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

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.

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