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Machine learning approaches using structural magnetic resonance imaging (sMRI) can be informative for disease classification, although their ability to predict psychosis is largely unknown. We created a model with individuals at CHR who developed psychosis later (CHR-PS+) from healthy controls (HCs) that can differentiate each other. We also evaluated whether we could distinguish CHR-PS+ individuals from those who did not develop psychosis later (CHR-PS-) and those with uncertain follow-up status (CHR-UNK). T1-weighted structural brain MRI scans from 1165 individuals at CHR (CHR-PS+, n = 144; CHR-PS-, n = 793; and CHR-UNK, n = 228), and 1029 HCs, were obtained from 21 sites. We used ComBat to harmonize measures of subcortical volume, cortical thickness and surface area data and corrected for non-linear effects of age and sex using a general additive model. CHR-PS+ (n = 120) and HC (n = 799) data from 20 sites served as a training dataset, which we used to build a classifier. The remaining samples were used external validation datasets to evaluate classifier performance (test, independent confirmatory, and independent group [CHR-PS- and CHR-UNK] datasets). The accuracy of the classifier on the training and independent confirmatory datasets was 85% and 73% respectively. Regional cortical surface area measures-including those from the right superior frontal, right superior temporal, and bilateral insular cortices strongly contributed to classifying CHR-PS+ from HC. CHR-PS- and CHR-UNK individuals were more likely to be classified as HC compared to CHR-PS+ (classification rate to HC: CHR-PS+, 30%; CHR-PS-, 73%; CHR-UNK, 80%). We used multisite sMRI to train a classifier to predict psychosis onset in CHR individuals, and it showed promise predicting CHR-PS+ in an independent sample. The results suggest that when considering adolescent brain development, baseline MRI scans for CHR individuals may be helpful to identify their prognosis. Future prospective studies are required about whether the classifier could be actually helpful in the clinical settings.

Screening for psychosis spectrum disorders in primary care could improve early identification and reduce the duration of untreated psychosis. However, the accuracy of psychosis screening in this setting is unknown. To address this, we conducted a diagnostic accuracy study of screening for psychosis spectrum disorders in eight behavioral health services integrated into primary care clinics. Patients attending an integrated behavioral health appointment at their primary care clinic completed the Prodromal Questionnaire - Brief (PQ-B) immediately prior to their intake assessment. This was compared to a diagnostic phone interview based on the Structured Interview for Psychosis Risk Syndromes (SIPS). In total, 145 participants completed all study procedures, of which 100 screened positive and 45 negative at a provisional PQ-B threshold of ≥20. The PQ-B was moderately accurate at differentiating psychosis spectrum from no psychosis spectrum disorders; a PQ-B distress score of ≥27 had a sensitivity and specificity of 71.2 % and 57.0 % respectively. In total, 66 individuals (45.5 %) met criteria for a psychosis spectrum disorder and 24 (16.7 %) were diagnosed with full psychosis, indicating a high prevalence of psychosis in the sample. Overall, screening for psychosis spectrum disorders in an IBH primary care setting identified a relatively high number of individuals and may identify people that would otherwise be missed. The PQ-B performed slightly less well than in population-based screening in community mental health settings. However, the findings suggest this may represent an effective way to streamline the pathway between specialty early psychosis programs and primary care clinics for those in need.

BackgroundA longer duration of untreated psychosis (DUP) is associated with poorer treatment outcomes. Screening for psychosis spectrum disorders in the primary care setting could help support the earlier detection and treatment of individuals in need. However, the acceptability of screening for psychosis in this setting as part of routine care is currently unknown.MethodsWe conducted a qualitative interview study with providers and service users who participated in an early psychosis screening program conducted in an integrated behavioral health primary care (IBH-PC) setting. Interviews were recruited from one of eight WellSpace Federally Qualified Health Center IBH-PC clinics in the Sacramento, CA area. Transcripts of the recorded interviews were analyzed using thematic analysis.ResultsIn total, 12 providers and eight service users participated in the interviews. Most service user and provider participants were supportive of psychosis screening in an IBH-PC setting, but not as part of the general practitioner consultation due to the brief, non-behavioral health nature of many of the appointments, and the expected low prevalence of psychosis in this population. The support of leadership, adequate training and support, staff turnover, and organizational changes were all seen to impact the successful implementation of the program. Different barriers and facilitators were considered important at each stage of the process from introducing the screening procedures to service users; to determining when, where, and how to screen; and how to effectively manage the referral and post-referral stages.ConclusionsDespite the additional challenges of screening in an IBH-PC setting relative to secondary mental health services, the process was considered acceptable and feasible to providers and service users. Services that plan to conduct psychosis screening in their clinics need to consider the challenges and their potential solutions to implementation at each stage of the screening process.

ImportanceClinical trials have not established the optimal type, sequence, and duration of interventions for people at ultrahigh risk of psychosis.ObjectiveTo determine the effectiveness of a sequential and adaptive intervention strategy for individuals at ultrahigh risk of psychosis.Design, setting, and participantsThe Staged Treatment in Early Psychosis (STEP) sequential multiple assignment randomized trial took place within the clinical program at Orygen, Melbourne, Australia. Individuals aged 12 to 25 years who were seeking treatment and met criteria for ultrahigh risk of psychosis according to the Comprehensive Assessment of At-Risk Mental States were recruited between April 2016 and January 2019. Of 1343 individuals considered, 342 were recruited.InterventionsStep 1: 6 weeks of support and problem solving (SPS); step 2: 20 weeks of cognitive-behavioral case management (CBCM) vs SPS; and step 3: 26 weeks of CBCM with fluoxetine vs CBCM with placebo with an embedded fast-fail option of ω-3 fatty acids or low-dose antipsychotic medication. Individuals who did not remit progressed through these steps; those who remitted received SPS or monitoring for up to 12 months.Main outcomes and measuresGlobal Functioning: Social and Role scales (primary outcome), Brief Psychiatric Rating Scale, Scale for the Assessment of Negative Symptoms, Montgomery-Åsberg Depression Rating Scale, quality of life, transition to psychosis, and remission and relapse rates.ResultsThe sample comprised 342 participants (198 female; mean [SD] age, 17.7 [3.1] years). Remission rates, reflecting sustained symptomatic and functional improvement, were 8.5%, 10.3%, and 11.4% at steps 1, 2, and 3, respectively. A total of 27.2% met remission criteria at any step. Relapse rates among those who remitted did not significantly differ between SPS and monitoring (step 1: 65.1% vs 58.3%; step 2: 37.7% vs 47.5%). There was no significant difference in functioning, symptoms, and transition rates between SPS and CBCM and between CBCM with fluoxetine and CBCM with placebo. Twelve-month transition rates to psychosis were 13.5% (entire sample), 3.3% (those who ever remitted), and 17.4% (those with no remission).Conclusions and relevanceIn this sequential multiple assignment randomized trial, transition rates to psychosis were moderate, and remission rates were lower than expected, partly reflecting the ambitious criteria set and challenges with real-world treatment fidelity and adherence. While all groups showed mild to moderate functional and symptomatic improvement, this was typically short of remission. While further adaptive trials that address these challenges are needed, findings confirm substantial and sustained morbidity and reveal relatively poor responsiveness to existing treatments.Trial registrationClinicalTrials.gov Identifier: NCT02751632.

ObjectiveThe authors investigated associations between rates of contact with individuals in distress during field visits by mobile crisis teams and client and referral source characteristics.MethodsIn this retrospective observational study of an urban mobile crisis program, call logs (N=2,581) were coded for whether an attempted field visit resulted in a client evaluation. Logistic regression analyses examined potential associations with client age, gender, race-ethnicity, primary language, living situation, insurance, and referral source.ResultsContact was made with 77% of adults and 97% of children referred to mobile crisis teams. Field visit contact rates differed by age. Unsuccessful visits were more likely when the referral source was from institutional settings than from individuals.ConclusionsApproximately one-quarter of attempted field visits with adults by an urban mobile crisis team were not completed, particularly among referrals from institutional settings. As mobile crisis services proliferate, field visit contact rate could be a key performance metric for these critical services.

Brain dysconnectivity has been posited as a biological marker of schizophrenia. Emerging schizophrenia connectome research has focused on rich-club organization, a tendency for brain hubs to be highly-interconnected but disproportionately vulnerable to dysconnectivity. However, less is known about rich-club organization in individuals at clinical high-risk for psychosis (CHR-P) and how it compares with abnormalities early in schizophrenia (ESZ). Combining diffusion tensor imaging (DTI) and magnetic resonance imaging (MRI), we examined rich-club and global network organization in CHR-P (n = 41) and ESZ (n = 70) relative to healthy controls (HC; n = 74) after accounting for normal aging. To characterize rich-club regions, we examined rich-club MRI morphometry (thickness, surface area). We also examined connectome metric associations with symptom severity, antipsychotic dosage, and in CHR-P specifically, transition to a full-blown psychotic disorder. ESZ had fewer connections among rich-club regions (ps

ImportanceReducing the duration of untreated psychosis (DUP) is essential to improving outcomes for people with first-episode psychosis (FEP). Current US approaches are insufficient to reduce DUP to international standards of less than 90 days.ObjectiveTo determine whether population-based electronic screening in addition to standard targeted clinician education increases early detection of psychosis and decreases DUP, compared with clinician education alone.Design, setting, and participantsThis cluster randomized clinical trial included individuals aged 12 to 30 years presenting for services between March 2015 and September 2017 at participating sites that included community mental health clinics and school support and special education services. Eligible participants were referred to the Early Diagnosis and Preventative Treatment (EDAPT) Clinic. Data analyses were performed in September and October 2019 for the primary and secondary analyses, with the exploratory subgroup analyses completed in May 2021.InterventionsAll sites in both groups received targeted education about early psychosis for health care professionals. In the active screening group, clients also completed the Prodromal Questionnaire-Brief using tablets at intake; referrals were based on those scores and clinical judgment. In the group receiving treatment as usual (TAU), referrals were based on clinical judgment alone.Main outcomes and measuresPrimary outcomes included DUP, defined as the period from full psychosis onset to the date of the EDAPT diagnostic telephone interview, and the number of individuals identified with FEP or a psychosis spectrum disorder. Exploratory analyses examined differences by site type, completion rates between conditions, and days from service entry to telephone interview.ResultsTwenty-four sites agreed to participate, and 12 sites were randomized to either the active screening or TAU group. However, only 10 community clinics and 4 school sites were able to fully implement population screening and were included in the final analysis. The total potentially eligible population size within each study group was similar, with 2432 individuals entering at active screening group sites and 2455 at TAU group sites. A total of 303 diagnostic telephone interviews were completed (178 [58.7%] female individuals; mean [SD] age, 17.09 years [4.57]). Active screening sites reported a significantly higher detection rate of psychosis spectrum disorders (136 cases [5.6%], relative to 65 [2.6%]; P

BackgroundImpairments in cognition and motivation are core features of psychosis and strong predictors of social and occupational functioning. Accumulating evidence indicates that cognitive deficits in psychosis can be improved by computer-based cognitive training programs; however, barriers include access and adherence to cognitive training exercises. Limited evidence-based methods have been established to enhance motivated behavior. In this study, we tested the effects of web-based targeted cognitive and social cognitive training (TCT) delivered in conjunction with an innovative digital smartphone app called Personalized Real-Time Intervention for Motivational Enhancement (PRIME). The PRIME app provides users with a motivational coach to set personalized goals and secure social networking for peer support.ObjectiveThis study investigated whether deficits in cognition and motivation in people with a psychosis spectrum disorder (N=100) can be successfully addressed with 30 hours of TCT+PRIME as compared with 30 hours of a computer games control condition (CG) plus PRIME (CG+PRIME). Here, we describe our study procedures, the feasibility and acceptability of the intervention, and the results on all primary outcomes.MethodsIn this double-blind randomized controlled trial, English-speaking participants completed all cognitive training, PRIME activities, and assessments remotely. Participants completed a diagnostic interview and remote cognitive, clinical, and self-report measures at baseline, posttraining, and at a 6-month follow-up.ResultsThis study included participants from 27 states across the United States and 8 countries worldwide. The study population was 58% (58/100) female, with a mean age of 33.77 (SD 10.70) years. On average, participants completed more than half of the cognitive training regimen (mean 18.58, SD 12.47 hours of training), and logged into the PRIME app 4.71 (SD 1.58) times per week. The attrition rate of 22% (22/100) was lower than that reported in our previous studies on remote cognitive training. The total sample showed significant gains in global cognition (P=.03) and attention (P

AimResearch has shown that preventative intervention in individuals at ultra-high risk of psychosis (UHR) improves symptomatic and functional outcomes. The staged treatment in early psychosis (STEP) trial aims to determine the most effective type, timing and sequence of interventions in the UHR population by sequentially studying the effectiveness of (1) support and problem solving, (2) cognitive-behavioural case management and (3) antidepressant medication with an embedded fast-fail option of (4) omega-3 fatty acids or low-dose antipsychotic medication. This paper presents the recruitment flow and baseline clinical characteristics of the sample.MethodsSTEP is a sequential multiple assignment randomized trial. We present the baseline demographics, clinical characteristics and acceptability and feasibility of this treatment approach as indicated by the flow of participants from first contact up until enrolment into the trial. Recruitment took place between April 2016 and January 2019.ResultsOf 1343, help-seeking young people who were considered for participation, 402 participants were not eligible and 599 declined/disengaged, resulting in a total of 342 participants enrolled in the study. The most common reason for exclusion was an active prescription of antidepressant medication. Eighty-five percent of the enrolled sample had a non-psychotic DSM-5 diagnosis and symptomatic/functional measures showed a moderate level of clinical severity and functional impairment.DiscussionThe present study demonstrates the acceptability and participant's general positive appraisal of sequential treatment. It also shows, in line with other trials in UHR individuals, a significant level of psychiatric morbidity and impairment, demonstrating the clear need for care in this group and that treatment is appropriate.

N-methyl-D-aspartate receptor (NMDAR) hypofunction is a leading pathophysiological model of schizophrenia. Resting-state functional magnetic resonance imaging (rsfMRI) studies demonstrate a thalamic dysconnectivity pattern in schizophrenia involving excessive connectivity with sensory regions and deficient connectivity with frontal, cerebellar, and thalamic regions. The NMDAR antagonist ketamine, when administered at sub-anesthetic doses to healthy volunteers, induces transient schizophrenia-like symptoms and alters rsfMRI thalamic connectivity. However, the extent to which ketamine-induced thalamic dysconnectivity resembles schizophrenia thalamic dysconnectivity has not been directly tested. The current double-blind, placebo-controlled study derived an NMDAR hypofunction model of thalamic dysconnectivity from healthy volunteers undergoing ketamine infusions during rsfMRI. To assess whether ketamine-induced thalamic dysconnectivity was mediated by excess glutamate release, we tested whether pre-treatment with lamotrigine, a glutamate release inhibitor, attenuated ketamine's effects. Ketamine produced robust thalamo-cortical hyper-connectivity with sensory and motor regions that was not reduced by lamotrigine pre-treatment. To test whether the ketamine thalamic dysconnectivity pattern resembled the schizophrenia pattern, a whole-brain template representing ketamine's thalamic dysconnectivity effect was correlated with individual participant rsfMRI thalamic dysconnectivity maps, generating "ketamine similarity coefficients" for people with chronic (SZ) and early illness (ESZ) schizophrenia, individuals at clinical high-risk for psychosis (CHR-P), and healthy controls (HC). Similarity coefficients were higher in SZ and ESZ than in HC, with CHR-P showing an intermediate trend. Higher ketamine similarity coefficients correlated with greater hallucination severity in SZ. Thus, NMDAR hypofunction, modeled with ketamine, reproduces the thalamic hyper-connectivity observed in schizophrenia across its illness course, including the CHR-P period preceding psychosis onset, and may contribute to hallucination severity.

Childhood psychotic-like experiences (PLEs) are associated with a range of impairments; a subset of children experiencing PLEs will develop psychiatric disorders, including psychotic disorders. A potential distinguishing factor between benign PLEs versus PLEs that are clinically relevant is whether PLEs are distressing and/or persistent. The current study used three waves of Adolescent Brain Cognitive Development℠ (ABCD) study PLEs assessments to examine the extent to which persistent and/or distressing PLEs were associated with relevant baseline risk factors (e.g., cognition) and functioning/mental health service utilization domains. Four groups varying in PLE persistence and distress endorsement were created based on all available data in ABCD Release 3.0, with group membership not contingent on complete data: persistent distressing PLEs (n = 272), transient distressing PLEs (n = 298), persistent non-distressing PLEs (n = 221), and transient non-distressing PLEs (n = 536) groups. Using hierarchical linear models, results indicated youth with distressing PLEs, whether transient or persistent, showed delayed developmental milestones (β = 0.074, 95%CI:0.013,0.134) and altered structural MRI metrics (β = -0.0525, 95%CI:-0.100,-0.005). Importantly, distress interacted with PLEs persistence for the domains of functioning/mental health service utilization (β = 0.079, 95%CI:0.016,0.141), other reported psychopathology (β = 0.101, 95%CI:0.030,0.170), cognition (β = -0.052, 95%CI:0.-0.099,-0.002), and environmental adversity (β = 0.045, 95%CI:0.003,0.0.86; although no family history effects), with the interaction characterized by greatest impairment in the persistent distressing PLEs group. These results have implications for disentangling the importance of distress and persistence for PLEs with regards to impairments, including functional, pathophysiological, and environmental outcomes. These novel longitudinal data underscore that it is often only in the context of distress that persistent PLEs were related to impairments.

ObjectiveCognitive impairment in schizophrenia predicts functional outcomes and is largely unresponsive to pharmacology or psychotherapy; it is thus a critical unmet treatment need. This article presents the impact of remotely completed, intensive, targeted auditory training (AT) vs control condition computer games (CG) in a double-blind randomized trial in young adults with recent-onset schizophrenia.MethodParticipants (N = 147) were assessed for cognition, symptoms, and functioning at baseline, post-intervention, and at 6-month follow-up. All participants were provided with laptop computers and were instructed to complete 40 hours remotely of training or computer games. An intent-to-treat analysis (N = 145) was performed using linear mixed models with time modeled as a continuous variable. Planned contrasts tested the change from baseline to post-training, baseline to 6-month follow-up, and post-training to 6-month follow-up.ResultsGlobal Cognition, which had improved in the AT group relative to the CG group at post-training, showed durable gains at 6-month follow-up in an omnibus group-by-time interaction test (F(1,179) = 4.80, P = .030), as did Problem-Solving (F(1,179) = 5.13, P = .025), and Speed of Processing improved at trend level significance (F(1,170) = 3.80, P = .053). Furthermore, the AT group showed significantly greater improvement than the CG group in positive symptoms (F(1,179) = 4.06, P = .045).ConclusionsThese results provide the first evidence of durable cognitive gains and symptom improvement at follow-up of cognitive training (CT) in early schizophrenia completed independently and remotely. While functioning did not show significant improvement, these findings suggest that intensive targeted CT of auditory processing is a promising component of early intervention to promote recovery from psychosis.

Individuals at Clinical High Risk for Psychosis (CHR-P) demonstrate heterogeneity in clinical profiles and outcome features. However, the extent of neuroanatomical heterogeneity in the CHR-P state is largely undetermined. We aimed to quantify the neuroanatomical heterogeneity in structural magnetic resonance imaging measures of cortical surface area (SA), cortical thickness (CT), subcortical volume (SV), and intracranial volume (ICV) in CHR-P individuals compared with healthy controls (HC), and in relation to subsequent transition to a first episode of psychosis. The ENIGMA CHR-P consortium applied a harmonised analysis to neuroimaging data across 29 international sites, including 1579 CHR-P individuals and 1243 HC, offering the largest pooled CHR-P neuroimaging dataset to date. Regional heterogeneity was indexed with the Variability Ratio (VR) and Coefficient of Variation (CV) ratio applied at the group level. Personalised estimates of heterogeneity of SA, CT and SV brain profiles were indexed with the novel Person-Based Similarity Index (PBSI), with two complementary applications. First, to assess the extent of within-diagnosis similarity or divergence of neuroanatomical profiles between individuals. Second, using a normative modelling approach, to assess the 'normativeness' of neuroanatomical profiles in individuals at CHR-P. CHR-P individuals demonstrated no greater regional heterogeneity after applying FDR corrections. However, PBSI scores indicated significantly greater neuroanatomical divergence in global SA, CT and SV profiles in CHR-P individuals compared with HC. Normative PBSI analysis identified 11 CHR-P individuals (0.70%) with marked deviation (>1.5 SD) in SA, 118 (7.47%) in CT and 161 (10.20%) in SV. Psychosis transition was not significantly associated with any measure of heterogeneity. Overall, our examination of neuroanatomical heterogeneity within the CHR-P state indicated greater divergence in neuroanatomical profiles at an individual level, irrespective of psychosis conversion. Further large-scale investigations are required of those who demonstrate marked deviation.

Individuals with schizophrenia exhibit widespread cortical thinning associated with illness severity and deficits in cognition. However, intact cortical thickness (CTh) may serve as a protective factor. The current study sought to examine changes in CTh in response to auditory targeted cognitive training (TCT) in individuals with recent onset schizophrenia. Participants underwent MRI scanning and a cognitive assessment before and after being randomly assigned to 40 h of either TCT (N = 21) or a computer games control condition (CG; N = 22) over 16 weeks. Groups did not differ at baseline on demographic variables or measures of CTh. At the level of group averages, neither group showed significant pre-post changes in CTh in any brain region. However, changes in CTh related to individual differences in treatment outcome, as improved global cognition in the TCT group corresponded to reduced cortical thinning in frontal, temporal, parietal, and occipital lobes. These relationships were not observed in the CG group. The current findings suggest that TCT may be neuroprotective in early schizophrenia, such that individuals who improved in response to training also showed a reduction in cortical thinning that may be otherwise hastened due to age and illness.

BackgroundPrior studies have shown that the auditory N1 event-related potential component elicited by self-generated vocalizations is reduced relative to played back vocalizations, putatively reflecting a corollary discharge mechanism. Schizophrenia patients and psychosis risk syndrome (PRS) youth show deficient N1 suppression during vocalization, consistent with corollary discharge dysfunction. Because N1 is an admixture of theta (4-7 Hz) power and phase synchrony, we examined their contributions to N1 suppression during vocalization, as well as their sensitivity, relative to N1, to corollary discharge dysfunction in schizophrenia and PRS individuals.MethodsTheta phase and power values were extracted from electroencephalography data acquired from PRS youth (n = 71), early illness schizophrenia patients (ESZ; n = 84), and healthy controls (HCs; n = 103) as they said "ah" (Talk) and then listened to the playback of their vocalizations (Listen). A principal component analysis extracted theta intertrial coherence (ITC; phase consistency) and event-related spectral power, peaking in the N1 latency range. Talk-Listen suppression scores were analyzed.ResultsTalk-Listen suppression was greater for theta ITC (Cohen's d = 1.46) than for N1 in HC (d = 0.63). Both were deficient in ESZ, but only N1 suppression was deficient in PRS. When deprived of variance shared with theta ITC suppression, N1 suppression no longer differentiated ESZ and PRS individuals from HC. Deficits in theta ITC suppression were correlated with delusions (P = .007) in ESZ. Theta power suppression did not differentiate groups.ConclusionsTheta ITC-suppression during vocalization is a more sensitive index of corollary discharge-mediated auditory cortical suppression than N1 suppression and is more sensitive to corollary discharge dysfunction in ESZ than in PRS individuals.

Patients with schizophrenia exhibit disrupted thalamocortical connections that relate to aspects of symptoms and deficits in cognition. Targeted cognitive training (TCT) of the auditory system in schizophrenia has been shown to improve cognition, but its impact on thalamocortical connectivity is not known. Here we examined thalamocortical connections that may be neuroplastic in response to TCT using a region of interest (ROI) approach. Participants were randomly assigned to either 40 h of TCT (N = 24) or an active control condition (CG; N = 20). Participants underwent resting state fMRI and cognitive testing both before and after training. Changes in thalamocortical connectivity were measured in 15 ROIs derived from a previous study comparing a large sample of schizophrenia subjects with healthy controls. A significant group by time interaction was observed in a left superior temporal ROI which was previously found to exhibit thalamocortical hyper-connectivity in patients with schizophrenia. Changes in this ROI reflected thalamic connectivity increases in the TCT group, while the CG group showed decreases. Additionally, the relationship between connectivity change and change in global cognition showed a slope difference between groups, with increases in thalamo-temporal connectivity correlating with improvements in global cognition in TCT. No significant relationships were observed with changes in clinical symptoms or functioning. These findings demonstrate that TCT may influence intrinsic functional connections in young individuals with schizophrenia, such that improvements in cognition correspond to compensatory increases in connectivity in a temporal region previously shown to exhibit thalamic hyper-connectivity.

BACKGROUND: We previously demonstrated that the high heterogeneity of response to computerized Auditory Training (AT) in psychosis can be ascribed to individual differences in sensory processing efficiency and neural plasticity. In particular, we showed that Auditory Processing Speed (APS) serves as a behavioral measure of target engagement, with faster speed predicting greater transfer effects to untrained cognitive domains. Here, we investigate whether the ability of APS to function as a proxy for target engagement is unique to AT, or if it applies to other training interventions, such as Executive Functioning Training (EFT). Additionally, we examine whether changes in APS are durable after these two forms of training. METHODS: One hundred and twenty-five participants with Recent Onset Psychosis (ROP) were randomized to AT (n = 66) and EFT (n = 59), respectively. APS was captured at baseline, after treatment, and at 6-month follow-up. Mixed models repeated measures analysis with restricted maximum likelihood was used to examine whether training condition differentiated APS trajectories. Within-group correlational analyses were used to study the relationship between APS and performance improvements in each of the training exercises. RESULTS: The two groups were matched for age, gender, education, and baseline APS. Participants showed high inter-individual variability in APS at each time point. The mixed model showed a significant effect of time (F = 5.99, p = .003) but not a significant group-by-time effect (F = .73, p = .48). This was driven by significant APS improvements AT patients after treatment (d = .75) that were maintained after 6 months (d = .63). Conversely, in EFT patients, APS improvements did not reach statistical significance after treatment (p = .33) or after 6 months (p = .24). In AT patients, baseline APS (but not APS change) highly predicted peak performance for each training exercise (all rs >.42). CONCLUSIONS: Participant-specific speed in processing basic auditory stimuli greatly varies in ROP, and strongly influences the magnitude of response to auditory but not executive functioning training. Importantly, enhanced auditory processing efficiency persists 6 months after AT, suggesting the durability of neuroplasticity processes induced by this form of training. Future studies should aim to identify markers of target engagement and durability for cognitive training interventions that target sensory modalities beyond the auditory domain.

BackgroundDevelopmental stages characterized by greater neural plasticity might be critical periods during which the effects of cognitive training (CT) could theoretically be maximized. However, experiencing a first episode of schizophrenia during childhood or adolescence (ie, early-onset schizophrenia [EOS]) may reduce the brain's ability to benefit from CT. This study examined the effects of EOS versus onset at > 18 years of age (ie, adult-onset schizophrenia [AOS]) as a predictor of response to CT and the relationship between duration of illness and cognitive improvements.MethodsThis study is a secondary analysis of data from 2 randomized trials that examined the cognitive effects of neuroscience-informed auditory training (AT) exercises in 84 outpatients with schizophrenia (26 EOS, 58 AOS, recruited between 2004 and 2014).ResultsThere was a significant effect of time in all cognitive domains (F > 10.22, P < .002). The effect of EOS was significant only for verbal learning and memory (F = 5.79, P = .018). AOS increased the mean change score by 5.70 points in this domain, whereas EOS showed no change (t = -2.280, P = .025). However, the difference between AOS and EOS was no longer statistically significant after control for multiple comparisons. Shorter duration of illness was associated with greater improvement in problem solving in the AOS group (r = -0.27, P = .040).ConclusionsAuditory training is effective in improving cognition in both EOS and AOS. Treatment effects in all cognitive domains were similar, with the exception of verbal learning and memory. This result requires replication. Cognitive training provided earlier in the course of the illness results in greater improvements in executive functions.Trial registrationClinicalTrials.gov identifiers: NCT00312962, NCT00694889​​.

The fields of psychology and psychiatry are increasingly recognizing the importance of replication efforts. The current study aimed to replicate previous findings examining the construct validity and psychometric properties of a psychotic-like experiences (PLEs) measure in middle childhood using an independent subset of the baseline Adolescent Brain Cognitive Development (ABCD) sample. Using a remainder baseline sample of 7013 nine- to eleven-year-old children with complete data, we examined measurement invariance across race/ethnicity and sex, and examined the associations between the Prodromal Questionnaire Brief-Child Version (PQ-BC) and other measures of PLEs, internalizing symptoms, neuropsychological test performance, and developmental milestones, to determine whether previously obtained results replicated in this nonoverlapping baseline sample subset. The results replicated measurement invariance across ethnicity and sex, and analyses again found higher PQ-BC scores for African American (β = .364, 95% CI = 0.292, 0.435) and Hispanic (β = .255, 95% CI = 0.185, 0.324) groups. We also replicated that higher PQ-BC scores were associated with psychosis risk measures, higher rates of child-reported internalizing symptoms (Distress: β = .378, 95% CI = 0.357,0.398), neuropsychological test performance deficits (eg, working memory; Distress: β = -.069, 95% CI = -0.096, -0.042), and motor (Distress: β = .026, 95% CI = 0.003, 0.049) and speech (Distress: β = .042, 95% CI = 0.018, 0.065) developmental milestone delays. The current results replicated many findings from the original study examining the PQ-BC. We replicated evidence for mean differences in race/ethnicity, and associations with other PLE measures, greater internalizing symptoms, cognitive impairments, and developmental milestone delays. These findings indicate robust and reliable associations between PLEs and hypothesized correlates can be found in middle childhood nonclinical samples.

IntroductionDuring vocalization, efference copy/corollary discharge mechanisms suppress the auditory cortical response to self-generated sounds as reflected in the N1 component of the auditory event-related potential (ERP). N1 suppression during talking is reduced in patients with schizophrenia. We hypothesized that these deficits would recover with auditory training that targets the speech processing system.MethodsForty-nine individuals early in the course of a schizophrenia-spectrum illness (ESZ) were randomly assigned to 40 h of Targeted Auditory Training (TAT; n = 23) or Computer Games (CG; n = 26). The N1 ERP component was elicited during production (Talk) and playback (Listen) of vocalization. Effects of Treatment on Global Cognition, N1 suppression (Talk-Listen), N1 during Talking and Listening were assessed. Simple effects of the passage of time were also assessed in the HC after 28 weeks.ResultsThere was a Treatment × Time interaction revealing that N1 suppression was improved with TAT, but not with CG. TAT, but not CG, also improved Global Cognition. However, TAT and CG groups differed in their pre-treatment N1 suppression, and greater N1-suppression abnormalities were strongly associated with greater improvement in N1 suppression.ConclusionsIn this sample of ESZ individuals, targeted auditory training appeared to improve the function of the efference copy/corollary discharge mechanism which tended to deteriorate with computer games. It remains to be determined if baseline N1 suppression abnormalities are necessary for TAT treatment to have a positive effect on efference copy/corollary discharge function or if improvements observed in this study represent a regression to the mean N1 suppression in ESZ.Trial registrationClinicalTrials.govNCT00694889. Registered 1 August 2007.

IntroductionAmong patients with psychotic disorders, the 'duration of untreated psychosis' (DUP) is a predictor of key outcomes such as symptom remission and quality of life. In sub-Saharan Africa, DUP is up to five times longer than in high-income countries, with many patients going without antipsychotic medication for 5 years or longer. One contributor to this high DUP may relate to cultural norms that drive use of alternative and complementary therapies (ACTs) as first-line treatment strategies, rather than biomedical care with antipsychotic medicine. We aim to1 determine the prevalence and factors associated with DUP and ACT use in Uganda, and2 Identify factors that drive patient and family choices to use ACT as a first-line treatment strategy.Methods and analysisWe will leverage on an ongoing cohort study at the national psychiatric and teaching hospital in Uganda. The parent study is an observational cohort design following antipsychotic naïve adults with a first episode of psychosis without substance use, HIV/AIDS or syphilis. The embedded study will use a mixed methods design including quantitative assessment of parent study participants with the Nottingham Onset Schedule-DUP to determine the DUP. Qualitative assessment will focus on patient and caregiver perceptions and use of ACT and its impact on DUP among patients with psychosis using in-depth interviews.Ethics and disseminationThe study has received ethical approval from the school of medicine research and ethics committee of the college of health sciences at Makerere University. It has also received institutional support to perform the study from the Infectious Diseases Institute and Butabika hospital. Besides publication of the work in reputable peer-reviewed journals, we hope that this work will lead to evidence-based discussions on the need for early interventions to reduce DUP in Uganda.

Reducing the duration of untreated psychosis (DUP) is a key aim of early psychosis (EP) care. However, substantial variability in how the start and end points of DUP are defined impact its utility in clinical decision-making, and as an outcome measure. In this study, qualitative interviews were conducted with providers to assess how EP services and providers define, operationalize, and measure DUP. Twenty-five providers across 14 clinics were interviewed. Participants emphasized symptom frequency, conviction, distress caused, and impact when determining psychosis onset. DUP endpoint was typically identified as the first assessment in an episode of care that included an accurate diagnosis, leading to specialty EP treatment. Participants proposed a more structured operationalization of DUP, relative to those historically adopted in the literature. Integrating front-line provider perspectives could improve the accuracy of DUP measurement and address the heterogeneity in how the construct is operationalized across research and practice.

Cognitive impairment in schizophrenia is often severe, enduring, and contributes significantly to chronic disability. A standardized platform for identifying cognitive impairments and measuring treatment effects in cognition is a critical aspect of comprehensive evaluation and treatment for individuals with schizophrenia. In this project, we developed and tested a suite of ten web-based, neuroscience-informed cognitive assessments that are designed to enable the interpretation of specific deficits that could signal that an individual is experiencing cognitive difficulties. The assessment suite assays speed of processing, sustained attention, executive functioning, learning and socio-affective processing in the auditory and visual modalities. We have obtained data from 283 healthy individuals who were recruited online and 104 individuals with schizophrenia who also completed formal neuropsychological testing. Our data show that the assessments 1) are acceptable and tolerable to users, with successful completion in an average of under 40 min; 2) reliably measure the distinct theoretical cognitive constructs they were designed to assess; 3) can discriminate schizophrenia patients from healthy controls with a fair degree of accuracy (AUROC > 0.70); and 4) have promising construct, convergent, and external validity. Further optimization and validation work is in progress to finalize the evaluation process prior to promoting the dissemination of these assessments in real-world settings.

AimSpecialized early interventions improve outcomes in early psychosis (EP). Experts have proposed a number of essential treatment components. However, it is unclear whether these reflect the views of senior clinic staff charged with implementing this model in practice.MethodTwenty-Five senior EP clinic staff across California completed a survey indicating which features of EP treatment they considered most important.ResultsComponents related to the service structure and the need for a prompt, comprehensive assessment and care planning were considered most important, despite the limited evidence base evaluating these aspects of care. Administration of clozapine to treatment-refractory patients and weight gain interventions were considered the least important, despite the relatively strong evidence base supporting these treatment components.ConclusionThe findings suggest a bi-directional dissemination gap, where components considered most important by senior providers receive limited research attention, while some areas with supporting evidence may be underappreciated in clinical practice.

As a risk factor for psychosis, childhood trauma rates are elevated in the clinical-high-risk (CHR) syndrome compared to the general population. However, it is unknown whether trauma is typically experienced in childhood or adolescence/young adulthood, whether it occurred prior to CHR syndrome onset, and how severe trauma relates to presenting symptoms. In this study, we examined the relationship of trauma history to symptoms and functioning in individuals diagnosed with the CHR syndrome on the Structured Interview for Psychosis-Risk Syndromes (N = 103). Trauma, defined as meeting the DSM-IV A1 criterion of actual or threatened death or injury, was assessed by semi-structured interview. A large proportion of CHR participants (61%) reported trauma exposure, including interpersonal trauma, trauma prior to CHR onset, and childhood trauma prior to age 12. Those with a trauma history (versus those without trauma) were rated as having more severe perceptual disturbances, general/affective symptoms and more impairment on the Global Assessment of Functioning Scale. The number of traumatic events correlated with more severe ratings in those three domains. Additionally, the number of interpersonal traumas was correlated with ratings of suspiciousness. Trauma was unrelated to specific measures of social and role functioning. A small proportion of CHR participants were diagnosed with formal PTSD (14%), which was unrelated to symptom severity or functioning. Thus, we demonstrate that trauma exposure is often early in life (before age 12), occurs prior to the onset of the CHR syndrome, and is related to both positive and affective symptoms.

Schizophrenia shows abnormal dynamic functional network connectivity (dFNC), but it is unclear whether these abnormalities are present early in the illness course or precede illness onset in individuals at clinical high risk (CHR) for psychosis. We examined dFNC from resting-state functional magnetic resonance imaging data in CHR (n = 53), early illness schizophrenia (ESZ; n = 58), and healthy control (HC; n = 70) individuals. We applied a sliding temporal window approach capturing five distinct dFNC states. In ESZ patients, the likelihood of transitioning from state 4, a state that exhibited greater cortical-subcortical hyperconnectivity and also lacked typically observed anticorrelation between the default mode network and other functional networks, to a hypoconnected state was increased compared with HC and CHR groups. Furthermore, we investigated the interaction of group and state on dFNC. Overall, HC individuals showed significant changes of connectivity between states that were absent or altered in ESZ patients and CHR individuals. Connectivity differences between groups were identified primarily in two out of the five states, in particular, between HC and ESZ groups. In summary, it appears that the interaction effect was mostly driven by (1) dynamic connectivity changes in HC that were abnormal in CHR and ESZ individuals and (2) the fact that dysconnectivity between groups was only present in some states. These findings underscore the likelihood that abnormalities are present not only in static FNC but also in dFNC, in individuals at CHR for schizophrenia.

ObjectiveThe emphasis on reducing the duration of untreated psychosis (DUP) has highlighted complex barriers to accessing appropriate services. Internet and social media use by individuals with first-episode psychosis (FEP) was examined to explore how these platforms might be used to facilitate treatment initiation.MethodsParticipants ages 15-35 were interviewed with the Pathways to Care for Psychosis Questionnaire, an 81-item instrument designed to explore online activity during symptom emergence.ResultsOf 112 participants, 90% used the Internet and social media daily. The Internet was listed as the most used resource (62%) for information while symptoms were emerging. A minority (19%) shared concerns via social media, and 76% responded favorably to the possibility of receiving online mental health support.ConclusionsThe Internet and social media were part of daily life for participants with FEP. Activity continued throughout the DUP, offering the prospect of earlier intervention. Participants expressed positive attitudes toward Internet-based outreach and engagement efforts.

Background and Hypothesis Brain development/aging is not uniform across individuals, spawning efforts to characterize brain age from a biological perspective to model the effects of disease and maladaptive life processes on the brain. The brain age gap represents the discrepancy between estimated brain biological age and chronological age (in this case, based on structural magnetic resonance imaging, MRI). Structural MRI studies report an increased brain age gap (biological age > chronological age) in schizophrenia, with a greater brain age gap related to greater negative symptom severity. Less is known regarding the nature of this gap early in schizophrenia (ESZ), if this gap represents a psychosis conversion biomarker in clinical high-risk (CHR-P) individuals, and how altered brain development and/or aging map onto specific symptom facets. Study Design Using structural MRI, we compared the brain age gap among CHR-P (n  = 51), ESZ (n  = 78), and unaffected comparison participants (UCP; n  = 90), and examined associations with CHR-P psychosis conversion (CHR-P converters n  = 10; CHR-P non-converters; n  = 23) and positive and negative symptoms. Study Results ESZ showed a greater brain age gap relative to UCP and CHR-P (P s < .010). CHR-P individuals who converted to psychosis showed a greater brain age gap (P  = .043) relative to CHR-P non-converters. A larger brain age gap in ESZ was associated with increased experiential (P  = .008), but not expressive negative symptom severity. Conclusions Consistent with schizophrenia pathophysiological models positing abnormal brain maturation, results suggest abnormal brain development is present early in psychosis. An increased brain age gap may be especially relevant to motivational and functional deficits in schizophrenia. [ABSTRACT FROM AUTHOR]

Objective: Learning health care networks can significantly improve the effectiveness, consistency, and cost-effectiveness of care delivery. As part of a data harmonization process, incorporation of the perspectives of community partners to maximize the relevance and utility of the data is critical. Methods: A mixed-methods focus group study was conducted with early psychosis program providers, leadership, service users, and family members to explore their priorities regarding data collection in early psychosis care. Focus group transcripts were analyzed through thematic analysis. Results: Twenty-two focus groups comprising 178 participants were conducted across 10 early psychosis programs. Participants considered functioning, quality of life, recovery, and symptoms of psychosis as key outcomes to assess, although variation by participants' roles was also evident. Participants emphasized the clinical utility of assessing a broad range of predictors of care outcomes, favored a broad conceptualization of the constructs assessed, and indicated a preference for client-reported measures. Participants also emphasized the importance of surveys adopting a recovery-oriented, strengths-based approach. Conclusions: Large-scale aggregation of health care data collected as part of routine care offers opportunities for research and may have a positive impact on care delivery and quality improvement activities. However, these benefits are contingent on the data being both relevant and accessible to those who deliver and receive such care. This study highlights an approach that may inform the development of core assessment batteries used, optimizing the utility of such data for all community partners. [ABSTRACT FROM AUTHOR]

New techniques to investigate functional network connectivity in resting state functional magnetic resonance imaging data have recently emerged. One novel approach, called meta-state analysis, goes beyond the mere cross-correlation of time courses of distinct brain areas and explores temporal dynamism in more detail, allowing for connectivity states to overlap in time and capturing global dynamic behavior. Previous studies have shown that patients with chronic schizophrenia exhibit reduced neural dynamism compared to healthy controls, but it is not known whether these alterations extend to earlier phases of the illness. In this study, we analyzed individuals at clinical high-risk (CHR, n = 53) for developing psychosis, patients in an early stage of schizophrenia (ESZ, n = 58), and healthy controls (HC, n = 70). ESZ individuals exhibit reduced neural dynamism across all domains compared to HC. CHR individuals also show reduced neural dynamism but only in 2 out of 4 domains investigated. Overall, meta-state analysis adds information about dynamic fluidity of functional connectivity.

Self-generated speech produces a smaller N1 amplitude in the auditory-evoked potential than externally generated speech; this phenomenon is known as N1-suppression. Schizophrenia patients show less N1-suppression than healthy controls. This failure to self-suppress may underlie patients' characteristic tendency to misattribute self-generated thoughts and actions to external sources. While the cause of N1-suppression deficits to speech in schizophrenia remains unclear, structural damage to the arcuate fasciculus is a candidate, due to its ostensible role in transmitting the efference copy of the motor plan to speak. Fifty-one patients with early illness schizophrenia (ESZ), 40 individuals at clinical high-risk for psychosis (CHR), and 59 healthy control (HC) participants underwent an electroencephalogram while they spoke and then listened to a recording of their speech. N1-suppression to the spoken sounds was calculated. Participants also underwent a diffusion-tensor imaging (DTI) scan, from which the arcuate fasciculus and pyramidal tract were extracted with deterministic tractography. ESZ patients exhibited significantly less N1-suppression to self-generated speech than HC participants, with CHR participants exhibiting intermediate levels. ESZ patients also exhibited structural abnormalities in the arcuate fasciculus-specifically, reduced fractional anisotropy and increased radial diffusivity-relative to both HC and CHR. There were no between-group differences in the structural integrity of the pyramidal tract. Finally, level of N1-suppression was linearly related to the structural integrity of the arcuate fasciculus, but not the pyramidal tract, across groups. These results suggest that the self-suppression deficits to willed speech consistently observed in schizophrenia patients may be caused, at least in part, by structural damage to the arcuate fasciculus.

Individuals at clinical high-risk (CHR) for psychosis are characterized by attenuated psychotic symptoms. Only a minority of CHR individuals convert to full-blown psychosis. Therefore, there is a strong interest in identifying neurobiological abnormalities underlying the psychosis risk syndrome. Dynamic functional connectivity (DFC) captures time-varying connectivity over short time scales, and has the potential to reveal complex brain functional organization. Based on resting-state functional magnetic resonance imaging (fMRI) data from 70 healthy controls (HCs), 53 CHR individuals, and 58 early illness schizophrenia (ESZ) patients, we applied a novel group information guided ICA (GIG-ICA) to estimate inherent connectivity states from DFC, and then investigated group differences. We found that ESZ patients showed more aberrant connectivities and greater alterations than CHR individuals. Results also suggested that disease-related connectivity states occurred in CHR and ESZ groups. Regarding the dominant state with the highest contribution to dynamic connectivity, ESZ patients exhibited greater impairments than CHR individuals primarily in the cerebellum, frontal cortex, thalamus and temporal cortex, while CHR and ESZ populations shared common aberrances mainly in the supplementary motor area, parahippocampal gyrus and postcentral cortex. CHR-specific changes were also found in the connections between the superior frontal gyrus and calcarine cortex in the dominant state. Our findings suggest that CHR individuals generally show an intermediate functional connectivity pattern between HCs and SZ patients but also have unique connectivity alterations.

ImportanceChildhood psychoticlike experiences (PLEs) are associated with greater odds of a diagnosis of a psychotic disorder during adulthood. However, no known, well-validated self-report tools have been designed to measure childhood PLEs.ObjectiveTo examine the construct validity and psychometric properties of a measure of PLEs, the Prodromal Questionnaire-Brief Child Version (PQ-BC).Design, setting, and participantsThis validation study used data from the first wave of the Adolescent Brain and Cognitive Development (ABCD) Study, a prospective longitudinal study aimed at assessing risk factors associated with adverse physical and mental health outcomes from ages 9 to 10 years into late adolescence and early adulthood. The population-based sample of 3984 children within the ABCD data set was recruited from 20 research sites across the United States. Data for this study were collected from June 1, 2016, through August 31, 2017.Main outcomes and measuresThe PQ-BC Total and Distress scores were analyzed for measurement invariance across race/ethnicity and sex, their associations with measures of PLEs, and their associations with known correlates of PLEs, including internalizing and externalizing symptoms, neuropsychological test performance, and developmental milestones.ResultsThe study analyses included 3984 participants (1885 girls [47.3%] and 2099 boys [52.7%]; mean [SE] age, 10.0 [0.01] years). The results demonstrated measurement invariance across race/ethnicity and sex. A family history of psychotic disorder was associated with higher mean (SE) PQ-BC Total (3.883 [0.352]; β = 0.061; 95% CI, 0.027-0.094) and Distress (10.210 [1.043]; β = 0.051; 95% CI, 0.018-0.084) scores, whereas a family history of depression or mania was not. Higher PQ-BC scores were associated with higher rates of child-rated internalizing symptoms (Total score: β range, 0.218 [95% CI, 0.189-0.246] to 0.273 [95% CI, 0.245-0.301]; Distress score: β range, 0.248 [95% CI, 0.220-0.277] to 0.310 [95% CI, 0.281-0.338]), neuropsychological test performance deficits such as working memory (Total score: β = -0.042 [95% CI, -0.077 to -0.008]; Distress score: β = -0.051 [95% CI, -0.086 to -0.017]), and motor and speech developmental milestone delays (Total score: β = 0.057 [95% CI, 0.026-0.086] for motor; β = 0.042 [95% CI, 0.010-0.073] for speech; Distress score: β = 0.048 [95% CI, 0.017-0.079] for motor; β = 0.049 [95% CI, 0.018-0.081] for speech).Conclusions and relevanceThese results provide support for the construct validity and demonstrate adequate psychometric properties of a self-report instrument designed to measure childhood PLEs, providing evidence that the PQ-BC may be a useful measure of early risk for psychotic disorders. Furthermore, these data suggest that PLEs at school age are associated with many of the same familial, cognitive, and emotional factors associated with psychotic symptoms in older populations, consistent with the dimensionality of psychosis across the lifespan.

ObjectiveAlthough screening for psychosis may reduce the duration of untreated psychosis, the barriers and facilitators associated with implementing such a procedure in various care settings have not been explored.MethodsInvestigators conducted in-depth, semistructured interviews with 17 members of school counseling services or community mental health staff at sites that administer a psychosis screening tool. Using an inductive approach to thematic analysis, they evaluated the acceptability of psychosis screening and barriers to and facilitators of implementation.ResultsParticipants reported few barriers to implementation. However, several service-, client-, and program-level factors were considered to significantly affect the implementation of screening. Most participants found that using the screening tool did not significantly affect their overall workload. Facilitators included leadership support, the novelty of using a technology-based screener, regular staff training, and the importance of establishing an effective link between community services and specialty care, with these factors important at different stages of the process. Screening for psychosis was associated with significant advantages over referrals based on clinical judgment alone, including increased speed and accuracy of identification, increased confidence in diagnosis, and the provision of a clear pathway to specialty treatment.ConclusionsThe experiences of school counseling and community mental health teams suggest that incorporating a technology-based screening procedure for early psychosis is feasible. Identifying barriers and facilitators at various stages of the screening procedure may reduce the dropout of clients potentially eligible for early psychosis care.

AimPrevious research indicates that preventive intervention is likely to benefit patients "at risk" of psychosis, in terms of functional improvement, symptom reduction and delay or prevention of onset of threshold psychotic disorder. The primary aim of the current study is to test outcomes of ultra high risk (UHR) patients, primarily functional outcome, in response to a sequential intervention strategy consisting of support and problem solving (SPS), cognitive-behavioural case management and antidepressant medication. A secondary aim is to test biological and psychological variables that moderate and mediate response to this sequential treatment strategy.MethodsThis is a sequential multiple assignment randomised trial (SMART) consisting of three steps: Step 1: SPS (1.5 months); Step 2: SPS vs Cognitive Behavioural Case Management (4.5 months); Step 3: Cognitive Behavioural Case Management + Antidepressant Medication vs Cognitive Behavioural Case Management + Placebo (6 months). The intervention is of 12 months duration in total and participants will be followed up at 18 months and 24 months post baseline.ConclusionThis paper reports on the rationale and protocol of the Staged Treatment in Early Psychosis (STEP) study. With a large sample of 500 UHR participants this study will investigate the most effective type and sequence of treatments for improving functioning and reducing the risk of developing psychotic disorder in this clinical population.

Predicting treatment outcomes in psychiatric populations remains a challenge, but is increasingly important in the pursuit of personalized medicine. Patients with schizophrenia have deficits in cognition, and targeted cognitive training (TCT) of auditory processing and working memory has been shown to improve some of these impairments; but little is known about the baseline patient characteristics predictive of cognitive improvement. Here we use a model selection and regression approach called least absolute shrinkage and selection operator (LASSO) to examine predictors of cognitive improvement in response to TCT for patients with recent onset schizophrenia. Forty-three individuals with recent onset schizophrenia randomized to undergo TCT were assessed at baseline on measures of cognition, symptoms, functioning, illness duration, and demographic variables. We carried out 10-fold cross-validation of LASSO for model selection and regression. We followed up on these results using linear models for statistical inference. No individual variable was found to correlate with improvement in global cognition using a Pearson correlation approach, and a linear model including all variables was also found not to be significant. However, the LASSO model identified baseline global cognition, education, and gender in a model predictive of improvement on global cognition following TCT. These findings offer guidelines for personalized approaches to cognitive training for patients with schizophrenia.

AIM: Diagnosing individuals at ultra high risk (UHR) for psychosis can improve early access to treatment, and a two-stage model utilizing self-report screening followed by a clinical interview can be accurate and efficient. However, it is currently unclear which screening cut-offs to adopt with different populations. METHODS: A systematic review of diagnostic accuracy studies evaluating the Prodromal Questionnaire (PQ) as a preliminary screener for UHR and psychosis was conducted to examine screening effectiveness in different contexts. MedLine, PsycInfo, SCOPUS and ProQuest Dissertations and Abstracts databases were electronically searched, along with a review screen and citation search of key papers. Findings were summarized in a narrative synthesis. RESULTS: In total, 14 diagnostic accuracy studies and 45 studies using the PQ as a screening tool for UHR and psychosis were included. In all settings, the 3 different versions of the PQ were all found to accurately identify UHR and full psychosis. Higher cut-off points were required in non-help-seeking samples, relative to general help-seeking populations, which in turn were higher than those needed in samples highly enriched with UHR participants. CONCLUSION: The findings support the use of the PQ as a preliminary screening tool for UHR in different settings; however, higher thresholds in lower UHR-prevalence populations are necessary to minimize false positives. Including the distress criteria, rather than just number of symptoms, may improve screening effectiveness. Different thresholds may be appropriate in different contexts depending on the importance of sensitivity vs specificity. Protocol registration: CRD42016033004.

Reduced thalamic volume is consistently observed in schizophrenia, and correlates with cognitive impairment. Targeted cognitive training (TCT) of auditory processing in schizophrenia drives improvements in cognition that are believed to result from functional neuroplasticity in prefrontal and auditory cortices. In this study, we sought to determine whether response to TCT is also associated with structural neuroplastic changes in thalamic volume in patients with early schizophrenia (ESZ). Additionally, we examined baseline clinical, cognitive, and neural characteristics predictive of a positive response to TCT. ESZ patients were randomly assigned to undergo either 40 h of TCT (N=22) or a computer games control condition (CG; N=22 s). Participants underwent MRI, clinical, and neurocognitive assessments before and after training (4-month interval). Freesurfer automated segmentation of the subcortical surface was carried out to measure thalamic volume at both time points. Left thalamic volume at baseline correlated with baseline global cognition, while a similar trend was observed in the right thalamus. The relationship between change in cognition and change in left thalamus volume differed between groups, with a significant positive correlation in the TCT group and a negative trend in the CG group. Lower baseline symptoms were related to improvements in cognition and left thalamic volume preservation following TCT. These findings suggest that the cognitive gains induced by TCT in ESZ are associated with structural neuroplasticity in the thalamus. Greater symptom severity at baseline reduced the likelihood of response to TCT both with respect to improved cognition and change in thalamic volume.

Although individuals at clinical high risk (CHR) for psychosis exhibit a psychosis-risk syndrome involving attenuated forms of the positive symptoms typical of schizophrenia (SZ), it remains unclear whether their resting-state brain intrinsic functional networks (INs) show attenuated or qualitatively distinct patterns of functional dysconnectivity relative to SZ patients. Based on resting-state functional magnetic imaging data from 70 healthy controls (HCs), 53 CHR individuals (among which 41 subjects were antipsychotic medication-naive), and 58 early illness SZ (ESZ) patients (among which 53 patients took antipsychotic medication) within five years of illness onset, we estimated subject-specific INs using a novel group information guided independent component analysis (GIG-ICA) and investigated group differences in INs. We found that when compared to HCs, both CHR and ESZ groups showed significant differences, primarily in default mode, salience, auditory-related, visuospatial, sensory-motor, and parietal INs. Our findings suggest that widespread INs were diversely impacted. More than 25% of voxels in the identified significant discriminative regions (obtained using all 19 possible changing patterns excepting the no-difference pattern) from six of the 15 interrogated INs exhibited monotonically decreasing Z-scores (in INs) from the HC to CHR to ESZ, and the related regions included the left lingual gyrus of two vision-related networks, the right postcentral cortex of the visuospatial network, the left thalamus region of the salience network, the left calcarine region of the fronto-occipital network and fronto-parieto-occipital network. Compared to HCs and CHR individuals, ESZ patients showed both increasing and decreasing connectivity, mainly hypo-connectivity involving 15% of the altered voxels from four INs. The left supplementary motor area from the sensory-motor network and the right inferior occipital gyrus in the vision-related network showed a common abnormality in CHR and ESZ groups. Some brain regions also showed a CHR-unique alteration (primarily the CHR-increasing connectivity). In summary, CHR individuals generally showed intermediate connectivity between HCs and ESZ patients across multiple INs, suggesting that some dysconnectivity patterns evident in ESZ predate psychosis in attenuated form during the psychosis risk stage. Hence, these connectivity measures may serve as possible biomarkers to predict schizophrenia progression.

Individuals with schizophrenia have heterogeneous impairments of the auditory processing system that likely mediate differences in the cognitive gains induced by auditory training (AT). Mismatch negativity (MMN) is an event-related potential component reflecting auditory echoic memory, and its amplitude reduction in schizophrenia has been linked to cognitive deficits. Therefore, MMN may predict response to AT and identify individuals with schizophrenia who have the most to gain from AT. Furthermore, to the extent that AT strengthens auditory deviance processing, MMN may also serve as a readout of the underlying changes in the auditory system induced by AT. Fifty-six individuals early in the course of a schizophrenia-spectrum illness (ESZ) were randomly assigned to 40 h of AT or Computer Games (CG). Cognitive assessments and EEG recordings during a multi-deviant MMN paradigm were obtained before and after AT and CG. Changes in these measures were compared between the treatment groups. Baseline and trait-like MMN data were evaluated as predictors of treatment response. MMN data collected with the same paradigm from a sample of Healthy Controls (HC; n = 105) were compared to baseline MMN data from the ESZ group. Compared to HC, ESZ individuals showed significant MMN reductions at baseline (p = .003). Reduced Double-Deviant MMN was associated with greater general cognitive impairment in ESZ individuals (p = .020). Neither ESZ intervention group showed significant change in MMN. We found high correlations in all MMN deviant types (rs = .59-.68, all ps < .001) between baseline and post-intervention amplitudes irrespective of treatment group, suggesting trait-like stability of the MMN signal. Greater deficits in trait-like Double-Deviant MMN predicted greater cognitive improvements in the AT group (p = .02), but not in the CG group. In this sample of ESZ individuals, AT had no effect on auditory deviance processing as assessed by MMN. In ESZ individuals, baseline MMN was significantly reduced relative to HCs, and associated with global cognitive impairment. MMN did not show changes after AT and exhibited trait-like stability. Greater deficits in the trait aspects of Double-Deviant MMN predicted greater gains in global cognition in response to AT, suggesting that MMN may identify individuals who stand to gain the most from AT. NCT00694889. Registered 1 August 2007.

The experience of childhood trauma (CT) and stressful life events (SLEs) is associated with subsequent development of a variety of mental health conditions, including psychotic illness. Recent research identifying adolescents and young adults at clinical high risk (CHR) for psychosis allows for prospective evaluation of the impact of trauma and adverse life events on psychosis onset and other outcomes, addressing etiological questions that cannot be answered in studies of fully psychotic or non-clinical populations. This article provides a comprehensive review of the current emerging literature on trauma and adverse life events in the CHR population. Up to 80% of CHR youth endorse a lifetime history of childhood traumatic events and victimization (e.g., bullying). Several studies have shown that the experience of CT predicts psychosis onset among CHR individuals, while the literature on the influence of recent SLEs (e.g., death of a loved one) remains inconclusive. Multiple models have been proposed to explain the link between trauma and psychosis, including the stress-vulnerability and stress-sensitivity hypotheses, with emphases on both cognitive processes and neurobiological mechanisms (e.g., the hypothalamic-pituitary-adrenal axis). Despite the preponderance of CHR individuals who endorse either CT or SLEs, no clinical trials have been conducted evaluating interventions for trauma in CHR youth to date. Furthermore, the current process of formal identification and assessment of trauma, SLEs, and their impact on CHR youth is inconsistent in research and clinical practice. Recommendations for improving trauma assessment, treatment, and future research directions in the CHR field are provided.