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

Schizophrenia Clinical Trial

— CANGLIA  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02932605
• Other study ID #: ABR58805
• Secondary ID: 2016-003529-41
• Status: Completed
• Phase: N/A
• Start date: November 3, 2017
• Est. completion date: January 31, 2020

Study information

• Verified date: March 2020
• Source: UMC Utrecht
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 32
• Est. completion date: January 31, 2020
• Est. primary completion date: January 31, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 16 Years to 40 Years

Eligibility

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

Related Conditions & MeSH terms

• Schizophrenia

Intervention

Drug:
• Placebo
Placebo
• Cannabidiol
Cannabidiol

Locations

Country	Name	City	State
Netherlands	University Medical Center Utrecht	Utrecht

Sponsors (1)

Lead Sponsor	Collaborator
UMC Utrecht

Country where clinical trial is conducted

Netherlands, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Tolerability associated with CBD treatment	Number of treatment-related adverse events as assessed by the study physician	4 weeks
Secondary	Psychotic symptoms	Measured with the Positive and Negative Syndrome Scale (PANSS)	4 weeks
Secondary	Depressive symptoms	Measured with the Hamilton Depression Rating Scale (HAM-D)	4 weeks
Secondary	Anxiety	Measured with the State-Trait Anxiety Inventory (STAI)	4 weeks
Secondary	Clinical impression	Measured with the Clinical Global Impressions Scale (CGI)	4 weeks
Secondary	Psychosocial functioning	Measured with the Global Assessment of Functioning scale (GAF)	4 weeks
Secondary	Social and Occupational functioning	Measured with the Social and Occupational Functional Assessment Scale (SOFAS)	4 weeks
Secondary	Role functioning	Measured with the Global Functioning Role (GF:R) scale	4 weeks
Secondary	Social functioning	Measured with the Global Functioning Social (GF:S) scale	4 weeks
Secondary	Cognitive function	Measured with the Brief Assessment of Cognition in Schizophrenia (BACS)	4 weeks
Secondary	CBD plasma concentrations		4 weeks
Secondary	Blood cytokine concentrations	Examples of cytokines that could be assessed in the current study include but are not restricted to interferon-?, interleukin (IL)-1a, IL-1RA, IL-6, IL-10, IL-12, IL-15, tumour necrosis factor-a, and S100B	4 weeks
Secondary	Haematological blood parameters	Platelet activation and platelet aggregate formation are measured	4 weeks
Secondary	MRI measures	Brain structure and function	4 weeks