Utilizing Danish nationwide registers we have consistently displayed that infections and autoimmune diseases increases the risk of developing severe mental disorders in a dose-response relationship, where the risk of severe mental disorders particularly increases with the number of infections exposed to and in a temporal manner. Utilizing large national biobank data, we have shown a small immunogenetic contribution with moderate correlation between the genetic susceptibility for infections and mental disorders. Moreover, at diagnosis there are elevated levels of inflammatory markers in the blood and studies on the cerebrospinal fluid surrounding the brain have shown some evidence for elevated immune markers in the CSF and signs of disrupted blood-brain barrier in some of the patients. Interestingly, our meta-analyses of randomized clinical trials have shown that anti-inflammatory treatment seems to be effective for depression and depressive symptoms and to some extent also for psychotic disorders. However, studies identifying subgroups that would be most likely to respond to immune modulating add-on treatment are still warranted to pave the field forward.

Background: Several lines of evidence point to low-grade inflammation as implicated in the pathophysiology of schizophrenia. Findings in miscellaneous, generally low potency, anti-inflammatory drug trials in schizophrenia remain equivocal regarding antipsychotic efficacy.

Objectives: In a proof of principle study the inflammatory hypothesis is put to the clinical test, investigating if the broad-based and high potency anti-inflammatory drug prednisolone can be of benefit to patients with psychosis. The primary outcome measure is overall change in the Positive and Negative Syndrome Scale (PANSS) 6 weeks after baseline.

Methods: In a randomized, double-blind design, symptomatic patients using stable antipsychotic medication were randomized to prednisolone or placebo and followed for 12 months. Study medication was initiated with 40 mg/day and tapered off and discontinued in 6 weeks.

Results: A total of 12 patients were randomized. The results are not yet published and will be presented in the congress.

Conclusions: The findings were generally promising, but need confirmation in an adequately powered clinical trial.

Conflict of interest: No conflict of interest.

Genetic and experimental data have led to the emerging hypothesis that excessive synaptic elimination is a key disease mechanism in the development of psychosis, with immune factors potentially underlying this process. Crucial knowledge gaps include determining when these biological changes occur during disease development and identifying which patients are affected. These gaps have hindered progress toward intervention studies. This presentation will illustrate how molecular imaging techniques are employed to address these knowledge gaps by targeting brain glial and synaptic markers, in combination with cerebrospinal fluid measurements using a longitudinal, multimodal design. The described work focuses particularly on the early stages of the disease, including individuals at clinical high risk for psychosis.

The endocannabinoid system (ECS) is a ubiquitous signaling system capable of modulating excitatory and inhibitory neurotransmission in the human brain. Cumulating evidence suggests that a dysfunction of the ECS plays a part in the biological etiology of psychoses. For example, the availability of the endocannabinoid type 1 (CB1R) is altered in male patients suffering from first-episode psychosis when compared to healthy controls (HC).¹ A sex difference of the endocannabinoid system has also been documented in both human and animal studies. A difference in the ECS could potentially explain part of the demographic and clinical sex differences seen in psychotic disorders, but studies comparing brain ECS functioning between male and female psychosis patients are lacking.

In this cross-sectional case-control study brain endocannabinoid receptor type 1 (CB1R) availability was measured in medicated male (n=8) and female (n=10) patients with first-episode psychosis (FEP), and age matched male (n=11) and female (n=10) HC subjects. CB1R availability was measured as distribution volumes (VT) of the selective CB1R radiotracer [¹⁸F]FMPEP-d2 using positron emission tomography (PET) and metabolite corrected arterial input. Group status was assigned according to the structured clinical interview for DSM-IV diagnoses. Subjects using oral hormonal contraception were excluded.

A total of 39 male and female subjects were included in the analyses. An rmANOVA model of CB1R availability in the anterior cingulate, hippocampus, thalamus and putamen revealed main effects of group (F(1, 35) = 6.87, p = .013), and sex*group interaction (F(1, 35) = 4.30, p = .045). Within-subjects analyses showed regionally differential effects of group (F(1, 105) = 5.96, p = .0009), and group*sex (F(1, 105) = 4.31, p = .007). There were no significant differences between female FEP and HC subjects (F(3, 54) = 0.10, p = .96). Female and male FEP showed a significant main effect of sex (F(3, 48) = 3.429, p = .024) in post-hoc pair-wise group analyses.

Our results suggest that brain ECS dysregulation is more emphasized in male FEP compared to female FEP, whose CB1R availability did not differ from female HC subjects. The changes also seem to be regionally differential between key areas associated to psychotic disorders and their symptoms. Demographically and regionally selective dysregulation of a pharmacologically targetable signaling system could provide avenues for individualized approaches for treatment and prevention.