Psychotic disorders have been linked to immune-system abnormalities, increased inflammatory markers, and subtle neuroinflammation. Studies further suggest a dysfunctional blood brain barrier (BBB). The endothelial Glycocalyx (GLX) functions as a protective layer in the BBB, and GLX shedding leads to BBB dysfunction. This study aimed to investigate whether a panel of 11 GLX molecules derived from peripheral blood could differentiate antipsychotic-naïve first-episode psychosis patients (n47) from healthy controls (HC, n49) and whether GLX shedding correlated with symptom severity. Blood samples were collected at baseline and serum was isolated for GLX marker detection. Machine learning models were applied to test whether patterns in GLX markers could classify patient groups. Associations between GLX markers and symptom severity were explored. Patients showed significantly increased levels of three GLX markers compared to HC. Based on the panel of 11 GLX markers, machine learning models achieved a significant mean classification accuracy of 81%. Post hoc analysis revealed associations between increased GLX markers and symptom severity. This study demonstrates the potential of GLX molecules as immuno-neuropsychiatric biomarkers for early diagnosis of psychosis, as well as indicate a compromised BBB. Further research is warranted to explore the role of GLX in the early detection of psychotic disorders.

BACKGROUND: GABAergic (gamma-aminobutyric acidergic) function in the prefrontal cortex seems dysfunctional in patients with first-episode psychosis, but the impact of longer-term treatment and relationship to clinical outcomes and striatal activity are unknown. METHODS: A longitudinal study of 39 antipsychotic-naive and benzodiazepine-free patients with psychosis (22.4 +/- 5.4 years, 64% women) and 54 matched healthy control participants (HCs) (22.2 +/- 4.3 years, 61% women) who were followed up after 6 weeks (28 patients, 51 HCs), 6 months (17 patients, 47 HCs), and 2 years (21 patients, 43 HCs) was completed. GABA levels in the dorsal anterior cingulate cortex and striatal resting cerebral blood flow were assessed on a 3T magnetic resonance scanner at all visits. RESULTS: GABA levels in the dorsal anterior cingulate cortex were significantly lower in patients at baseline and after 6 weeks but not after 6 months or 2 years. Analyses of groups separately revealed decreased GABA levels after 2 years in HCs but stable levels in patients. Treatment increased striatal resting cerebral blood flow after 6 weeks and 6 months but not after 2 years. GABA levels were negatively associated with striatal resting cerebral blood flow in both groups at all visits. Last, lower baseline GABA levels in patients were related to less functional improvement after 2 years. CONCLUSIONS: The findings suggest a different trajectory of GABA levels and striatal perfusion in first-episode patients over 2 years of antipsychotic treatment compared with HCs and indicate a downregulatory role of prefrontal GABAergic function on the striatum. Moreover, abnormally low prefrontal GABA level at illness onset may be a marker for a more severe prognosis.

Aberrant neuronal coding of reward processing has been linked to psychosis. It remains unresolved how treatment with a partial dopamine agonist affects reward processing, and whether treatment affects reward processing differently in patients responding and not responding to treatment. Here, 33 antipsychotic-naïve psychosis patients and 33 matched healthy controls underwent functional magnetic resonance imaging before and after patients received aripiprazole monotherapy for six weeks. Processing of motivational salient events and negative outcome evaluation (NOE) was examined using a monetary incentive delay task. Psychopathology was assessed with the Positive and Negative Syndrome Scale, and responders were identified by having ≥30% reduction in positive symptoms (N=21). At baseline, patients displayed an increased NOE signal in the caudate and dorsolateral prefrontal cortex compared to healthy controls. In the caudate, the NOE signal was normalized at follow-up, and normalization was driven by responders. In responders only, there was a significant improvement in the motivational salience signal in the caudate at follow-up. Motivational salience and NOE signals in the caudate may be associated with a dopaminergic mechanism in patients characterized as responders which may not be the case in non-responders. Likewise, non-dopaminergic mechanism may underly abnormal NOE processing in dorsolateral prefrontal cortex.

BACKGROUND: Disturbances in presynaptic dopamine activity and levels of GABA (gamma-aminobutyric acid) and glutamate plus glutamine collectively may have a role in the pathophysiology of psychosis, although separately they are poor diagnostic markers. We tested whether these neurotransmitters in combination improve the distinction of antipsychotic-naive patients with first-episode psychosis from healthy control subjects.METHODS: We included 23 patients (mean age 22.3 years, 9 male) and 20 control subjects (mean age 22.4 years, 8 male). We determined dopamine metabolism in the nucleus accumbens and striatum from 18F-fluorodopa (18F-FDOPA) positron emission tomography. We measured GABA levels in the anterior cingulate cortex (ACC) and glutamate plus glutamine levels in the ACC and left thalamus with 3T proton magnetic resonance spectroscopy. We used binominal logistic regression for unimodal prediction when we modeled neurotransmitters individually and for multimodal prediction when we combined the 3 neurotransmitters. We selected the best combination based on Akaike information criterion. RESULTS: Individual neurotransmitters failed to predict group. Three triple neurotransmitter combinations signifi-cantly predicted group after Benjamini-Hochberg correction. The best model (Akaike information criterion 48.5) carried 93.5% of the cumulative model weight. It reached a classification accuracy of 83.7% (p = .003) and included dopamine synthesis capacity (Ki4p) in the nucleus accumbens (p = .664), GABA levels in the ACC (p = .019), glutamate plus glutamine levels in the thalamus (p = .678), and the interaction term Ki4p 3 GABA (p = .016).CONCLUSIONS: Our multimodal approach proved superior classification accuracy, implying that the pathophysi-ology of patients represents a combination of neurotransmitter disturbances rather than aberrations in a single neurotransmitter. Particularly aberrant interrelations between Ki4p in the nucleus accumbens and GABA values in the ACC appeared to contribute diagnostic information.

BACKGROUND:Resting cerebral blood flow (rCBF) in striatum and thalamus is increased in medicated patients with psychosis, but whether this is caused by treatment or illness pathology is unclear. Specifically, effects of partial dopamine agonism, sex, and clinical correlates on rCBF are sparsely investigated. We therefore assessed rCBF in antipsychotic-naïve psychosis patients before and after aripiprazole monotherapy and related findings to sex and symptom improvement. METHODS:We assessed rCBF with the pseudo-Continuous Arterial Spin Labeling (PCASL) sequence in 49 first-episode patients (22.6 ± 5.2 years, 58% females) and 50 healthy controls (HCs) (22.3 ± 4.4 years, 63% females) at baseline and in 29 patients and 49 HCs after six weeks. RCBF in striatum and thalamus was estimated with a region-of-interest (ROI) approach. Psychopathology was assessed with the positive and negative syndrome scale. RESULTS:Baseline rCBF in striatum and thalamus was not altered in the combined patient group compared with HCs, but female patients had lower striatal rCBF compared with male patients (p = 0.009). Treatment with a partial dopamine agonist increased rCBF significantly in striatum (p = 0.006) in the whole patient group, but not significantly in thalamus. Baseline rCBF in nucleus accumbens was negatively associated with improvement in positive symptoms (p = 0.046), but baseline perfusion in whole striatum and thalamus was not related to treatment outcome. CONCLUSIONS:The findings suggest that striatal perfusion is increased by partial dopamine agonism and decreased in female patients prior to first treatment. This underlines the importance of treatment effects and sex differences when investigating the neurobiology of psychosis.

BACKGROUND: Dopamine activity has been associated with the response to antipsychotic treatment. Our study used a four-parameter model to test the association between the striatal decarboxylation rate of F-18-DOPA to F-18 dopamine (k(3)) and the effect of treatment on psychotic symptoms in antipsychotic-naive patients with first episode psychosis. We further explored the effect of treatment with a partial dopamine D-2 receptor agonist (aripiprazole) on k(3) and dopamine synthesis capacity (DSC) determined by the four-parameter model and by the conventional tissue reference method. METHODS: Sixty-two individuals (31 patients and 31 control subjects) underwent F-18-DOPA positron emission tomography at baseline, and 15 patients were re-examined after 6 weeks. Clinical re-examinations were completed after 6 weeks (n = 28) and 6 months (n = 15). Symptoms were evaluated with the Positive and Negative Syndrome Scale. RESULTS: High baseline decarboxylation rates (k(3)) were associated with more positive symptoms at baseline (p , .001) and with symptom improvement after 6 weeks (p = .006). Subregion analyses showed that baseline k(3) for the putamen (p = .003) and nucleus accumbens (p = .013) and DSC values for the nucleus accumbens (p = .003) were associated with psychotic symptoms. The tissue reference method yielded no associations between DSC and symptoms or symptom improvement. Neither method revealed any effects of group or treatment on average magnitudes of k(3) or DSC, whereas changes in dopamine synthesis were correlated with higher baseline values, implying a potential effect of treatment. CONCLUSIONS: Striatal decarboxylation rate at baseline was associated with psychotic symptoms and treatment response. The strong association between k(3) and treatment effect potentially implicate on new treatment strategies.

Background:The human dopamine synthesis capacity can be analyzed in vivo using 18F-FDOPA PET.This tracer kinetic model is known to be complex due to the presence of multiple compartments, as well as prominent metabolites that also enter the brain.Several methods have been proposed to analyze the data, but there is no general consensus of an optimal method.Classical compartment modeling is complicated by the need for sequential arterial samples that may be difficult to obtain in a clinical setting.Replacing the arterial input function (AIF) with a population based input function has been suggested to avoid the need for invasive samples.Graphical analysis on the other hand is computationally simpler, and can be performed with or, in a modified version, without arterial input.In the present study we compare non-linear compartment modeling to two graphical methods, using both simulated and real data.We further evaluate different strategies for estimating and scaling a population based arterial input function.Methods: We collected experimental data in a study of 62 subjects (first episode psychosis and controls (ref 1), using 18F-FDOPA and arterial blood sampling with estimation of peripheral metabolites.Values of the clearance parameters (K1,k2,k3,k4) of the compartment model were estimated using non-linear fitting (in-house software, Matlab v. 2020a).We used either the true plasma input function, or population based AIF, estimated by scaling the averaged AIF of all other subjects.Further, values of the influx parameter (Ki) were estimated from striatal regions using Gjedde-Patlak graphical analysis with input functions based either on arterial plasma or a cerebellar reference region.The true value of Ki depends on the underlying clearance parameters of the compartment model (K1,k2,k3,k4).For reference region method they also depend on the values of (K1,k2) in the reference region.Finally, simulated data were constructed using known values of the variables and analyzed using the same methods.Results: Simulated data revealed that the graphical analysis estimate of Ki is highly informative of K1 with plasma input values (r > 0.8), but only modestly so (r < 0.46) when using cerebellum reference.Graphical analysis was not informative of any other kinetic parameters.For real data Ki values of the graphical method correlated significantly (r = 0.64, p < 0.001) with K1 based on the compartment model, but only with the plasma input function.Results based on populations based AIF's were generally only weakly correlated with those based on the true plasma AIF.A maximum correlation of 0.54 (p < 0.001) was found between Ki based on a population based AIF scaled with injected dose, and Ki based on the true AIF.Conclusions: With real data from an arterially derived input function, the graphical tissue reference method outcome parameter Ki is suitable as a proxy for the vascular clearance rate K1, although with a rather low correlation.The method is not informative of the remaining underlying kinetic parameters.Population based AIFs were not suitable to replace plasma samples with sufficient accuracy.The current data therefore suggest that an individual arterial input function may not be left out without significant loss of precision.Furthermore, studies to elucidate the relationship between the graphical reference tissue method and the underlying tracer kinetic parameters seems warranted.

BACKGROUND:Aberrant anticipation of motivational salient events and processing of outcome evaluation in striatal and prefrontal regions have been suggested to underlie psychosis. Altered glutamate levels have likewise been linked to schizophrenia. Glutamatergic abnormalities may affect the processing of motivational salience and outcome evaluation. It remains unresolved, whether glutamatergic dysfunction is associated with the coding of motivational salience and outcome evaluation in antipsychotic-naïve patients with first-episode psychosis.METHODS:Fifty-one antipsychotic-naïve patients with first-episode psychosis (22 ± 5.2 years, female/male: 31/20) and 52 healthy controls (HC) matched on age, sex, and parental education underwent functional magnetic resonance imaging and magnetic resonance spectroscopy (3T) in one session. Brain responses to motivational salience and negative outcome evaluation (NOE) were examined using a monetary incentive delay task. Glutamate levels were estimated in the left thalamus and anterior cingulate cortex using LCModel.RESULTS:Patients displayed a positive signal change to NOE in the caudate (p = 0.001) and dorsolateral prefrontal cortex (DLPFC; p = 0.003) compared to HC. No group difference was observed in motivational salience or in levels of glutamate. There was a different association between NOE signal in the caudate and DLPFC and thalamic glutamate levels in patients and HC due to a negative correlation in patients (caudate: p = 0.004, DLPFC: p = 0.005) that was not seen in HC.CONCLUSIONS:Our findings confirm prior findings of abnormal outcome evaluation as a part of the pathophysiology of schizophrenia. The results also suggest a possible link between thalamic glutamate and NOE signaling in patients with first-episode psychosis.

BACKGROUND: Abnormal glutamate and GABA (gamma-aminobutyric acid) levels have been found in the early phase of schizophrenia and may underlie cognitive deficits. However, the association between cognitive function and levels of glutamatergic metabolites and GABA has not been investigated in a large group of antipsychotic-naive patients. METHODS: In total, 56 antipsychotic-naive patients with schizophrenia or psychotic disorder and 51 healthy control subjects underwent magnetic resonance spectroscopy to measure glutamate, glutamate+glutamine (Glx), and GABA levels in dorsal anterior cingulate cortex (ACC) and glutamate and Glx levels in left thalamus. The cognitive domains of attention, working memory, and IQ were assessed. RESULTS: The whole group of antipsychotic-naive patients had lower levels of GABA in dorsal ACC (p = .03), and the subgroup of patients with a schizophrenia diagnosis had higher glutamate levels in thalamus (p = .01), but Glx levels in dorsal ACC and thalamus did not differ between groups. Glx levels in dorsal ACC were positively associated with working memory (logarithmically transformed: b = -.016 [higher score indicates worse performance], p = .005) and attention (b = .056, p = .035) in both patients and healthy control subjects, although the association with attention did not survive adjustment for multiple comparisons. CONCLUSIONS: The findings suggest a positive association between glutamatergic metabolites and cognitive function that do not differ between patients and healthy control subjects. Moreover, our data indicate that decreased GABAergic levels in dorsal ACC are involved in schizophrenia and psychotic disorder, whereas increased glutamate levels in thalamus seem to be implicated in schizophrenia pathophysiology. The findings imply that first-episode patients with cognitive deficits may gain from glutamate-modulating compounds.

Abstract 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.

Abstract Background The typical onset of schizophrenia coincides with the maturational peak in cognition; however, for a significant proportion of patients the onset is before age 18 and after age 30 years. While cognitive deficits are considered core features of schizophrenia, few studies have directly examined the impact of age of illness onset on cognition. Methods The aim of the study was to examine if the effects of age on cognition differ between healthy controls (HCs) and patients with schizophrenia at illness onset. We examined 156 first-episode antipsychotic-naïve patients across a wide age span (12–43 years), and 161 age- and sex-matched HCs. Diagnoses were made according to ICD-10 criteria. Cognition was assessed using the Brief Assessment of Cognition in Schizophrenia (BACS), and IQ was estimated using subtests from the Wechsler adult- or child-intelligence scales. Multivariate analysis of covariance (MANCOVA) was used to examine linear and quadratic effects of age on cognitive scores and interactions by group, including sex and parental socioeconomic status as covariates. Results There was a significant overall effect of age on BACS and IQ (p < 0.001). Significant group-by-age interactions for verbal memory (for age-squared, p = 0.009), and digit sequencing (for age, p = 0.01; age-squared, p < 0.001), indicated differential age-related trajectories between patients and HCs. Conclusions Cognitive functions showing protracted maturation into adulthood, such as verbal memory and verbal working memory, may be particularly impaired in both early- and late-schizophrenia onset. Our findings indicate a potential interaction between the timing of neurodevelopmental maturation and a possible premature age effect in late-onset schizophrenia.

Abstract 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<0.001). 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.

Disturbances in the interacting dopaminergic, glutamatergic and GABAergic systems in the cortico-striato-thalamo-cortical circuits in the brain have been implicated in the pathophysiology of psychosis. Preclinical literature suggests that these disturbances are linked to each other, whereas recent clinical data have pointed to separate subgroups of patients characterized by either glutamatergic or dopaminergic abnormalities. In the present study we explore the associations between dopamine synthesis capacity and glutamate and GABA levels in antipsychotic-naïve first-episode psychosis (FEP) patients. The study is ongoing. We have now processed magnetic resonance spectroscopy (MRS) and positron emission tomography (18F-FDOPA-PET) data on 22 patients (32% males, mean age 22 (±4.3)) and 18 controls (50% males, mean age 22 (±2.7)). All patients are strictly antipsychotic-naïve and have no substance abuse. The diagnosis is validated with a diagnostic interview. The patients fulfill the criteria for schizophrenia (n:15), non-organic psychosis (n:5), schizoaffective disorder (n:1) or paranoid psychosis (n:1). They are moderately ill with a mean total score of 78 (±9.6) on the Positive and Negative Syndrome Scale. Glutamate and GABA-levels in the anterior cingulate cortex (ACC) are obtained with MRS. Dopamine synthesis capacity in striatum is measured with 18F-FDOPA-PET. The mean dopamine synthesis capacity is extracted from the whole striatum. Additionally, striatal subregions are defined anatomically (nucleus accumbens, nucleus caudatus and putamen, left and right) and subregional dopamine synthesis capacities are obtained. The association between dopamine synthesis capacity and levels of glutamate and GABA in patients and controls is assessed with linear regression with dopamine synthesis capacity as dependent variable and group and GABA or glutamate as independent variables. Analyses are performed with and without adjustment for age and sex. High dopamine synthesis capacity in the total striatum is associated with low ACC glutamate levels in patients (p=.03), but not in controls. This association remains significant after adjusting for age and sex (p=.02). In all subjects, dopamine synthesis capacity in the left caudate is positively correlated with ACC GABA (p<.05), although not after adjusting for age and sex (p=.08). In controls only, there is a positive association between dopamine synthesis capacity in right caudate and putamen and ACC GABA levels (p<.01 and p=.01 respectively). The present data shows an inverse relationship between glutamate levels in the ACC in antipsychotic-naïve FEP patients and striatal dopamine synthesis capacity, hereby contradicting the notion of two distinct subgroups of patients characterized by either abnormal striatal dopamine or cortical glutamate activity. In healthy controls we find a strong positive association between ACC GABA levels and dopamine synthesis capacity, which is only present unilaterally and to a much smaller degree in patients. Taken together, the data supports that disturbances in the interacting dopaminergic, glutamatergic and GABAergic systems in the macro circuits in the brain are implicated in the pathophysiology of psychosis. Since the patients had never received any antipsychotic medication (lifetime), these disturbances are not related to antipsychotic treatment. The data represents work in progress. Inclusion and data processing are ongoing hence more detailed data analysis on a larger sample size and analyses including psychopathology will be presented at the conference.

BACKGROUND:Poor response to dopaminergic antipsychotics constitutes a major challenge in the treatment of psychotic disorders and markers for non-response during first-episode are warranted. Previous studies have found increased levels of glutamate and γ-aminobutyric acid (GABA) in non-responding first-episode patients compared to responders, but it is unknown if non-responders can be identified using reference levels from healthy controls (HCs). METHODS:Thirty-nine antipsychotic-naïve patients with first-episode psychosis and 36 matched HCs underwent repeated assessments with the Positive and Negative Syndrome Scale and 3T magnetic resonance spectroscopy. Glutamate scaled to total creatine (/Cr) was measured in the anterior cingulate cortex (ACC) and left thalamus, and levels of GABA/Cr were measured in ACC. After 6 weeks, we re-examined 32 patients on aripiprazole monotherapy and 35 HCs, and after 26 weeks we re-examined 30 patients on naturalistic antipsychotic treatment and 32 HCs. The Andreasen criteria defined non-response. RESULTS:Before treatment, thalamic glutamate/Cr was higher in the whole group of patients but levels normalized after treatment. ACC levels of glutamate/Cr and GABA/Cr were lower at all assessments and unaffected by treatment. When compared with HCs, non-responders at week 6 (19 patients) and week 26 (16 patients) had higher baseline glutamate/Cr in the thalamus. Moreover, non-responders at 26 weeks had lower baseline GABA/Cr in ACC. Baseline levels in responders and HCs did not differ. CONCLUSION:Glutamatergic and GABAergic abnormalities in antipsychotic-naïve patients appear driven by non-responders to antipsychotic treatment. If replicated, normative reference levels for glutamate and GABA may aid estimation of clinical prognosis in first-episode psychosis patients.

Alterations of the brain reward system have been found in schizophrenia patients and prediction error coding has been suggested to underlie the formations of psychotic symptoms. Prediction errors are the discrepancy between what actually happens and what we expect to happen. This misprediction has been suggested to contribute to misallocation of attention leading to generation of psychotic symptoms. Recent data from our group have shown that thalamic glutamate levels are not only heritable and linked to liability for schizophrenia, but also increased in the thalamus at illness onset; the latter was driven by patients that subsequently did not respond to treatment. However, it remains unresolved if glutamatergic dysfunction is correlated to striatal reward processing and prediction errors. In the present study, we aim to explore the relationship between thalamic glutamate levels and striatal prediction error coding in psychosis before the patients first antipsychotic treatment. 40 antipsychotic-naïve patients with first-episode psychosis (age 22.8±5.7, 15(38%) males) and 38 healthy controls matched on age and gender (age 21.8±3.2, 17(45%) males) underwent functional Magnetic Resonance imaging (fMRI) and magnetic resonance spectroscopy (1H-MRS) (3 Tesla scanner). The patients were moderately ill with a mean PANSS total score of 74 (15). Glutamate levels scaled to creatine was estimated using the PRESS sequence in a 2.0x1.5x2.0 cm voxel in the left thalamus and analyzed using LCModel. Reward related brain activity was examined using a Monetary Delay Task. Analyses were focused on evaluation of outcome during trials where the outcome was worse than expected indicating negative prediction error (miss-contrast). Tools from the FMRIB Software Library were used to extract ROI parameter estimates from the left nucleus caudatus. Psychopathology was assessed with the Positive and Negative Syndrome Scale (PANSS). For reward related brain activity, significant group difference was observed in the miss-contrast (p=0.019) with patients having a higher contrast activity. For thalamic glutamate there was a trend towards higher levels in the patients (p=0.057). In patients, a significant negative correlation was observed between glutamate levels and activity in the miss-contrast (r=-0.41; p= 0.009), which was not present in healthy controls. There was no significant correlation between symptom severity and prediction error activity or glutamate levels. Our findings support that patients have aberrant prediction error signaling and increased thalamic glutamate levels. However, patients with increased thalamic glutamate levels display a more normal prediction error signaling, whereas patients with lower thalamic glutamate levels display abnormal prediction error signaling. This could suggest a role of thalamic glutamate in the neural coding of prediction errors in antipsychotic-naïve first-episode psychosis patients but not in healthy controls.

Abstract 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<0.001) and GAF total of 49 (SD 11.2, p=0.002). Six patients were characterized as responders, and six as non-responders using the Nancy Andreasen remission criteria. There were no baseline differences in PANSS or GAF scores between responders and non-responders. Nor did the dose of Aripiprazole differ between these groups. There was however significant difference in the GAF total score at follow up (p =0.001), as GAF was 59 (SD 9.3) for responders and 39 (SD 5.3) for non-responders. Mean Ki-values at baseline was 0.79 (SD 0.2) for non-responders, 0.88 (SD 0.2) for responders and 0.91 (SD 0.2) for HC. One way ANOVA showed no significant group difference. Discussion Although not significant, we found a slightly lower Ki-value at baseline for non-responders compared to baseline Ki-values for responders and HC in these preliminary analyses. This was unexpected, but should be taken with precaution, as the results represent work in progress. Inclusion of subjects and data-analyses is ongoing, and data analysis will be more extensive in spring 2018, especially regarding the methodology: The current image derived input function suffers from partial volume effects (PVE). To account for PVE and other factors the image data will be co-registered with T1-weighted MRI data and normalized to standard space in order to use a standard anatomical atlas to help define the ROIs. Finally, as mentioned earlier, arterial samples are collected and we plan to use arterial input functions to correct for the complicated kinetics of the tracer. To improve the Ki estimation we will use the metabolite corrected arterial plasma curve as input function and compare these results with the current method.

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. 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. 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<0.05), whereas R and HC did not differ. In the ACC, NR after 1.5 months showed a trend for lower GABA/Cr at baseline (p=0.06), and in NR after 6 months baseline GABA/Cr was significantly lower compared with HC (p=0.03), whereas R and HC did not differ. In the ACC, there was no baseline difference in glutamate/Cr of NR patients after 1.5 and 6 months compared with HC. The findings indicate increased glutamatergic turnover in the left thalamus and decreased GABAergic neurotransmission in the ACC in the pathophysiology of schizophrenia. Treatment normalises glutamate levels in the left thalamus, but does not affect GABA and glutamate levels in the ACC. Importantly, NR patients are characterized by more pronounced glutamatergic and GABAergic disturbances in the antipsychotic-naïve state. Compounds that modify glutamatergic and GABAergic neurotransmission might have therapeutic potential in this subgroup.