A Functional Connectome-Based Neural Signature for Individualized Prediction of Antipsychotic Response in First-Episode Psychosis.

OBJECTIVE: Identification of robust biomarkers that predict individualized response to antipsychotic treatment at the early stage of psychotic disorders remains a challenge in precision psychiatry. The aim of this study was to investigate whether any functional connectome-based neural traits could serve as such a biomarker. METHODS: In a discovery sample, 49 patients with first-episode psychosis received multi-paradigm fMRI scans at baseline and were clinically followed up for 12 weeks under antipsychotic monotherapies. Treatment response was evaluated at the individual level based on the psychosis score of the Brief Psychiatric Rating Scale. Cross-paradigm connectivity and connectome-based predictive modeling were employed to train a predictive model that uses baseline connectomic measures to predict individualized change rates of psychosis scores, with model performance evaluated as the Pearson correlations between the predicted change rates and the observed change rates, based on cross-validation. The model generalizability was further examined in an independent validation sample of 24 patients in a similar design. RESULTS: The results revealed a paradigm-independent connectomic trait that significantly predicted individualized treatment outcome in both the discovery sample (predicted-versus-observed r=0.41) and the validation sample (predicted-versus-observed r=0.47, mean squared error=0.019). Features that positively predicted psychosis change rates primarily involved connections related to the cerebellar-cortical circuitry, and features that negatively predicted psychosis change rates were chiefly connections within the cortical cognitive systems. CONCLUSIONS: This study discovers and validates a connectome-based functional signature as a promising early predictor for individualized response to antipsychotic treatment in first-episode psychosis, thus highlighting the potential clinical value of this biomarker in precision psychiatry.

Patient and Healthcare Professional Preferences for Characteristics of Long-Acting Injectable Antipsychotic Agents for the Treatment of Schizophrenia.

INTRODUCTION: Studies evaluating patient and healthcare professional (HCP) preferences regarding long-acting injectable (LAI) antipsychotic agent attributes are lacking. METHODS: Surveys were administered to physicians, nurses, and patients who had at least two experiences with TV-46000, an investigational subcutaneous LAI antipsychotic agent for the treatment of schizophrenia, as part of the SHINE study (NCT03893825). Survey topics included preferences for route of administration, potential LAI dosing intervals (once-weekly, twice a month, once a month [q1m], every 2 months [q2m]), injection location, ease of use, syringe type, needle length, and need for reconstitution. RESULTS: Patients (n = 63) had a mean (SD) age of 35.6 (9.6) years, age at diagnosis of 18 (10) years, and were mostly male (75%). There were 49 HCPs: 24 physicians and 25 nurses. Patients rated "a short needle" (68%), a "choice of [q1m or q2m] dosing interval" (59%), and "injection instead of oral tablet" (59%) as the most important features. HCPs rated "single injection to initiate treatment" (61%), "flexible dosing interval" (84%), and "injection instead of oral tablet" (59%) as the most important features. Subcutaneous injections were rated "easy to [receive/administer]" by 62% of patients and 84% of HCPs. When choosing between subcutaneous injections and intramuscular injections, 65% of HCPs preferred subcutaneous injections and 57% of patients preferred intramuscular injections. It was important to most HCPs to have four dose strength options (78%), a prefilled syringe (96%), and no need for reconstitution (90%). CONCLUSIONS: Patients had a range of responses, and on some issues patient and HCP preferences differed. Altogether, this suggests the importance of providing patients with a range of options and the importance of patient-HCP discussions on treatment preference for LAIs.

Several medications for treating schizophrenia are available as long-acting injections. One advantage of these medications is that patients do not need to take pills daily. In this study, patients, doctors, and nurses were asked what medication characteristics they preferred. Question topics were similar to the following: "how often should it be taken?"; "what method of delivery do you prefer?"; "where on the body should it be injected?"; "how easy was it to use?"; "what physical properties do you like?"; and "do preparation steps matter?" Patients thought that being able to be given monthly or every other month was one of the most important features of an injection (59%). Patients also liked a short needle (68%) and an injection instead of an oral pill (59%). Doctors and nurses responded that it was important to have a single injection to start treatment (61%). They also liked having options for how often the medication was given (84%), and an injection instead of an oral pill (59%). An injection was "easy to [get/give]" for most patients (62%) and doctors and nurses (84%). Most doctors and nurses (65%) liked giving injections under the skin. Most patients (57%) liked injections into the muscle. Overall, patients and doctors/nurses agreed on most topics. There were, however, a range of patient responses; therefore, it is important for patients and doctors and nurses to talk about the available treatment options. Each individual patient may have their own preferences.

Relapse prevention through health technology program reduces hospitalization in schizophrenia.

BACKGROUND: Psychiatric hospitalization is a major driver of cost in the treatment of schizophrenia. Here, we asked whether a technology-enhanced approach to relapse prevention could reduce days spent in a hospital after discharge. METHODS: The Improving Care and Reducing Cost (ICRC) study was a quasi-experimental clinical trial in outpatients with schizophrenia conducted between 26 February 2013 and 17 April 2015 at 10 different sites in the USA in an outpatient setting. Patients were between 18 and 60 years old with a diagnosis of schizophrenia, schizoaffective disorder, or psychotic disorder not otherwise specified. Patients received usual care or a technology-enhanced relapse prevention program during a 6-month period after discharge. The health technology program included in-person, individualized relapse prevention planning with treatments delivered via smartphones and computers, as well as a web-based prescriber decision support program. The main outcome measure was days spent in a psychiatric hospital during 6 months after discharge. RESULTS: The study included 462 patients, of which 438 had complete baseline data and were thus used for propensity matching and analysis. Control participants (N = 89; 37 females) were enrolled first and received usual care for relapse prevention followed by 349 participants (128 females) who received technology-enhanced relapse prevention. During 6-month follow-up, 43% of control and 24% of intervention participants were hospitalized (χ2 = 11.76, p<0.001). Days of hospitalization were reduced by 5 days (mean days: b = -4.58, 95% CI -9.03 to -0.13, p = 0.044) in the intervention condition compared to control. CONCLUSIONS: These results suggest that technology-enhanced relapse prevention is an effective and feasible way to reduce rehospitalization days among patients with schizophrenia.

Frontal lobe fALFF measured from resting-state fMRI as a prognostic biomarker in first-episode psychosis.

Clinical response to antipsychotic drug treatment is highly variable, yet prognostic biomarkers are lacking. The goal of the present study was to test whether the fractional amplitude of low-frequency fluctuations (fALFF), as measured from baseline resting-state fMRI data, can serve as a potential biomarker of treatment response to antipsychotics. Patients in the first episode of psychosis (n = 126) were enrolled in two prospective studies employing second-generation antipsychotics (risperidone or aripiprazole). Patients were scanned at the initiation of treatment on a 3T MRI scanner (Study 1, GE Signa HDx, n = 74; Study 2, Siemens Prisma, n = 52). Voxelwise fALFF derived from baseline resting-state fMRI scans served as the primary measure of interest, providing a hypothesis-free (as opposed to region-of-interest) search for regions of the brain that might be predictive of response. At baseline, patients who would later meet strict criteria for clinical response (defined as two consecutive ratings of much or very much improved on the CGI, as well as a rating of ≤3 on psychosis-related items of the BPRS-A) demonstrated significantly greater baseline fALFF in bilateral orbitofrontal cortex compared to non-responders. Thus, spontaneous activity in orbitofrontal cortex may serve as a prognostic biomarker of antipsychotic treatment.

Outcomes During and After Early Intervention Services for First-Episode Psychosis: Results Over 5 Years From the RAISE-ETP Site-Randomized Trial.

To examine long-term effects of early intervention services (EIS) for first-episode psychosis, we compared Heinrichs-Carpenter Quality of Life (QLS) and Positive and Negative Syndrome Scale (PANSS) scores and inpatient hospitalization days over 5 years with data from the site-randomized RAISE-ETP trial that compared the EIS NAVIGATE (17 sites; 223 participants) and community care (CC) (17 sites; 181 participants). Inclusion criteria were: age 15-40 years; DSM-IV diagnoses of schizophrenia, schizoaffective disorder, schizophreniform disorder, brief psychotic disorder, or psychotic disorder not otherwise specified; first psychotic episode; antipsychotic medication taken for ≤6 months. NAVIGATE-randomized participants could receive NAVIGATE from their study entry date until NAVIGATE ended when the last-enrolled NAVIGATE participant completed 2 years of treatment. Assessments occurred every 6 months. 61% of participants had assessments conducted ≥2 years; 31% at 5 years. Median follow-up length was CC 30 months and NAVIGATE 38 months. Primary analyses assumed data were not-missing-at-random (NMAR); sensitivity analyses assumed data were missing-at-random (MAR). MAR analyses found no significant treatment-by-time interactions for QLS or PANSS. NMAR analyses revealed that NAVIGATE was associated with a 13.14 (95%CI:6.92,19.37) unit QLS and 7.73 (95%CI:2.98,12.47) unit PANSS better improvement and 2.53 (95%CI:0.59,4.47) fewer inpatient days than CC (all comparisons significant). QLS and PANSS effect sizes were 0.856 and 0.70. NAVIGATE opportunity length (mean 33.8 (SD = 5.1) months) was not associated (P = .72) with QLS outcome; duration of untreated psychosis did not moderate (P = .32) differential QLS outcome. While conclusions are limited by the low rate of five-year follow-up, the data support long-term benefit of NAVIGATE compared to community care.

Longitudinal investigation of the relationship between omega-3 polyunsaturated fatty acids and neuropsychological functioning in recent-onset psychosis: A randomized clinical trial.

Alterations in polyunsaturated fatty acids (PUFAs), including omega-3 and omega-6, have been implicated in the pathophysiology of psychotic disorders, but little is known about their associations with neuropsychological functioning. The present study includes 46 recent-onset psychosis patients who participated in a larger (n = 50) double blind, placebo-controlled randomized clinical trial comparing 16 weeks of treatment with either risperidone + fish oil (FO) (EPA 740 mg and DHA 400 mg daily) or risperidone + placebo and completed neuropsychological assessments at the baseline timepoint. We investigated the relationship between baseline omega-3 (i.e., eicosapentaenoic acid, EPA; docosapentaenoic acid, DPA and docosahexaenoic acid, DHA) and omega-6 (i.e., arachidonic acid, AA) PUFA with baseline MATRICS Consensus Cognitive Battery (MCCB) and Brief Psychiatric Rating Scale (BPRS) scores. Twenty-five patients had neuropsychological data available at 16 weeks following participation in the clinical trial, which included 12 patients assigned to risperidone + FO and 13 patients assigned to risperidone + placebo. At baseline both higher DHA and EPA correlated significantly with better social cognition after controlling for functioning on other neuropsychological domains, total BPRS score, AA level and substance use. Also, at baseline higher AA correlated significantly with hostility/uncooperativeness after controlling for DHA + EPA + DPA, overall neuropsychological functioning and substance use. Patients treated with risperidone + FO demonstrated a significant longitudinal increase in social cognition that was significantly higher at 16 weeks compared to patients treated with risperidone + placebo. DHA also correlated significantly with social cognition at the 16-week timepoint. This study provides novel evidence for a differential role of omega-3 vs. omega-6 PUFA in neuropsychological deficits and symptoms in recent-onset psychosis and its treatment.

A 16-week randomized placebo-controlled trial investigating the effects of omega-3 polyunsaturated fatty acid treatment on white matter microstructure in recent-onset psychosis patients concurrently treated with risperidone.

We examined the impact of treatment with fish oil (FO), a rich source of omega-3 polyunsaturated fatty acids (n-3 PUFA), on white matter in 37 recent-onset psychosis patients receiving risperidone in a double-blind placebo-controlled randomized clinical trial. Patients were scanned at baseline and randomly assigned to receive 16-weeks of treatment with risperidone + FO or risperidone + placebo. Eighteen patients received follow-up MRIs (FO, n = 10/Placebo, n = 8). Erythrocyte levels of n-3 PUFAs eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and docosapentaenoic acid (DPA) were obtained at both time points. We employed Free Water Imaging metrics representing the extracellular free water fraction (FW) and fractional anisotropy of the tissue (FA-t). Analyses were conducted using Tract-Based-Spatial-Statistics and nonparametric permutation-based tests with family-wise error correction. There were significant positive correlations of FA-t with DHA and DPA among all patients at baseline. Patients treated with risperidone + placebo demonstrated reductions in FA-t and increases in FW, whereas patients treated with risperidone + FO exhibited no significant changes in FW and FA-t reductions were largely attenuated. The correlations of DPA and DHA with baseline FA-t support the hypothesis that n-3 PUFA intake or biosynthesis are associated with white matter abnormalities in psychosis. Adjuvant FO treatment may partially mitigate against white matter alterations observed in recent-onset psychosis patients following risperidone treatment.

Interaction of Cannabis Use Disorder and Striatal Connectivity in Antipsychotic Treatment Response.

Antipsychotic (AP) medications are the mainstay for the treatment of schizophrenia spectrum disorders (SSD), but their efficacy is unpredictable and widely variable. Substantial efforts have been made to identify prognostic biomarkers that can be used to guide optimal prescription strategies for individual patients. Striatal regions involved in salience and reward processing are disrupted as a result of both SSD and cannabis use, and research demonstrates that striatal circuitry may be integral to response to AP drugs. In the present study, we used functional magnetic resonance imaging (fMRI) to investigate the relationship between a history of cannabis use disorder (CUD) and a striatal connectivity index (SCI), a previously developed neural biomarker for AP treatment response in SSD. Patients were part of a 12-week randomized, double-blind controlled treatment study of AP drugs. A sample of 48 first-episode SSD patients with no more than 2 weeks of lifetime exposure to AP medications, underwent a resting-state fMRI scan pretreatment. Treatment response was defined a priori as a binary (response/nonresponse) variable, and a SCI was calculated in each patient. We examined whether there was an interaction between lifetime CUD history and the SCI in relation to treatment response. We found that CUD history moderated the relationship between SCI and treatment response, such that it had little predictive value in SSD patients with a CUD history. In sum, our findings highlight that biomarker development can be critically impacted by patient behaviors that influence neurobiology, such as a history of CUD.

Effect of Long-Acting Injectable Antipsychotics vs Usual Care on Time to First Hospitalization in Early-Phase Schizophrenia: A Randomized Clinical Trial.

Importance: Long-acting injectable antipsychotics (LAIs) can potentially reduce hospitalization risk by enhancing medication adherence but are rarely considered for early-phase schizophrenia treatment. Objective: To determine whether encouraging use of a LAI compared with usual care delays the time to first hospitalization with patients with early-phase illness. Design, Setting, and Participants: The Prevention of Relapse in Schizophrenia (PRELAPSE) trial was cluster randomized with a follow-up duration of 2 years. The study began in December 2014, was completed in March 2019, and was conducted in 39 mental health centers in 19 US states. Site randomization assigned 19 clinics to encourage treatment with long-acting aripiprazole monohydrate (aripiprazole once monthly [AOM] condition) and 20 to provide treatment as usual (clinician's choice [CC] condition). Participant eligibility criteria included (1) schizophrenia diagnosis confirmed by a structured clinical interview, (2) fewer than 5 years of lifetime antipsychotic use, and (3) age 18 to 35 years. The AOM sites identified 576 potentially eligible participants, of whom 234 (40.6%) enrolled; CC sites identified 685 potentially eligible participants, of whom 255 (37.2%) enrolled. Interventions: There were no restrictions on treatment at CC sites (including using LAIs) or at AOM sites with the exception that aripiprazole monohydrate had to be prescribed within US Food and Drug Administration-approved guidelines. Main Outcomes and Measures: The primary outcome was time to first psychiatric hospitalization based on participant interviews every 2 months, the service use resource form administered every 4 months, and other sources (eg, health records) as available. Potential events were adjudicated by an independent committee masked to treatment assignment. Results: The 489 participants (368 men [75.3%]) had a mean (SD) age of 25.2 (4.2) years and 225 (46.0%) had 1 year or less lifetime antipsychotic use. Fifty-two AOM (22%) and 91 CC participants (36%) had at least 1 hospitalization. The mean survival time until first hospitalization was 613.7 days (95% CI, 582.3-645.1 days) for AOM participants and 530.6 days (95% CI, 497.3-563.9 days) for CC participants. For time to first hospitalization, the hazard ratio was 0.56 (95% CI, 0.34- 0.92; P = .02), favoring AOM. Survival probabilities were 0.73 (95% CI, 0.65-0.83) for AOM participants and 0.58 (95% CI, 0.50-0.67) for CC participants. The number needed to treat to prevent 1 additional hospitalization was 7 participants treated with AOM compared with CC. Conclusions and Relevance: Long-acting injectable antipsychotic use by patients with early-phase schizophrenia can significantly delay time to hospitalization, a personally and economically important outcome. Clinicians should more broadly consider LAI treatment for patients with early-phase illness. Trial Registration: ClinicalTrials.gov Identifier: NCT02360319.

Blood Levels to Optimize Antipsychotic Treatment in Clinical Practice: A Joint Consensus Statement of the American Society of Clinical Psychopharmacology and the Therapeutic Drug Monitoring Task Force of the Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie.

OBJECTIVE: The quantification of antipsychotic levels in blood, also known as therapeutic drug monitoring (TDM), is a potentially useful tool of modern personalized therapy that can be applied to augment antipsychotic use and dosing decisions. The application of TDM for antipsychotics can be helpful in numerous challenging clinical scenarios, such as lack of therapeutic response, relapse, or adverse drug reactions (ADRs) related to antipsychotic treatment. The benefits of TDM may be particularly evident in the treatment of highly vulnerable patient subgroups, such as children, adolescents, pregnant women, and the elderly. The main aim of this article is to aid clinicians who routinely prescribe antipsychotics to successfully apply TDM in routine clinical practice in order to help optimize the efficacy and safety of those antipsychotics. PARTICIPANTS: Participants were clinicians and researchers, members of the American Society of Clinical Psychopharmacology, and the Therapeutic Drug Monitoring Task Force of the Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie (Association of Neuropsychopharmacology and Pharmacopsychiatry). EVIDENCE: TDM literature on antipsychotics was critically reviewed to provide a condensed clinical decision-making algorithm with therapeutic reference ranges for blood antipsychotic levels, within which patients are most likely to respond and tolerate treatment, although TDM is not equally recommended/supported for all antipsychotics. CONSENSUS PROCESS: A preliminary draft was prepared and circulated to the writing group members. Consensus was achieved in all cases, and resulting recommendations focused on following areas: steady-state and sampling time, levels of recommendations, indications, therapeutic reference ranges and laboratory alert levels, practical issues, and interpretation, as well as limitations. CONCLUSIONS: The utilization of TDM as a tool for problem solving in antipsychotic treatment offers a unique method to improve safety and efficacy. This consensus statement summarizes essential information on the routine use of TDM for antipsychotics and encourages clinicians to perform TDM with the appropriate indications as part of the clinical decision-making process.

Focused Ethnographic Examination of Barriers to Use of Long-Acting Injectable Antipsychotics.

OBJECTIVE: The authors designed this project to identify barriers to using long-acting formulations of antipsychotics. METHODS: The authors used a focused ethnographic approach. Patients, psychiatrists, nurses, therapists and administrators were interviewed about barriers to use of long-acting injectable (LAI) antipsychotics at six facilities in New York State, as were representatives from insurance firms, a pharmaceutical company, and a national professional organization. Interviews were conducted and analyzed by a central team not affiliated with the institutions. RESULTS: Interviews were obtained with 23 patients, 16 psychiatrists, three nurses, 23 therapists, 14 administrators, four insurers, one representative from a pharmaceutical industry, and one representative from a national organization. Major barriers identified from the interviews included restricting discussions about LAI medication to only patients with nonadherence or repeated hospitalizations; inadequate education efforts with patients about LAI antipsychotics; inadequate support for patients making medication decisions; lack of communication within the treatment team about issues relevant to use of LAI formulations by patients; therapists' limited knowledge about LAI antipsychotics, which restricted their role in supporting patients making treatment decisions; psychiatrist concerns about the pharmacologic properties of LAI formulations; lack of clinic infrastructure to support LAI prescriptions; and payer concerns about whether the immediate costs of LAI administration would translate into later potential cost benefits. CONCLUSIONS: Effective shared decision making about use of LAI antipsychotics requires that patients receive accurate information and support for their decision making. The training needs and administrative support requirements of all team members should be considered to provide patients with the information and support required.

Striatal volume and functional connectivity correlate with weight gain in early-phase psychosis.

Second-generation antipsychotic drugs (SGAs) are essential in the treatment of psychotic disorders, but are well-known for inducing substantial weight gain and obesity. Critically, weight gain may reduce life expectancy for up to 20-30 years in patients with psychotic disorders, and prognostic biomarkers are generally lacking. Even though other receptors are also implicated, the dorsal striatum, rich in dopamine D2 receptors, which are antagonized by antipsychotic medications, plays a key role in the human reward system and in appetite regulation, suggesting that altered dopamine activity in the striatal reward circuitry may be responsible for increased food craving and weight gain. Here, we measured striatal volume and striatal resting-state functional connectivity at baseline, and weight gain over the course of 12 weeks of antipsychotic treatment in 81 patients with early-phase psychosis. We also included a sample of 58 healthy controls. Weight measurements were completed at baseline, and then weekly for 4 weeks, and every 2 weeks until week 12. We used linear mixed models to compute individual weight gain trajectories. Striatal volume and whole-brain striatal connectivity were then calculated for each subject, and used to assess the relationship between striatal structure and function and individual weight gain in multiple regression models. Patients had similar baseline weights and body mass indices (BMI) compared with healthy controls. There was no evidence that prior drug exposure or duration of untreated psychosis correlated with baseline BMI. Higher left putamen volume and lower sensory motor connectivity correlated with the magnitude of weight gain in patients, and these effects multiplied when the structure-function interaction was considered in an additional exploratory analysis. In conclusion, these results provide evidence for a correlation of striatal structure and function with antipsychotic-induced weight gain. Lower striatal connectivity was associated with more weight gain, and this relationship was stronger for higher compared with lower left putamen volumes.

Patients With Early-Phase Schizophrenia Will Accept Treatment With Sustained-Release Medication (Long-Acting Injectable Antipsychotics): Results From the Recruitment Phase of the PRELAPSE Trial.

OBJECTIVE: To document the acceptability of treatment with long-acting injectable (LAI) antipsychotic medication to early-phase schizophrenia patients as demonstrated by enrollment in a cluster-randomized LAI clinical trial. METHODS: Eligible patients aged 18-35 years with a DSM-5 diagnosis of schizophrenia and less than 5 years of lifetime antipsychotic use were recruited between December 2014 and December 2016. Training for LAI antipsychotic site staff included education regarding the role of nonadherence in relapse/hospitalization and the rationale for LAI antipsychotic use with early-psychosis patients, training in shared decision-making and communication strategies, review of frequently asked questions about LAI antipsychotics, and role-playing to develop skills and solutions to overcoming LAI antipsychotic logistical barriers. Study prescribers also received training on prescribing guidelines. RESULTS: At the 19 US outpatient clinics randomized to provide LAI antipsychotic treatment, 576 potential participants were identified who met inclusion criteria based on a screening interview. Of these, 83 (14.4%) declined participation because they would not consider LAI antipsychotic treatment and 165 (28.6%) declined for other reasons, resulting in 328 providing written study consent. The first post-consent visit included detailed evaluations to confirm inclusion/exclusion criteria. Thirty-nine participants who consented did not complete this evaluation and 55 were found to not meet criteria, resulting in a final sample of 234 participants. Two hundred thirteen (91.0%) accepted at least one LAI antipsychotic injection during their first 3 months of study participation. CONCLUSIONS: Large numbers of early-phase patients with schizophrenia were willing to participate in an LAI antipsychotic trial and by inference in non-study LAI antipsychotic treatment. LAI antipsychotic-focused staff training has the potential to substantially enhance the use of LAI antipsychotics. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02360319.

Predictors of Hospitalization of Individuals With First-Episode Psychosis: Data From a 2-Year Follow-Up of the RAISE-ETP.

OBJECTIVE: Despite treatment advances in other domains, inpatient psychiatric hospitalization rates for individuals with first-episode psychosis remain high. Even with early intervention services, a third or more of individuals are hospitalized over the first 2 years of treatment. Reducing hospitalization is desirable from the individual's perspective and for public health reasons because hospitalization costs are a major component of treatment costs. METHODS: Univariate and multivariate baseline and time-varying covariate analyses were conducted to identify predictors of hospitalization in the Recovery After an Initial Schizophrenia Episode-Early Treatment Program (RAISE-ETP) study, a 2-year cluster randomized trial for participants experiencing a first episode of psychosis who were outpatients at study entry. The trial compared an early intervention treatment model (NAVIGATE) with usual community care at 34 clinics across the United States. RESULTS: RAISE-ETP enrolled 404 participants of whom 382 had one or more postbaseline assessments that included hospitalization data. Thirty-four percent of NAVIGATE and 37% of usual-care participants were hospitalized during the trial. Risk analyses revealed significant predictors of hospitalization to be the number of hospitalizations before study entry; duration of untreated psychosis; and time-varying days of substance misuse, presence of positive symptoms, and beliefs about the value of medication. CONCLUSIONS: These results indicate that hospital use may be decreased by reducing the duration of untreated psychosis and prior hospitalizations, minimizing residual symptoms, preventing substance misuse, and facilitating adherence to medication taking. Addressing these factors could enhance the impact of first-episode early intervention treatment models and also enhance outcomes of people with first-episode psychosis treated using other models.

Structural similarity networks predict clinical outcome in early-phase psychosis.

Despite recent advances, there is still a major need for prediction of treatment success in schizophrenia, a condition long considered a disorder of dysconnectivity in the brain. Graph theory provides a means to characterize the connectivity in both healthy and abnormal brains. We calculated structural similarity networks in each participant and hypothesized that the "hubness", i.e., the number of edges connecting a node to the rest of the network, would be associated with clinical outcome. This prospective controlled study took place at an academic research center and included 82 early-phase psychosis patients (23 females; mean age [SD] = 21.6 [5.5] years) and 58 healthy controls. Medications were administered in a double-blind randomized manner, and patients were scanned at baseline prior to treatment with second-generation antipsychotics. Symptoms were assessed with the Brief Psychiatric Rating Scale at baseline and over the course of 12 weeks. Nodal degree of structural similarity networks was computed for each subject and entered as a predictor of individual treatment response into a partial least squares (PLS) regression. The model fit was significant in a permutation test with 1000 permutations (P = 0.006), and the first two PLS regression components explained 29% (95% CI: 27; 30) of the variance in treatment response after cross-validation. Nodes loading strongly on the first PLS component were primarily located in the orbito- and prefrontal cortex, whereas nodes loading strongly on the second PLS component were primarily located in the superior temporal, precentral, and middle cingulate cortex. These data suggest a link between brain network morphology and clinical outcome in early-phase psychosis.

Frontal lobe functioning during a simple response conflict task in first-episode psychosis and its relationship to treatment response.

Prior functional magnetic resonance imaging (fMRI) studies have investigated the neural mechanisms underlying cognitive control in patients with psychosis with findings of both hypo- and hyperfrontality. One factor that may contribute to inconsistent findings is the use of complex and polyfactorial tasks to investigate frontal lobe functioning. In the current study we employed a simple response conflict task during fMRI to examine differences in brain activation between patients experiencing their first-episode of psychosis (n = 33) and age- and sex-matched healthy volunteers (n = 33). We further investigated whether baseline brain activation among patients predicted changes in symptom severity and treatment response following 12 weeks of controlled antipsychotic treatment. During the task subjects were instructed to press a response button on the same side or opposite side of a circle that appeared on either side of a central fixation point. Imaging data revealed that for the contrast of opposite-side vs. same-side, patients showed significantly greater activation compared with healthy volunteers in the anterior cingulate cortex and intraparietal sulcus. Among patients, greater baseline anterior cingulate cortex, temporal-parietal junction, and superior temporal cortex activation predicted greater symptom reduction and therapeutic response following treatment. All findings remained significant after covarying for task performance. Intact performance on this relatively parsimonious task was associated with frontal hyperactivity suggesting the need for patients to utilize greater neural resources to achieve task performance comparable to healthy individuals. Moreover, frontal hyperactivity observed using a simple fMRI task may provide a biomarker for predicting treatment response in first-episode psychosis.

Implementation and fidelity assessment of the NAVIGATE treatment program for first episode psychosis in a multi-site study.

The NAVIGATE program was developed for the Recovery After Initial Schizophrenia Episode-Early Treatment Program (RAISE-ETP) study, which compared NAVIGATE to usual Community Care in a cluster randomized design involving 34 sites and 404 patients. This article describes the approach to training and implementing the NAVIGATE program at the 17 sites (including 134 practitioners) randomized to provide it, and to evaluating the fidelity of service delivery to the NAVIGATE model. Fidelity was evaluated to five different components of the program, all of which were standardized in manuals in advance of implementation. The components included four interventions (Individualized Resiliency Training, Family Education Program, Supported Employment and Education, Personalized Medication Management) and the overall organization (staffing and structure) of the NAVIGATE team. Most of the sites demonstrated acceptable or higher levels of fidelity in their implementation of the four interventions and the organization of the program, with all 17 sites demonstrating at least acceptable overall fidelity to the NAVIGATE program. The results indicate that the NAVIGATE program can be implemented with good fidelity to the treatment model in a diverse array of community mental health care settings serving persons with a first episode psychosis.

A potential role for adjunctive omega-3 polyunsaturated fatty acids for depression and anxiety symptoms in recent onset psychosis: Results from a 16 week randomized placebo-controlled trial for participants concurrently treated with risperidone.

Omega-3 treatment studies for multi-episode schizophrenia or clinical high risk for conversion to psychosis states have had variable, and often negative, results. To examine adjunctive omega-3 treatment for recent onset psychosis, participants aged 15-40 years with recent onset schizophrenia-spectrum (n = 46) or bipolar (n = 4) disorders and current psychotic symptoms were treated for 16 weeks with risperidone and randomly-assigned omega-3 (EPA 740 mg and DHA 400 mg daily) or matching placebo. The primary outcome measure was the Brief Psychiatric Rating Scale (BPRS) total score. Mean lifetime antipsychotic exposure was 18.1 days. Length of time in treatment, risperidone dose and number of omega-3/placebo capsules taken did not differ between conditions. Longitudinal analysis of the total BPRS score revealed a trend level (p = 0.0826) treatment effect favoring omega-3 treatment. Lorazepam was an allowed concomitant medication. Among the subgroup (N = 23) who did not receive lorazepam, the treatment effect on BPRS total scores favoring omega-3 was significant (p = 0.0406) and factor scores analyses revealed a substantial decrease in depression-anxiety with omega-3 but no change with placebo (treatment-by-time interaction, p = 0.0184). Motor side effects did not differ between conditions. Analysis of Systematic Assessment for Treatment Emergent Events assessments revealed fewer adverse events overall with omega-3 compared with placebo with the largest differences between conditions (all favoring omega-3) on confusion, anxiety, depression, irritability, and tiredness/fatigue. These results suggest that omega-3 adjuvant treatment is a potential option for depression and anxiety symptoms of people with recent onset psychosis. Further research is needed to confirm this potential. Clinical trial registration: NCT01786239.

Off-hours use of a smartphone intervention to extend support for individuals with schizophrenia spectrum disorders recently discharged from a psychiatric hospital.

INTRODUCTION: Technology-delivered healthcare interventions may enhance dissemination of evidence-based treatments in low-resource areas. These interventions may be accessed 'on-demand,' including after hours. Patients with schizophrenia do engage with technological aids but when/how they would utilize these tools is not known. METHODS: We conducted a large, prospective, ten-site, longitudinal study of four technology-assisted interventions for patients with schizophrenia spectrum disorders within 60 days of psychiatric hospital discharge, a high risk period. One tool employed was a smartphone intervention called 'FOCUS,' which could be used by patients as needed, providing help in five content areas: medications, mood, social, sleep and voices. Each login was date- and time-stamped as occurring during normal clinic hours, or 'off-hours,' and the pattern of use described. RESULTS: 347 of 368 patients utilized FOCUS during the 6-month study. There were a total of 75,447 FOCUS logins; 35,739 (47.4%) were self-initiated and 38,139 (50.6%) were off-hours. 18,450 of the logins during off-hours were self-initiated (24.5%). No differences in average usage per month were found based on race/ethnicity. A subset of 'high utilizers' (n = 152, 43.8%) self-initiated use of all five FOCUS modules both on- and off-hours. They tended to be women, >35 years old, and had a high school diploma or greater. CONCLUSION: Most patients with schizophrenia spectrum disorders recently discharged from the hospital utilized a smartphone intervention targeted to address troublesome residual symptoms. One quarter of the total smartphone utilization was self-initiated off-hours, indicating the potential utility of this tool to extend support for patients during periods of elevated risk.

Frequency specific resting state functional abnormalities in psychosis.

Resting state functional magnetic resonance imaging studies of psychosis have focused primarily on the amplitude of low-frequency fluctuations in the blood oxygen level dependent (BOLD) signal ranging from .01 to 0.1 Hz. Few studies, however, have investigated the amplitude of frequency fluctuations within discrete frequency bands and higher than 0.1 Hz in patients with psychosis at different illness stages. We investigated BOLD signal within three frequency ranges including slow-4 (.027-.073 Hz), slow-3 (.074-0.198 Hz) and slow-2 (0.199-0.25 Hz) in 89 patients with either first-episode or chronic psychosis and 119 healthy volunteers. We investigated the amplitude of frequency fluctuations within three frequency bands using 47 regions-of-interest placed within 14 known resting state networks derived using group independent component analysis. There were significant group x frequency interactions for the visual and motor cortex networks, with the largest significant group differences (patients < healthy volunteers) evident in slow-4 and slow-3, respectively. Also, healthy volunteers had an overall higher amplitude of frequency fluctuations compared to patients across the three frequency ranges in the visual cortex, dorsal attention and motor cortex networks with the opposite effect (patients > healthy volunteers) evident within the salience and frontal gyrus networks. Subsequent analyses indicated that these effects were evident in both first-episode and chronic patients. Our study provides new data regarding the importance of BOLD signal fluctuations within different frequency bands in the neurobiology of psychosis.