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In contrast to the validated scales for face-to-face assessment of negative symptoms, no widely accepted tools currently exist for remote monitoring of negative symptoms. Remote assessment of negative symptoms can be broadly divided into 3 categories: (1) remote administration of an existing negative-symptom scale by a clinician, in real time, using videoconference technology to communicate with the patient; (2) direct inference of negative symptoms through detection and analysis of the patient’s voice, appearance, or activity by way of the patient’s smartphone or other device; and (3) ecological momentary assessment, in which the patient self-reports their condition upon receipt of periodic prompts from a smartphone or other device during their daily routine. These modalities vary in cost, technological complexity, and applicability to the different negative-symptom domains. Each modality has unique strengths, weaknesses, and issues with validation. As a result, an optimal solution may be more likely to employ several techniques than to use a single tool. For remote assessment of negative symptoms to be adopted as primary or secondary endpoints in regulated clinical trials, appropriate psychometric standards will need to be met. Standards for substituting 1 set of measures for another, as well as what constitutes a “gold” reference standard, will need to be precisely defined and a process for defining them developed. Despite over 4 decades of progress toward this goal, significant work remains to be done before clinical trials addressing negative symptoms can utilize remotely assessed secondary or primary outcome measures.

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.

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.

Background Schizophrenia is a chronic disabling disorder for which current treatments are only partially effective. While the evaluation of novel interventions is a high priority, loss to follow-up is a major threat to validity. Methods Pattern mixture modeling is a statistical technique that incorporates information on patterns of retention that may bias comparisons between randomized treatment groups. This study used pattern mixture mixed model (PMMM) in the analysis of outcomes of a two-year cluster-randomized trial, the Recovery after an Initial Schizophrenia Episode-Early Treatment Program, which compared a coordinated specialty care intervention called NAVIGATE to usual community care (CC). PMM-adjusted outcome differences between NAVIGATE and CC were estimated by the weighted-average of effects across the retention patterns. Results Compared to the original analysis, PMMM improved model fit and the estimated effectiveness of NAVIGATE as compared to CC. On the Quality of Life Scale NAVIGATE effectiveness increased by 1.50 points (25.4%); on the Positive and Negative Syndrome Scale, by 1.72 points (39.8%), and on the Calgary Depression Scale by 0.49 points (62.1%). PMMM did not improve model fit for employment days, substance use days, or hospital days. Conclusion Use of PMMM improved model fit and increased the estimated differences between NAVIGATE and CC for major outcomes. Patients with differential retention patterns may have different outcome trajectories. PMMM is a useful tool for addressing potential biases arising from these differences.

Recovery-oriented practices that promote client-centered care, collaboration, and functional outcome have been recommended to improve treatment engagement, especially for individuals with serious mental illness (SMI). Psychological well-being (PWB) is related to recovery and refers to experiencing purpose and meaning in life through realizing one's potential. The recently completed Recovery After an Initial Schizophrenia Episode Early Treatment Program (RAISE ETP) study sought to improve quality of life, functional outcome, and well-being in individuals with first episode psychosis (FEP). Therefore, the primary aims of the present analysis were: 1) to examine the impact of treatment on PWB and mental health recovery trajectories, 2) to examine the impact of duration of untreated psychosis (DUP) on these outcomes, and 3) to examine the relationships among these outcomes and quality of life. Multilevel modeling was used given the nested data structure. Results revealed that PWB and mental health recovery improved over the course of the 2-year treatment; there were no significant treatment differences. In addition, DUP was associated with the Positive Relationships and Environmental Mastery dimensions of PWB. Finally, PWB, mental health recovery, and quality of life were all significantly correlated at baseline while controlling for depressive symptoms. Overall, the findings indicate that PWB and mental health recovery can improve in FEP, are related to yet distinct from quality of life, and that DUP may play a role in certain facets of these constructs.

Background Participation in work and school are central objectives for first episode psychosis (FEP) programs, but evidence effectiveness has been mixed in studies not focused exclusively on supported employment and education (SEE). Requirements for current motivation to work or go to school limit the generalizability of such studies. Methods FEP participants (N = 404) at thirty-four community treatment clinics participated in a cluster randomized trial that compared usual Community Care (CC) to NAVIGATE, a comprehensive, team-based treatment program that included ≥ 5 h of SEE services per week, , grounded in many of the principles of the Individual Placement and Support model of supported employment combined with supported education services. All study participants were offered SEE regardless of their initial interest in work or school. Monthly assessments over 24 months recorded days of employment and attendance at school, days of participation in SEE, and both employment and public support income (including disability income). General Estimation Equation models were used to compare CC and NAVIGATE on work and school participation, employment and public support income, and the mediating effect of receiving ≥ 3 SEE visits on these outcomes. Results NAVIGATE treatment was associated with a greater increase in participation in work or school (p = 0.0486) and this difference appeared to be mediated by SEE. No group differences were observed in earnings or public support payments. Conclusion A comprehensive, team-based FEP treatment approach was associated with greater improvement in work or school participation, and this effect appears to be mediated, in part, by participation in SEE.

Background Psychiatric hospitalization is a major driver of cost in the treatment of schizophrenia. During the first six months after a hospitalization, patients are at increased risk for return to the hospital. Targeting treatment during this period may be especially valuable. Mobilizing a range of treatment enhancements using both smart phones and computers to support patients by individualizing treatment to specific needs may be especially beneficial. The Improving Care Reducing Cost (ICRC) program sought to determine whether a novel, multicomponent, and technology-enhanced approach to relapse prevention in outpatients following a psychiatric hospitalization could reduce days spent in a hospital after discharge. Methods The ICRC study was a quasi-experimental clinical trial in outpatients with schizophrenia conducted between February 2013 and April 2015 at 10 sites in the US that provide both in and outpatient. Data were obtained from 89 participants who received usual relapse prevention services, followed by a second cohort of 349 participants who received technology-enhanced relapse prevention program. Both groups were followed for 6 months. Patients were between 18 and 60 years old; had a diagnosis of schizophrenia, schizoaffective disorder, or psychotic disorder not otherwise specified; and were currently hospitalized or had been hospitalized within the past 30 days at consent. The first cohort received usual care; the second cohort received the Health Technology Program (HTP) a technology-enhanced relapse prevention program. HTP included medication treatment guided by a computer decision support system for the prescriber, a smartphone application for patients that supported medication adherence and other coping strategies, a web-based patient and family psycho-educational intervention, and web-accessed cognitive behavioral therapy for paranoia and hallucinations. A mental health technology coach provided technical support, and developed a personalized, structured, relapse prevention plan with each participant that identified individual relapse precipitants and determined which HTP components should be employed to address them. All patients received computers and Android smartphones to insure access to the interventions. Days spent in a psychiatric hospital during 6 months after discharge was assessed. The Heinrichs Carpenter Quality of Life Scale was completed at baseline and six months. Results The study included 438 patients. Control participants (N = 89; 37 females) were enrolled first and received usual care for relapse prevention, and followed by 349 participants (128 females) who received the HTP. Days of hospitalization were reduced by 4 days (Mean days: b = -4.25, 95% CI: -8.29; -0.21, P = 0.039) during follow-up in the intervention condition compared to control. Finally, using Heinrichs Carpenter Quality of Life total score at month 6 as an outcome, we found no significant effect of HTP (β = 0.02, t (345) = 0.43, P = 0.668). Discussion Recently hospitalized patients with schizophrenia who received an integrated technology informed relapse prevention program (HTP) experienced fewer days in the hospital compared to those who received usual care in the six months following their discharge. Given the high patient burden and costs of even a single day spent in a psychiatric hospital, estimated at $1358 per day based on inflation adjusted results from a recent study, our findings imply total savings in psychiatric inpatient expenditures of $5772 during the first 6 months after discharge on average. However, reduction in hospitalization days did not result in a parallel improvement in functioning as assessed by the Quality of Life Scale. Although the control and experimental cohorts were comparable in many characteristics, the quasi–experimental design represented by sequential cohorts rather than a true concurrent randomized controlled trial represents a limitation. The results of the study suggest that technology enhanced treatments that are tailored to patient needs can be implemented in a range of clinical settings in the US to patients at high risk of hospitalization and that the intervention can reduce subsequent hospitalization days. Future research should address limitations in the current study design and will benefit from the development of technology applications that can be available on a single flexible platform.

Background Early intervention services (EIS) for first episode psychosis (FEP) are now implemented worldwide and these integrated and team-based treatment programs improve FEP outcomes while patients are participating. EIS service and treatment models provide care for limited periods followed by return to standard services. Cross sectional follow-up studies conducted after EIS participation ends have not been able to find advantages compared with standard care. The RAISE-ETP study was the first US-based, multi-center randomized clinical trial to compare an EIS, labeled NAVIGATE, to usual clinical care. Those who received NAVIGATE experienced significant improvement in symptoms and functioning compared to those who received usual care during the initial two-year treatment period. We now report clinical outcomes covering five years, a time frame that includes care after EIS participation ended. Methods RAISE-ETP was a cluster randomized clinical trial conducted at 34 US sites; 17 sites provided NAVIGATE to 223 participants and 17 sites provided usual clinical care to 181 participants. NAVIGATE was available until the last randomized subject had the opportunity for two years of services. Participants were assessed every six months for up to 60 months by masked, centralized assessors utilizing live two-way video and with the Heinrichs-Carpenter Quality of Life Scale (QLS) and the Positive and Negative Syndrome Scale (PANSS). Results Participants had a mean age of 23 years and the majority were male; (78% in NAVIGATE and 66% in usual care). The mean opportunity for NAVIGATE treatment was 33.8 (SD=5.1) months; the longest 44.4 months. Compared with usual care, NAVIGATE over 5 years was associated with a 13.14 unit QLS (p Discussion RAISE-ETP provides compelling evidence of a substantial long-term benefit for FEP treatment with the NAVIGATE EIS compared with standard care.

ImportancePsychiatric hospitalization is a major driver of cost in the treatment of schizophrenia. Symptom relapses are a frequent cause of hospitalization and both are primary source of burden to patients and their supporters.ObjectiveTo determine whether a novel, multicomponent, and technology-enhanced approach to relapse prevention in outpatients following a psychiatric hospitalization could reduce days spent in a hospital after discharge.DesignThe Improving Care and Reducing Cost (ICRC) study was a quasi-experimental clinical trial in outpatients with schizophrenia conducted between February 2013 and April 2015 at 10 different sites in the US. Data were obtained from 89 participants who received usual relapse prevention services, followed by a second cohort of 349 participants who received the technology-enhanced relapse prevention program. Both groups were followed for 6 months.SettingOutpatient setting.ParticipantsPatients were between 18 and 60 years old; had a diagnosis of schizophrenia, schizoaffective disorder, or psychotic disorder not otherwise specified; and were currently hospitalized or had been hospitalized within the past 30 days.InterventionPatients received usual care or a technology-enhanced relapse prevention program during a 6-month period after discharge.Main Outcome(s) and Measure(s)Days spent in a psychiatric hospital during 6 months after discharge.ResultsThe study included 438 patients. Control participants (N = 89; 37 females) were enrolled first and received usual care for relapse prevention, and followed by 349 participants (128 females) who received technology-enhanced relapse prevention. Days of hospitalization were reduced by 4 days (Mean days: b = −4.25, 95% CI: −8.29; −0.21, P = 0.039) during follow-up in the intervention condition compared to control.Conclusions and RelevanceThe reduction in days spent in the hospital for participants in the technology-informed relapse prevention program compared to those who received usual care, and the previously reported high satisfaction and usability suggest that technology-enhanced relapse prevention is an effective and feasible way to reduce rehospitalization days among patients with schizophrenia.Key pointsQuestionCan rehospitalizations in schizophrenia be prevented at reduced cost by innovative mobile technology-delivered interventions?FindingsIn this clinical trial with 438 patients, a technology-enhanced relapse prevention program compared to usual services reduced an average of four days of hospitalization per patient during the first 6 months following an index hospitalization.MeaningRelapse prevention through a health technology may improve care while reducing costs associated with hospitalization.

Background Even with early intervention services, a third or more of first-episode patients are hospitalized over the first 2 yrs. of treatment. Non-adherence is a major factor in increasing risk of hospitalization. Long-acting injectable antipsychotics (LAI’s) have shown effectiveness in addressing this concern in both mirror image and cohort studies. However, randomized controlled trials (RCT’s) have reported mixed results. RCT’s can change the ecology of care and do not reflect “real world” conditions, particularly when adherence is a focus of study. The large simple trial (LST) is a design intended to address such concerns. Methods The PRELAPSE trial was a LST involving cluster randomization of 39 clinics. 19 sites were randomized to provide LAI treatment-the Aripiprazole Once Monthly (AOM) condition and 20 sites to treatment as usual-Clinician’s Choice (CC). The primary hypothesis was that the opportunity for treatment with AOM would significantly delay time to first hospitalization. Inclusion criteria were: 1) schizophrenia diagnosis confirmed by a Structured Clinical Interview for DSM-5, Research Version (SCID-5); 2) A key challenge in conducting this study was facilitating the acceptance of LAI’s among early phase patients at the experimental sites. AOM-specific training included information on the role of non-adherence in relapse/hospitalization, the effectiveness of LAIs in this context, the rationale for LAI use and selection of aripiprazole; shared decision-making principles; discussing LAIs with patients/ families; discussion of transition to LAI’s and prescribing guidelines consistent with the package insert for AOM. Training included providing suggested “scripts,” frequently asked questions, role-playing and overcoming logistical barriers to the use of LAIs across different healthcare settings. Results The 489 participating subjects had a mean age of 25, 75% were male, 44% African-American and 35% Caucasian. 46.0% had There were 489 subjects (234 AOM and 255 CC). A total of 52 AOM subjects had at least one hospitalization (22.2%) and 90 CC subjects had a least one (35.3%). For time to first hospitalization, under the proportional hazards assumption, the hazard ratio was HR=0.56 (95% CI = 0.34, 0.92), p=0.02.The estimated survival probabilities and 95% CI’s from the Cox model were 0.73 (0.65, 0.83) for AOM subjects and 0.58 (0.50, 0.67) for CC subjects. This translates to a number needed to treat (NNT) for prevention of one additional hospitalization for every 6.67 subjects treated with AOM relative to CC. Discussion This study demonstrates the feasibility of engaging the overwhelming majority of early phase patients in the use of LAI’s if clinical staff are well trained. The use of LAI’s in this population produced a significant delay in time to hospitalization and a NNT of 7 for the prevention of hospitalization.

Memory impairment in schizophrenia has been linked to abnormal functioning of fronto-temporal networks. In this pilot study, we investigated whether 12-weeks of exercise improved hippocampal-dependent memory functions and resting-state functional connectivity in middle-aged adults with schizophrenia. The exercise regimen was feasible, well-attended, and safe. There was a pre- to post-intervention increase in spatial memory accuracy that was correlated to an increase in hippocampal-prefrontal cortex connectivity. No increase was found in pattern separation performance or hippocampal volume. A controlled trial is needed to replicate these findings and elucidate the functional brain networks underlying exercise-induced cognitive improvement in schizophrenia.

Until relatively recently, long-acting injectable (LAI) formulations were only available for first-generation antipsychotics and their utilization decreased as use of oral second-generation antipsychotics (SGA) increased. Although registry-based naturalistic studies show LAIs reduce rehospitalization more than oral medications in clinical practice, this is not seen in recent randomized clinical trials. PROACTIVE (Preventing Relapse Oral Antipsychotics Compared to Injectables Evaluating Efficacy) relapse prevention study incorporated efficacy and effectiveness features. At 8 US academic centers, 305 patients with schizophrenia or schizoaffective disorder were randomly assigned to LAI risperidone (LAI-R) or physician's choice oral SGAs. Patients were evaluated during the 30-month study by masked, centralized assessors using 2-way video, and monitored biweekly by on-site clinicians and assessors who knew treatment assignment. Relapse was evaluated by a masked Relapse Monitoring Board. Differences between LAI-R and oral SGA treatment in time to first relapse and hospitalization were not significant. Psychotic symptoms and Brief Psychiatric Rating Scale total score improved more in the LAI-R group. In contrast, the LAI group had higher Scale for Assessment of Negative Symptoms Alogia scale scores. There were no other between-group differences in symptoms or functional improvement. Despite the advantage for psychotic symptoms, LAI-R did not confer an advantage over oral SGAs for relapse or rehospitalization. Biweekly monitoring, not focusing specifically on patients with demonstrated nonadherence to treatment and greater flexibility in changing medication in the oral treatment arm, may contribute to the inability to detect differences between LAI and oral SGA treatment in clinical trials.

Combination antipsychotics (CAs) are prescribed in schizophrenia despite limited evidence of efficacy. To explore the effect of switching from CA to monotherapy, we performed an exploratory analysis of the PROACTIVE (Preventing Relapse in Schizophrenia: Oral Antipsychotics Compared with Injectables: Evaluating Efficacy) study data, in which 305 patients with schizophrenia and schizoaffective disorder were followed for 30 months after randomization to long-acting injectable (LAI) risperidone or second-generation oral antipsychotic (OA).Patients who entered the PROACTIVE study on CA (n = 50), LAI (n = 20), or OA (n = 206) were compared in terms of time to relapse and clinical measures.The OA group had significantly fewer hospitalizations than the CA group (P = 0.009) at baseline. In the CA group, 68% patients relapsed versus 53% in the LAI, and 52% in the OA groups. Although there was no significant difference in the relapse rate among groups on χ test (χ = 3.85, P = 0.146), the log-rank test showed a significant difference among the groups in time to first relapse (χ = 6.81, P = 0.033), with significantly longer time to relapse in the OA group (mean, 562.8 days) than in the CA group (mean, 409.5; P = 0.011). The LAI group's mean time to first relapse (594 days) was not significantly different from the other groups. However, after adjusting for number of hospitalizations, group was no longer significant (hazard ratio, 1.541; P = 0.052).Based on our exploratory analysis, taking antipsychotic combinations predicts earlier relapse and calls for additional treatment guidance in schizophrenia.

Background The Recovery After an Initial Schizophrenia Episode Early Treatment Program (RAISE-ETP) is a US NIMH-funded 34 site cluster randomized controlled trial which evaluated the benefits of participation in a multicomponent intervention, entitled NAVIGATE, for first episode psychosis (FEP). Previously, participation in NAVIGATE was reported to yield significant participant benefits, compared to customary care (Kane et al, 2016). NAVIGATE included tailored medication, individual resiliency training, family education, and supported education and employment. Here we examine the absolute rate of family engagement in professional support services in the intent to treat sample, as well identify predictors of participation. Methods A total of 404 individuals between ages 15 and 40 were enrolled. DSM-IV diagnoses of non-affective psychosis were included. All participants had experienced only one episode of psychosis, had been prescribed less than 6 months of lifetime psychotic medication, spoke English, and provided informed consent. Participants were offered a minimum of two years of NAVIGATE or customary care (CC). At baseline, participants provided demographic and clinical history information; they were administered the Heinrichs-Carpenter Quality of Life Scale (QOL) and the Positive and Negative Symptom Scale (PANSS). Site research assistants interviewed participants monthly to capture participation in the four types of NAVIGATE interventions, allowing treatment groups to be compared on receipt of key services. Results One hundred nineteen of the 404 participants (29.4%) reported their relatives attending five or more family sessions within the first year of randomization (102 families (45.74%) in NAVIGATE; 17 (9.39%) in CC). In a simultaneous logistic regression analysis predicting meeting this five family sessions threshold or not, significant independent predictors (all p

Alpha7 nicotinic acetylcholine receptor (α7 nAChR) agonists may be valuable treatments for negative symptoms and cognitive impairment in schizophrenia. Unfortunately, chronic exposure to an agonist may reduce the receptor’s sensitivity. Therefore, we combined CDP-choline, a dietary source of the direct agonist choline, with galantamine, a positive allosteric modulator (PAM) of nicotinic acetylcholine receptors, to improve the efficiency of transducing the choline signal and, possibly, preserve the receptor in a sensitive state. We conducted a single-site, double-blind randomized clinical trial comparing galantamine/CDP-choline to placebos in schizophrenia patients with negative symptoms who were receiving second generation antipsychotics. Forty-three subjects received galantamine and CDP-choline or matching placebos for 16 weeks. The primary outcome measure was the 5-item Marder negative-symptoms factor of the Positive and Negative Syndrome Scale (PANSS). Cognition and functioning were also assessed. Trial completion was high; 79%. There was no significant treatment effect on negative symptoms, other PANSS symptom factors, or the MATRICS Cognitive Consensus Battery. There were significant treatment effects in overall functioning and a test of free verbal recall. Three subjects discontinued treatment in the active treatment group for gastro-intestinal adverse events (AE). The most common AE for galantamine/CDP-choline was abdominal pain; for placebo it was headache and sweating. Although there was no significant treatment effect on negative symptoms, the direction of effect mirrored the effects on a cognitive measure and overall functioning. Further study of α7 nAChR agonist/PAMs are warranted in larger studies that will have greater power.

Aim/background: Tramadol is a synthetic opiate and a centrally acting weak µ-opioid receptor agonist. The potential advantages of tramadol include ease of administration, low abuse potential, and being nonscheduled. This study compared tramadol and buprenorphine for controlling withdrawal symptoms in patients with opioid dependence syndrome. Methods: Consenting male subjects between 20 and 45 years of age who fulfilled the ICD-10-DCR criteria for opiate dependence syndrome were randomly assigned in a double-blind, double-dummy placebo-controlled trial for detoxification. Those with multiple drug dependence, abnormal cardiac, renal and hepatic functions, psychosis, or organic mental illness were excluded. Assessments included Subjective Opiate Withdrawal Scale (SOWS), Objective Opiate Withdrawal Scale (OOWS), Visual Analog Scale (VAS), and Side Effect Check List. Subjects were evaluated daily and study duration was 10 days. Results: Sixty two subjects were enrolled. The mean SOWS and OOWS and VAS were significantly lower in the buprenorphine group on second and third day of detoxification as compared to the tramadol group. Although the retention rate was higher for buprenorphine group throughout the study, when compared with tramadol the difference was not significant on any day. Three subjects in the tramadol group had seizures. Conclusions: Tramadol was found to have limited detoxification efficacy in moderate to severe opioid withdrawal and substantial risk of seizures as compared to buprenorphine. Further studies are warranted to examine its efficacy in mild opioid withdrawal symptoms and its potential use in outpatient settings where its administration advantages may be valuable. Keywords: tramadol, buprenorphine, detoxification, opioids, heroin, randomized DOI:10.5055/jom.2013.0145

Background mHealth interventions that use mobile phones as instruments for illness management are gaining popularity. Research examining mobile phone‒based mHealth programs for people with psychosis has shown that these approaches are feasible, acceptable, and clinically promising. However, most mHealth initiatives involving people with schizophrenia have spanned periods ranging from a few days to several weeks and have typically involved participants who were clinically stable. Objective Our aim was to evaluate the viability of extended mHealth interventions for people with schizophrenia-spectrum disorders following hospital discharge. Specifically, we set out to examine the following: (1) Can individuals be engaged with a mobile phone intervention program during this high-risk period?, (2) Are age, gender, racial background, or hospitalization history associated with their engagement or persistence in using a mobile phone intervention over time?, and (3) Does engagement differ by characteristics of the mHealth intervention itself (ie, pre-programmed vs on-demand functions)? Methods We examined mHealth intervention use and demographic and clinical predictors of engagement in 342 individuals with schizophrenia-spectrum disorders who were given the FOCUS mobile phone intervention as part of a technology-assisted relapse prevention program during the 6-month high-risk period following hospitalization. Results On average, participants engaged with FOCUS for 82% of the weeks they had the mobile phone. People who used FOCUS more often continued using it over longer periods: 44% used the intervention over 5-6 months, on average 4.3 days a week. Gender, race, age, and number of past psychiatric hospitalizations were associated with engagement. Females used FOCUS on average 0.4 more days a week than males. White participants engaged on average 0.7 days more a week than African-Americans and responded to prompts on 0.7 days more a week than Hispanic participants. Younger participants (age 18-29) had 0.4 fewer days of on-demand use a week than individuals who were 30-45 years old and 0.5 fewer days a week than older participants (age 46-60). Participants with fewer past hospitalizations (1-6) engaged on average 0.2 more days a week than those with seven or more. mHealth program functions were associated with engagement. Participants responded to prompts more often than they self-initiated on-demand tools, but both FOCUS functions were used regularly. Both types of intervention use declined over time (on-demand use had a steeper decline). Although mHealth use declined, the majority of individuals used both on-demand and system-prompted functions regularly throughout their participation. Therefore, neither function is extraneous. Conclusions The findings demonstrated that individuals with schizophrenia-spectrum disorders can actively engage with a clinically supported mobile phone intervention for up to 6 months following hospital discharge. mHealth may be useful in reaching a clinical population that is typically difficult to engage during high-risk periods.

Supplemental digital contents are available in the text., The optimal treatment for schizoaffective disorder (SCA) is not well established. In this initial 6-month open-label treatment period of a large, multiphase, relapse-prevention study, the efficacy and safety of paliperidone palmitate once-monthly (PP1M) injectable were evaluated in subjects with symptomatic SCA. Subjects with acute exacerbation of SCA (ie, with psychotic and either depressive and/or manic symptoms) were enrolled and treated with PP1M either as monotherapy or in combination with antidepressants or mood stabilizers (combination therapy group). After flexible-dose treatment with PP1M for 13 weeks, stabilized subjects continued into a 12-week fixed-dose PP1M treatment period. A total of 667 subjects were enrolled; 320 received monotherapy and 347 received PP1M as combination therapy; 334 subjects completed the entire 25-week treatment. Statistically significant and clinically meaningful improvements from baseline were observed for all efficacy measures in psychosis (per Positive and Negative Syndrome Scale), mood symptoms (per Young Mania Rating Scale and Hamilton Depression Rating Scale—21 items), and functioning (per Personal and Social Performance Scale) from week 1 to all time points during the 25-week treatment period (P < 0.001). Similar improvements in efficacy measures were observed between subjects receiving monotherapy or combination therapy. Efficacy benefits persisted throughout the 25-week period. The most common adverse events were akathisia (11.1%), injection-site pain (10.6%), and insomnia (10.0%). Paliperidone palmitate once-monthly administered as monotherapy or in combination with mood stabilizers or antidepressants in patients with an acute exacerbation of SCA provided rapid, broad, and persistent reduction in psychotic, depressive, and manic symptoms, as well as improved functioning.

Robin Emsley and colleagues question the use of placebos when established treatment is effective and lack of harm has not been proved

Objective This multisite randomized trial addressed risks and benefits of staying on long-acting injectable haloperidol or fluphenazine versus switching to long-acting injectable risperidone microspheres.

Published guidelines recommend metabolic monitoring for patients prescribed second-generation antipsychotic (SGA) medications. This study determined monitoring rates, and examined predictors of monitoring, for total cholesterol and weight among patients prescribed SGAs during a period when awareness of metabolic side effects was emerging, but prior to the wide promulgation of guidelines.This retrospective study used administrative data from four Veterans Health Administration facilities to examine monitoring rates for total cholesterol and weight during baseline and follow-up periods from October 1, 2000-September 30, 2003 among patients with schizophrenia initiating SGA treatment. The study used logistic regression to identify characteristics that predicted monitoring. Background monitoring rates during routine care were estimated using a resampling procedure.Initiating SGA treatment did not appear to trigger annual monitoring above estimated background rates of 54% for total cholesterol and 47% for weight. Patients with metabolic risk factors were monitored at higher rates independent of the start of treatment with an SGA.This paper provides a window into side effect monitoring practices prior to the widespread promulgation of guidelines and associated quality improvement efforts and serves as a benchmark for future interventions. Prior to publication of monitoring guidelines, patients initiating treatment with SGAs did not receive adequate metabolic monitoring routinely, nor did SGA treatment appear to trigger additional monitoring. Some studies that have assessed the impact of monitoring guidelines on clinical practice show only limited impact. Quality improvement strategies to increase metabolic monitoring over the rates seen here and in other studies should be developed and implemented.

Background The Recovery After an Initial Schizophrenia Episode Early Treatment Program (RAISE-ETP) is a US NIMH-funded 34 site cluster randomized controlled trial evaluating the benefits of participation in a multicomponent intervention for first episode psychosis (FEP). Previously, participation in the RAISE-ETP comprehensive specialty care (CSC) program, entitled NAVIGATE, was reported to yield significant participant clinical and functional improvements, compared to customary care (Kane et al, 2016). NAVIGATE included tailored medication, individual resiliency training, family education, and supported education and employment. Family burden has been identified as a key factor in FEP, with high levels of distress often found in relatives. Here, we look at the presence and predictors of family burden in relatives in the RAISE-ETP sample over the two years of study participation. Methods A total of 404 individuals between ages 15 and 40 were enrolled. DSM-IV diagnoses of non-affective psychosis were included. All participants had experienced only one episode of psychosis, had been prescribed less than 6 months of lifetime psychotic medication, spoke English, and provided informed consent. Participants were offered a minimum of two years of CSC or customary care. At baseline, participants provided demographic and clinical history information; they were administered the Heinrichs-Carpenter Quality of Life Scale (QOL) and the Positive and Negative Symptom Scale (PANSS) regularly throughout the study. Each participant was asked to nominate a family member for administration of the Burden Assessment Scale (BAS) throughout the study. The BAS yields a total score, as well as subscales assessing disrupted activities, personal distress, guilt, time perspective, and worry. Results Fifty-seven percent of the participants nominated a relative who was assessed with the BAS. Interestingly, the only statistically significant independent predictors of baseline family burden were relatives’ reports of their loved ones’ dependence and lack of help with chores; no consumer demographic, PANSS, or QOL variables were identified. BAS total scores improved significantly in both conditions, but significantly more in NAVIGATE. Consumer report of better family relationship quality on the QOL was associated with significantly less family burden on the BAS over time, but neither PANSS positive, negative or symptom total, total QOL, nor participation in specific CSC psychosocial components mediated the observed BAS total burden reductions. With regard to the BAS burden components, there was a main effect of improvement over time on family disrupted activities, guilt, time perspective, and worry, with disrupted activities, personal distress, and guilt all evidencing a time by group interaction favoring greater reductions in NAVIGATE. Discussion As anticipated, family burden is widely evidenced in the relatives of US FEP consumers who are new to treatment. This burden does not appear to reflect unique consumer characteristics. There appears to be a reduction in family burden during the loved one’s FEP treatment, with that reduction enhanced when the consumer is participating in a more intensive CSC program. Interestingly, while many potential intervening variables were tested as mediators of the CSC impact on family burden, none were identified. The overall pattern of results suggests that it maybe the very fact of a loved one being enrolled in a treatment program, especially if it is a comprehensive FEP intervention, rather than engagement in specific program components or consumer improvements, that are associated with reductions in family burden over the first year of treatment.

Gerard E. Hogarty was a scholar and clinician whose career was dedicated to improving the lives of persons with schizophrenia through the rigorous development and testing of novel psychosocial treatment approaches. During the course of his career, he is credited with the development of many of the psychosocial treatments that have become the pillars of evidence-based practices for schizophrenia today. This review outlines the evolution of Hogarty's contributions to the development of psychosocial approaches for schizophrenia by presenting a chronological history of the 4 distinct treatments he developed during the course of his career. These include major role therapy, an early precursor to clinical case management; family psychoeducation, an approach to ally with and educate family members to reduce intrafamilial distress; personal therapy, a flexible, individual psychotherapy, aimed at teaching patients stress management and affective regulation techniques; and finally, cognitive enhancement therapy, a comprehensive, developmental approach to the remediation of social- and nonsocial-cognitive deficits. Each of these treatments built upon the findings of the previous one, and as a consequence, each significantly improved the lives of persons with schizophrenia and expanded the treatment possibilities available to such individuals. These efforts represent a lifelong dedication to advancing the treatment of schizophrenia through rigorous scientific inquiry and exemplify a unique combination of science and humanism that has left a lasting impact on the field and the lives of many individuals suffering from this disease.

Objective:This study is the first to examine duration of untreated psychosis (DUP) among persons receiving care in community mental health centers in the United States.Methods:Participants were 404 individuals (ages 15–40) who presented for treatment for first-episode psychosis at 34 nonacademic clinics in 21 states. DUP and individual- and site-level variables were measured.Results:Median DUP was 74 weeks (mean=193.5±262.2 weeks; 68% of participants had DUP of greater than six months). Correlates of longer DUP included earlier age at first psychotic symptoms, substance use disorder, positive and general symptom severity, poorer functioning, and referral from outpatient treatment settings.Conclusions:This study reported longer DUP than studies conducted in academic settings but found similar correlates of DUP. Reducing DUP in the United States will require examination of factors in treatment delay in local service settings and targeted strategies for closing gaps in pathways to specialty FEP care.

The first episode of psychotic illness is a key intervention point. The initial experience with medication can affect willingness to accept treatment. Further, relapse prevention is a treatment cornerstone during the first years of illness because active psychotic illness may affect lifetime outcomes. Thus, initial treatment of active symptoms and subsequent relapse prevention are central goals of pharmacotherapy. This study compared long-term effectiveness of risperidone versus haloperidol in first-episode psychosis patients.First-episode psychosis patients (N=555, mean age=25.4 years) participated in a double-blind, randomized, controlled flexible-dose trial that compared risperidone (mean modal dose=3.3 mg) and haloperidol (mean modal dose=2.9 mg). The median treatment length was 206 days (maximum=1,514).Positive and Negative Syndrome Scale scores and Clinical Global Impression ratings improved significantly relative to baseline, with no significant differences between groups. Three-quarters of the patients achieved initial clinical improvement, defined as20% reduction in total Positive and Negative Syndrome Scale score. However, among those who achieved clinical improvement, 42% of the risperidone group experienced a relapse compared with 55% of the haloperidol group. The median time to relapse was 466 days for risperidone-treated subjects and 205 days for those given haloperidol. These differences were statistically significant based on Kaplan-Meier survival analysis. Adverse effects distinguished the treatments: there were significantly more extrapyramidal signs and symptoms and adjunctive medication use in the haloperidol group and greater prolactin elevation in the risperidone group. There was less weight gain with haloperidol initially but no significant differences between groups at endpoint.Relatively low doses of antipsychotic drugs lead to significant symptom amelioration in the majority of first-episode psychosis patients. In the long term, risperidone prevents relapse in more patients and for a longer time and also induces less abnormal movements than haloperidol.

Background: Few treatment studies of schizotypal personality disorder (SPD) have investigated the new, atypical antipsychotic drugs. This study examined the efficacy and tolerability of olanzapine, an atypical antipsychotic drug, in a series of patients with DSM-IV diagnosed schizotypal personality disorder. Method: This was a 26-week, open-label study with flexible dose design in 11 subjects with a diagnosis of schizotypal personality disorder based on Structured Clinical Interview for DSM-IV (SCID) and Personality Disorder Examination (PDE Journal of Psychiatric Disorders 1 (1987) 1). Subjects were treated with a low dose (average 9.32 mg/day) of olanzapine. Psychopathology was assessed at baseline and at the end of the study and analyzed with last observation carried forward analysis. Results: Patients showed significant improvements in psychosis and depression ratings, as well as in overall functioning. Olanzapine was well tolerated, though significant weight gain was observed. Conclusion: This study provides preliminary data regarding olanzapine efficacy and tolerability in schizotypal personality disorder subjects. These data need to be confirmed in larger controlled clinical trials.

Objectives: To review the evidence for the safety and efficacy of nonpharmacological and pharmacological treatments for aggression in children and adolescents. Method: Medline and PsycINFO searches (1990–present) were conducted for double-blind, placebo-controlled studies of atypical antipsychotics for aggression and for literature on the use of other pharmacological agents and psychosocial interventions for aggression. Case reports and adult literature regarding the safety of atypical antipsychotics were used where controlled data for youth were lacking. Results: Controlled data on the treatment of aggression in youth is scarce. Psychosocial interventions may be effective alone or in combination with pharmacological treatments. Psychotropic agents (e.g., stimulants, mood stabilizers, β-blockers) have also been shown to have limited efficacy in reducing aggression. Antipsychotics, particularly the atypical antipsychotics, show substantial efficacy in the treatment of aggression in selected pediatric popul...

To review the evidence for the safety and efficacy of nonpharmacological and pharmacological treatments for aggression in children and adolescents.and searches (1990-present) were conducted for double-blind, placebo-controlled studies of atypical antipsychotics for aggression and for literature on the use of other pharmacological agents and psychosocial interventions for aggression. Case reports and adult literature regarding the safety of atypical antipsychotics were used where controlled data for youth were lacking.Controlled data on the treatment of aggression in youth is scarce. Psychosocial interventions may be effective alone or in combination with pharmacological treatments. Psychotropic agents (e.g., stimulants, mood stabilizers, beta-blockers) have also been shown to have limited efficacy in reducing aggression. Antipsychotics, particularly the atypical antipsychotics, show substantial efficacy in the treatment of aggression in selected pediatric populations. Atypical antipsychotics are generally associated with fewer extrapyramidal symptoms than are typical antipsychotics.Psychosocial interventions and atypical antipsychotics are promising treatments for aggression in youth. Double-blind studies should examine the safety and efficacy of atypical antipsychotics compared to each other and to medications from other classes, the efficacy of specific medications for different subtypes of aggression, combining various psychotropic medications, optimal dosages, and long-term safety.

This report summarizes the recommendations from a consensus meeting that focused on specific questions regarding the pharmacotherapy of schizophrenia. The issues were selected because there was evidence that experts had recently disagreed about the evidence supporting a particular practice or when there were substantial variations in a clinical practice indicating that there was disagreement among clinicians. The group of experts was able to reach a consensus regarding the evidence base pertaining to the following issues: First generation (FGAs) and second generation (SGAs) antipsychotics as first line agents; the duration of antipsychotic trials; the effectiveness of clozapine and other agents for treatment refractory schizophrenia; risk of tardive dyskinesia on FGAs and SGAs; differences among antipsychotics for different dimensions of psychopathology; and side effect monitoring for various antipsychotics.

Background: Significant cognitive impairment is already seen in first-episode psychosis (FEP) and degree of impairment is a moderator of long-term outcomes. Does specialized FEP treatment improve cognitive functioning? The NIMH sponsored RAISE-ETP study allows comparison of NAVIGATE, a coordinated specialty care intervention designed for FEP, to Community Care (CC) in a randomized clinical trial. (RCT)

Objective:Treatment guidelines suggest distinctive medication strategies for first-episode and multiepisode patients with schizophrenia. To assess the extent to which community clinicians adjust their usual treatment regimens for first-episode patients, the authors examined prescription patterns and factors associated with prescription choice in a national cohort of early-phase patients.Method:Prescription data at study entry were obtained from 404 participants in the Recovery After an Initial Schizophrenia Episode Project’s Early Treatment Program (RAISE-ETP), a nationwide multisite effectiveness study for patients with first-episode schizophrenia spectrum disorders. Treatment with antipsychotics did not exceed 6 months at study entry.Results:The authors identified 159 patients (39.4% of the sample) who might benefit from changes in their psychotropic prescriptions. Of these, 8.8% received prescriptions for recommended antipsychotics at higher than recommended dosages; 32.1% received prescriptions for ol...

Background: In spite of some inherent limitations, naturalistic data can provide information on populations that have greater heterogeneity than can controlled clinical trials and on functional outcomes that may be especially important in clinical practice. In the present retrospective naturalistic study, we evaluated key clinical outcomes among the first wave of risperidone-treated patients at a state psychiatric hospital. Method: Outcome data were extracted from the charts of 142 patients 2 years after initiation of treatment with risperidone. Their diagnoses included DSM-III-R schizophrenia (57%), schizoaffective disorder (22%), dementia and other organic conditions (7%), bipolar disorder (5%), and other psychiatric disorders (9%). Results: During the 2-year period, 92 of 142 patients were discharged from the hospital: 61 (43%) were discharged on risperidone treatment and 31 (22%) were discharged on treatment with other drugs. At the time of the study, 50 of 142 patients were still in the hospital: of these, 18 (13%) were still receiving risperidone. The modal maximum daily dose of risperidone was 4.1 mg in patients discharged on risperidone treatment and 7.5 mg in patients still in the hospital. All groups were granted more ward privileges after starting risperidone, the most being granted to patients discharged from the hospital on risperidone treatment (p

Background Studies of first-episode patients allow investigation of the biological basis of psychotic disorders without the potential confounds of prior treatment and illness chronicity. Prospective studies of this population can clarify the impact of illness course and treatment on neurobiology.Method We summarise preliminary findings from our ongoing magnetic resonance imaging and spectroscopy studies of first-episode schizophrenia patients being conducted prospectively from index evaluations through a period of two years; during this period, patients were treated with either a conventional antipsychotic such as haloperidol, or the atypical risperidone.Results Baseline neurobiological evaluations in first-episode schizophrenia patients have revealed evidence for structural and functional brain abnormalities consistent with a neurodevelopmental model of this illness. Our preliminary data support the value of risperidone as an antipsychotic drug of first choice among patients with early schizophrenic illness.Conclusions Focused studies of first-episode patients have the potential to unravel pathophysiology of schizophrenic illness. Such knowledge is critical for more effective early detection, intervention and even prevention of this enigmatic disorder.

It is often asserted that maintenance treatment in schizophrenia requires the integration of both medication and psychosocial treatment for maximum benefit. A review of research on one psychosocial treatment, psychoeducational family treatment, suggests that it provides benefits beyond other psychosocial treatments or usual care, but there is no evidence of differences among family treatments. Research designs that include comparisons of both medication and psychosocial treatment provide the strongest evidence regarding the contribution of each to outcome. Two studies have incorporated comparisons of both medication and family treatment. In a short-term study that compared family treatment to routine care, family treatment had an additive effect to that of medication. Goldstein and his colleagues found that subjects who received both a higher dose of medication and family treatment had the best outcome. In a longer term study that compared two forms of family treatment and three doses of antipsychotic medication, Schooler and her colleagues found significant effects of the medication condition but no differential effects between the two family treatments. Taken together, these studies support a clinical recommendation that when family members are available, a psychoeducational family treatment should be part of an overall treatment program for schizophrenia.

OBJECTIVE The Scale for the Assessment of Negative Symptoms is a widely used instrument for measuring negative symptoms in schizophrenia, but few studies have examined its reliability. This study examined the interrater, internal, and test-retest reliabilities of the scale and its factor structure in the context of a multisite study. METHOD Two hundred seven patients with schizophrenia who were participating in the Treatment Strategies in Schizophrenia study were assessed with the Scale for the Assessment of Negative Symptoms following a symptom exacerbation and again 3-6 months later. All assessments were performed by trained psychiatrists who were treating the patients. RESULTS Interrater reliabilities ranged from low to high for the items on the Scale for the Assessment of Negative Symptoms but were statistically significant in most cases. Most correlations between individual items and subscale total scores were moderate to high, as were coefficient alphas for each subscale, indicating adequate internal consistency. Test-retest correlations were of moderate magnitude. Few differences in reliability statistics between sites were found, although differences in mean scale ratings between sites were present. A factor analysis indicated three factors corresponding to the Affective Flattening or Blunting subscale, the Avolition-Apathy and Anhedonia-Asociality subscales, and the Alogia and Inattention subscales. CONCLUSIONS The results suggest that the Scale for the Assessment of Negative Symptoms has good reliability and is a useful instrument for the measurement of negative symptoms in multisite clinical studies. The internal reliability of the Alogia, Avolition-Apathy, and Inattention subscales could be improved by replacing some items and including additional items.

Two randomized, double-blind, 26-week core studies (Eastern [EH] and Western Hemisphere [WH]) tested the hypothesis that asenapine is superior to olanzapine for persistent negative symptoms of schizophrenia; 26-week extension studies assessed the comparative long-term efficacy and safety of these agents. In the core studies, 949 people were randomized to asenapine (n = 241 and 244) or olanzapine (n = 240 and 224); 26-week completion rates with asenapine were 64.7% and 49.6% (olanzapine, 80.4% and 63.8%) in the EH and WH, respectively. In the EH and WH extensions, respectively (asenapine, n = 134 and 86; olanzapine, n = 172 and 110), 52-week completion rates were 84.3% and 66.3% with asenapine (olanzapine, 89.0% and 80.9%). Asenapine was not superior to olanzapine in change in the 16-item Negative Symptom Assessment Scale total score in either core study, but asenapine was superior to olanzapine at week 52 in the WH extension study. Olanzapine was associated with modest, but significantly greater, changes in PANSS positive subscale score at various assessment times in both core studies and the WH extension study. Incidence of treatment-emergent adverse events was comparable between treatments across studies. Weight gain was consistently lower with asenapine. Extrapyramidal symptom-related adverse event incidence was higher with asenapine (EH: 8.3%; 95% confidence interval [CI], 5.1%-12.5%; WH: 16.4%; 95% CI, 11.9%-21.6%) than olanzapine (EH: 3.3%; 95% CI, 1.4%-6.4%; WH: 12.1%; 95% CI, 8.1%-17.0%), but Extrapyramidal Symptom Rating Scale-Abbreviated total score changes did not significantly differ between treatments. In conclusion, asenapine superiority over olanzapine was not observed in the core studies. Both treatments improved persistent negative symptoms, but discontinuation rates were higher with asenapine.

This 6-week, double-blind, placebo-controlled study evaluated paliperidone extended-release (ER) as both monotherapy and adjunctive therapy to mood stabilizers and/or antidepressants (MS/ADs) for schizoaffective disorder. Included subjects had a schizoaffective disorder diagnosis; a Positive and Negative Syndrome Scale (PANSS) total score of 60 or higher; a score of 4 or higher on 2 or more of the PANSS items for hostility, excitement, tension, uncooperativeness, or poor impulse control; and prominent mood symptoms (≥16 on the Young Mania Rating Scale and/or the 21-item Hamilton Rating Scale for Depression). Subjects were randomized to 6 mg/d paliperidone ER or placebo with flexible dosing (3-12 mg/d) until day 15. Randomization was stratified by use of MS/AD and study site. The primary analysis outcome was change in PANSS total score at week 6 last observation carried forward end point. A total of 311 subjects received paliperidone ER (n = 216) or placebo (n = 95); 52.0% received MS/AD. The mean (SD) modal dose of paliperidone ER was 8.6 (2.5) mg/d. Greater improvement was observed with paliperidone ER than placebo on mean (SE) PANSS total scores: -20.0 (1.3) and -10.8 (1.9), respectively. Subjects with prominent manic or depressive symptoms showed greater improvement with paliperidone ER versus placebo: mean (SE) Young Mania Rating Scale (-10.6 [0.9] vs -5.7 [1.2], respectively) and 21-item Hamilton Rating Scale for Depression (-10.2 [0.7] vs -6.2 [1.1], respectively). The most common adverse events with paliperidone ER were headache, akathisia, dizziness, insomnia, and dyspepsia. Paliperidone ER improved psychotic and affective symptoms both as monotherapy and as an adjunct to MS/AD. No new safety findings were observed in this population.

On September 18, 2007, a collaborative session between the International Society for CNS Clinical Trials and Methodology and the International Society for CNS Drug Development was held in Brussels, Belgium. Both groups, with membership from industry, academia, and governmental and nongovernmental agencies, have been formed to address scientific, clinical, regulatory, and methodological challenges in the development of central nervous system therapeutic agents. The focus of this joint session was the apparent diminution of drug-placebo differences in recent multicenter trials of antipsychotic medications for schizophrenia. To characterize the nature of the problem, some presenters reported data from several recent trials that indicated higher rates of placebo response and lower rates of drug response (even to previously established, comparator drugs), when compared with earlier trials. As a means to identify the possible causes of the problem, discussions covered a range of methodological factors such as participant characteristics, trial designs, site characteristics, clinical setting (inpatient vs outpatient), inclusion/exclusion criteria, and diagnostic specificity. Finally, possible solutions were discussed, such as improving precision of participant selection criteria, improving assessment instruments and/or assessment methodology to increase reliability of outcome measures, innovative methods to encourage greater subject adherence and investigator involvement, improved rater training and accountability metrics at clinical sites to increase quality assurance, and advanced methods of pharmacokinetic/pharmacodynamic modeling to optimize dosing prior to initiating large phase 3 trials. The session closed with a roundtable discussion and recommendations for data sharing to further explore potential causes and viable solutions to be applied in future trials.

Impaired insight is common in schizophrenia and may be related to poor treatment adherence. Few studies have examined the clinical and neurocognitive correlates of insight in early schizophrenia. Early course schizophrenia, schizoaffective, and schizophreniform disorder patients (n=535) were studied. The Positive and Negative Symptom Scale (PANSS) was used to assess psychopathology, and a broad range of neuropsychological functions was assessed. Using hierarchical stepwise multiple regression analyses, we examined the association of clinical, neurocognitive, and premorbid measures with the level of insight. Impaired insight was associated with overall symptomatology, including positive, negative, and general psychopathology and with deficits in cognitive functioning. In descending order of robustness, the significant variables were PANSS general psychopathology (p

Maintenance medication is critical in the prevention of psychotic relapse and rehospitalization among patients with schizophrenia. Given potential adverse effects, identification of the minimum effective dose is clinically important.A multicenter, double-blind study was conducted to determine rates of symptomatic exacerbation and adverse effects in 105 outpatients with schizophrenia randomly assigned to four different fixed doses of haloperidol decanoate and treated for 1 year or until relapse. The doses used were 25, 50, 100, and 200 mg given intramuscularly once per month.Rates of symptomatic exacerbation were 15% in the 200-mg group, 23% with 100 mg, 25% with 50 mg, and 60% with 25 mg. No significant differences in outcome were found between the groups treated with 200, 100, and 50 mg. Among the patients who completed the trial with no symptomatic exacerbation, there were no differences between dose groups on measures of psychopathology at the final rating point.The results of this study suggest that the 200-mg/month dose of haloperidol decanoate is associated with the lowest rate of symptomatic exacerbation (15%) with minimal increased risk of adverse effects or subjective discomfort in comparison to 100 or 50 mg. At the same time, the rates of worsening with 100 mg (23%) and 50 mg (25%) were not significantly greater than that seen with 200 mg. These results provide some guidance as to effective dose ranges of haloperidol decanoate.