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

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.

Study Overview

• Status: Completed
• Conditions: Schizophrenia
• Intervention / Treatment: Drug: Placebo; Drug: Cannabidiol

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.

• Study Type: Interventional
• Enrollment (Actual): 32
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Netherlands
  • Utrecht, Netherlands
    • University Medical Center Utrecht

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 40 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cannabidiol; Patients will be treated with 600mg CBD daily for 4 weeks (28 days)	Drug: Cannabidiol; Cannabidiol
Placebo Comparator: Placebo; Patients will be treated with placebo daily for 4 weeks (28 days)	Drug: Placebo; Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	4 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Tolerability associated with CBD treatment	Number of treatment-related adverse events as assessed by the study physician	4 weeks
Psychotic symptoms	Measured with the Positive and Negative Syndrome Scale (PANSS)	4 weeks
Depressive symptoms	Measured with the Hamilton Depression Rating Scale (HAM-D)	4 weeks
Anxiety	Measured with the State-Trait Anxiety Inventory (STAI)	4 weeks
Clinical impression	Measured with the Clinical Global Impressions Scale (CGI)	4 weeks
Psychosocial functioning	Measured with the Global Assessment of Functioning scale (GAF)	4 weeks
Social and Occupational functioning	Measured with the Social and Occupational Functional Assessment Scale (SOFAS)	4 weeks
Role functioning	Measured with the Global Functioning Role (GF:R) scale	4 weeks
Social functioning	Measured with the Global Functioning Social (GF:S) scale	4 weeks
Cognitive function	Measured with the Brief Assessment of Cognition in Schizophrenia (BACS)	4 weeks
CBD plasma concentrations		4 weeks
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	4 weeks
Haematological blood parameters	Platelet activation and platelet aggregate formation are measured	4 weeks
MRI measures	Brain structure and function	4 weeks

Collaborators and Investigators

• Sponsor: UMC Utrecht
• Investigators: Principal Investigator: Matthijs Bossong, PhD, UMC Utrecht

Study record dates

Study Major Dates

• Study Start (Actual): November 3, 2017
• Primary Completion (Actual): January 31, 2020
• Study Completion (Actual): January 31, 2020

Study Registration Dates

• First Submitted: September 21, 2016
• First Submitted That Met QC Criteria: October 10, 2016
• First Posted (Estimate): October 13, 2016

Study Record Updates

• Last Update Posted (Actual): March 27, 2020
• Last Update Submitted That Met QC Criteria: March 26, 2020
• Last Verified: March 1, 2020

More Information

Terms related to this study

• Keywords: Schizophrenia; Cannabidiol; Microglia; Magnetic Resonance Spectroscopy (1H-MRS)
• Additional Relevant MeSH Terms: Mental Disorders; Schizophrenia Spectrum and Other Psychotic Disorders; Schizophrenia; Anticonvulsants; Cannabidiol
• Other Study ID Numbers: ABR58805; 2016-003529-41 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No