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Individuals with psychoses have brain alterations, particularly in frontal and temporal cortices, that may be particularly prominent, already at illness onset, in those more likely to have poorer symptom remission following treatment with the first antipsychotic. The identification of strong neuroanatomical markers of symptom remission could thus facilitate stratification and individualized treatment of patients with schizophrenia. We used magnetic resonance imaging at baseline to examine brain regional and network correlates of subsequent symptomatic remission in 167 medication-naïve or minimally treated patients with first-episode schizophrenia, schizophreniform disorder, or schizoaffective disorder entering a three-phase trial, at seven sites. Patients in remission at the end of each phase were randomized to treatment as usual, with or without an adjunctive psycho-social intervention for medication adherence. The final follow-up visit was at 74 weeks. A total of 108 patients (70%) were in remission at Week 4, 85 (55%) at Week 22, and 97 (63%) at Week 74. We found no baseline regional differences in volumes, cortical thickness, surface area, or local gyrification between patients who did or did not achieved remission at any time point. However, patients not in remission at Week 74, at baseline showed reduced structural connectivity across frontal, anterior cingulate, and insular cortices. A similar pattern was evident in patients not in remission at Week 4 and Week 22, although not significantly. Lack of symptom remission in first-episode psychosis is not associated with regional brain alterations at illness onset. Instead, when the illness becomes a stable entity, its association with the altered organization of cortical gyrification becomes more defined.

Whether aberrant cerebral blood flow (CBF) in schizophrenia is affected by genetic influences, and consequently a potential marker for genetic susceptibility, is unknown. Our aims were to determine the heritability of CBF in thalamic, frontal, and striatal areas, and to ascertain if associations with disease were under genetic influence. Monozygotic (MZ) twin pairs concordant (n = 2) or discordant (n = 20) for schizophrenia spectrum disorders (ICD-10 F2x.x), matched on sex and age with dizygotic (DZ; n = 20) and healthy control pairs (MZ: n = 27; DZ: n = 18; total: n = 181 individuals), were recruited via the National Danish Twin Register. CBF in thalamus, frontal lobes, and putamen was measured with pseudo-continuous arterial spin labeling on a 3 T magnetic resonance scanner. Twin statistics were performed with structural equation modeling. CBF in the frontal lobes was heritable (h2 = 0.44, 95% CI [0.22–0.60]) but not correlated to disease. CBF correlated to schizophrenia spectrum disorders in the left thalamus (r = 0.17, [0.03–0.31]; P = 0.02), as well as in the left putamen (r = 0.19, [0.05–0.32]; P = 0.007) and the right putamen (r = 0.18, [0.03–0.32]; P = 0.02). When restricting the sample to schizophrenia (F20.x) only, shared genetic influences between CBF in the left putamen and schizophrenia liability (phenotypic correlation = 0.44, [0.28–0.58], P < 0.001) were found. Our results provide heritability estimates of CBF in the frontal lobes, and we find CBF in thalamus and putamen to be altered in schizophrenia spectrum disorders. Furthermore, shared genetic factors influence schizophrenia liability and striatal perfusion. Specifically, higher perfusion in the left putamen may constitute a marker of genetic susceptibility for schizophrenia.

Background The treatment response of patients with schizophrenia is heterogeneous, and markers of clinical response are missing. Studies using machine learning approaches have provided encouraging results regarding prediction of outcomes, but replicability has been challenging. In the present study, we present a novel methodological framework for applying machine learning to clinical data. Herein, algorithm selection and other methodological choices were based on model performance on a simulated dataset, to minimize bias and avoid overfitting. We subsequently applied the best performing machine learning algorithm to a rich, multimodal neuropsychiatric dataset. We aimed to 1) classify patients from controls, 2) predict short- and long-term clinical response in a sample of initially antipsychotic-naïve first-episode schizophrenia patients, and 3) validate our methodological framework. Methods We included data from 138 antipsychotic-naïve, first-episode schizophrenia patients, who had undergone assessments of psychopathology, cognition, electrophysiology, structural magnetic resonance imaging (MRI). Perinatal data and long-term outcome measures were obtained from Danish registers. Baseline diagnostic classification algorithms also included data from 151 matched healthy controls. Short-term treatment response was defined as change in psychopathology after the initial antipsychotic treatment period. Long-term treatment response (4–16 years) was based on data from Danish registers. The simulated dataset was generated to resemble the real data with respect to dimensionality, multimodality, and pattern of missing data. Noise levels were tunable to enable approximation to the signal-to-noise ratio in the real data. Robustness of the results was ensured by running two parallel, fundamentally different machine learning pipelines, a ‘single algorithm approach’ and an ‘ensemble approach’. Both pipelines included nested cross-validation, missing data imputation, and late integration. Results We significantly classified patients from controls with a balanced accuracy of 64.2% (95% CI = [51.7, 76.7]) for the single algorithm approach and 63.1% (95% CI = [50.4, 75.8]) for the ensemble approach. Post hoc analyses showed that the classification primarily was driven by the cognitive data. Neither approach predicted short- and long-term clinical response. To validate our methodological framework based on simulated data, we selected the best, a medium, and the most poorly performing algorithm on the simulated data and applied them to the real data. We found that the ranking of the algorithms was kept in the real data. Discussion Our rigorous modelling framework incorporating simulated data and parallel pipelines discriminated patients from controls, but our extensive, multimodal neuropsychiatric data from antipsychotic-naïve schizophrenia patients were not predictive of the clinical outcome. Nevertheless, our novel approach holds promise as an important step to obtain reliable, unbiased results with modest sample sizes when independent replication samples are not available.

Background Prediction error is the mismatch between expected and obtained outcome, and psychosis has been linked to aberrant striatal prediction error signal. Several lines of evidence indicate alterations of the glutamatergic system to be involved in the pathophysiology of schizophrenia. We have previously reported abnormal thalamic glutamate levels at illness onset in schizophrenia patients driven by increased levels in non-responding patients, and that glutamatergic levels in the thalamus in twins dis- or concordant for psychosis were heritable and associated with the illness. Glutamatergic abnormalities may affect processing of prediction error; however, it remains unresolved if prediction error is affected by antipsychotic treatment, and to which extend treatment effect on prediction error is predicted by glutamatergic levels in patients characterized as responders or non-responders. Here, we explore treatment effects of aripiprazole on striatal prediction error signal in initially antipsychotic-naïve patients characterized as responders and non-responders and relate the findings to thalamic glutamate levels. We hypothesize a different treatment response in prediction error signal in responders and non-responders, and an association to baseline glutamate levels. Methods Thirty-three patients (age 22 ± 4 years) and 33 healthy controls (HC) matched on age and gender underwent functional Magnetic Resonance imaging (fMRI) and magnetic resonance spectroscopy (1H-MRS) (3T) at baseline and after 6 weeks of treatment with aripiprazole. Prediction error related brain activity was examined using a Monetary Incentive Delay Task. Glutamate levels were estimated in the left thalamus and analyzed using LCModel. In patients, symptom severity was assessed with the Positive and Negative Syndrome Scale. The Andreasen criteria defined responders (N=10) and non- responders (N=23). Repeated measures analysis of variance was used to test the effect of time in prediction error signal with group (responders vs non-responders vs HC) as between subject factor and time as within factor. Analysis of variance, two sample t-test and paired sample t-test evaluated group differences at baseline and follow up. In a multiple regression analyses we investigated the influence of baseline glutamate levels, symptom severity and p-aripiprazole on changes in prediction error signal in both responders and non-responders. Results Repeated measures analysis of prediction error showed an effect of group (p=0.007) and no effect of time (p=0.29) or interaction (p=0.29). The effect of group was explained by an abnormal increased prediction error signal in responders (p=0.047) and non-responders (p=0.011) compared to HC at baseline, which was normalized at follow up in responders (p=0.94) but not in non-responders (p=0.02) compared to HC. Changes in prediction error signal following treatment were predicted by glutamate levels in non-responders (p=0.03) but not in responders (p=0.85) whereas p-aripiprazole and symptom severity did not predict changes in prediction error signal (all p>0.05). Discussion The findings suggest that treatment with a partial dopamine agonist normalizes prediction error signal in patients characterized as responders. Thalamic glutamate seems to play a role in the neural coding of prediction error in patients characterized as non-responders, where increased levels of glutamate in the thalamus seems to predict a less pronounced changes in prediction error signal.

Background Decreased functional magnetic resonance (fMRI) signaling in ventral striatum during reward anticipation has been a consistent finding in unmedicated patients with schizophrenia. Antipsychotic medication may normalize this, which has been associated with improvement in psychotic symptoms. Whether this initial treatment response predict long term clinical outcome have not been examined previously. We here present unique data from a cohort of antipsychotic näive patients, who was examined before and after six weeks of antipsychotic monotherapy, and again after six years of naturalistic treatment. We hypothesized that improved reward related fMRI-signaling in striatum during initial treatment will be associated with less severe symptoms and a higher level of function after six years. Methods Antipsychotic-naïve, first episode patients with schizophrenia and matched healthy controls were examined at three timepoints: Baseline, after six weeks and after six years. During the first six weeks, patients were treated with a D2/3 antagonist, after which they switched to a naturalistic clinical setting. At all three timepoints, fMRI was obtained while participants played a monetary rewarding game. Mean contrast signal during anticipation of salient events was extracted from predefined regions of interest in nucleus accumbens and caudatus. Additionally, symptom severity and level of function were assessed in patients. Remission after six years was defined by the Andreasen criteria. Long term changes in patients were analyzed with paired t-test. Repeated measures ANOVA was used to compare fMRI signal in patients and controls over time. Changes in fMRI signal during the first six weeks was compared between remitted and unremitted patients with students t-test. Correlations between symptom severity, level of function and fMRI signal up were analyzed with Spearman or Pearson as appropriate. Results Long term follow-up data on fMRI and psychopathology was obtained from 25 patients and 28 controls 6.7 (4.3–8.7) years after baseline examinations. In patients, symptomatology and level of function was improved (all p Repeated measures ANOVA of the extracted fMRI contrast signal at baseline and six years showed a group*time interaction in left Nucleus accumbens (F=4.8, p= 0.038) and left caudatus (F= 4.08, p=0=049). Mean contrast signal increased in patients but decreased in healthy controls. Change in contrast signal in left caudatus during the first six weeks of treatment differed between remitted and non-remitted patients (t=2.2, p=0.044). An increase in signal during initial treatment was found in patients later being in remission, which was not observed in non-remitted patients. Decreased fMRI contrast signal in left caudatus at six years follow up was associated with a higher level of negative symptoms (r=-0.44, p=0.02) and a lower level of function (r=0.45, p=0.02). Discussion In this long-term follow up study, half of the patients were in remission 4–8 years after their first schizophrenia diagnosis. These individuals were characterized by a normalization of reward anticipation signaling in left striatal regions during their initial treatment with a selective D2/3 antagonist. Schizophrenia is a diagnosis with a heterogeneous outcome, and prognostic biomarkers are still missing. The present results suggest that normalization in reward processing during initial antipsychotic treatment may predict remission six years later. Although these results need to be reproduced, they do support the notion, that patients responding to antipsychotic treatment are characterized by changes in striatal function, which may be predictive for long-term outcome.

Background Dysfunctional glutamatergic and gamma-aminobutyric acid (GABA)ergic neurotransmission may be part of the schizophrenia pathophysiology and underlie cognitive deficits. Abnormal levels of glutamate and GABA have been found in patients with first-episode psychosis or schizophrenia, and studies of mainly medicated patients have reported correlations between cortical glutamate and GABA levels and cognitive performance. However, the association between metabolites and cognitive deficits may be altered by treatment. Therefore, we investigated if glutamate and GABA levels in dorsal anterior cingulate cortex were associated with cognitive function in a large group of antipsychotic-naïve patients compared with matched healthy controls and tested the hypothesis that cognitive deficits in patients are related to altered levels of glutamate and GABA. Methods We recruited 56 antipsychotic-naïve patients with schizophrenia or psychotic disorder and 51 healthy controls matched for age, sex, and parental education. Magnetic resonance spectroscopy was used to measure glutamate and GABA levels in dorsal anterior cingulate cortex (ACC) on a 3T scanner. The cognitive domains attention (outcome was rapid visual information processing A’ (RVP A’)) and working memory (outcome was spatial working memory (SWM) strategy) were assessed with the Cambridge Neuropsychological Test Automated Battery, and premorbid intelligence estimated with the Danish Adult Reading Test (DART) (outcome was number of words correctly pronounced). A multivariate linear regression model was used to evaluate if levels of glutamate and GABA were different in patients compared with healthy controls, and thereafter to test if glutamate and GABA levels were associated with cognitive performance in the two groups (significant main effect) and if the association differed (significant interaction). SWM strategy score were logarithmically transformed because of non-normality. Results Levels of GABA in dorsal ACC were lower in the antipsychotic-naïve patients compared with healthy controls (SCZ: 2.24±0.35; HC: 2.40±0.33, p=0.03), but glutamate levels did not differ significantly between patients and healthy controls (SCZ: 10.75±1.45; HC: 10.91±1.17, p=0.54). Patients performed significantly worse than healthy controls in tests of attention (mean RVP A’ score SCZ: 0.89±0.05; HC: 0.94±0.04, p There were no significant associations between cognitive function and levels of GABA in dorsal ACC. Discussion This is the largest study of antipsychotic-naïve patients to date to investigate the association between cortical glutamate and GABA levels and cognitive function. We found no group differences in levels of glutamate, but lower GABA levels, which indicates reduced GABAergic neurotransmission in dorsal ACC in the pathophysiology of schizophrenia and psychosis. Higher levels of glutamate in dorsal ACC were associated with better cognitive function. However, glutamate levels did not explain the differences in cognitive performance between patients and healthy controls, indicating that other neurotransmitters are important as well.

Background Schizophrenia is suggested to stem from dysfunction of cortico-striato-thalamo-cortical networks. Supporting this, we have recently found increased glutamate levels in thalamus in antipsychotic-naïve patients with schizophrenia or psychosis. Moreover, higher baseline glutamate levels were related to less improvement of psychotic symptoms after treatment. Other groups have reported that striatal dopaminergic function in patients with psychosis is increased and associated with psychotic symptoms. Regional cerebral blood flow (rCBF) is considered a marker of neuronal activity and can be used to study the cortico-striato-thalamo-cortical networks. Here, we investigated rCBF in a large group of initially antipsychotic-naïve patients with schizophrenia or psychosis before and after treatment and related the findings to changes in psychotic symptoms. Methods rCBF was acquired in 49 initially antipsychotic-naïve patients and 50 matched healthy controls at baseline, and in 32 patients and 53 healthy controls after 6 weeks with the pseudo-Continuous Arterial Spin Labelling (pCASL) sequence. Patients were treated with a partial dopamine D2 receptor agonist (aripiprazole) as monotherapy (mean dose: 10.6±5.4mg). Primary regions of interest of rCBF were thalamus, limbic- and associative striatum. In explorative analyses, we estimated rCBF in sensorimotor striatum, hippocampus-amygdala, and frontal lobe. Psychopathology was assessed with the positive and negative syndrome scale (PANSS). A linear mixed model was used to test if the change in rCBF was different in patients compared with healthy controls (significant interaction) with adjustment for age, sex, and whole brain rCBF. Post hoc tests evaluated possible group differences at baseline and after 6 weeks. In a general linear model, we investigated associations between baseline rCBF in striatum and thalamus and improvement in psychotic symptoms. Results rCBF changed over 6 weeks in all striatal regions (associative striatum: p=0.023; limbic striatum: p=0.004; sensorimotor striatum: p=0.004). Post hoc tests of associative striatum indicated no baseline group differences in rCBF (SCZ/HC: 63.4/65.1 mL/100g/min, p=0.59), however rCBF was higher in patients after 6 weeks (SCZ/HC: 68.8/63.2 mL/100g/min, p=0.049). Post hoc tests of limbic striatum indicated no baseline group differences in rCBF (SCZ/HC: 62.7/65.3 mL/100g/min, p=0.25) and no group differences rCBF after 6 weeks (SCZ/HC: 69.3/63.3 mL/100g/min, p=0.12). Post hoc tests of sensorimotor striatum indicated no baseline group differences in rCBF (SCZ/HC: 72.6/71.2 mL/100g/min, p=0.18), however, rCBF was significantly higher in patients after 6 weeks (SCZ/HC: 80.0/67.2 mL/100g/min, p There were no group differences in the rCBF changes in thalamus (p=0.09), hippocampus-amygdala (p=0.24), frontal lobe (p=0.90), and the whole brain (p=0.14). In patients, higher baseline rCBF in limbic striatum was associated with less improvement in PANSS positive symptoms (p=0.025). We found no other associations between rCBF and psychopathy. Discussion The findings suggest that treatment with a partial dopamine D2 agonist increases rCBF in associative and sensorimotor striatum in initially antipsychotic-naïve patients and that higher rCBF in limbic striatum at baseline is related to poorer treatment outcome. Future studies should investigate the associations between different neurotransmitters and rCBF in vivo. This could further characterize disturbances in cortico-striato-thalamo-cortical networks in schizophrenia or psychosis as well as the effect of treatment.

One of best validated findings in schizophrenia research is the association between blockade of dopamine D2 receptors and the effects of antipsychotics on positive psychotic symptoms. The aim of the present study was to examine correlations between baseline striatal D(2/3) receptor binding potential (BP(p)) values and treatment outcome in a cohort of antipsychotic-naïve first-episode schizophrenia patients. Additionally, we wished to investigate associations between striatal dopamine D(2/3) receptor blockade and alterations of negative symptoms as well as functioning and subjective well-being. Twenty-eight antipsychotic-naïve schizophrenia patients and 26 controls were included in the study. Single-photon emission computed tomography (SPECT) with [(123)I]iodobenzamide ([(123)I]-IBZM) was used to examine striatal D(2/3) receptor BP(p). Patients were examined before and after 6 weeks of treatment with the D(2/3) receptor antagonist amisulpride. There was a significant negative correlation between striatal D(2/3) receptor BP(p) at baseline and improvement of positive symptoms in the total group of patients. Comparing patients responding to treatment to nonresponders further showed significantly lower baseline BP(p) in the responders. At follow-up, the patients demonstrated a negative correlation between the blockade and functioning, whereas no associations between blockade and negative symptoms or subjective well-being were observed. The results show an association between striatal BP(p) of dopamine D(2/3) receptors in antipsychotic-naïve first-episode patients with schizophrenia and treatment response. Patients with a low BP(p) have a better treatment response than patients with a high BP(p). The results further suggest that functioning may decline at high levels of dopamine receptor blockade.

Background Insufficient response to antipsychotics constitutes a challenge in the treatment of patients suffering from schizophrenia. Treatment resistances have been linked to a normal striatal dopamine system. We aim to stratify antipsychotic-naïve first-episode patients based on striatal dopamine synthesis capacity (DSC) measured with positron emission tomography (PET). We hypothesize that patients who respond to treatment have an increased DSC at baseline compared to non-responders and healthy controls (HC). Methods The current data have been collected as a part of a multimodal first episode study. Patients are examined before and after 6 weeks treatment with flexible doses of Aripiprazole. PET: Dynamic scans are performed in an integrated PET-CT scanner using the tracer 3,4-dihydroxy-6-[18F]fluoro-L-phenylalanine (18F-FDOPA). Duration of scanning is two times one hour, with half an hour break. Arterial blood samples are collected during the scanning sessions and provide information on the ratio between intact 18F-FDOPA and the primary metabolite. The input functions used for this data analysis are image derived based on the largest cerebral vessels and metabolite corrected. Regions of interest (ROIs) are manually drawn around the cerebellum and semi automatically around the basal ganglia. In this preliminary work, DSC values are based on Ki parameters obtained from slopes on Patlak plots. Results DSC has been measured at baseline on 16 patients (mean age 22.6 years, 5 males) and 18 HC (mean age 21.7 years, 9 males), with no significant difference in age or gender between groups. At baseline patients had a PANSS total score of 74 (SD 9.6) and GAF total score of 35 (SD 5.2). No significant difference in Ki at baseline was shown between patients and HC. Clinical follow-up data was available on 12 patients. They received a mean Aripiprazole-dose of 9.3 (SD 3.9). Paired t-test at showed a significant effect of treatment with a follow up PANSS total of 55 (SD 11.9, p

Background Higher glutamate levels are found in the anterior cingulate cortex (ACC) of non-responder (NR) patients with schizophrenia in cross-sectional studies. However, it remains unclear if this reflects the pathophysiology of NR patients or the effect of antipsychotics and illness chronicity. Also, no previous study has assessed if levels of GABA in the ACC and glutamate in the thalamus are abnormal in NR patients from illness onset. To investigate this, we examined antipsychotic-naïve schizophrenia (SCZ) patients before and after treatment. Methods Longitudinal study of 38 initially antipsychotic naïve SCZ patients and 34 matched healthy controls (HC) assessed at baseline, after 1.5 months (NSCZ=29, NHC=33), and 6 months (NSCZ=26, NHC=28) of treatment. Patients were treated with aripiprazole for the first 1.5 months (open label). Hereafter, treatment could be modified. Responders (R) and non-responders (NR) were assessed using the Andreasen criteria. Glutamate spectra in the ACC and left thalamus were acquired with a PRESS sequence, and GABA spectra in the ACC with a MEGA-PRESS on a 3T MR scanner. Results First, the trajectory of glutamate/Cr and GABA/Cr levels were evaluated in SCZ patients and HC with a linear mixed model. In the left thalamus, a significant time*group interaction was observed (p=0.01) due to higher levels of glutamate/Cr in SCZ patients at baseline (p=0.03), but not after 1.5 and 6 months’ treatment as compared with HC. In the ACC, a significant main effect of group was found for both glutamate/Cr (p=0.04) and GABA/Cr (p=0.003) due to lower levels in SCZ patients at all examinations, and the time*group interactions were non-significant. Secondly, we investigated if baseline levels of glutamate/Cr and GABA/Cr differed in NR patients after 1.5 and 6 months’ treatment using ANOVA. In the left thalamus, NR patients after both 1.5 and 6 months had significantly higher baseline glutamate/Cr compared with HC (P1.5months=0.03 and P6months

Background: The relation between cognition and cerebral white matter microstructure (WMM) is well known in healthy people and has been studied in schizophrenia as well. Most studies are limited to a few cognitive measures and white matter tracts. The aim of the study was to explore the relationships between several cognitive measures and the complete cerebral WMM and examine whether these relationships differ between schizophrenia patients (PT) and healthy controls (HC).

Background: Preclinical and clinical studies have reported subtle white matter alterations after antipsychotic exposure (Dorph-Petersen et al 2005; Ho et al 2011). It has been debated whether these changes reflect a regulatory effect on oligodendroglial development (Ren et al 2013), or should be ascribed an anti-inflammatory effect due to the inhibition of microglial activation (Kato et al., 2008). In initially antipsychotic naïve patients with schizophrenia, we have previously demonstrated a decreased radial diffusivity (RD) after 6 weeks of treatment with the relative selective D2/3 antagonist, amisulpride (Ebdrup et al, 2015). It is however not clear whether this decrease in RD is due to reduced inflammation or increased myelination. To identify the specific mechanism driving these changes, we combined diffusion tensor imaging (DTI) with magnetization transfer imaging (MTI) in a multi-model design and re-analyzed the effect of 6 weeks of medication.

Background Alterations of the brain reward system is a common finding in patients with psychoses and it may be affected by antipsychotic medication. There are however only few longitudinal studies on medication effect and the effect of a partial dopamine agonist have not previously been examined in patients. The aim of the present study is to explore reward abnormalities in first episode psychotic patients and matched heathy controls (HC) before and after treatment with a partial dopamine agonist (aripiprazole), and relate the findings to dopamine synthesis capacity (F-DOPA-PET), glutamate and GABA levels in the brain (MRS at 3T) and treatment outcome. Here we present preliminary baseline and follow up analyses on functional magnetic resonance imaging (fMRI) only. Methods The project is a part of a multimodal prospective cohort study. Reward related brain activity was examined with fMRI using a variant of the Monetary Incentive Delay Task before and after 6 weeks, where patients were treated with individual doses of aripiprazole. Psychopathology was measured with the Positive and Negative Syndrome Scale (PANSS). Whole brain voxel-wise group comparison was performed at baseline and follow up using two sample t-test with a corrected cluster significant threshold of P=0.05. Likewise, the effect of time and group time interaction was analyzed voxel-wise. Results Inclusion is ongoing and data have been analyzed for 19 patients, age 22.9(4.6), 9 males (47%) and 24 HC, age 22.1(2.7), 11 males (46%). Mean medication dose was 11.7 (6) mg aripiprazole at follow up. Psychopathology: At baseline patients were moderately ill with a mean PANSS total score of 69 (14). Paired t-test showed a significant reduction over time for PANSS total score to 57 (12) (P

Background Glutamatergic changes in schizophrenia may precede dopaminergic alterations leading to psychopathology as part of a dopaminergic pathway, or they may represent a distinct pathophysiology. It is unknown if these glutamatergic alterations are due to genetic influences, although findings in gene studies implicate the NMDA receptor. Higher levels of glutamate and glutamine have been reported in the thalamus of patients with schizophrenia, while studies of the anterior cingulate cortex (ACC) have reported increased, decreased, and unaltered levels compared to healthy controls. By studying discordant mono- (MZ) and dizygotic (DZ) twins it is possible to estimate heritability and correlation to disease in the same population. This kind of study has only been done once on glutamate levels, but no heritability estimates were reported.1 A study of older healthy twins found N-acetyl aspartate (NAA), choline (Cho), creatinine (Cr), and myo-inositol (MI) levels to be heritable in posterior cingulate cortex.2 Of these metabolites, NAA has generally been found to correlate negatively with schizophrenia. Here we present our final results on heritability, and correlation to liability for schizophrenia spectrum disorder (ICD-10 F2x.x) of the neurometabolite levels in the ACC and the left thalamus. Methods By linking The Danish Twin Register and The Danish Psychiatric Central Research Register, 25 complete MZ and 21 complete DZ twin pairs con- or discordant for schizophrenia spectrum disorder (ICD 10 F2x.x) and 29 complete MZ and 20 complete DZ healthy control pairs were included. Thirteen additional twins were scanned without their siblings. Spectra of glutamate, Glx, NAA, Cho, Cr and MI were obtained by [1H]-MR spectroscopy at 3 tesla and analyzed by using LCModel. Additive genetic, common environmental and unique environmental effects on metabolite levels were calculated by structural equation modeling with openMX software. The best fitting model was determined by the Akaike Information Criterion. Results In the ACC heritability estimates were significant for glutamate (29%), Glx (31%), NAA (39%), Cho (38%), Cr (37%) and MI (33%). In the left thalamus we found significant estimates of heritability for glutamate (16%), Glx (31%), Cho (60%), and of common environment for Cr (29%). A significant positive correlation to schizophrenia spectrum liability was found for glutamate in the left thalamus (r=0.16; p = 0.03), and negative correlations were found for NAA (r = -0.16; p = 0.02) and Cr (r = -0.25; p = 0.006) in the ACC. For glutamate in the thalamus and Cr in the ACC the significant correlation to disease was due to overlapping genetic effects influencing both metabolite and disease. Discussion In this the first study to estimate heritability of glutamate levels in the brain, the primary findings are that glutamate levels in both the ACC and the left thalamus are heritable, and in the left thalamus also correlated to disease with a significant genetic overlap. This emphasizes glutamate levels in the left thalamus as a potential endophenotypic marker for schizophrenia. NAA and Cr were negatively correlated to disease in the ACC, which could point to disturbances of neuronal health and metabolism. For Cr an overlap of genes influencing both metabolite levels and disease suggests Cr as a possible candidate endophenotype. References 1. Lutkenhoff ES, van Erp TG, Thomas M a, Therman S, Manninen M, Huttunen MO et al. Proton MRS in twin pairs discordant for schizophrenia. Mol Psychiatry 2010; 15: 308–18. 2. Batouli SAH, Sachdev PS, Wen W, Wright MJ, Suo C, Ames D et al. The heritability of brain metabolites on proton magnetic resonance spectroscopy in older individuals. Neuroimage 2012; 62: 281–289.

Background The search for biomarkers may prove significant for short-term identification of UHR individuals (remission/non-remission). On a long-term basis, biomarkers might give the opportunity to delay or prevent psychotic episodes. Disturbances of the neurotransmitters glutamate and GABA have long been suspected to be involved in the pathophysiology of psychosis. These disorders have also found been found in people at UHR, making it a promising area for early detection. Cognitive deficits in schizophrenia are present prior to the onset of psychosis, and may be linked to perturbed glutamate and GABA function. Data suggest that this link is already present in UHR states. Methods Participants: UHR individuals who meet the CAARMS criteria recruited from Mental Health Services in the Capital Region of Denmark and matching healthy controls. Examinations 1H-MRS of the ACC and thalamus. Diagnostic and psychopathological tests: CAARMS, SCID, SOFAS, PSP, Cornblatt, SANS, BPRS, MADRS, YMRS, CGI, PAS, SPI-A, AQoL Cognitive tests as part of collaborative studies. Results So far 116 UHR individuals and 42 healthy controls have been scanned (December 2017) Very early preliminary analysis of the baseline data finds no significant difference in glutamate levels (in ACC and thalamus) in UHR patients compared to matched healthy controls. Baseline data remains to be analysed in relation to relevant subgroups of patients e.g. based on clinical outcome. GABA analysis and analysis of follow-up data are also yet to be performed. Data will be ready for the meeting, and will be presented. Discussion More studies are needed in this field, since results so far have been diverging. Baseline data remains to be analysed in relation to relevant subgroups of patients e.g. based on clinical outcome. GABA analysis and analysis of follow-up data are also yet to be performed. Glutamate data will be presented at the meeting.

Background Disturbances of the brain reward system is a common finding among patients with schizophrenia. Recent studies have found similar alterations in healthy relatives to patients with schizophrenia and reward disturbances have been suggested to be an endophenotype for schizophrenia. Here we compare brain reward activity between patients with schizophrenia, their healthy co-twin and a sample of matched healthy controls (HC). We hypothesize that patients as well as the healthy co-twins will show reward alterations compared to HC. Methods By coupling information from The Danish Twin register to the Danish Psychiatric Central Research Register, twins with a diagnosis of schizophrenia spectrum disorder were identified and invited to participate in the study. A sample of age and gender matched HC twins were invited as well. All participants went through a diagnostic interview, and psychopathology was characterized with the Positive and Negative Syndrome Scale (PANSS) and Clinical Global Impression (CGI). Current level of function was estimated with Global Assessment of Function (GAF). The reward system was examined with a modified version of the monetary incentive delay task during functional magnetic resonance imaging (fMRI). Results A total of 219 participants were included in the study. Of these, 162 participants completed the fMRI scanning. For statistical reasons (independent observations), only one healthy twin from each HC couple was included in the analyses, which resulted in 116 participants: 42 patients with schizophrenia spectrum disorder, 34 healthy co-twins and 40 HC. Mean age for the whole group was 40.7(10.6) and 64 (55%) were males. There were no group differences in age and sex (p>0.6). Psychopathology Patients had a PANSS total score of 60(18.9), a CGI score of 4.1(1.5) and a GAF score of 55 (14.9). For the co-twins, PANSS-total was 36(7.1), CGI was 1.5(0.9) and a GAF was 78(11.1), whereas the HC had a PANSS total score of 31(1.6), CGI was 1(0.2) and a GAF was 86(5.6). One-way ANOVA showed a significant effect of group for PANSS total, all PANSS sub-scores, CGI and GAF. For all measures, post hoc t-tests showed significant group-differences between co-twins and HC (all p

Background Schizophrenia has been associated with changes in both cortical thickness and surface area, but antipsychotic exposure, illness progression, and substance use may confound the observations. We investigated cortical thickness and surface area, as well as mean curvature, before and after antipsychotic monotherapy with a relatively selective dopamine D2/3 antagonist (amisulpride), in antipsychotic-naïve schizophrenia patients. Methods Fifty-six patients and 59 matched healthy controls (HC) underwent T1-weighted 3T magnetic resonance imaging. Forty-one patients and 51 HCs were re-scanned. FreeSurfer-processed baseline values and symmetrized percentage changes (SPC) in cortical structures were analysed using univariate ANOVA. Clinical measures comprised psychopathology ratings, assessment of functioning, and tests of premorbid and current intelligence. Results At baseline, groups did not differ in cortical thickness or surface area, while left curvature was higher in patients (p=0.015). In the complete sample, a higher curvature was associated with lower premorbid- (p=0.009) and current intelligence (p0.43). A decrease in cortical thickness SPC was associated with less symptom improvement (p=0.002) and increase in surface area SPC was associated with improvement in GAF (p=0.047). Discussion Our results indicate that schizophrenia may be associated with subtle aberrations in cortical structures and these changes appear clinically relevant. Mean curvature holds promise as a sensitive supplement to cortical thickness and surface area, to detect complex structural brain abnormalities.

Background: The cognitive impairments in schizophrenia have been found predictive of poor long-term prognosis and functional outcome. In the search for improving existing intervention strategies, contemporary psychological treatments have combined knowledge from neuroscientific approaches with third-wave cognitive–behavioral therapies. Several studies have examined the effect of cognitive interventions on the brains functional networks, while intervention studies applying structural plasticity as outcome still is in its infancy. This review aims to summarize the evidence on how active interventions can alter structural connectivity and discuss the relevance of using cerebral white matter organization as a biological outcome measure in nonpharmacological psychiatric intervention studies.

Background: Schizophrenia is widely associated with brain structural and dopamine receptor abnormalities, but the relation between these parameters is unknown. In these preliminary analyses, we investigated associations between cortical thickness and striatal D2/3 binding potentials (BP) changes in antipsychotic-naive patients with schizophrenia.