan to Share IPD
No

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Endocannabinoid Control of Microglia Activation as a New Therapeutic Target in the Treatment of Schizophrenia

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