Connectivity-guided intermittent theta burst versus repetitive transcranial magnetic stimulation for treatment-resistant depression: a randomized controlled trial.

Disruption in reciprocal connectivity between the right anterior insula and the left dorsolateral prefrontal cortex is associated with depression and may be a target for neuromodulation. In a five-center, parallel, double-blind, randomized controlled trial we personalized resting-state functional magnetic resonance imaging neuronavigated connectivity-guided intermittent theta burst stimulation (cgiTBS) at a site based on effective connectivity from the right anterior insula to the left dorsolateral prefrontal cortex. We tested its efficacy in reducing the primary outcome depression symptoms measured by the GRID Hamilton Depression Rating Scale 17-item over 8, 16 and 26 weeks, compared with structural magnetic resonance imaging (MRI) neuronavigated repetitive transcranial magnetic stimulation (rTMS) delivered at the standard stimulation site (F3) in patients with 'treatment-resistant depression'. Participants were randomly assigned to 20 sessions over 4-6 weeks of either cgiTBS (n = 128) or rTMS (n = 127) with resting-state functional MRI at baseline and 16 weeks. Persistent decreases in depressive symptoms were seen over 26 weeks, with no differences between arms on the primary outcome GRID Hamilton Depression Rating Scale 17-item score (intention-to-treat adjusted mean, -0.31, 95% confidence interval (CI) -1.87, 1.24, P = 0.689). Two serious adverse events were possibly related to TMS (mania and psychosis). MRI-neuronavigated cgiTBS and rTMS were equally effective in patients with treatment-resistant depression over 26 weeks (trial registration no. ISRCTN19674644).

Measurement of brain glutathione with magnetic Resonance spectroscopy in Schizophrenia-Spectrum disorders - A systematic review and Meta-Analysis.

Oxidative stress may contribute to declining course and poor outcomes in psychosis. However, in vivo Magnetic Resonance Spectroscopy studies yield disparate results due to clinical stage, sample demographics, neuroanatomical focus, sample size, and acquisition method variations. We investigated glutathione in brain regions from participants with psychosis, and the relation of glutathione to clinical features and spectroscopy protocols. Meta-analysis comprised 21 studies. Glutathione levels did not differ between total psychosis patients (N = 639) and controls (N = 704) in the Medial Prefrontal region (k = 21, d = -0.09, CI = -0.28 to 0.10, p = 0.37). Patients with stable schizophrenia exhibited a small but significant glutathione reduction compared to controls (k = 14, d = -0.20, CI = -0.40 to -0.00, p = 0.05). Meta-regression showed older studies had greater glutathione reductions, possibly reflecting greater accuracy related to spectroscopy advancements in more recent studies. No significant effects of methodological variables, such as voxel size or echo time were found. Reduced glutathione in patients with stable established schizophrenia may provide novel targets for precision medicine. Standardizing MRS acquisition methods in future studies may help address discrepancies in glutathione levels.

A Positron Emission Tomography Study of Dopamine Transporter Density in Patients With Bipolar Disorder With Current Mania and Those With Recently Remitted Mania.

Importance: Although dopamine is implicated in the pathophysiology of bipolar disorder (BD), the precise alterations in the dopaminergic system remain unknown. Objective: To assess dopamine transporter (DAT) density in the striatum in patients with BD with current and recently remitted mania in comparison to healthy control individuals and its correlation with severity of manic symptoms. Design, Setting, and Participants: This cross-sectional study conducted in a tertiary care referral center for mood disorders in Vancouver, British Columbia, Canada, recruited 26 patients with BD (9 with current mania; 17 with recently remitted mania) and 21 matched healthy control individuals. DAT density was measured using positron emission tomography with [11C]d-threo-methylphenidate (MP). The differences between the groups in nondisplaceable binding potential (BPND) for DAT was assessed using statistical parametric mapping. The study was conducted from November 2001 to February 2007 and the data were analyzed from November 2020 to December 2021. Main Outcomes and Measures: DAT density as indexed by BPND for MP across groups; manic symptom severity as measured with the Young Mania Rating Scale (YMRS) and correlated with BPND values in patients with BD. Results: Of 47 total participants (mean [SD] age, 37.8 [14.4] years), 27 (57.4%) were female; 26 individuals had BD (9 with current mania and 17 with recently remitted mania) and there were 21 healthy control individuals. MP BPND was significantly lower in patients with BD in the right putamen and nucleus accumbens (mean reduction [MR] = 22%; cluster level familywise error [FWE]-corrected P < .001) as well as left putamen and caudate (MR = 24%; cluster level FWE-corrected P < .001). The reduction in BPND was more extensive and pronounced in patients with current mania, while patients with recently remitted mania had lower BPND in the left striatum but not the right. There was a significant negative correlation between YMRS scores and MP BPND in the right striatum in patients with current mania (ρ = -0.93; 95% CI, -0.99 to -0.69; P < .001) and those with recently remitted mania (ρ = 0.64; 95% CI, -0.86 to -0.23; P = .005) but not in the left striatum in either group. Conclusions and Relevance: These findings indicate that mania was associated with reduced DAT density and remitted mania was associated with DAT levels that approximated those present in individuals without BD. These results have potential implications for drug development for mania.

Cortical impoverishment in a stable subgroup of schizophrenia: Validation across various stages of psychosis.

BACKGROUND: Cortical thinning is a well-known feature in schizophrenia. The considerable variation in the spatial distribution of thickness changes has been used to parse heterogeneity. A 'cortical impoverishment' subgroup with a generalized reduction in thickness has been reported. However, it is unclear if this subgroup is recoverable irrespective of illness stage, and if it relates to the glutamate hypothesis of schizophrenia. METHODS: We applied hierarchical cluster analysis to cortical thickness data from magnetic resonance imaging scans of three datasets in different stages of psychosis (n = 288; 160 patients; 128 healthy controls) and studied the cognitive and symptom profiles of the observed subgroups. In one of the samples, we also studied the subgroup differences in 7-Tesla magnetic resonance spectroscopy glutamate concentration in the dorsal anterior cingulate cortex. RESULTS: Our consensus-based clustering procedure consistently produced 2 subgroups of participants. Patients accounted for 75%-100% of participants in one subgroup that was characterized by significantly lower cortical thickness. Both subgroups were equally symptomatic in clinically unstable stages, but cortical impoverishment indicated a higher symptom burden in a clinically stable sample and higher glutamate levels in the first-episode sample. There were no subgroup differences in cognitive and functional outcome profiles or antipsychotic exposure across all stages. CONCLUSIONS: Cortical thinning does not vary with functioning or cognitive impairment, but it is more prevalent among patients, especially those with glutamate excess in early stages and higher residual symptom burden at later stages, providing an important mechanistic clue to one of the several possible pathways to the illness.

Imprecise Predictive Coding Is at the Core of Classical Schizophrenia.

Current diagnostic criteria for schizophrenia place emphasis on delusions and hallucinations, whereas the classical descriptions of schizophrenia by Kraepelin and Bleuler emphasized disorganization and impoverishment of mental activity. Despite the availability of antipsychotic medication for treating delusions and hallucinations, many patients continue to experience persisting disability. Improving treatment requires a better understanding of the processes leading to persisting disability. We recently introduced the term classical schizophrenia to describe cases with disorganized and impoverished mental activity, cognitive impairment and predisposition to persisting disability. Recent evidence reveals that a polygenic score indicating risk for schizophrenia predicts severity of the features of classical schizophrenia: disorganization, and to a lesser extent, impoverishment of mental activity and cognitive impairment. Current understanding of brain function attributes a cardinal role to predictive coding: the process of generating models of the world that are successively updated in light of confirmation or contradiction by subsequent sensory information. It has been proposed that abnormalities of these predictive processes account for delusions and hallucinations. Here we examine the evidence provided by electrophysiology and fMRI indicating that imprecise predictive coding is the core pathological process in classical schizophrenia, accounting for disorganization, psychomotor poverty and cognitive impairment. Functional imaging reveals aberrant brain activity at network hubs engaged during encoding of predictions. We discuss the possibility that frequent prediction errors might promote excess release of the neurotransmitter, dopamine, thereby accounting for the occurrence of episodes of florid psychotic symptoms including delusions and hallucinations in classical schizophrenia. While the predictive coding hypotheses partially accounts for the time-course of classical schizophrenia, the overall body of evidence indicates that environmental factors also contribute. We discuss the evidence that chronic inflammation is a mechanism that might link diverse genetic and environmental etiological factors, and contribute to the proposed imprecision of predictive coding.

Characterization of Hemodynamic Alterations in Schizophrenia and Bipolar Disorder and Their Effect on Resting-State fMRI Functional Connectivity.

Common and distinct neural bases of Schizophrenia (SZ) and bipolar disorder (BP) have been explored using resting-state fMRI (rs-fMRI) functional connectivity (FC). However, fMRI is an indirect measure of neural activity, which is a convolution of the hemodynamic response function (HRF) and latent neural activity. The HRF, which models neurovascular coupling, varies across the brain within and across individuals, and is altered in many psychiatric disorders. Given this background, this study had three aims: quantifying HRF aberrations in SZ and BP, measuring the impact of such HRF aberrations on FC group differences, and exploring the genetic basis of HRF aberrations. We estimated voxel-level HRFs by deconvolving rs-fMRI data obtained from SZ (N = 38), BP (N = 19), and matched healthy controls (N = 35). We identified HRF group differences (P < .05, FDR corrected) in many regions previously implicated in SZ/BP, with mediodorsal, habenular, and central lateral nuclei of the thalamus exhibiting HRF differences in all pairwise group comparisons. Thalamus seed-based FC analysis revealed that ignoring HRF variability results in false-positive and false-negative FC group differences, especially in insula, superior frontal, and lingual gyri. HRF was associated with DRD2 gene expression (P < .05, 1.62 < |Z| < 2.0), as well as with medication dose (P < .05, 1.75 < |Z| < 3.25). In this first study to report HRF aberrations in SZ and BP, we report the possible modulatory effect of dopaminergic signalling on HRF, and the impact that HRF variability can have on FC studies in clinical samples. To mitigate the impact of HRF variability on FC group differences, we suggest deconvolution during data preprocessing.

Development and Validation of a Nonremission Risk Prediction Model in First-Episode Psychosis: An Analysis of 2 Longitudinal Studies.

Psychosis is a major mental illness with first onset in young adults. The prognosis is poor in around half of the people affected, and difficult to predict. The few tools available to predict prognosis have major weaknesses which limit their use in clinical practice. We aimed to develop and validate a risk prediction model of symptom nonremission in first-episode psychosis. Our development cohort consisted of 1027 patients with first-episode psychosis recruited between 2005 and 2010 from 14 early intervention services across the National Health Service in England. Our validation cohort consisted of 399 patients with first-episode psychosis recruited between 2006 and 2009 from a further 11 English early intervention services. The one-year nonremission rate was 52% and 54% in the development and validation cohorts, respectively. Multivariable logistic regression was used to develop a risk prediction model for nonremission, which was externally validated. The prediction model showed good discrimination C-statistic of 0.73 (0.71, 0.75) and adequate calibration with intercept alpha of 0.12 (0.02, 0.22) and slope beta of 0.98 (0.85, 1.11). Our model improved the net-benefit by 15% at a risk threshold of 50% compared to the strategy of treating all, equivalent to 15 more detected nonremitted first-episode psychosis individuals per 100 without incorrectly classifying remitted cases. Once prospectively validated, our first episode psychosis prediction model could help identify patients at increased risk of nonremission at initial clinical contact.

Oxidative Stress and the Pathophysiology and Symptom Profile of Schizophrenia Spectrum Disorders.

Schizophrenia is associated with increased levels of oxidative stress, as reflected by an increase in the concentrations of damaging reactive species and a reduction in anti-oxidant defences to combat them. Evidence has suggested that whilst not the likely primary cause of schizophrenia, increased oxidative stress may contribute to declining course and poor outcomes associated with schizophrenia. Here we discuss how oxidative stress may be implicated in the aetiology of schizophrenia and examine how current understanding relates associations with symptoms, potentially via lipid peroxidation induced neuronal damage. We argue that oxidative stress may be a good target for future pharmacotherapy in schizophrenia and suggest a multi-step model of illness progression with oxidative stress involved at each stage.

Regional Brain Correlates of Beta Bursts in Health and Psychosis: A Concurrent Electroencephalography and Functional Magnetic Resonance Imaging Study.

BACKGROUND: There is emerging evidence for abnormal beta oscillations in psychosis. Beta oscillations are likely to play a key role in the coordination of sensorimotor information that is crucial to healthy mental function. Growing evidence suggests that beta oscillations typically manifest as transient beta bursts that increase in probability following a motor response, observable as post-movement beta rebound. Evidence indicates that post-movement beta rebound is attenuated in psychosis, with greater attenuation associated with greater symptom severity and impairment. Delineating the functional role of beta bursts therefore may be key to understanding the mechanisms underlying persistent psychotic illness. METHODS: We used concurrent electroencephalography and functional magnetic resonance imaging to identify blood oxygen level-dependent correlates of beta bursts during the n-back working memory task and intervening rest periods in healthy control participants (n = 30) and patients with psychosis (n = 48). RESULTS: During both task blocks and intervening rest periods, beta bursts phasically activated regions implicated in task-relevant content while suppressing currently tonically active regions. Patients showed attenuated post-movement beta rebound that was associated with persisting disorganization symptoms as well as impairments in cognition and role function. Patients also showed greater task-related reductions in overall beta burst rate and showed greater, more extensive, beta burst-related blood oxygen level-dependent activation. CONCLUSIONS: Our evidence supports a model in which beta bursts reactivate latently maintained sensorimotor information and are dysregulated and inefficient in psychosis. We propose that abnormalities in the mechanisms by which beta bursts coordinate reactivation of contextually appropriate content can manifest as disorganization, working memory deficits, and inaccurate forward models and may underlie a core deficit associated with persisting symptoms and impairment.

Motor-related oscillatory activity in schizophrenia according to phase of illness and clinical symptom severity.

Magnetoencephalography (MEG) measures magnetic fields generated by synchronised neural current flow and provides direct inference on brain electrophysiology and connectivity, with high spatial and temporal resolution. The movement-related beta decrease (MRBD) and the post-movement beta rebound (PMBR) are well-characterised effects in magnetoencephalography (MEG), with the latter having been shown to relate to long-range network integrity. Our previous work has shown that the PMBR is diminished (relative to controls) in a group of schizophrenia patients. However, little is known about how this effect might differ in patients at different stages of illness and degrees of clinical severity. Here, we extend our previous findings showing that the MEG derived PMBR abnormality in schizophrenia exists in 29 recent-onset and 35 established cases (i.e., chronic patients), compared to 42 control cases. In established cases, PMBR is negatively correlated with severity of disorganization symptoms. Further, using a hidden Markov model analysis, we show that transient pan-spectral oscillatory "bursts", which underlie the PMBR, differ between healthy controls and patients. Results corroborate that PMBR is associated with disorganization of mental activity in schizophrenia.

Effective connectivity of the right anterior insula in schizophrenia: The salience network and task-negative to task-positive transition.

Triple network dysfunction theory of schizophrenia postulates that the interaction between the default-mode and the fronto-parietal executive network is disrupted by aberrant salience signals from the right anterior insula (rAI). To date, it is not clear how the proposed resting-state disruption translates to task-processing inefficiency in subjects with schizophrenia. Using a contiguous resting and 2-back task performance fMRI paradigm, we quantified the change in effective connectivity that accompanies rest-to-task state transition in 29 clinically stable patients with schizophrenia and 31 matched healthy controls. We found an aberrant task-evoked increase in the influence of the rAI to both executive (Cohen's d = 1.35, p = 2.8 × 10-6) and default-mode (Cohen's d = 1.22, p = 1.5 × 10-5) network regions occur in patients when compared to controls. In addition, the effective connectivity from middle occipital gyrus (dorsal visual cortex) to insula is also increased in patients as compared with healthy controls. Aberrant insula to executive network influence is pronounced in patients with more severe negative symptom burden. These findings suggest that control signals from rAI are abnormally elevated and directed towards both task-positive and task-negative brain regions, when task-related demands arise in schizophrenia. This aberrant, undiscriminating surge in salience signalling may disrupt contextually appropriate allocation of resources in the neuronal workspace in patients with schizophrenia.

Quantifying the Core Deficit in Classical Schizophrenia.

In the classical descriptions of schizophrenia, Kraepelin and Bleuler recognized disorganization and impoverishment of mental activity as fundamental symptoms. Their classical descriptions also included a tendency to persisting disability. The psychopathological processes underlying persisting disability in schizophrenia remain poorly understood. The delineation of a core deficit underlying persisting disability would be of value in predicting outcome and enhancing treatment. We tested the hypothesis that mental disorganization and impoverishment are associated with persisting impairments of cognition and role function, and together reflect a latent core deficit that is discernible in cases diagnosed by modern criteria. We used Confirmatory Factor Analysis to determine whether measures of disorganization, mental impoverishment, impaired cognition, and role functioning in 40 patients with schizophrenia represent a single latent variable. Disorganization scores were computed from the variance shared between disorganization measures from 3 commonly used symptom scales. Mental impoverishment scores were computed similarly. A single factor model exhibited a good fit, supporting the hypothesis that these measures reflect a core deficit. Persisting brain disorders are associated with a reduction in post-movement beta rebound (PMBR), the characteristic increase in electrophysiological beta amplitude that follows a motor response. Patients had significantly reduced PMBR compared with healthy controls. PMBR was negatively correlated with core deficit score. While the symptoms constituting impoverished and disorganized mental activity are dissociable in schizophrenia, nonetheless, the variance that these 2 symptom domains share with impaired cognition and role function, appears to reflect a pathophysiological process that might be described as the core deficit of classical schizophrenia.

Parietal lobe and disorganisation syndrome in schizophrenia and psychotic bipolar disorder: A bimodal connectivity study.

Given the emerging evidence in support of parietal brain stimulation to treat speech disorder in psychosis, we investigated structural and functional parietal dysconnectivity in schizophrenia (n = 34) and bipolar disorder with psychotic symptoms (n = 16). We found that both patient groups demonstrated reduced left parietal structural connectivity compared to healthy controls (n = 32). The three groups also differed significantly on the variability of left and right parietal dynamic functional connectivity. In patients with schizophrenia, parietal dysconnectivity predicted the severity of disorganisation symptoms. These findings suggest that dysconnectivity between the parietal lobe and the rest of the brain plays a key role in disorganisation symptoms of schizophrenia.

Cortical thickness and formal thought disorder in schizophrenia: An ultra high-field network-based morphometry study.

BACKGROUND: Persistent formal thought disorder (FTD) is a core feature of schizophrenia. Recent cognitive and neuroimaging studies indicate a distinct mechanistic pathway underlying the persistent positive FTD (pFTD or disorganized thinking), though its structural determinants are still elusive. Using network-based cortical thickness estimates from ultra-high field 7-Tesla Magnetic Resonance Imaging (7T MRI), we investigated the structural correlates of pFTD. METHODS: We obtained speech samples and 7T MRI anatomical scans from medicated clinically stable patients with schizophrenia (n = 19) and healthy controls (n = 20). Network-based morphometry was used to estimate the mean cortical thickness of 17 functional networks covering the entire cortical surface from each subject. We also quantified the vertexwise variability of thickness within each network to quantify the spatial coherence of the 17 networks, estimated patients vs. controls differences, and related the thickness of the affected networks to the severity of pFTD. RESULTS: Patients had reduced thickness of the frontoparietal and default mode networks, and reduced spatial coherence affecting the salience and the frontoparietal control network. A higher burden of positive FTD related to reduced frontoparietal thickness and reduced spatial coherence of the salience network. The presence of positive FTD, but not its severity, related to the reduced thickness of the language network comprising of the superior temporal cortex. CONCLUSIONS: These results suggest that cortical thickness of both cognitive control and language networks underlie the positive FTD in schizophrenia. The structural integrity of cognitive control networks is a critical determinant of the expressed severity of persistent FTD in schizophrenia.

Glutathione and glutamate in schizophrenia: a 7T MRS study.

In schizophrenia, abnormal neural metabolite concentrations may arise from cortical damage following neuroinflammatory processes implicated in acute episodes. Inflammation is associated with increased glutamate, whereas the antioxidant glutathione may protect against inflammation-induced oxidative stress. We hypothesized that patients with stable schizophrenia would exhibit a reduction in glutathione, glutamate, and/or glutamine in the cerebral cortex, consistent with a post-inflammatory response, and that this reduction would be most marked in patients with "residual schizophrenia", in whom an early stage with positive psychotic symptoms has progressed to a late stage characterized by long-term negative symptoms and impairments. We recruited 28 patients with stable schizophrenia and 45 healthy participants matched for age, gender, and parental socio-economic status. We measured glutathione, glutamate and glutamine concentrations in the anterior cingulate cortex (ACC), left insula, and visual cortex using 7T proton magnetic resonance spectroscopy (MRS). Glutathione and glutamate were significantly correlated in all three voxels. Glutamine concentrations across the three voxels were significantly correlated with each other. Principal components analysis (PCA) produced three clear components: an ACC glutathione-glutamate component; an insula-visual glutathione-glutamate component; and a glutamine component. Patients with stable schizophrenia had significantly lower scores on the ACC glutathione-glutamate component, an effect almost entirely leveraged by the sub-group of patients with residual schizophrenia. All three metabolite concentration values in the ACC were significantly reduced in this group. These findings are consistent with the hypothesis that excitotoxicity during the acute phase of illness leads to reduced glutathione and glutamate in the residual phase of the illness.

The Core Deficit of Classical Schizophrenia: Implications for Predicting the Functional Outcome of Psychotic Illness and Developing Effective Treatments.

Many people suffering from psychotic illnesses experience persisting impairment of occupational and social function. Evidence assembled since the classical description of schizophrenia over a century ago indicates that both disorganization and impoverishment of mental activity are associated with persisting impairment. Longitudinal studies of young people at risk of schizophrenia reveal that both mental impoverishment and disorganization predict poor long-term outcome. These clinical features are related to cognitive impairments. Evidence from brain imaging indicates overlap in the brain abnormalities implicated in these phenomena, including impaired function of long-range connections between sensory cortex and the salience network, a network engaged in recruiting cerebral systems for processing of information salient to current circumstances. The evidence suggests that the common features underlying these two groups of symptoms might reflect a core pathological process distinguishing nonaffective from affective psychosis. This pathological process might therefore justifiably be designated the "core deficit" of classical schizophrenia. To develop more effective treatments to prevent persisting disability, we require the ability to identify individuals at risk at an early stage. Recent studies provide pointers toward effective strategies for identifying cases at risk of poor outcome. Accumulating evidence confirms that appreciable potential for neuroplastic change in the brain persists into adult life. Furthermore, brain function can be enhanced by targeted neuromodulation treatments. We now have promising tools not only for investigating the psychological and neural mechanisms that underlie persisting functional impairment but also for identifying individuals at risk and for harnessing brain plasticity to improve treatment.

Reduced Prefrontal Gyrification in Carriers of the Dopamine D4 Receptor 7-Repeat Allele With Attention Deficit/Hyperactivity Disorder: A Preliminary Report.

Objective: Structural and functional abnormalities have been noted in the prefrontal cortex of individuals with neurodevelopmental disorders such as attention deficit/hyperactivity disorder (ADHD). Cortical thickness and gyrification, both of which have been reported as abnormal in the prefrontal cortex in ADHD, are thought to be modulated by genetic influences during neural development. This study aimed to investigate the effects of a polymorphism of the dopamine DRD4 gene (the 7-repeat (7R) "risk" allele) on thickness and gyrification as distinct parameters of prefrontal cortical structure in children with ADHD. Method: Structural images and genetic samples were obtained from 49 children aged 9-15 years (25 with ADHD and 24 matched controls), and measures of cortical thickness and gyrification for inferior, middle, and superior frontal cortex were calculated. Results: A significant interaction between diagnosis and genotype on prefrontal gyrification was observed, largely driven by reduced inferior frontal gyrification in patients who carried the DRD4 7R allele. Furthermore, inferior frontal gyrification-but not thickness-related to everyday executive functioning in 7R allele carriers across groups. Conclusions: Prefrontal gyrification is reduced in children with ADHD who also carry the DRD4 7R allele, and it relates to critical functional skills in the executive domain in carriers of the risk allele. More broadly, these effects highlight the importance of considering precise neurodevelopmental mechanisms through which risk alleles influence cortical neurogenesis and migration.

Effective connectivity within a triple network brain system discriminates schizophrenia spectrum disorders from psychotic bipolar disorder at the single-subject level.

OBJECTIVE: Schizophrenia spectrum disorders (SSD) and psychotic bipolar disorder share a number of genetic and neurobiological features, despite a divergence in clinical course and outcome trajectories. We studied the diagnostic classification potential that can be achieved on the basis of the structure and connectivity within a triple network system (the default mode, salience and central executive network) in patients with SSD and psychotic bipolar disorder. METHODS: Directed static connectivity and its dynamic variance was estimated among 8 nodes of the three large-scale networks. Multivariate autoregressive models of deconvolved resting state functional magnetic resonance imaging time series were obtained from 57 patients (38 with SSD and 19 with bipolar disorder and psychosis). We used 2/3 of the patients for training and validation of the classifier and the remaining 1/3 as an independent hold-out test data for performance estimation. RESULTS: A high level of discrimination between bipolar disorder with psychosis and SSD (combined balanced accuracy = 96.2%; class accuracies 100% for bipolar and 92.3% for SSD) was achieved when effective connectivity and morphometry of the triple network nodes was combined with symptom scores. Patients with SSD were discriminated from patients with bipolar disorder and psychosis as showing higher clinical severity of disorganization and higher variability in the effective connectivity between salience and executive networks. CONCLUSIONS: Our results support the view that the study of network-level connectivity patterns can not only clarify the pathophysiology of SSD but also provide a measure of excellent clinical utility to identify discrete diagnostic/prognostic groups among individuals with psychosis.