Bipolar disorder has been hypothesized to, at least partially, be a neuroprogressive illness, characterized by worsening clinical features and potential brain changes over time. This neuroprogression hypothesis suggests that repeated mood episodes lead to cumulative structural and functional brain alterations, potentially exacerbating the course of the disorder. We have addressed this hypothesis through the extensive longitudinal St. Göran study, encompassing individuals with bipolar disorder and healthy controls. Study participants have been followed for up to 14 years, providing a long-term perspective on the neurobiological underpinnings of bipolar disorder.

This presentation will detail findings from repeated magnetic resonance imaging brain scans, biomarker investigations of cerebrospinal fluid, and assessments of cognitive performance. In the brain imaging studies, we find faster ventricular enlargement in bipolar disorder compared with controls, which provide partial support for neuroprogression. However, contrary to what might be expected under a neuroprogressive framework, we did not find accelerated cortical thinning in bipolar disorder, except in relation to manic episodes. Nor do we find accelerated worsening of cognitive performance in bipolar disorder compared with controls. Further, we do not detect signs of an Alzheimer-like neurodegeneration among individuals with bipolar disorder, although certain biomarkers associate with cognitive function. Taken together, our findings challenge some aspects of the neuroprogression theory.

The presentation will discuss these findings, exploring their implications for our understanding of the bipolar disorder pathophysiology and its impact on the brain and cognition over time. We will also consider the limitations of our data and propose directions for future investigations to further elucidate the pathophysiology bipolar disorder.

Abstract not available

Background: Alcohol Use Disorder (AUD) is a devistating disease, afflicting 100 million people and causing 3 million deaths/year and generating enormous costs. With a treatment gap of 90% and few available pharmacothreapies, with low efficacy, there is a need for new treatment options. Based on the reward deficiency hypothesis of AUD, a novel path for developing new treatments is targeting the negative reinforcement generated by a low dopamine state in the brain.

Objective: Exploring if co-administration of two drugs with complementary dopamine enhancing actions, varenicline (a partial nicotinic acetylcholine receptor agonist; 1 mg b.i.d.) and bupropion (a weak dopamine reuptake inhibitor; 150 mg b.i.d.) reduces alcohol intake in moderate/severe AUD.

Methods: A thirteen-week, four-armed, multicenter Randomized Controlled Study (RCT) (n=388; ClinicalTrials.gov NCT04167306) with co-primary outcomes; specific alcohol biomarker phosphatidylethanol (B-PEth), and % heavy drinking days (%HDD) by Time Line Follow Back.

Results: In the modified Intention to Treat (ITT)-analysis (n=384), varenicline+bupropion significantly reduced B-PEth (p<0.004, Cohen´s d=0.39) and %HDD (p<0.008, Cohen´s d=0.31), compared to placebo. Varenicline+placebo also reduced B-PEth (p<0.005, Cohen´s d=0.30) and %HDD (p<0.023, Cohen´s d=0.36), whereas placebo+bupropion was ineffective. In the Per Protocol (PP)-analyses (n=257(B-PEth)/264(%HDD)) effect sizes compared to placebo were larger for varenicline+bupropion (Cohen’s d=0.43 (B-PEth); 0.41 (%HDD)) than for varenicline+placebo (Cohen’s d=0.29 (B-PEth); 0.34 (%HDD)). Secondary outcome alcohol intake (g/day) was also significantly reduced in the varenicline+bupropion group (ITT p<0.002, Cohen´s d=0.44; PP p<0.005, Cohen’s d=0.47). Also, varenicline induced nausea was significantly counteracted both in incidence (p<0.048) and duration (number of days; p<0.010) by bupropion

Conclusion: The results support the reward deficiency hypothesis of AUD by demonstrating that drugs elevating brain dopamine levels reduce alcohol consumption. Effects sizes were largest for the var+bup combination, in the high compliance (PP) population. Bupropion counteracted varenicline-induced nausea. The study further supports B-PEth as an outcome variable in AUD RCTs.

New approaches for the treatment of alcohol dependence (AD) may improve patient outcomes. Substitution maintenance therapy is one of the most effective treatment options for opioid and nicotine use disorders. So far, there has been little attention to substitution therapy for the treatment of AD. This session will explain the main mechanistic foundations of alcohol substitution maintenance therapy. Alcohol has many primary targets in the brain (and other organs) and the physical interaction of ethanol molecules with these specific ethanol-sensitive sites on a variety of ionotropic receptors (e.g. GABA-A, NMDA, and nicotinic acetylcholine (nACh) receptors) and ion channels provides the rationale for substitution. As such, a variety of compounds can interact with those ethanol-sensitive sites and can thus substitute for some of the effects of alcohol. For some of these compounds, alcohol discrimination studies have shown their substitution potential. Accordingly, potential substitution treatments include agonists acting at GABA receptors such as sodium oxybate (SMO). This session will explore whether SMO fulfills the criteria of substitution therapy for AD and will present a detailed analysis of the international clinical development of SMO for AD, focusing on efficacy and safety data in the treatment of Alcohol Withdrawal Syndrome (AWS) and in the maintenance of abstinence. Results will show that SMO is probably the closest to a substitution therapy for AD and is already approved for the treatment of AWS and in the long-term treatment of AD in some countries.

Introduction: Bipolar disorder (BD) is a severe psychiatric condition with unknown etiology and no established biomarkers. This study aimed to characterize the cerebrospinal fluid (CSF) proteome in BD and identify potential protein biomarkers for the disease.

Method: We employed high-resolution nano-liquid chromatography-mass spectrometry to quantify over 2,000 CSF proteins in a total of 375 individuals from two independent cohorts. Case-control comparisons of protein abundance were conducted, followed by differential abundance analyses across BD subtypes.

Results: A total of 135 proteins were associated with BD in the first cohort (5% FDR), with 41 replicated in the second cohort. Compared to controls, BD cases exhibited lower abundance of brain-expressed proteins involved in neuronal cell-cell-interactions and synaptic functions (e.g., APP, NPTX2, NRXN1, NRXN2), and higher abundance of peripherally expressed proteins involved in for example lipid metabolic processes (e.g., APOA4, APOL1), complement pathways (e.g., C4, C4BPA) and extracellular matrix organization (e.g., VTN, LUM). Differential abundance analyses across the bipolar subtypes revealed that these alterations were primarily driven by the BD1 subtype of bipolar disorder.

Conclusion: This study represents the first large-scale untargeted profiling of the CSF proteome in BD. The identified proteins suggest potential contributions from both neuronal and peripheral processes to BD pathophysiology. Further studies are warranted to validate these findings and elucidate the functional roles of these proteins in BD.

Background: While displaying the in vitro pharmacological profile of a dopamine D₂ antagonist and partial 5-HT_2A agonist, the so-called dopamine stabiliser (-)-OSU6162 enhances locomotion in inactive animals but dampens it in active animals. While this profile could be due to preferential antagonism of dopaminergic autoreceptors combined with antagonism of a subpopulation of postsynaptic D₂ receptors, it cannot explain the plethora of behavioural effects displayed by (-)-OSU6162, including antidepressant-like, anxiolytic-like, and antipsychotic-like effects, while (unlike other D₂ antagonists) never causing catalepsy.

Objectives: To explore the mechanisms of action of (-)-OSU6162.

Methods: First, the interaction between (-)-OSU6162 and the dopamine releaser amphetamine with respect to impact on extracellular dopamine levels (assessed using in vivo microdialysis) and on locomotor activity was assessed in rats. Second, the impact of (-)-OSU6162 on locomotion in mice treated with the D₁/D₂ agonist apomorphine after having been deprived of presynaptic dopamine activity by reserpine pre-treatment was explored.

Results: (-)-OSU6162 potentiated an amphetamine-induced increase in extracellular dopamine levels in the dorsal rat striatum but blocked the locomotor response to amphetamine. While these results might suggest that (-)-OSU6162 antagonizes both D₂ autoreceptors and postsynaptic D₂ receptors, the compound did not counter a locomotor-stimulatory effect of the D₁/D₂ agonist apomorphine in monoamine-depleted mice. On the contrary, the combined administration of (-)-OSU6162 and apomorphine caused a synergistic impact on locomotion that was blocked by the 5-HT_2A antagonist MDL 100907. Arguing against (-)-OSU6162 acting merely as a 5-HT_2A partial agonist in this situation, a similar synergistic effect could however not be achieved with the combined treatment of apomorphine and the 5-HT_2A agonist psilocybin.

Conclusion: The results suggest the impact of (-)-OSU6162 to include the interaction of antagonism of D₂autoreceptors, positive allosteric modulation of postsynaptic D₂ receptors, and partial agonism of the 5-HT_2Areceptor.

Background: The Karolinska Schizophrenia Project (KaSP) focuses on exploring the underlying mechanisms of schizophrenia. The project recruits first-episode psychosis (FEP) patients and healthy controls (HC) for comparative studies.

Objectives: The project's goals are to assist in schizophrenia diagnosis, predict the efficacy of antipsychotic treatments, and understand psychosis pathophysiology by examining related metabolic pathways and proteomics signatures.

Methods: Our recent study employed untargeted metabolomics, utilizing ultra-high pressure liquid chromatography and time-of-flight mass spectroscopy. We analyzed cerebrospinal fluid (CSF) and serum samples from 25 FEP patients at baseline and 18-month follow-up, alongside samples from 21 HCs. In another study, we sought to investigate the CSF proteomic signatures associated with FEP. Using 16-plex tandem mass tag (TMT) mass spectrometry, we examined the relative protein quantification of CSF samples from 15 individuals diagnosed with FEP and 15 age-and-sex-matched healthy controls (HC). We have used unsupervised and supervised multi-omics integration to methods to identify signature proteins in CSF.

Findings: The metabolomic analysis revealed distinct psychosis-associated metabolites in both CSF (eight) and serum (32). Notably, increased CSF serotonin (5-HT) levels were observed in FEP patients. This finding was further validated in an extended cohort through reversed-phase high-pressure liquid chromatography. The proteomics analysis revealed sixteen differentially expressed proteins. Unsupervised multi-omics approach revealed different factors associated with immune response and complement activation systems which was not revealed in single omics data modalities.

Conclusion: The integrative multi-omics analysis offers important insights into the pathophysiology of schizophrenia. Through a comprehensive approach combining both metabolomics and proteomics, we have identified important pathway that could help us understand schizophrenia pathophysiology. Notably, the application of unsupervised and supervised multi-omics integration methods unveiled critical factors related to immune response and complement activation systems, aspects not discernible through single-omics analyses.

Background: Chemotherapy cause severe sickness and cognitive disturbances (chemo-brain) in up to 75% of the patients receiving this treatment. These adverse effects are believed to be caused in part by an imbalance of pro- and anti-inflammatory cytokines and it has also been shown that the microbiota modulate the efficacy and toxicity of chemotherapy. Parasitic worms (helminths) can reduce inflammation, restore the gut barrier, and beneficially modulate the host microbiota. Molecules derived from parasite. Helminths are a novel source of biologic therapies, which directly modulate the immune response and microbiota.

Objectives: The objective of this project is to examine the protective effects of the parasite on chemotherapy-induced sickness and chemo-brain. Further, we will explore which underlying biological mechanims that are altered by the parasite. The ultimate goal is to alleviate chemotherapy-induced sickness and chemo-brain.

Methods: Once weekly for 4 weeks, Sprague-Dawley rats are treated with the chemotherapy drug doxorubicin (DOX) and parasite or vehicle. During the DOX+PARASITE treatment the animals are housed in Noldus Phenotyper cages which allow us to record home-cage behaviour. Subsequently, the animals undergo a battery of behavioural tests and tissue is collected. Microbiome, inflammatory markers, and monoamine levels will be examined.

Results: We have shown that parasite ameliorates chemotherapy induced weightloss – a proxy for sickness. We expect parasite to improve cognitive deficits caused by DOX and potentially depressive- and anxiety-like behaviour as well, likely through direct effects on the microbiota and restoration of gut integrity via replenishment of intestinal stem cells

Conclusion: Helminth improve chemotherapy-induced sickness and we expect that cognitive disturbances (chemo-brain) are also improved.

Examining the premise that changes in hormone levels impact mood, as evidenced in conditions such as premenstrual dysphoric disorder, perinatal depression, postpartum depression, and premenopausal depression, along with the consistent observation that major depressive disorder disproportionately affects women, with a lifetime prevalence twice as high as that in men, our objective was to investigate whether antidepressants might engage with the biological elements of this system, particularly estrogen receptor alpha (ERα), to produce their therapeutic effects.

We suggested that antidepressants may alter the activity of ERα. Furthermore, we proposed the possibility of a direct interaction with ERα for all antidepressants, irrespective of their pharmacological classification, with rapid-acting antidepressants preferentially interacting with membrane ERα and initiating non-genomic signaling.

We utilized various molecular and computational tools to demonstrate that ERα may mediate the effect of antidepressants. To further assess whether rapid-acting antidepressants preferentially affect membrane ERα, distinct genes whose expressions are dependent on the activation of either membrane-initiated or nuclear-initiated ERα signaling were studied. Finally, we studied the impact of essential heat-shock proteins in the response evoked by treatment with antidepressants.

Our findings suggested that almost all antidepressants are able to directly interact with ERα, in silico. Subsequent in vitro studies revealed that ketamine and imipramine increased the phosphorylation of ERα, an effect mitigated by pretreatment with fulvestrant. Inhibition of the palmitoylation process, through which ERα is localized to the membrane, resulted in reduced receptor activation, supporting the involvement of membrane-bound ERα in the observed molecular impact exerted by antidepressants. Rapid activation of ERα in MCF-7 cells further corroborated the potential involvement of extranuclear ERα that are associated with immediate estrogen signaling. These findings were also confirmed by employing immunoassay techniques and confocal microscopy.

In an attempt to explore whether estrogen can influence the antidepressant-like behavioral effects of ketamine in a selectively bred genetic animal model of depression, we examined whether such effects could be sex-specific and whether they varied across the estrous cycle in female depressed and non-depressed rats. However, we could not observe any significant sex-specific or estrous cycle-specific behavioral differences in these animals.

This work emphasizes the role of ERα in mood regulation, identifies ERα as a therapeutic target, and raises the possibility that the mechanism of action of all antidepressants may converge on sex steroid receptors. While further studies are warranted, targeting sex steroid receptors could hold promise for the development of novel antidepressant treatments.

The link between schizophrenia and dopamine (DA) is well established, and most antipsychotic medications work via DA D2-receptor antagonism. However, negative symptomatology is often either unaffected or exacerbated by treatment with D2-receptor blockade. This, taken together with imagining studies showing a connection between negative symptoms and low dopaminergic activity in the ventral striatum, suggests that negative symptoms might be alleviated by selective manipulation of ventral striatum DA. In this project we wanted to investigate the dopaminergic profiles of known psychosis-generating drugs versus non-psychosis-generating drugs in the ventral (nucleus accumbens, nAc) and dorsal subregions (dorsomedial striatum, DMS) of the striatum, and to find a way by which we can selectively elevate DA in the nAc in Wistar rats. To this end we used a custom-made dual microdialysis probe which allows for simultaneous sampling of the two brain regions within the same animal. In the first set of experiments, we investigated the dopaminergic profiles of psychosis-generating and non-psychosis-generating drugs. We found that psychosis-generating drugs (amphetamine and cocaine) robustly elevated extracellular DA in both nAc and DMS, whereas the other substances (ethanol, nicotine and morphine) primarily affected DA in the nAc. Building on this, and previous findings showing that, when combined, ethanol and nicotine have an additive effect on accumbal DA, we decided to attempt a selective manipulation of nAc DA by utilising similar pathways by which ethanol and nicotine elevate DA. To do we combined the partial nicotine acetylcholine receptor agonist varenicline with the glycine reuptake inhibitor Org24598. We showed that combination of partial nicotine agonism and glycine reuptake inhibition results in a pronounced elevation of nAc DA, whereas there was no significant effect on DMS DA. This suggest a pathway through which dopamine can be selectively manipulated as a potential route of treatment for negative symptoms in schizophrenia.

(Meth)amphetamine use disorders (MAUD) are increasing substantially, and are associated with increased risk of morbidity and mortality. However, there are no medications approved by authorities for the treatment of amphetamine or methamphetamine dependence, and studies investigating the effectiveness of pharmacological treatments in hard outcomes, such as hospitalization and death, are lacking. Also, borderline personality disorder (BPD) has no established pharmaceutical treatment, even though BPD affects about 1%–2% of the general population. Nevertheless, up to 94% of patients with BPD receive psychotropic medication.

The current knowledge of the effectiveness of pharmacological treatments of MAUD and BPD is largely based on randomized controlled trials (RCTs). RCTs provide information on the efficacy of treatments in standardized settings in selected patient populations, i.e. they tell us if the treatment can work in optimal conditions. Observational studies can inform us about the effectiveness of drugs, indicating whether or not these treatments actually work in a real-life setting. Both of these approaches (RCTs and observational studies) have their pros and cons. In RCTs, randomization eliminates the selection bias, which is a problem in observational studies. On the other hand, highly selected patient populations, limited number of participants, and relatively short follow-up periods in RCTs make it very difficult to study relatively rare outcomes such as death, suicide, or severe adverse effects of medications. Using large unselected nation-wide patient cohorts can overcome these obstacles.

Nordic countries with comprehensive nation-wide registers provide good possibilities for pharmacoepidemiological research. During the last decade, within-individual analysis has been utilized increasingly to eliminate selection bias related to time-invariant characteristics, such as sex, genetics, and initial severity of illness. This research has increased the knowledge on the effectiveness of the pharmacological treatments, for example in schizophrenia, and has contributed to national treatment guidelines in several countries. This lecture will review how the big data have provided new insights to the associations between various pharmacological treatments and mortality and hospitalizations among patients with MAUD and BPD. Especially the ADHD-medication lisdexamphetamine have shown some promising results in reducing mortality, hospitalizations and suicides among persons with either MAUD or BPD. In the cohort of nearly 14 000 persons with MAUD, lisdexamphetamine was associated with reduced risk of hospitalization due to substance use disorders, any hospitalization or death and all-cause mortality. In the other study, concerning the cohort of over 17 500 persons with BPD found that the use of lisdexamphetamine was associated with reduced risk of psychiatric hospitalizations and all-cause hospitalization or death. The use of lisdexamphetamine was also associated with reduced risk of attempted or completed suicide in the cohort of over 22 000 persons with BPD.

Background

Treatment with stimulants is considered the most efficacious treatment for ADHD. Large high-quality studies have estimated the prevalence of AHDH to be 3,4-7,2% for children and adolescents and 2,5-6,8% for young adults. Psychosis and manias are rare but serious side effects of ADHD medications.

Objectives

The aim of this study was to estimate the prevalence of ADHD in Iceland based on ADHD drug prescriptions as well as the risk of hospitalization for first-onset psychosis or mania among adults prescribed ADHD drugs in Iceland.

Materials and Methods

Every citizen receiving a medication prescription is included in the Icelandic Prescription Medicines Registry (IPMR). When assessing the prevalence of ADHD diagnosis, the study included all Icelanders 7-70 years old who received a prescription for an ADHD medication from 1.1.2004-31.12.2023. The risk of psychosis or mania was estimated for adults who were hospitalized within a year after initiation of ADHD drug therapy. To identify individuals who were admitted to hospitals due to psychosis or mania records were linked from the Icelandic Prescription Drug Register to the Icelandic Hospital Discharge Register. There was full access to all relevant hospital records.

Results

In 2023 14,7% of youth, 7-17 years of age, received a prescription for an ADHD medication, 17,7% of boys and 11,6% of girls. For 18-44 years old adults the proportion was 10,2%, 9,4% for males and 11,0% for girls. The incidence of new ADHD prescriptions for 7-17 years old boys from 2021-2023 was 10,9 and 13,5 for girls per 1000, respectively. For 18-44 years old the incidence in the years 2021-2023 was 18,7 for males and 19,2 for females per 1000, respectively.

16,125 individuals 18 years or older initiated ADHD drug therapy from 2010-2022 and 112 were admitted for psychosis or mania within a year of commencing treatment. Of these 61 (54.5%) were hospitalized due to first-onset psychosis or mania, 48 for psychosis and 13 for mania. This corresponds to an estimated absolute risk of 0.38% for first-onset psychosis or mania. Within one year of hospital discharge, 42 of 61 patients had been represcribed an ADHD drug.

Conclusion

The prevalence of Icelanders who have received an ADHD diagnosis is much higher than is observed in larger studies elsewhere. One out of every 264 (0,38%) adults that initiated ADHD drug therapy was hospitalized due to first-onset psychosis or mania within one year of starting ADHD medication .

Introduction The use of medications for attention-deficit/hyperactivity disorder (ADHD) has grown significantly in recent decades. Yet, the long-term cardiovascular risks linked to these medications are not well understood.

Methods A nationwide, nested case-control study was conducted using data from individuals aged 6 to 64 diagnosed with ADHD from 2007 to 2020, through the linkage of various Swedish national databases. The study measured the cumulative duration of ADHD medication use, with a maximum follow-up of 14 years from pharmacy records. The main variable of interest was the occurrence of new-onset cardiovascular diseases (CVDs). Risk association was analysed by calculating adjusted odds ratios (ORs), with their 95% confidence intervals (CIs).

Results The study included 278,027 ADHD patients, identifying 10,388 CVD cases and 51,672 matched controls. The median participant age was 34.6, and 59.2% were male. The median duration of follow-up was 4.1 years. Results indicated a higher CVD risk with longer ADHD medication use compared to no use. Across the 14-year follow-up, a one-year increase of ADHD medication use was associated with a 4% increased risk of CVDs on average (OR, 1.04 [95% CI, 1.03-1.05]), with the increase in risk being more pronounced in the first 3 years of cumulative use (one-year OR, 1.08 [95% CI, 1.04-1.11]) and stable over the remaining extended follow-up. This risk was primarily attributed to hypertension and arterial disease. Both children/adolescents and adults showed similar risk patterns.

Conclusion Long-term use of ADHD medications is associated with heightened CVD risk, particularly for hypertension and arterial diseases. These findings underscore the need for careful risk-benefit assessment in long-term ADHD medication therapy and consistent monitoring of cardiovascular health throughout treatment.

Psychiatry has been standing on the sidelines while oncology and other medical fields have advanced precision medicine. The goal of my research group, the Unit for Biological and Precision Psychiatry at Lund University, is to change this trajectory and word towards “precision psychiatry”. Tailored interventions based on biomarkers and symptom profiles does not only lead to greater efficacy and improved health outcomes, but can also reduce costs (avoiding expenditure on treatment of individuals who will not respond) and improve risk-benefit relationships (avoiding toxicity in people who likely would not benefit from a treatment). Our overreaching aim is to identify biomarkers of antidepressant treatment response and use novel clinical trial designs to redefine the Diagnostic and Statistical Manual of Mental Disorders-based categorical definition of depression into smaller, more homogenous, subgroups that are more likely to respond to specific mechanism-based treatments. In this talk, I will provide examples of ongoing and completed antidepressant clinical trials that use novel study designs including predictive enrichment and match/mismatch approaches. We hope that such approaches could be small pieces of the precision psychiatry puzzle that we and many others are trying to solve.

Classical psychedelics in general and psilocybin in particular has emerged as a potential new class of antidepressants, based on the resluts reported from several small unclontrolled long term follow ups and two larger acute effect RCTs.

Preclinical data suggest the meachanism of action of these drugs to involve rapid generation of novel synapses in eg PFC.

This talk will give a representative overview of the research to-date, and also present preliminary results from PSIPET, a small, single center, double-blind, parallel group RCT of psilocybin in the treatment of remitting MDD.

Pharmacological treatment of pregnant women with depression balances between the woman and her fetus: Untreated maternal depression may negatively influence fetal - and later child brain development and could lead to maternal morbidity and mortality. On the other hand, psychiatric medication may influence the developing fetal brain. The talk will view this dilema from a clinical perspective while giving an overview of the existing literature. The aim is not to give answers but to discuss aspects of the difficult decisions pregnant women with depression may face.

Background: Approximately ¼ of patients with first-episode psychosis do not respond well to standard antipsychotics and are considered treatment-resistant (TR). Patients with treatment resistance have more frequent and severe symptoms, more comorbidities, and are more hospitalized. Approximately ½ of TR patients respond to clozapine, and most guidelines recommend the use of clozapine after two unsuccessful trials of standard antipsychotics. The use of clozapine is, however, often delayed, and an unknown number do not receive any offers to try it at all.

Material and methods: A group of 102 patients with a first episode of schizophrenia spectrum psychosis were recruited during their first treatment, underwent a comprehensive assessment battery at baseline, and were followed up after ten years of treatment.

Results: A total of 28% met the criteria for clinical recovery, 32% met the criteria for treatment resistance, and 40% did not meet either of these criteria (“middle group”). Of the latter group, 11 had at least moderately severe symptoms and dysfunction corresponding to the clinical criteria for TR but had not received two adequate trials of antipsychotics and did thus not meet the full criteria for TR. In addition, only seven patients in the TR group had received a trial of clozapine.

Conclusion: This means that ½ of the poor outcome patients had not received treatment as recommended by current guidelines.

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.