In Vivo Availability of Cannabinoid 1 Receptor Levels in Patients With First-Episode Psychosis

Faith Borgan, Heikki Laurikainen, Mattia Veronese, Tiago Reis Marques, Merja Haaparanta-Solin, Olof Solin, Tarik Dahoun, Maria Rogdaki, Raimo KR Salokangas, Max Karukivi, Marta Di Forti, Federico Turkheimer, Jarmo Hietala, Oliver Howes for the METSY Group

JAMA Psychiatry, 2019.

doi : 10.1001/jamapsychiatry.2019.1427

 

IMPORTANCE

Experimental and epidemiological studies implicate the cannabinoid 1 receptor (CB1R) in the pathophysiology of psychosis. However, whether CB1R levels are altered in the early stages of psychosis and whether they are linked to cognitive function or symptom severity remain unknown.

OBJECTIVE

To investigate CB1R availability in first-episode psychosis (FEP) without the confounds of illness chronicity or the use of illicit substances or antipsychotics.

DESIGN, SETTING, AND PARTICIPANTS

This cross-sectional, case-control study of 2 independent samples included participants receiving psychiatric early intervention services at 2 independent centers in Turku, Finland (study 1) and London, United Kingdom (study 2). Study 1 consisted of 18 volunteers, including 7 patients with affective or nonaffective psychoses taking antipsychotic medication and 11 matched controls; study 2, 40 volunteers, including 20 antipsychotic-naive or antipsychotic-free patients with schizophrenia or schizoaffective disorder and 20 matched controls. Data were collected from January 5, 2015, through September 26, 2018, and analyzed from June 20, 2016, through February 12, 2019.

MAIN OUTCOMES AND MEASURES

The availability of CB1Rwas indexed using the distribution volume (VT, in milliliters per cubic centimeter) of 2 CB1R-selective positron emission tomography radiotracers: fluoride 18–labeled FMPEP-d2 (study 1) and carbon 11–labeled MePPEP (study 2). Cognitive function was measured using the Wechsler Digit Symbol Coding Test. Symptom severity was measured using the Brief Psychiatric Rating Scale for study 1 and the Positive and Negative Syndrome Scale for study 2.

RESULTS

A total of 58 male individuals were included in the analyses (mean [SD] age of controls, 27.16 [5.93] years; mean [SD] age of patients, 26.96 [4.55] years). In study 1, 7 male patients with FEP (mean [SD] age, 26.80 [5.40] years) were compared with 11 matched controls (mean [SD] age, 27.18 [5.86] years); in study 2, 20 male patients with FEP (mean [SD] age, 27.00 [5.06] years) were compared with 20 matched controls (mean [SD] age, 27.15 [6.12] years). In study 1, a significant main effect of group on [18F]FMPEP-d2 VT was found in the anterior cingulate cortex (ACC) (t16 = −4.48; P < .001; Hedges g = 1.2), hippocampus (t16 = −2.98; P = .006; Hedges g = 1.4), striatum (t16 = −4.08; P = .001; Hedges g = 1.9), and thalamus (t16 = −4.67; P < .001; Hedges g = 1.4). In study 2, a significant main effect of group on [11C]MePPEP VT was found in the ACC (Hedges g = 0.8), hippocampus (Hedges g = 0.5), striatum (Hedges g = 0.4), and thalamus (Hedges g = 0.7). In patients, [11C]MePPEP VT in the ACC was positively associated with cognitive functioning (R = 0.60; P = .01), and [11C]MePPEP VT in the hippocampus was inversely associated with Positive and Negative Syndrome Scale total symptom severity (R = −0.50; P = .02).

CONCLUSIONS AND RELEVANCE

The availability of CB1R was lower in antipsychotic-treated and untreated cohorts relative to matched controls. Exploratory analyses indicated that greater reductions in CB1R levels were associated with greater symptom severity and poorer cognitive functioning in male patients. These findings suggest that CB1R may be a potential target for the treatment of psychotic disorders.

 

Schizophrenia and other psychotic disorders affect approximately 1% of the population1 and are rankedwithin the top 10most disabling health conditionsworldwide.2 Meta-analytic findings indicate that cannabis use increases the relative risk of psychosis.3 The main psychoactive chemical in cannabis, delta-9-tetrahydrocannabinol (THC), acts as a partial cannabinoid 1 receptor (CB1R) agonist.4 Short-term use of THC induces psychotic symptoms and cognitive deficits in controls5-7 and exacerbates these symptoms in patients with schizophrenia.8 The most widely studied endogenous CB1R agonist, anandamide (AEA), is also elevated in vivo in cerebrospinal fluid in individuals at risk for psychosis9 and in patients with first-episode psychosis (FEP) who have not received medication and who do not use cannabis.10,11

Cannabinoid 1 receptors are G-protein–coupled receptors expressed on presynaptic nerve terminals of excitatory and inhibitory neurons throughout the cortex, thalamus, hippocampus, and striatum.12 Ex vivo studies in schizophrenia have reported lower CB1R messenger RNA and protein levels13-15 but higher CB1R density.16-19 In vivo studies in schizophrenia have also reported higher20,21 and lower22 CB1R availability. Although higher levels were reported in vivo when no arterial blood sampling was used,20 arterial blood sampling is needed to estimate the proportion of the radiotracer that is available to enter the brain.23 Although higher levels were also reported in the pons (N = 9) when using arterial blood sampling,21 a larger study using the same radiotracer with arterial blood sampling reported lower CB1R availability (N = 25).22 However, both studies21,22 included patients with chronic schizophrenia who were receiving antipsychotics, and in some cases the exclusion of cannabis use or dependence was unclear.21

We therefore investigated in vivo CB1R availability in 2 independent cohorts of patients with FEP. Given the findings from the largest in vivo study,22 we hypothesized that patients would show lower CB1R availability relative to matched controls. Because previous work has shown that CB1R agonists induce cognitive impairments,5,6,8 exploratory analyses investigated the association between CB1R availability and cognition.

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