Detecting schizophrenia with 3D structural brain MRI using deep learning.

Schizophrenia is a chronic neuropsychiatric disorder that causes distinct structural alterations within the brain. We hypothesize that deep learning applied to a structural neuroimaging dataset could detect disease-related alteration and improve classification and diagnostic accuracy. We tested this hypothesis using a single, widely available, and conventional T1-weighted MRI scan, from which we extracted the 3D whole-brain structure using standard post-processing methods. A deep learning model was then developed, optimized, and evaluated on three open datasets with T1-weighted MRI scans of patients with schizophrenia. Our proposed model outperformed the benchmark model, which was also trained with structural MR images using a 3D CNN architecture. Our model is capable of almost perfectly (area under the ROC curve = 0.987) distinguishing schizophrenia patients from healthy controls on unseen structural MRI scans. Regional analysis localized subcortical regions and ventricles as the most predictive brain regions. Subcortical structures serve a pivotal role in cognitive, affective, and social functions in humans, and structural abnormalities of these regions have been associated with schizophrenia. Our finding corroborates that schizophrenia is associated with widespread alterations in subcortical brain structure and the subcortical structural information provides prominent features in diagnostic classification. Together, these results further demonstrate the potential of deep learning to improve schizophrenia diagnosis and identify its structural neuroimaging signatures from a single, standard T1-weighted brain MRI.

Dose-Dependent Augmentation of Neuroplasticity-Based Auditory Learning in Schizophrenia: A Double-Blind, Placebo-Controlled, Randomized, Target Engagement Clinical Trial of the NMDA Glutamate Receptor Agonist d-serine.

BACKGROUND: Patients with schizophrenia show reduced NMDA glutamate receptor-dependent auditory plasticity, which is rate limiting for auditory cognitive remediation (AudRem). We evaluate the utility of behavioral and neurophysiological pharmacodynamic target engagement biomarkers, using a d-serine+AudRem combination. METHODS: Forty-five participants with schizophrenia or schizoaffective disorder were randomized to 3 once-weekly AudRem visits + double-blind d-serine (80, 100, or 120 mg/kg) or placebo in 3 dose cohorts of 12 d-serine and 3 placebo-treated participants each. In AudRem, participants indicated which paired tone was higher in pitch. The primary outcome was plasticity improvement, operationalized as change in pitch threshold between AudRem tones [(test tone Hz - reference tone Hz)/reference tone Hz] between the initial plateau pitch threshold (mean of trials 20-30 of treatment visit 1) to pitch threshold at the end of visit(s). Target engagement was assessed by electroencephalography outcomes, including mismatch negativity (pitch primary). RESULTS: There was a significant overall treatment effect for plasticity improvement (p = .014). Plasticity improvement was largest within the 80 and 100 mg/kg groups (p < .001, d > 0.67), while 120 mg/kg and placebo-treated participants showed nonsignificant within-group changes. Plasticity improvement was seen after a single treatment and was sustained on subsequent treatments. Target engagement was demonstrated by significantly larger mismatch negativity (p = .049, d = 1.0) for the 100 mg/kg dose versus placebo. CONCLUSIONS: Our results demonstrate sufficient proof of principle for continued development of both the d-serine+AudRem combination and our target engagement methodology. The ultimate utility is dependent on the results of an ongoing larger, longer study of the combination for clinically relevant outcomes.

Variability and magnitude of brain glutamate levels in schizophrenia: a meta and mega-analysis.

Glutamatergic dysfunction is implicated in schizophrenia pathoaetiology, but this may vary in extent between patients. It is unclear whether inter-individual variability in glutamate is greater in schizophrenia than the general population. We conducted meta-analyses to assess (1) variability of glutamate measures in patients relative to controls (log coefficient of variation ratio: CVR); (2) standardised mean differences (SMD) using Hedges g; (3) modal distribution of individual-level glutamate data (Hartigan's unimodality dip test). MEDLINE and EMBASE databases were searched from inception to September 2022 for proton magnetic resonance spectroscopy (1H-MRS) studies reporting glutamate, glutamine or Glx in schizophrenia. 123 studies reporting on 8256 patients and 7532 controls were included. Compared with controls, patients demonstrated greater variability in glutamatergic metabolites in the medial frontal cortex (MFC, glutamate: CVR = 0.15, p < 0.001; glutamine: CVR = 0.15, p = 0.003; Glx: CVR = 0.11, p = 0.002), dorsolateral prefrontal cortex (glutamine: CVR = 0.14, p = 0.05; Glx: CVR = 0.25, p < 0.001) and thalamus (glutamate: CVR = 0.16, p = 0.008; Glx: CVR = 0.19, p = 0.008). Studies in younger, more symptomatic patients were associated with greater variability in the basal ganglia (BG glutamate with age: z = -0.03, p = 0.003, symptoms: z = 0.007, p = 0.02) and temporal lobe (glutamate with age: z = -0.03, p = 0.02), while studies with older, more symptomatic patients associated with greater variability in MFC (glutamate with age: z = 0.01, p = 0.02, glutamine with symptoms: z = 0.01, p = 0.02). For individual patient data, most studies showed a unimodal distribution of glutamatergic metabolites. Meta-analysis of mean differences found lower MFC glutamate (g = -0.15, p = 0.03), higher thalamic glutamine (g = 0.53, p < 0.001) and higher BG Glx in patients relative to controls (g = 0.28, p < 0.001). Proportion of males was negatively associated with MFC glutamate (z = -0.02, p < 0.001) and frontal white matter Glx (z = -0.03, p = 0.02) in patients relative to controls. Patient PANSS total score was positively associated with glutamate SMD in BG (z = 0.01, p = 0.01) and temporal lobe (z = 0.05, p = 0.008). Further research into the mechanisms underlying greater glutamatergic metabolite variability in schizophrenia and their clinical consequences may inform the identification of patient subgroups for future treatment strategies.

Neurodegenerative model of schizophrenia: Growing evidence to support a revisit.

Multidimensional progressive declines in the absence of standard biomarkers for neurodegeneration are observed commonly in the development of schizophrenia, and are accepted as consistent with neurodevelopmental etiological hypotheses to explain the origins of the disorder. Far less accepted is the possibility that neurodegenerative processes are involved as well, or even that key dimensions of function, such as cognition and aspects of biological integrity, such as white matter function, decline in chronic schizophrenia beyond levels associated with normal aging. We propose that recent research germane to these issues warrants a current look at the question of neurodegeneration. We propose the view that a neurodegenerative hypothesis provides a better explanation of some features of chronic schizophrenia, including accelerated aging, than is provided by neurodevelopmental hypotheses. Moreover, we suggest that neurodevelopmental influences in early life, including those that may extend to later life, do not preclude the development of neurodegenerative processes in later life, including some declines in cognitive and biological integrity. We evaluate these views by integrating recent findings in representative domains such as cognition and white and gray matter integrity with results from studies on accelerated aging, together with functional implications of neurodegeneration for our understanding of chronic schizophrenia.

Striatal glutamate, subcortical structure and clinical response to first-line treatment in first-episode psychosis patients.

INTRODUCTION: Recent studies have observed that patients with treatment-resistant schizophrenia as well as patients with schizophrenia who do not respond within a medication trial exhibit excess activity of the glutamate system. In this study we sought to replicate the within-trial glutamate abnormality and to investigate the potential for structural differences and treatment-induced changes to improve identification of medication responders and non-responders. METHODS: We enrolled 48 medication-naïve patients in a 4-week trial of risperidone and classified them retrospectively into responders and non-responders using clinical criteria. Proton magnetic resonance spectroscopy and T1-weighted structural MRI were acquired pre- and post-treatment to quantify striatal glutamate levels and several measures of subcortical brain structure. RESULTS: Patients were classified as 29 responders and 19 non-responders. Striatal glutamate was higher in the non-responders than responders both pre- and post-treatment (F1,39 = 7.15, p = .01). Volumetric measures showed a significant group x time interaction (t = 5.163, <1%FDR), and group x time x glutamate interaction (t = 4.23, <15%FDR) were seen in several brain regions. Striatal volumes increased at trend level with treatment in both groups, and a positive association of striatal volumes with glutamate levels was seen in the non-responders. CONCLUSIONS: Combining anatomic measures with glutamate levels offers the potential to enhance classification of responders and non-responders to antipsychotic medications as well as to provide mechanistic understanding of the interplay between neuroanatomical and neurochemical changes induced by these medications. Ethical statement The study was approved by the Ethics and Scientific committees of the Instituto Nacional de Neurología y Neurocirugía in Mexico City. All participants over 18 years fully understood and signed the informed consent; in case the patient was under 18 years, informed consent was obtained from both parents. Participants did not receive a stipend.

Ventromedial prefrontal cortex/anterior cingulate cortex Glx, glutamate, and GABA levels in medication-free major depressive disorder.

Glutamate (Glu) and gamma-aminobutyric acid (GABA) are implicated in the pathophysiology of major depressive disorder (MDD). GABA levels or GABAergic interneuron numbers are generally low in MDD, potentially disinhibiting Glu release. It is unclear whether Glu release or turnover is increased in depression. Conversely, a meta-analysis of prefrontal proton magnetic resonance spectroscopy (1H MRS) studies in MDD finds low Glx (combination of glutamate and glutamine) in medicated MDD. We hypothesize that elevated Glx or Glu may be a marker of more severe, untreated MDD. We examined ventromedial prefrontal cortex/anterior cingulate cortex (vmPFC/ACC) Glx and glutamate levels using 1H MRS in 34 medication-free, symptomatic, chronically ill MDD patients and 32 healthy volunteers, and GABA levels in a subsample. Elevated Glx and Glu were observed in MDD compared with healthy volunteers, with the highest levels seen in males with MDD. vmPFC/ACC GABA was low in MDD. Higher Glx levels correlated with more severe depression and lower GABA. MDD severity and diagnosis were both linked to higher Glx in vmPFC/ACC. Low GABA in a subset of these patients is consistent with our hypothesized model of low GABA leading to glutamate disinhibition in MDD. This finding and model are consistent with our previously reported findings that the NMDAR-antagonist antidepressant effect is proportional to the reduction of vmPFC/ACC Glx or Glu levels.

Association of Age, Antipsychotic Medication, and Symptom Severity in Schizophrenia With Proton Magnetic Resonance Spectroscopy Brain Glutamate Level: A Mega-analysis of Individual Participant-Level Data.

Importance: Proton magnetic resonance spectroscopy (1H-MRS) studies indicate that altered brain glutamatergic function may be associated with the pathophysiology of schizophrenia and the response to antipsychotic treatment. However, the association of altered glutamatergic function with clinical and demographic factors is unclear. Objective: To assess the associations of age, symptom severity, level of functioning, and antipsychotic treatment with brain glutamatergic metabolites. Data Sources: The MEDLINE database was searched to identify journal articles published between January 1, 1980, and June 3, 2020, using the following search terms: MRS or magnetic resonance spectroscopy and (1) schizophrenia or (2) psychosis or (3) UHR or (4) ARMS or (5) ultra-high risk or (6) clinical high risk or (7) genetic high risk or (8) prodrome* or (9) schizoaffective. Authors of 114 1H-MRS studies measuring glutamate (Glu) levels in patients with schizophrenia were contacted between January 2014 and June 2020 and asked to provide individual participant data. Study Selection: In total, 45 1H-MRS studies contributed data. Data Extraction and Synthesis: Associations of Glu, Glu plus glutamine (Glx), or total creatine plus phosphocreatine levels with age, antipsychotic medication dose, symptom severity, and functioning were assessed using linear mixed models, with study as a random factor. Main Outcomes and Measures: Glu, Glx, and Cr values in the medial frontal cortex (MFC) and medial temporal lobe (MTL). Results: In total, 42 studies were included, with data for 1251 patients with schizophrenia (mean [SD] age, 30.3 [10.4] years) and 1197 healthy volunteers (mean [SD] age, 27.5 [8.8] years). The MFC Glu (F1,1211.9 = 4.311, P = .04) and Glx (F1,1079.2 = 5.287, P = .02) levels were lower in patients than in healthy volunteers, and although creatine levels appeared lower in patients, the difference was not significant (F1,1395.9 = 3.622, P = .06). In both patients and volunteers, the MFC Glu level was negatively associated with age (Glu to Cr ratio, F1,1522.4 = 47.533, P < .001; cerebrospinal fluid-corrected Glu, F1,1216.7 = 5.610, P = .02), showing a 0.2-unit reduction per decade. In patients, antipsychotic dose (in chlorpromazine equivalents) was negatively associated with MFC Glu (estimate, 0.10 reduction per 100 mg; SE, 0.03) and MFC Glx (estimate, -0.11; SE, 0.04) levels. The MFC Glu to Cr ratio was positively associated with total symptom severity (estimate, 0.01 per 10 points; SE, 0.005) and positive symptom severity (estimate, 0.04; SE, 0.02) and was negatively associated with level of global functioning (estimate, 0.04; SE, 0.01). In the MTL, the Glx to Cr ratio was positively associated with total symptom severity (estimate, 0.06; SE, 0.03), negative symptoms (estimate, 0.2; SE, 0.07), and worse Clinical Global Impression score (estimate, 0.2 per point; SE, 0.06). The MFC creatine level increased with age (estimate, 0.2; SE, 0.05) but was not associated with either symptom severity or antipsychotic medication dose. Conclusions and Relevance: Findings from this mega-analysis suggest that lower brain Glu levels in patients with schizophrenia may be associated with antipsychotic medication exposure rather than with greater age-related decline. Higher brain Glu levels may act as a biomarker of illness severity in schizophrenia.

Comparison of social cognition using an adapted Chinese version of the Reading the Mind in the Eyes Test in drug-naive and regularly medicated individuals with chronic schizophrenia and healthy controls in rural China.

BACKGROUND: Social cognition has not previously been assessed in treatment-naive patients with chronic schizophrenia, in patients over 60 years of age, or in patients with less than 5 years of schooling. METHODS: We revised a commonly used measure of social cognition, the Reading the Mind in the Eyes Test (RMET), by expanding the instructions, using both self-completion and interviewer-completion versions (for illiterate respondents), and classifying each test administration as 'successfully completed' or 'incomplete'. The revised instrument (RMET-CV-R) was administered to 233 treatment-naive patients with chronic schizophrenia (UT), 154 treated controls with chronic schizophrenia (TC), and 259 healthy controls (HC) from rural communities in China. RESULTS: In bivariate and multivariate analyses, successful completion rates and RMET-CV-R scores (percent correct judgments about emotion exhibited in 70 presented slides) were highest in HC, intermediate in TC, and lowest in UT (adjusted completion rates, 97.0, 72.4, and 49.9%, respectively; adjusted RMET-CV-R scores, 45.4, 38.5, and 34.6%, respectively; all p < 0.02). Stratified analyses by the method of administration (self-completed v. interviewer-completed) and by education and age ('educated-younger' v. 'undereducated-older') show the same relationship between groups (i.e. NC>TC>UT), though not all differences remain statistically significant. CONCLUSIONS: We find poorer social cognition in treatment-naive than in treated patients with chronic schizophrenia. The discriminant validity of RMET-CV-R in undereducated, older patients demonstrates the feasibility of administering revised versions of RMET to patients who may otherwise be considered ineligible due to education or age by changing the method of test administration and carefully assessing respondents' ability to complete the task successfully.

Imaging synaptic dopamine availability in individuals at clinical high-risk for psychosis: a [11C]-(+)-PHNO PET with methylphenidate challenge study.

Patients at clinical high-risk (CHR) for psychosis show elevations in [18F]DOPA uptake, an estimate of dopamine (DA) synthesis capacity, in the striatum predictive of conversion to schizophrenia. Intrasynaptic DA levels can be inferred from imaging the change in radiotracer binding at D2 receptors due to a pharmacological challenge. Here, we used methylphenidate, a DA reuptake inhibitor, and [11C]-(+)-PHNO, to measure synaptic DA availability in CHR both in striatal and extra-striatal brain regions. Fourteen unmedicated, nonsubstance using CHR individuals and 14 matched control subjects participated in the study. Subjects underwent two [11C]-(+)-PHNO scans, one at baseline and one following administration of a single oral dose (60 mg) of methylphenidate. [11C]-(+)-PHNO BPND, the binding potential relative to the nondisplaceable compartment, was derived using the simplified reference tissue model with cerebellum as reference tissue. The percent change in BPND between scans, ΔBPND, was computed as an index of synaptic DA availability, and group comparisons were performed with a linear mixed model. An overall trend was found for greater synaptic DA availability (∆BPND) in CHR than controls (p = 0.06). This was driven entirely by ∆BPND in ventral striatum (-34 ± 14% in CHR, -20 ± 12% in HC; p = 0.023). There were no significant group differences in any other brain region. There were no significant differences in DA transmission in any striatal region between converters and nonconverters, although this finding is limited by the small sample size (N = 2). There was a strong and negative correlation between ΔBPND in VST and severity of negative symptoms at baseline in the CHR group (r = -0.66, p < 0.01). We show abnormally increased DA availability in the VST in CHR and an inverse relationship with negative symptoms. Our results suggest a potential early role for mesolimbic dopamine overactivity in CHR. Longitudinal studies are needed to ascertain the significance of the differential topography observed here with the [18F]DOPA literature.

Grant Report on d-Serine Augmentation of Neuroplasticity-Based Auditory Learning in Schizophrenia †.

We report on the rationale and design of an ongoing NIMH sponsored R61-R33 project in schizophrenia/schizoaffective disorder. This project studies augmenting the efficacy of auditory neuroplasticity cognitive remediation (AudRem) with d-serine, an N-methyl-d-aspartate-type glutamate receptor (NMDAR) glycine-site agonist. We operationalize improved (smaller) thresholds in pitch (frequency) between successive auditory stimuli after AudRem as improved plasticity, and mismatch negativity (MMN) and auditory θ as measures of functional target engagement of both NMDAR agonism and plasticity. Previous studies showed that AudRem alone produces significant, but small cognitive improvements, while d-serine alone improves symptoms and MMN. However, the strongest results for plasticity outcomes (improved pitch thresholds, auditory MMN and θ) were found when combining d-serine and AudRem. AudRem improvements correlated with reading and other auditory cognitive tasks, suggesting plasticity improvements are predictive of functionally relevant outcomes. While d-serine appears to be efficacious for acute AudRem enhancement, the optimal dose remains an open question, as does the ability of combined d-serine + AudRem to produce sustained improvement. In the ongoing R61, 45 schizophrenia patients will be randomized to receive three placebo-controlled, double-blind d-serine + AudRem sessions across three separate 15 subject dose cohorts (80/100/120 mg/kg). Successful completion of the R61 is defined by ≥moderate effect size changes in target engagement and correlation with function, without safety issues. During the three-year R33, we will assess the sustained effects of d-serine + AudRem. In addition to testing a potentially viable treatment, this project will develop a methodology to assess the efficacy of novel NMDAR modulators, using d-serine as a "gold-standard".

Assessment of Relationship of Ketamine Dose With Magnetic Resonance Spectroscopy of Glx and GABA Responses in Adults With Major Depression: A Randomized Clinical Trial.

Importance: A single subanesthetic dose of ketamine produces an antidepressant response in patients with major depressive disorder (MDD) within hours, but the mechanism of antidepressant effect is uncertain. Objective: To evaluate whether ketamine dose and brain glutamate and glutamine (Glx) and γ-aminobutyric acid (GABA) level responses to ketamine are related to antidepressant benefit and adverse effects. Design, Setting, and Participants: This randomized, parallel-group, triple-masked clinical trial included 38 physically healthy, psychotropic medication-free adult outpatients who were in a major depressive episode of MDD but not actively suicidal. The trial was conducted at Columbia University Medical Center. Data were collected from February 2012 to May 2015. Data analysis was conducted from January to March 2020. Intervention: Participants received 1 dose of placebo or ketamine (0.1, 0.2, 0.3, 0.4, or 0.5 mg/kg) intravenously during 40 minutes of a proton magnetic resonance spectroscopy scan that measured ventro-medial prefrontal cortex Glx and GABA levels in 13-minute data frames. Main Outcomes and Measures: Clinical improvement was measured using a 22-item version of the Hamilton Depression Rating Scale (HDRS-22) 24 hours after ketamine was administered. Ketamine and metabolite blood levels were measured after the scan. Results: A total of 38 individuals participated in the study, with a mean (SD) age of 38.6 (11.2) years, 23 (60.5%) women, and 25 (65.8%) White patients. Improvement in HDRS-22 score at 24 hours correlated positively with ketamine dose (t36 = 2.81; P = .008; slope estimate, 19.80 [95% CI, 5.49 to 34.11]) and blood level (t36 = 2.25; P = .03; slope estimate, 0.070 [95% CI, 0.007 to 0.133]). The lower the Glx response, the better the antidepressant response (t33 = -2.400; P = .02; slope estimate, -9.85 [95% CI, -18.2 to -1.50]). Although GABA levels correlated with Glx (t33 = 8.117; P < .001; slope estimate, 0.510 [95% CI, 0.382 to 0.638]), GABA response did not correlate with antidepressant effect. When both ketamine dose and Glx response were included in a mediation analysis model, ketamine dose was no longer associated with antidepressant effect, indicating that Glx response mediated the relationship. Adverse effects were related to blood levels in men only (t5 = 2.606; P = .048; estimated slope, 0.093 [95% CI, 0.001 to 0.186]), but Glx and GABA response were not related to adverse effects. Conclusions and Relevance: In this study, intravenous ketamine dose and blood levels correlated positively with antidepressant response. The Glx response correlated inversely with ketamine dose and with antidepressant effect. Future studies are needed to determine whether the relationship between Glx level and antidepressant effect is due to glutamate or glutamine. Trial Registration: ClinicalTrials.gov Identifier: NCT01558063.

Amphetamine-induced striatal dopamine release in schizotypal personality disorder.

RATIONALE: Previous research has suggested that schizotypal personality disorder (SPD), a condition that shares clinical and cognitive features with schizophrenia, may be associated with elevated striatal dopamine functioning; however, there are no published studies of dopamine release within subregions of the striatum in SPD. OBJECTIVES: To characterize dopamine release capacity in striatal subregions and its relation to clinical and cognitive features in SPD. METHODS: We used positron emission tomography with [11C]raclopride and an amphetamine challenge to measure dopamine D2-receptor availability (binding potential, BPND), and its percent change post-amphetamine (∆BPND) to index amphetamine-induced dopamine release, in subregions of the striatum in 16 SPD and 16 healthy control participants. SPD participants were evaluated with measures of schizotypal symptom severity and working memory. RESULTS: There were no significant group differences in BPND or ∆BPND in any striatal subregion or whole striatum. Among SPD participants, cognitive-perceptual symptoms were associated at trend level with ∆BPND in the ventral striatum, and disorganized symptoms were significantly negatively related to ∆BPND in several striatal subregions. CONCLUSIONS: In contrast to previous findings, SPD was not associated with elevated striatal dopamine release. However, in SPD, there was a moderate positive association between ventral striatal dopamine release and severity of cognitive-perceptual symptoms, and negative associations between striatal dopamine release and severity of disorganized symptoms. Future larger scale investigations that allow for the separate examination of subgroups of participants based on clinical presentation will be valuable in further elucidating striatal DA functioning in SPD.

Proof of mechanism and target engagement of glutamatergic drugs for the treatment of schizophrenia: RCTs of pomaglumetad and TS-134 on ketamine-induced psychotic symptoms and pharmacoBOLD in healthy volunteers.

Glutamate neurotransmission is a prioritized target for antipsychotic drug development. Two metabotropic glutamate receptor 2/3 (mGluR2/3) agonists (pomaglumetad [POMA] and TS-134) were assessed in two Phase Ib proof of mechanism studies of comparable designs and using identical clinical assessments and pharmacoBOLD methodology. POMA was examined in a randomized controlled trial under double-blind conditions for 10-days at doses of 80 or 320 mg/d POMA versus placebo (1:1:1 ratio). The TS-134 trial was a randomized, single-blind, 6-day study of 20 or 60 mg/d TS-134 versus placebo (5:5:2 ratio). Primary outcomes were ketamine-induced changes in pharmacoBOLD in the dorsal anterior cingulate cortex (dACC) and symptoms reflected on the Brief Psychiatric Rating Scale (BPRS). Both trials were conducted contemporaneously. 95 healthy volunteers were randomized to POMA and 63 to TS-134. High-dose POMA significantly reduced ketamine-induced BPRS total symptoms within and between-groups (p < 0.01, d = -0.41; p = 0.04, d = -0.44, respectively), but neither POMA dose significantly suppressed ketamine-induced dACC pharmacoBOLD. In contrast, low-dose TS-134 led to moderate to large within and between group reductions in both BPRS positive symptoms (p = 0.02, d = -0.36; p = 0.008, d = -0.82, respectively) and dACC pharmacoBOLD (p = 0.004, d = -0.56; p = 0.079, d = -0.50, respectively) using pooled across-study placebo data. High-dose POMA exerted significant effects on clinical symptoms, but not on target engagement, suggesting a higher dose may yet be needed, while the low dose of TS-134 showed evidence of symptom reduction and target engagement. These results support further investigation of mGluR2/3 and other glutamate-targeted treatments for schizophrenia.

Double blind, two dose, randomized, placebo-controlled, cross-over clinical trial of the positive allosteric modulator at the alpha7 nicotinic cholinergic receptor AVL-3288 in schizophrenia patients.

Despite their theoretical rationale, nicotinic alpha-7 acetylcholine (nα7) receptor agonists, have largely failed to demonstrate efficacy in placebo-controlled trials in schizophrenia. AVL-3288 is a nα7 positive allosteric modulator (PAM), which is only active in the presence of the endogenous ligand (acetylcholine), and thus theoretically less likely to cause receptor desensitization. We evaluated the efficacy of AVL-3288 in a Phase 1b, randomized, double-blind, placebo-controlled, triple cross-over study. Twenty-four non-smoking, medicated, outpatients with schizophrenia or schizoaffective disorder and a Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) ≥62 were randomized. Each subject received 5 days of AVL-3288 (10, 30 mg) and placebo across three separate treatment weeks. The primary outcome measure was the RBANS total scale score, with auditory P50 evoked potential suppression the key target engagement biomarker. Secondary outcome measures include task-based fMRI (RISE task), mismatch negativity, the Scale for the Assessment of Negative Symptoms of Schizophrenia (SANS) and the Brief Psychiatric Rating Scale (BPRS). Twenty-four subjects were randomized and treated without any clinically significant treatment emergent adverse effects. Baseline RBANS (82 ± 17) and BPRS (41 ± 13) scores were consistent with moderate impairment. Primary outcomes were negative, with non-significant worsening for both active groups vs. placebo in the P50 and minimal between group changes on the RBANS. In conclusion, the results did not indicate efficacy of the compound, consistent with most prior results for the nα7 target.

An imaging-based risk calculator for prediction of conversion to psychosis in clinical high-risk individuals using glutamate 1H MRS.

Risk calculators for prediction of conversion of Clinical High-Risk (CHR) individuals to syndromal psychosis have recently been developed and have generated considerable clinical use and research interest. Predictor variables in these calculators have been clinical rather than biological, and our goal was to incorporate a neurochemical imaging measure into this framework and assess its impact on prediction. We combined striatal glutamate 1H MRS data with the SIPS symptoms identified by the Columbia Risk Calculator as having the greatest predictive value in order to develop an imaging-based risk calculator for conversion to psychosis. We evaluated the calculator in 19 CHR individuals, 7 (36.84%) of whom converted to syndromal psychosis during the 2-year follow up. The receiver operating characteristic (ROC) curve for the logistic model including only striatal glutamate and visual perceptual abnormalities showed an AUC = 0.869 (95% CI = [0.667, 1.000]) and AUCoa = 0.823, with sensitivity of 0.714, specificity of 0.917, positive predictive value of 0.833, and negative predictive value of 0.846. These results represent modest improvements over each of the individual ROC curves based on either striatal glutamate or visual perceptual abnormalities alone. The preliminary model building and evaluation presented here in a small CHR sample suggests that the approach of incorporating predictive imaging measures into risk classification is not only feasible but offers the potential of enhancing risk assessment.

Effects of acute N-acetylcysteine challenge on cortical glutathione and glutamate in schizophrenia: A pilot in vivo proton magnetic resonance spectroscopy study.

Findings from in vivo brain proton magnetic resonance spectroscopy (1H MRS) and preclinical studies have suggested region- and medication status-dependent increases in glutamate (Glu) levels and deficiencies in glutathione (GSH) levels in schizophrenia. N-acetylcysteine (NAC), a GSH synthesis precursor, has demonstrated modest clinical benefit in schizophrenia. The objective of this study was to examine the effects of acute administration of NAC on GSH and Glu levels measured with 1H MRS in 19 patients with schizophrenia and 20 healthy control subjects. Levels of GSH were acquired in dorsal anterior cingulate cortex (dACC), and those of Glu in dACC and medial prefrontal cortex (mPFC), at baseline and 60 min following acute oral administration of 2400 mg of NAC. No differences in the levels of GSH or Glu were found at baseline or following NAC administration between patients with schizophrenia and control subjects in either of the targeted brain regions. Future studies measuring GSH levels in brain regions previously found to exhibit glutamatergic abnormalities or using genetic polymorphisms, while controlling for the age and medication status of the cohorts, are warranted to better identify groups of patients more likely to respond to NAC and its mode of action and mechanisms.

A multicenter study of ketamine effects on functional connectivity: Large scale network relationships, hubs and symptom mechanisms.

Ketamine is an uncompetitive N-methyl-d-aspartate (NMDA) glutamate receptor antagonist. It induces effects in healthy individuals that mimic symptoms associated with schizophrenia. We sought to root these experiences in altered brain function, specifically aberrant resting state functional connectivity (rsfMRI). In the present study, we acquired rsfMRI data under ketamine and placebo in a between-subjects design and analyzed seed-based measures of rsfMRI using large-scale networks, dorsolateral prefrontal cortex (DLPFC) and sub-nuclei of the thalamus. We found ketamine-induced alterations in rsfMRI connectivity similar to those seen in patients with schizophrenia, some changes that may be more comparable to early stages of schizophrenia, and other connectivity signatures seen in patients that ketamine did not recreate. We do not find any circuits from our regions of interest that correlates with positive symptoms of schizophrenia in our sample, although we find that DLPFC connectivity with ACC does correlate with a mood measure. These results provide support for ketamine's use as a model of certain biomarkers of schizophrenia, particularly for early or at-risk patients.

Neuromelanin-sensitive MRI as a noninvasive proxy measure of dopamine function in the human brain.

Neuromelanin-sensitive MRI (NM-MRI) purports to detect the content of neuromelanin (NM), a product of dopamine metabolism that accumulates with age in dopamine neurons of the substantia nigra (SN). Interindividual variability in dopamine function may result in varying levels of NM accumulation in the SN; however, the ability of NM-MRI to measure dopamine function in nonneurodegenerative conditions has not been established. Here, we validated that NM-MRI signal intensity in postmortem midbrain specimens correlated with regional NM concentration even in the absence of neurodegeneration, a prerequisite for its use as a proxy for dopamine function. We then validated a voxelwise NM-MRI approach with sufficient anatomical sensitivity to resolve SN subregions. Using this approach and a multimodal dataset of molecular PET and fMRI data, we further showed the NM-MRI signal was related to both dopamine release in the dorsal striatum and resting blood flow within the SN. These results suggest that NM-MRI signal in the SN is a proxy for function of dopamine neurons in the nigrostriatal pathway. As a proof of concept for its clinical utility, we show that the NM-MRI signal correlated to severity of psychosis in schizophrenia and individuals at risk for schizophrenia, consistent with the well-established dysfunction of the nigrostriatal pathway in psychosis. Our results indicate that noninvasive NM-MRI is a promising tool that could have diverse research and clinical applications to investigate in vivo the role of dopamine in neuropsychiatric illness.