Markus Leweke - Academia.edu (original) (raw)

Papers by Markus Leweke

British Journal of Psychiatry, 2009

SummaryAnandamide is a bioactive lipid binding to cannabinoid receptors. A homeostatic role for a... more SummaryAnandamide is a bioactive lipid binding to cannabinoid receptors. A homeostatic role for anandamide has been suggested in schizophrenia. We investigated its role in initial prodromal states of psychosis. We measured the levels of anandamide and its structural analog oleoylethanolamide in cerebrospinal fluid and serum of patients in the initial prodromal state (n=27) alongside healthy volunteers (n=81) using high-performance liquid chromatograph/mass spectrometry. Cerebrospinal anandamide levels in patients were significantly elevated. Patients with lower levels showed a higher risk for transiting to psychosis earlier. This anandamidergic up-regulation in the initial prodromal course may suggest a protective role of the endocannabinoid system in early schizophrenia.

Frontiers in Psychiatry

Adolescent individuals often present with subtle, sub-threshold psychiatric syndromes that fluctu... more Adolescent individuals often present with subtle, sub-threshold psychiatric syndromes that fluctuate or persist for years. These symptoms have been classified as Clinically High-Risk mental states (CHR), negatively affecting these individuals’ psychosocial development and integration by reducing performance and affecting interpersonal relations. The pathophysiological underpinnings have not been studied in detail, contributing to the current lack of appropriate intervention strategies. This case report sheds new light on potential pathophysiological mechanisms of this condition, which may be addressed by novel treatment approaches such as cannabidiol. A 19-year-old student presented to our early intervention center with a marked cognitive decline within 6 months, anhedonia, ambivalence, social withdrawal, poverty of speech, and brief intermittent psychotic symptoms (delusions and hallucinations). He was diagnosed with CHR state, and we decided to treat him with the non-psychotomimet...

BMJ Open

IntroductionSleep-wake and circadian disturbance is a key feature of mood disorders with a potent... more IntroductionSleep-wake and circadian disturbance is a key feature of mood disorders with a potential causal role and particular relevance to young people. Brexpiprazole is a second-generation antipsychotic medication with demonstrated efficacy as an adjunct to antidepressant treatment for major depressive disorder (MDD) in adults, with preliminary evidence suggesting greater effectiveness in subgroups of depressed patients with sleep disturbances. This clinical trial aims to evaluate the relationships between changes in sleep-wake and circadian parameters and changes in depressive symptoms following adjunctive brexpiprazole treatment in young adults with MDD and sleep-wake disturbance.Methods and analysisThis study is designed as a 16 week (8 weeks active treatment, 8 weeks follow-up) mechanistic, open-label, single-arm, phase IV clinical trial and aims to recruit 50 young people aged 18–30 with MDD and sleep-wake cycle disturbance through an early intervention youth mental health c...

Frontiers in Psychiatry

Schizophrenia spectrum disorders (SSD) are traditionally diagnosed and categorized through clinic... more Schizophrenia spectrum disorders (SSD) are traditionally diagnosed and categorized through clinical assessment, owing to their complex heterogeneity and an insufficient understanding of their underlying pathology. However, disease progression and accurate clinical diagnosis become problematic when differentiating shared aspects amongst mental health conditions. Hence, there is a need for widely accessible biomarkers to identify and track the neurobiological and pathophysiological development of mental health conditions, including SSD. High-throughput omics applications involving the use of liquid chromatography-mass spectrometry (LC-MS) are driving a surge in biological data generation, providing systems-level insight into physiological and pathogenic conditions. Lipidomics is an emerging subset of metabolomics, largely underexplored amongst the omics systems. Lipid profiles in the brain are highly enriched with well-established functions, including maintenance, support, and signal ...

Frontiers in Pharmacology, 2021

Cannabidiol (CBD), a principal phytocannabinoid constituent, has demonstrated antipsychotic prope... more Cannabidiol (CBD), a principal phytocannabinoid constituent, has demonstrated antipsychotic properties in recent clinical trials. While it has also been suggested a promising candidate for the treatment of neurodegenerative disorders, it failed to demonstrate efficacy in cognitive impairments associated with schizophrenia as an add-on treatment (600 mg/day for 6 weeks) in 18 chronically ill patients co-treated with a variety of psychopharmacologic drugs. Here, we report on the results of parallel-group, active-controlled, mono-therapeutic, double-blind, randomized clinical trial (CBD-CT1; ClinicalTrials.gov identifier: NCT00628290) in 42 acute paranoid schizophrenic patients receiving either CBD (up to 800 mg/day) or amisulpride (AMI, up to 800 mg/day) for four weeks in an inpatient setting with neurocognition as a secondary objective. Twentynine patients (15 and 14 in the CBD and AMI group, respectively) completed two cognitive assessments at baseline and the end of the treatment p...

Medical Journal of Australia, 2019

(Australian Government) has further supported Project Synergy through a significant investment ov... more (Australian Government) has further supported Project Synergy through a significant investment over 3 years (2017-2020) which led to the development of InnoWell Pty Ltd, a joint venture between the University of Sydney and PricewaterhouseCoopers (PwC) Australia. The InnoWell Platform is referred to in the Supplement as one example of a technology-enabled solution to reform mental health care services. The University of Sydney and PwC Australia each have a 45% shareholding in InnoWell. The remaining 10% shareholding is evenly shared between Professor Jane Burns and Professor Ian Hickie.

eLife, 2018

We examined alterations in E/I-balance in schizophrenia (ScZ) through measurements of resting-sta... more We examined alterations in E/I-balance in schizophrenia (ScZ) through measurements of resting-state gamma-band activity in participants meeting clinical high-risk (CHR) criteria (n = 88), 21 first episode (FEP) patients and 34 chronic ScZ-patients. Furthermore, MRS-data were obtained in CHR-participants and matched controls. Magnetoencephalographic (MEG) resting-state activity was examined at source level and MEG-data were correlated with neuropsychological scores and clinical symptoms. CHR-participants were characterized by increased 64–90 Hz power. In contrast, FEP- and ScZ-patients showed aberrant spectral power at both low- and high gamma-band frequencies. MRS-data showed a shift in E/I-balance toward increased excitation in CHR-participants, which correlated with increased occipital gamma-band power. Finally, neuropsychological deficits and clinical symptoms in FEP and ScZ-patients were correlated with reduced gamma band-activity, while elevated psychotic symptoms in the CHR gr...

Translational Psychiatry, 2017

Autoantibodies that bind the N-methyl-D-aspartate receptor (NMDAR) may underlie glutamate recepto... more Autoantibodies that bind the N-methyl-D-aspartate receptor (NMDAR) may underlie glutamate receptor hypofunction and related cognitive impairment found in schizophrenia. Exposure to neurotropic pathogens can foster an autoimmune-prone environment and drive systemic inflammation leading to endothelial barrier defects. In mouse model cohorts, we demonstrate that infection with the protozoan parasite, Toxoplasma gondii, caused sustained elevations of IgG class antibodies to the NMDAR in conjunction with compromised blood-gut and blood-brain barriers. In human cohorts, NMDAR IgG and markers of barrier permeability were significantly associated with T. gondii exposure in schizophrenia compared with controls and independently of antipsychotic medication. Combined T. gondii and NMDAR antibody seropositivity in schizophrenia resulted in higher degrees of cognitive impairment as measured by tests of delayed memory. These data underscore the necessity of disentangling the heterogeneous pathophysiology of schizophrenia so that relevant subsets eligible for NMDAR-related treatment can be identified. Our data aid to reconcile conflicting reports regarding a role of pathological NMDAR autoantibodies in this disorder.

Frontiers in pharmacology, 2016

There is urgent need for the development of mechanistically different and less side-effect prone ... more There is urgent need for the development of mechanistically different and less side-effect prone antipsychotic compounds. The endocannabinoid system has been suggested to represent a potential new target in this indication. While the chronic use of cannabis itself has been considered a risk factor contributing to the development of schizophrenia, triggered by the phytocannabinoid delta-9-tetrahydrocannabinol (Δ(9)-THC), cannabidiol, the second most important phytocannabinoid, appears to have no psychotomimetic potential. Although, results from animal studies are inconsistent to a certain extent and seem to depend on behavioral paradigms, treatment duration and experimental conditions applied, cannabidiol has shown antipsychotic properties in both rodents and rhesus monkeys. After some individual treatment attempts, the first randomized, double-blind controlled clinical trial demonstrated that in acute schizophrenia cannabidiol exerts antipsychotic properties comparable to the antips...

npj Schizophrenia, 2016

Immune aberrations in schizophrenia and bipolar disorder have led to the hypotheses that infectio... more Immune aberrations in schizophrenia and bipolar disorder have led to the hypotheses that infectious agents or corresponding immune responses might contribute to psychiatric etiopathogeneses. We investigated case–control differences in exposure to the opportunistic fungal pathogen, Candida albicans, and examined associations with cognition, medication, lifestyle, and somatic conditions. We quantified C. albicans IgG antibodies in two cohorts totaling 947 individuals and evaluated odds ratios (OR) of exposure with psychiatric disorder using multivariate regressions. The case–control cohort included 261 with schizophrenia, 270 with bipolar disorder, and 277 non-psychiatric controls; the second included 139 with first-episode schizophrenia, 78 of whom were antipsychotic naive. No differences in C. albicans exposures were found until diagnostic groups were stratified by sex. In males, C. albicans seropositivity conferred increased odds for a schizophrenia diagnosis (OR 2.04–9.53, P⩽0.000...

Biological Psychiatry, 2016

Over recent years, the interest in the endocannabinoid system (ECS) as a new target for the treat... more Over recent years, the interest in the endocannabinoid system (ECS) as a new target for the treatment of schizophrenia has evolved. The ECS represents one of the most relevant neurotransmitter systems in the brain and mainly fulfills a homeostatic role in terms of neurotransmission but also with respect to inflammatory processes. Two main approaches to the modulation of endocannabinoid functioning have been chosen so far. First, the selective blockade or inverse agonism of the type 1 cannabinoid receptor has been tested for the improvement of acute psychotic symptoms, as well as for the improvement of cognitive functions in schizophrenia. This was not effective in either case. Second, the modulation of endocannabinoid levels by use of the phytocannabinoid cannabidiol and selective fatty acid amide hydrolase inhibitors has been proposed, and the antipsychotic properties of cannabidiol are currently being investigated in humans. Unfortunately, for most of these trials that have focused on psychopathological and cognitive effects of cannabidiol, no published data are available. However, there is first evidence that cannabidiol may ameliorate psychotic symptoms with a superior side-effect profile compared with established antipsychotics. In conclusion, several clinical trials targeting the ECS in acute schizophrenia have either been completed or are underway. Although publicly available results are currently limited, preliminary data indicate that selected compounds modulating the ECS may be effective in acute schizophrenia. Nevertheless, so far, sample sizes of patients investigated are not sufficient to come to a final judgment, and no maintenance studies are available to ensure long-term efficacy and safety.

Brain, behavior, and immunity, Jan 2, 2015

Traditional schizophrenia pharmacotherapy remains a subjective trial and error process involving ... more Traditional schizophrenia pharmacotherapy remains a subjective trial and error process involving administration, titration and switching of drugs multiple times until an adequate response is achieved. Despite this time-consuming and costly process, not all patients show an adequate response to treatment. As a consequence, relapse is a common occurrence and early intervention is hampered. Here, we have attempted to identify candidate blood biomarkers associated with drug response in 121 initially antipsychotic-free recent-onset schizophrenia patients treated with widely-used antipsychotics, namely olanzapine (n=40), quetiapine (n=23), risperidone (n=30) and a mixture of these drugs (n=28). Patients were recruited and investigated as two separate cohorts to allow biomarker validation. Data analysis showed the most significant relationship between pre-treatment levels of heart-type fatty acid binding protein (H-FABP) and response to olanzapine (p=0.008, F=8.6, β=70.4 in the discovery c...

Translational Psychiatry, 2015

Recent research efforts have progressively shifted towards preventative psychiatry and prognostic... more Recent research efforts have progressively shifted towards preventative psychiatry and prognostic identification of individuals before disease onset. We describe the development of a serum biomarker test for the identification of individuals at risk of developing schizophrenia based on multiplex immunoassay profiling analysis of 957 serum samples. First, we conducted a meta-analysis of five independent cohorts of 127 first-onset drug-naive schizophrenia patients and 204 controls. Using least absolute shrinkage and selection operator regression, we identified an optimal panel of 26 biomarkers that best discriminated patients and controls. Next, we successfully validated this biomarker panel using two independent validation cohorts of 93 patients and 88 controls, which yielded an area under the curve (AUC) of 0.97 (0.95–1.00) for schizophrenia detection. Finally, we tested its predictive performance for identifying patients before onset of psychosis using two cohorts of 445 pre-onset ...

Frontiers in Bioscience, 2011

Translational psychiatry, 2012

Cannabidiol is a component of marijuana that does not activate cannabinoid receptors, but moderat... more Cannabidiol is a component of marijuana that does not activate cannabinoid receptors, but moderately inhibits the degradation of the endocannabinoid anandamide. We previously reported that an elevation of anandamide levels in cerebrospinal fluid inversely correlated to psychotic symptoms. Furthermore, enhanced anandamide signaling let to a lower transition rate from initial prodromal states into frank psychosis as well as postponed transition. In our translational approach, we performed a double-blind, randomized clinical trial of cannabidiol vs amisulpride, a potent antipsychotic, in acute schizophrenia to evaluate the clinical relevance of our initial findings. Either treatment was safe and led to significant clinical improvement, but cannabidiol displayed a markedly superior side-effect profile. Moreover, cannabidiol treatment was accompanied by a significant increase in serum anandamide levels, which was significantly associated with clinical improvement. The results suggest tha...

Brain, behavior, and immunity, 2015

Schizophrenia is a complex brain disorder that may be accompanied by idiopathic inflammation. Cla... more Schizophrenia is a complex brain disorder that may be accompanied by idiopathic inflammation. Classic central nervous system (CNS) inflammatory disorders such as viral encephalitis or multiple sclerosis can be characterized by incongruent serum and cerebrospinal fluid (CSF) IgG due in part to localized intrathecal synthesis of antibodies. The dietary antigens, wheat gluten and bovine milk casein, can induce a humoral immune response in susceptible individuals with schizophrenia, but the correlation between the food-derived serological and intrathecal IgG response is not known. Here, we measured IgG to wheat gluten and bovine milk casein in matched serum and CSF samples from 105 individuals with first-episode schizophrenia (n=75 antipsychotic-naïve), and 61 controls. We found striking correlations in the levels of IgG response to dietary proteins between serum and CSF of schizophrenia patients, but not controls (schizophrenia, R(2)=0.34-0.55, p⩽0.0001; controls R(2)=0.05-0.06, p>0...

Schizophrenia bulletin, Jan 18, 2015

Most of the 13 542 trials contained in the Cochrane Schizophrenia Group's register just teste... more Most of the 13 542 trials contained in the Cochrane Schizophrenia Group's register just tested the general efficacy of pharmacological or psychosocial interventions. Studies on the subsequent treatment steps, which are essential to guide clinicians, are largely missing. This knowledge gap leaves important questions unanswered. For example, when a first antipsychotic failed, is switching to another drug effective? And when should we use clozapine? The aim of this article is to review the efficacy of switching antipsychotics in case of nonresponse. We also present the European Commission sponsored "Optimization of Treatment and Management of Schizophrenia in Europe" (OPTiMiSE) trial which aims to provide a treatment algorithm for patients with a first episode of schizophrenia. We searched Pubmed (October 29, 2014) for randomized controlled trials (RCTs) that examined switching the drug in nonresponders to another antipsychotic. We described important methodological choic...

Schizophrenia bulletin, Jan 10, 2015

Successful treatment of first-episode psychosis is one of the major factors that impacts long-ter... more Successful treatment of first-episode psychosis is one of the major factors that impacts long-term prognosis. Currently, there are no satisfactory biological markers (biomarkers) to predict which patients with a first-episode psychosis will respond to which treatment. In addition, a non-negligible rate of patients does not respond to any treatment or may develop side effects that affect adherence to the treatments as well as negatively impact physical health. Thus, there clearly is a pressing need for defining biomarkers that may be helpful to predict response to treatment and sensitivity to side effects in first-episode psychosis. The present systematic review provides (1) trials that assessed biological markers associated with antipsychotic response or side effects in first-episode psychosis and (2) potential biomarkers associated with biological disturbances that may guide the choice of conventional treatments or the prescription of innovative treatments. Trials including first-e...

The Journal of Neuroscience, 2014

Schizophrenia is characterized by dysfunctions in neural circuits that can be investigated with e... more Schizophrenia is characterized by dysfunctions in neural circuits that can be investigated with electrophysiological methods, such as EEG and MEG. In the present human study, we examined event-related fields (ERFs), in a sample of medication-naive, first-episode schizophrenia (FE-ScZ) patients (n= 14) and healthy control participants (n= 17) during perception of Mooney faces to investigate the integrity of neuromagnetic responses and their experience-dependent modification. ERF responses were analyzed for M100, M170, and M250 components at the sensor and source levels. In addition, we analyzed peak latency and adaptation effects due to stimulus repetition. FE-ScZ patients were characterized by significantly impaired sensory processing, as indicated by a reduced discrimination index (A′). At the sensor level, M100 and M170 responses in FE-ScZ were within the normal range, whereas the M250 response was impaired. However, source localization revealed widespread elevated activity for M1...

Schizophrenia Research, 2013

The origin of inflammation in psychiatric disorders is not well understood. The translocation of ... more The origin of inflammation in psychiatric disorders is not well understood. The translocation of commensal microbiota across the gastrointestinal barrier can result in a persistent state of lowgrade immune activation and/or inflammation. We measured serological surrogate markers of bacterial translocation (soluble CD14 (sCD14) and lipopolysaccharide binding protein (LBP)) in two psychiatric cohorts and compared these levels to C-reactive protein (CRP), body mass index (BMI), and food-related and autoimmune antibodies. The two cohorts were composed of the following: (1) n=141 schizophrenia, n=75 bipolar disorder, n=78 controls; (2) n=78 antipsychoticnaïve first-episode schizophrenia, n=38 medicated first-episode schizophrenia. sCD14 seropositivity conferred a 3.1-fold increased odds of association with schizophrenia (multivariate regressions, OR=3.09, p<0.0001) compared to controls. Case-control differences in sCD14 were not matched by LBP. Quantitative levels of LBP, but not sCD14, correlated with BMI in schizophrenia (R 2 =0.21, p<0.0001). sCD14 and LBP also exhibited some congruency in schizophrenia with both significantly correlated with CRP (R 2 =0.26-0.27, p<0.0001) and elevated in females compared to males (p<0.01). Antipsychotic treatment generally did not impact sCD14 or LBP levels except for significant correlations, especially sCD14, with gluten antibodies in antipsychotic-naïve schizophrenia (R 2 =0.27, p<0.0001). In bipolar disorder, sCD14 levels were significantly correlated with anti-tissue transglutaminase IgG (R 2 =0.37, p<0.001). In conclusion, these bacterial translocation markers produced discordant and complex patterns of activity, a finding that may reflect an imbalanced, activated innate immune state. Whereas both markers may upregulate following systemic exposure to Gram-negative bacteria, non-lipopolysaccharide-based

British Journal of Psychiatry, 2009

SummaryAnandamide is a bioactive lipid binding to cannabinoid receptors. A homeostatic role for a... more SummaryAnandamide is a bioactive lipid binding to cannabinoid receptors. A homeostatic role for anandamide has been suggested in schizophrenia. We investigated its role in initial prodromal states of psychosis. We measured the levels of anandamide and its structural analog oleoylethanolamide in cerebrospinal fluid and serum of patients in the initial prodromal state (n=27) alongside healthy volunteers (n=81) using high-performance liquid chromatograph/mass spectrometry. Cerebrospinal anandamide levels in patients were significantly elevated. Patients with lower levels showed a higher risk for transiting to psychosis earlier. This anandamidergic up-regulation in the initial prodromal course may suggest a protective role of the endocannabinoid system in early schizophrenia.

Frontiers in Psychiatry

Adolescent individuals often present with subtle, sub-threshold psychiatric syndromes that fluctu... more Adolescent individuals often present with subtle, sub-threshold psychiatric syndromes that fluctuate or persist for years. These symptoms have been classified as Clinically High-Risk mental states (CHR), negatively affecting these individuals’ psychosocial development and integration by reducing performance and affecting interpersonal relations. The pathophysiological underpinnings have not been studied in detail, contributing to the current lack of appropriate intervention strategies. This case report sheds new light on potential pathophysiological mechanisms of this condition, which may be addressed by novel treatment approaches such as cannabidiol. A 19-year-old student presented to our early intervention center with a marked cognitive decline within 6 months, anhedonia, ambivalence, social withdrawal, poverty of speech, and brief intermittent psychotic symptoms (delusions and hallucinations). He was diagnosed with CHR state, and we decided to treat him with the non-psychotomimet...

BMJ Open

IntroductionSleep-wake and circadian disturbance is a key feature of mood disorders with a potent... more IntroductionSleep-wake and circadian disturbance is a key feature of mood disorders with a potential causal role and particular relevance to young people. Brexpiprazole is a second-generation antipsychotic medication with demonstrated efficacy as an adjunct to antidepressant treatment for major depressive disorder (MDD) in adults, with preliminary evidence suggesting greater effectiveness in subgroups of depressed patients with sleep disturbances. This clinical trial aims to evaluate the relationships between changes in sleep-wake and circadian parameters and changes in depressive symptoms following adjunctive brexpiprazole treatment in young adults with MDD and sleep-wake disturbance.Methods and analysisThis study is designed as a 16 week (8 weeks active treatment, 8 weeks follow-up) mechanistic, open-label, single-arm, phase IV clinical trial and aims to recruit 50 young people aged 18–30 with MDD and sleep-wake cycle disturbance through an early intervention youth mental health c...

Frontiers in Psychiatry

Schizophrenia spectrum disorders (SSD) are traditionally diagnosed and categorized through clinic... more Schizophrenia spectrum disorders (SSD) are traditionally diagnosed and categorized through clinical assessment, owing to their complex heterogeneity and an insufficient understanding of their underlying pathology. However, disease progression and accurate clinical diagnosis become problematic when differentiating shared aspects amongst mental health conditions. Hence, there is a need for widely accessible biomarkers to identify and track the neurobiological and pathophysiological development of mental health conditions, including SSD. High-throughput omics applications involving the use of liquid chromatography-mass spectrometry (LC-MS) are driving a surge in biological data generation, providing systems-level insight into physiological and pathogenic conditions. Lipidomics is an emerging subset of metabolomics, largely underexplored amongst the omics systems. Lipid profiles in the brain are highly enriched with well-established functions, including maintenance, support, and signal ...

Frontiers in Pharmacology, 2021

Cannabidiol (CBD), a principal phytocannabinoid constituent, has demonstrated antipsychotic prope... more Cannabidiol (CBD), a principal phytocannabinoid constituent, has demonstrated antipsychotic properties in recent clinical trials. While it has also been suggested a promising candidate for the treatment of neurodegenerative disorders, it failed to demonstrate efficacy in cognitive impairments associated with schizophrenia as an add-on treatment (600 mg/day for 6 weeks) in 18 chronically ill patients co-treated with a variety of psychopharmacologic drugs. Here, we report on the results of parallel-group, active-controlled, mono-therapeutic, double-blind, randomized clinical trial (CBD-CT1; ClinicalTrials.gov identifier: NCT00628290) in 42 acute paranoid schizophrenic patients receiving either CBD (up to 800 mg/day) or amisulpride (AMI, up to 800 mg/day) for four weeks in an inpatient setting with neurocognition as a secondary objective. Twentynine patients (15 and 14 in the CBD and AMI group, respectively) completed two cognitive assessments at baseline and the end of the treatment p...

Medical Journal of Australia, 2019

(Australian Government) has further supported Project Synergy through a significant investment ov... more (Australian Government) has further supported Project Synergy through a significant investment over 3 years (2017-2020) which led to the development of InnoWell Pty Ltd, a joint venture between the University of Sydney and PricewaterhouseCoopers (PwC) Australia. The InnoWell Platform is referred to in the Supplement as one example of a technology-enabled solution to reform mental health care services. The University of Sydney and PwC Australia each have a 45% shareholding in InnoWell. The remaining 10% shareholding is evenly shared between Professor Jane Burns and Professor Ian Hickie.

eLife, 2018

We examined alterations in E/I-balance in schizophrenia (ScZ) through measurements of resting-sta... more We examined alterations in E/I-balance in schizophrenia (ScZ) through measurements of resting-state gamma-band activity in participants meeting clinical high-risk (CHR) criteria (n = 88), 21 first episode (FEP) patients and 34 chronic ScZ-patients. Furthermore, MRS-data were obtained in CHR-participants and matched controls. Magnetoencephalographic (MEG) resting-state activity was examined at source level and MEG-data were correlated with neuropsychological scores and clinical symptoms. CHR-participants were characterized by increased 64–90 Hz power. In contrast, FEP- and ScZ-patients showed aberrant spectral power at both low- and high gamma-band frequencies. MRS-data showed a shift in E/I-balance toward increased excitation in CHR-participants, which correlated with increased occipital gamma-band power. Finally, neuropsychological deficits and clinical symptoms in FEP and ScZ-patients were correlated with reduced gamma band-activity, while elevated psychotic symptoms in the CHR gr...

Translational Psychiatry, 2017

Autoantibodies that bind the N-methyl-D-aspartate receptor (NMDAR) may underlie glutamate recepto... more Autoantibodies that bind the N-methyl-D-aspartate receptor (NMDAR) may underlie glutamate receptor hypofunction and related cognitive impairment found in schizophrenia. Exposure to neurotropic pathogens can foster an autoimmune-prone environment and drive systemic inflammation leading to endothelial barrier defects. In mouse model cohorts, we demonstrate that infection with the protozoan parasite, Toxoplasma gondii, caused sustained elevations of IgG class antibodies to the NMDAR in conjunction with compromised blood-gut and blood-brain barriers. In human cohorts, NMDAR IgG and markers of barrier permeability were significantly associated with T. gondii exposure in schizophrenia compared with controls and independently of antipsychotic medication. Combined T. gondii and NMDAR antibody seropositivity in schizophrenia resulted in higher degrees of cognitive impairment as measured by tests of delayed memory. These data underscore the necessity of disentangling the heterogeneous pathophysiology of schizophrenia so that relevant subsets eligible for NMDAR-related treatment can be identified. Our data aid to reconcile conflicting reports regarding a role of pathological NMDAR autoantibodies in this disorder.

Frontiers in pharmacology, 2016

There is urgent need for the development of mechanistically different and less side-effect prone ... more There is urgent need for the development of mechanistically different and less side-effect prone antipsychotic compounds. The endocannabinoid system has been suggested to represent a potential new target in this indication. While the chronic use of cannabis itself has been considered a risk factor contributing to the development of schizophrenia, triggered by the phytocannabinoid delta-9-tetrahydrocannabinol (Δ(9)-THC), cannabidiol, the second most important phytocannabinoid, appears to have no psychotomimetic potential. Although, results from animal studies are inconsistent to a certain extent and seem to depend on behavioral paradigms, treatment duration and experimental conditions applied, cannabidiol has shown antipsychotic properties in both rodents and rhesus monkeys. After some individual treatment attempts, the first randomized, double-blind controlled clinical trial demonstrated that in acute schizophrenia cannabidiol exerts antipsychotic properties comparable to the antips...

npj Schizophrenia, 2016

Immune aberrations in schizophrenia and bipolar disorder have led to the hypotheses that infectio... more Immune aberrations in schizophrenia and bipolar disorder have led to the hypotheses that infectious agents or corresponding immune responses might contribute to psychiatric etiopathogeneses. We investigated case–control differences in exposure to the opportunistic fungal pathogen, Candida albicans, and examined associations with cognition, medication, lifestyle, and somatic conditions. We quantified C. albicans IgG antibodies in two cohorts totaling 947 individuals and evaluated odds ratios (OR) of exposure with psychiatric disorder using multivariate regressions. The case–control cohort included 261 with schizophrenia, 270 with bipolar disorder, and 277 non-psychiatric controls; the second included 139 with first-episode schizophrenia, 78 of whom were antipsychotic naive. No differences in C. albicans exposures were found until diagnostic groups were stratified by sex. In males, C. albicans seropositivity conferred increased odds for a schizophrenia diagnosis (OR 2.04–9.53, P⩽0.000...

Biological Psychiatry, 2016

Over recent years, the interest in the endocannabinoid system (ECS) as a new target for the treat... more Over recent years, the interest in the endocannabinoid system (ECS) as a new target for the treatment of schizophrenia has evolved. The ECS represents one of the most relevant neurotransmitter systems in the brain and mainly fulfills a homeostatic role in terms of neurotransmission but also with respect to inflammatory processes. Two main approaches to the modulation of endocannabinoid functioning have been chosen so far. First, the selective blockade or inverse agonism of the type 1 cannabinoid receptor has been tested for the improvement of acute psychotic symptoms, as well as for the improvement of cognitive functions in schizophrenia. This was not effective in either case. Second, the modulation of endocannabinoid levels by use of the phytocannabinoid cannabidiol and selective fatty acid amide hydrolase inhibitors has been proposed, and the antipsychotic properties of cannabidiol are currently being investigated in humans. Unfortunately, for most of these trials that have focused on psychopathological and cognitive effects of cannabidiol, no published data are available. However, there is first evidence that cannabidiol may ameliorate psychotic symptoms with a superior side-effect profile compared with established antipsychotics. In conclusion, several clinical trials targeting the ECS in acute schizophrenia have either been completed or are underway. Although publicly available results are currently limited, preliminary data indicate that selected compounds modulating the ECS may be effective in acute schizophrenia. Nevertheless, so far, sample sizes of patients investigated are not sufficient to come to a final judgment, and no maintenance studies are available to ensure long-term efficacy and safety.

Brain, behavior, and immunity, Jan 2, 2015

Traditional schizophrenia pharmacotherapy remains a subjective trial and error process involving ... more Traditional schizophrenia pharmacotherapy remains a subjective trial and error process involving administration, titration and switching of drugs multiple times until an adequate response is achieved. Despite this time-consuming and costly process, not all patients show an adequate response to treatment. As a consequence, relapse is a common occurrence and early intervention is hampered. Here, we have attempted to identify candidate blood biomarkers associated with drug response in 121 initially antipsychotic-free recent-onset schizophrenia patients treated with widely-used antipsychotics, namely olanzapine (n=40), quetiapine (n=23), risperidone (n=30) and a mixture of these drugs (n=28). Patients were recruited and investigated as two separate cohorts to allow biomarker validation. Data analysis showed the most significant relationship between pre-treatment levels of heart-type fatty acid binding protein (H-FABP) and response to olanzapine (p=0.008, F=8.6, β=70.4 in the discovery c...

Translational Psychiatry, 2015

Recent research efforts have progressively shifted towards preventative psychiatry and prognostic... more Recent research efforts have progressively shifted towards preventative psychiatry and prognostic identification of individuals before disease onset. We describe the development of a serum biomarker test for the identification of individuals at risk of developing schizophrenia based on multiplex immunoassay profiling analysis of 957 serum samples. First, we conducted a meta-analysis of five independent cohorts of 127 first-onset drug-naive schizophrenia patients and 204 controls. Using least absolute shrinkage and selection operator regression, we identified an optimal panel of 26 biomarkers that best discriminated patients and controls. Next, we successfully validated this biomarker panel using two independent validation cohorts of 93 patients and 88 controls, which yielded an area under the curve (AUC) of 0.97 (0.95–1.00) for schizophrenia detection. Finally, we tested its predictive performance for identifying patients before onset of psychosis using two cohorts of 445 pre-onset ...

Frontiers in Bioscience, 2011

Translational psychiatry, 2012

Cannabidiol is a component of marijuana that does not activate cannabinoid receptors, but moderat... more Cannabidiol is a component of marijuana that does not activate cannabinoid receptors, but moderately inhibits the degradation of the endocannabinoid anandamide. We previously reported that an elevation of anandamide levels in cerebrospinal fluid inversely correlated to psychotic symptoms. Furthermore, enhanced anandamide signaling let to a lower transition rate from initial prodromal states into frank psychosis as well as postponed transition. In our translational approach, we performed a double-blind, randomized clinical trial of cannabidiol vs amisulpride, a potent antipsychotic, in acute schizophrenia to evaluate the clinical relevance of our initial findings. Either treatment was safe and led to significant clinical improvement, but cannabidiol displayed a markedly superior side-effect profile. Moreover, cannabidiol treatment was accompanied by a significant increase in serum anandamide levels, which was significantly associated with clinical improvement. The results suggest tha...

Brain, behavior, and immunity, 2015

Schizophrenia is a complex brain disorder that may be accompanied by idiopathic inflammation. Cla... more Schizophrenia is a complex brain disorder that may be accompanied by idiopathic inflammation. Classic central nervous system (CNS) inflammatory disorders such as viral encephalitis or multiple sclerosis can be characterized by incongruent serum and cerebrospinal fluid (CSF) IgG due in part to localized intrathecal synthesis of antibodies. The dietary antigens, wheat gluten and bovine milk casein, can induce a humoral immune response in susceptible individuals with schizophrenia, but the correlation between the food-derived serological and intrathecal IgG response is not known. Here, we measured IgG to wheat gluten and bovine milk casein in matched serum and CSF samples from 105 individuals with first-episode schizophrenia (n=75 antipsychotic-naïve), and 61 controls. We found striking correlations in the levels of IgG response to dietary proteins between serum and CSF of schizophrenia patients, but not controls (schizophrenia, R(2)=0.34-0.55, p⩽0.0001; controls R(2)=0.05-0.06, p>0...

Schizophrenia bulletin, Jan 18, 2015

Most of the 13 542 trials contained in the Cochrane Schizophrenia Group's register just teste... more Most of the 13 542 trials contained in the Cochrane Schizophrenia Group's register just tested the general efficacy of pharmacological or psychosocial interventions. Studies on the subsequent treatment steps, which are essential to guide clinicians, are largely missing. This knowledge gap leaves important questions unanswered. For example, when a first antipsychotic failed, is switching to another drug effective? And when should we use clozapine? The aim of this article is to review the efficacy of switching antipsychotics in case of nonresponse. We also present the European Commission sponsored "Optimization of Treatment and Management of Schizophrenia in Europe" (OPTiMiSE) trial which aims to provide a treatment algorithm for patients with a first episode of schizophrenia. We searched Pubmed (October 29, 2014) for randomized controlled trials (RCTs) that examined switching the drug in nonresponders to another antipsychotic. We described important methodological choic...

Schizophrenia bulletin, Jan 10, 2015

Successful treatment of first-episode psychosis is one of the major factors that impacts long-ter... more Successful treatment of first-episode psychosis is one of the major factors that impacts long-term prognosis. Currently, there are no satisfactory biological markers (biomarkers) to predict which patients with a first-episode psychosis will respond to which treatment. In addition, a non-negligible rate of patients does not respond to any treatment or may develop side effects that affect adherence to the treatments as well as negatively impact physical health. Thus, there clearly is a pressing need for defining biomarkers that may be helpful to predict response to treatment and sensitivity to side effects in first-episode psychosis. The present systematic review provides (1) trials that assessed biological markers associated with antipsychotic response or side effects in first-episode psychosis and (2) potential biomarkers associated with biological disturbances that may guide the choice of conventional treatments or the prescription of innovative treatments. Trials including first-e...

The Journal of Neuroscience, 2014

Schizophrenia is characterized by dysfunctions in neural circuits that can be investigated with e... more Schizophrenia is characterized by dysfunctions in neural circuits that can be investigated with electrophysiological methods, such as EEG and MEG. In the present human study, we examined event-related fields (ERFs), in a sample of medication-naive, first-episode schizophrenia (FE-ScZ) patients (n= 14) and healthy control participants (n= 17) during perception of Mooney faces to investigate the integrity of neuromagnetic responses and their experience-dependent modification. ERF responses were analyzed for M100, M170, and M250 components at the sensor and source levels. In addition, we analyzed peak latency and adaptation effects due to stimulus repetition. FE-ScZ patients were characterized by significantly impaired sensory processing, as indicated by a reduced discrimination index (A′). At the sensor level, M100 and M170 responses in FE-ScZ were within the normal range, whereas the M250 response was impaired. However, source localization revealed widespread elevated activity for M1...

Schizophrenia Research, 2013

The origin of inflammation in psychiatric disorders is not well understood. The translocation of ... more The origin of inflammation in psychiatric disorders is not well understood. The translocation of commensal microbiota across the gastrointestinal barrier can result in a persistent state of lowgrade immune activation and/or inflammation. We measured serological surrogate markers of bacterial translocation (soluble CD14 (sCD14) and lipopolysaccharide binding protein (LBP)) in two psychiatric cohorts and compared these levels to C-reactive protein (CRP), body mass index (BMI), and food-related and autoimmune antibodies. The two cohorts were composed of the following: (1) n=141 schizophrenia, n=75 bipolar disorder, n=78 controls; (2) n=78 antipsychoticnaïve first-episode schizophrenia, n=38 medicated first-episode schizophrenia. sCD14 seropositivity conferred a 3.1-fold increased odds of association with schizophrenia (multivariate regressions, OR=3.09, p<0.0001) compared to controls. Case-control differences in sCD14 were not matched by LBP. Quantitative levels of LBP, but not sCD14, correlated with BMI in schizophrenia (R 2 =0.21, p<0.0001). sCD14 and LBP also exhibited some congruency in schizophrenia with both significantly correlated with CRP (R 2 =0.26-0.27, p<0.0001) and elevated in females compared to males (p<0.01). Antipsychotic treatment generally did not impact sCD14 or LBP levels except for significant correlations, especially sCD14, with gluten antibodies in antipsychotic-naïve schizophrenia (R 2 =0.27, p<0.0001). In bipolar disorder, sCD14 levels were significantly correlated with anti-tissue transglutaminase IgG (R 2 =0.37, p<0.001). In conclusion, these bacterial translocation markers produced discordant and complex patterns of activity, a finding that may reflect an imbalanced, activated innate immune state. Whereas both markers may upregulate following systemic exposure to Gram-negative bacteria, non-lipopolysaccharide-based