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

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ClinicalTrials.gov Identifier: NCT02932605
Recruitment Status : Recruiting
First Posted : October 13, 2016
Last Update Posted : November 17, 2017
VU University Medical Center
Information provided by (Responsible Party):
M.G. Bossong, UMC Utrecht

Brief Summary:
The main objective of this study is to compare microglia activation as measured with PET in combination with the tracer [11C]-R-PK11195 between recent-onset schizophrenia patients who are randomised to CBD and those randomised to placebo.

Condition or disease Intervention/treatment
Schizophrenia 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 50 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 Positron Emission Tomography (PET) in combination with the tracer [11C]-R-PK11195. 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  (Clinical Trial)
Estimated Enrollment : 50 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Basic Science
Official Title: Endocannabinoid Control of Microglia Activation as a New Therapeutic Target in the Treatment of Schizophrenia
Anticipated Study Start Date : November 2017
Estimated Primary Completion Date : January 2020
Estimated Study Completion Date : January 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Schizophrenia
U.S. FDA Resources

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

Primary Outcome Measures :
  1. [11C]-R-PK11195 Binding Potential [ Time Frame: 4 weeks ]
    The main study parameter is the [11C]-R-PK11195 BPP, which is the binding potential relative to total plasma concentration after correction for radioactive metabolites. This is an assessment of microglia activation.

Secondary Outcome Measures :
  1. Tolerability associated with CBD treatment [ Time Frame: 4 weeks ]
    Number of treatment-related adverse events as assessed by the study physician

  2. Psychotic symptoms [ Time Frame: 4 weeks ]
    Measured with the Positive and Negative Syndrome Scale (PANSS)

  3. Depressive symptoms [ Time Frame: 4 weeks ]
    Measured with the Hamilton Depression Rating Scale (HAM-D)

  4. Anxiety [ Time Frame: 4 weeks ]
    Measured with the State-Trait Anxiety Inventory (STAI)

  5. Clinical impression [ Time Frame: 4 weeks ]
    Measured with the Clinical Global Impressions Scale (CGI)

  6. Psychosocial functioning [ Time Frame: 4 weeks ]
    Measured with the Global Assessment of Functioning scale (GAF)

  7. Social and Occupational functioning [ Time Frame: 4 weeks ]
    Measured with the Social and Occupational Functional Assessment Scale (SOFAS)

  8. Role functioning [ Time Frame: 4 weeks ]
    Measured with the Global Functioning Role (GF:R) scale

  9. Social functioning [ Time Frame: 4 weeks ]
    Measured with the Global Functioning Social (GF:S) scale

  10. Cognitive function [ Time Frame: 4 weeks ]
    Measured with the Brief Assessment of Cognition in Schizophrenia (BACS)

  11. CBD plasma concentrations [ Time Frame: 4 weeks ]
  12. Blood cytokine concentrations [ Time Frame: 4 weeks ]
    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

  13. RNA expression [ Time Frame: 4 weeks ]
    RNA expression of immune-related genes is measured

  14. Haematological blood parameters [ Time Frame: 4 weeks ]
    Platelet activation and platelet aggregate formation are measured

  15. MRI measures [ Time Frame: 4 weeks ]
    Brain structure and hippocampal glutamate and myoinositol levels are measured

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 40 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • A DSM diagnosis of schizophrenia or schizophreniform disorder as defined by the Comprehensive Assessment of Symptoms and History interview (CASH) (Andreasen et al., 1992)
  • Age 18 - 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 clinically relevant by a medical doctor
  • 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 benzodiazepines, 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)
  • Intake of investigational drug within one month prior to study inclusion
  • Current aggression or dangerous behaviour (PANSS G14 score 5 or above)
  • Current suicidality / self-harm (PANSS G6 score 7)
  • A history of alcohol or substance dependence (except nicotine) within six months prior to study inclusion as measured with CASH
  • 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
  • Significant radiation exposure such that inclusion in this study will take the total dose >10mSv within the preceding 12 months.
  • MRI contraindications, e.g. claustrophobia or metal objects in or around the body

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02932605

Contact: Matthijs Bossong, PhD 0031 88 7556369 m.bossong@umcutrecht.nl

University Medical Center Utrecht Recruiting
Utrecht, Netherlands
Contact: Matthijs Bossong         
Sponsors and Collaborators
UMC Utrecht
VU University Medical Center
Principal Investigator: Matthijs Bossong, PhD UMC Utrecht

Responsible Party: M.G. Bossong, Assistant Professor, UMC Utrecht
ClinicalTrials.gov Identifier: NCT02932605     History of Changes
Other Study ID Numbers: ABR58805
2016-003529-41 ( EudraCT Number )
First Posted: October 13, 2016    Key Record Dates
Last Update Posted: November 17, 2017
Last Verified: November 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by M.G. Bossong, UMC Utrecht:
Positron Emission Tomography (PET)

Additional relevant MeSH terms:
Schizophrenia Spectrum and Other Psychotic Disorders
Mental Disorders