Methods for Neuroscience Drug Development: Guidance on Standardization of the Process for Defining Clinical Outcome Strategies in Clinical Trials.

Neurosciences clinical trials continue to have notoriously high failure rates. Appropriate outcomes selection in early clinical trials is key to maximizing the likelihood of identifying new treatments in psychiatry and neurology. The field lacks good standards for designing outcome strategies, therefore The Outcomes Research Group was formed to develop and promote good practices in outcome selection. This article describes the first published guidance on the standardization of the process for clinical outcomes in neuroscience. A minimal step process is defined starting as early as possible, covering key activities for evidence generation in support of content validity, patient-centricity, validity requirements and considerations for regulatory acceptance. Feedback from expert members is provided, regarding the risks of shortening the process and examples supporting the recommended process are summarized. This methodology is now available to researchers in industry, academia or clinics aiming to implement consensus-based standard practices for clinical outcome selection, contributing to maximizing the efficiency of clinical research.

Ensuring Stakeholder Feedback in the Design and Conduct of Clinical Trials for Rare Diseases: ISCTM Position Paper of the Orphan Disease Working Group.

The 1983 Orphan Drug Act in the United States (US) changed the landscape for development of therapeutics for rare or orphan diseases, which collectively affect approximately 300 million people worldwide, half of whom are children. The act has undoubtedly accelerated drug development for orphan diseases, with over 6,400 orphan drug applications submitted to the US Food and Drug Administration (FDA) from 1983 to 2023, including 350 drugs approved for over 420 indications. Drug development in this population is a global and collaborative endeavor. This position paper of the International Society for Central Nervous System Clinical Trials and Methodology (ISCTM) describes some potential best practices for the involvement of key stakeholder feedback in the drug development process. Stakeholders include advocacy groups, patients and caregivers with lived experience, public and private research institutions (including academia and pharmaceutical companies), treating clinicians, and funders (including the government and independent foundations). The authors articulate the challenges of drug development in orphan diseases and propose methods to address them. Challenges range from the poor understanding of disease history to development of endpoints, targets, and clinical trials designs, to finding solutions to competing research priorities by involved parties.

The Extrapyramidal Symptom Rating Scale and Its Abbreviated Version: A Critical Review of Clinimetric Properties.

BACKGROUND: The Extrapyramidal Symptom Rating Scale - Abbreviated (ESRS-A) is an abbreviated version of the Extrapyramidal Symptom Rating Scale (ESRS) with instructions, definitions, and a semi-structured interview that follows clinimetric concepts of measuring clinical symptoms. Similar to the ESRS, the ESRS-A was developed to assess four types of drug-induced movement disorders (DIMD): parkinsonism, akathisia, dystonia, and tardive dyskinesia (TD). SUMMARY: The present review of the literature provides the most relevant clinimetric properties displayed by the ESRS and ESRS-A in clinical studies. Comprehensive ESRS-A definitions, official scale, and basic instructions are provided. ESRS inter-rater reliability was evaluated in two pivotal studies and in multicenter international studies. Inter-rater reliability was high for assessing both antipsychotic-induced movement disorders and idiopathic Parkinson's disease. Guidelines were also established for inter-rater reliability and the rater certification processes. The ESRS showed good concurrent validity with 96% agreement between Abnormal Involuntary Movement Scale (AIMS) for TD-defined cases and ESRS-defined cases. Similarly, concurrent validity for ESRS-A total and subscores for parkinsonism, akathisia, dystonia, and dyskinesia ranged from good to very good. The ESRS was particularly sensitive for detecting DIMD-related movement differences following treatment with placebo, antipsychotics, and antiparkinsonian and antidyskinetic medications. ESRS measurement of drug-induced extrapyramidal symptoms was shown to discriminate extrapyramidal symptoms from psychiatric symptoms. KEY MESSAGES: The ESRS and ESRS-A are valid clinimetric indices for measuring DIMD. They can be valuably implemented in clinical research, particularly in trials testing antipsychotic medications, and in clinics to detect the presence, severity, and response to treatment of movement disorders.

Earlier Use of Long-Acting Injectable Paliperidone Palmitate Versus Oral Antipsychotics in Patients With Schizophrenia: An Integrated Patient-Level Post Hoc Analysis.

Objective: To assess the efficacy and safety of paliperidone palmitate (PP) long-acting injectable antipsychotic (LAI) versus oral antipsychotic (OAP) treatment in adult patients diagnosed with schizophrenia (per DSM-IV or DSM-5 criteria) and varying duration of illness (0-3 years and > 3 years).Methods: Patient-level data from the PRIDE, PROSIPAL, and DREaM studies were included in a post hoc analysis. Efficacy and safety outcomes, including relapse assessments, Personal and Social Performance scale scores, Medication Satisfaction Questionnaire total scores, and treatment-emergent adverse events (TEAEs), were measured systematically. Treatment failure (TF) included relapses due to psychiatric hospitalizations, arrest or incarceration, suicidal or homicidal ideation or behavior, discontinuation due to inadequate efficacy and/or safety or tolerability, treatment supplementation due to inadequate efficacy, and significant worsening of symptoms.Results: Fewer TFs were observed with PP versus OAP in both the 0-3 years group (17.7% and 25.3%, respectively) and the > 3 years group (32.3% and 42.4%, respectively). Time to first TF was significantly longer with PP versus OAP treatment in both duration of illness groups. TEAE rates were similar between the PP and OAP groups, with no new safety signals identified.Conclusions: This post hoc analysis suggests that PP provides significant benefit in reducing TF or relapse compared with OAPs regardless of duration of illness and highlights the potential benefit of implementing PP earlier in the course of schizophrenia.Trial Registration: ClinicalTrials.gov identifiers NCT01157351 (PRIDE), NCT01081769 (PROSIPAL), and NCT02431702 (DREaM).

Feasibility study to evaluate capabilities for conducting psychiatric clinical research within the Rwandan mental healthcare system.

OBJECTIVE: To evaluate the feasibility of conducting a large clinical trial within the Rwandan mental healthcare system that would establish the safety, efficacy and benefit of paliperidone palmitate once-monthly (PP1M) and once-every-3-months (PP3M) long-acting injectable formulations in adults with schizophrenia. STUDY DESIGN: An open-label, prospective feasibility study. SETTING/PARTICIPANTS: 33 adult patients with schizophrenia were enrolled at 3 sites across Rwanda. INTERVENTIONS: The study design included 3 phases of treatment: an oral run-in to establish tolerability to risperidone (1 week), lead-in treatment with flexibly dosed PP1M to identify a stable dose (17 weeks) and maintenance treatment with PP3M (24 weeks). PRIMARY AND SECONDARY OUTCOME MEASURES: Feasibility endpoints included compliance with governmental and institutional requirements, acceptable supply chain delivery and proper onsite administration of risperidone/PP1M/PP3M, adequate site infrastructure, adequate training of clinical staff and successful completion of study procedures and scales. A variety of study scales were administered to assess outcomes relevant to patients, caregivers, clinicians and payers in Rwanda and other resource-limited settings. RESULTS: This study was terminated early by the sponsor because certain aspects of study conduct needed to be addressed to maintain Good Clinical Practice requirements and meet regulatory standards. Results identified areas for improvement in study execution, including study governance, site infrastructure, study preparation and conduct of procedures, study budget and study assessments. Despite the identification of areas in need of adjustment, none of these limitations were considered insurmountable. CONCLUSIONS: This work was designed to strengthen global research in schizophrenia by building the capacity of researchers to prepare and conduct pharmaceutical trials in resource-limited settings. Although the study was ended early, modifications motivated by the results will facilitate the successful design and completion of more comprehensive studies, including an ongoing, follow-up interventional trial of PP1M/PP3M in a larger population of patients in Rwanda. TRIAL REGISTRATION NUMBER: NCT03713658.

Dispersion of cognitive performance test scores on the MATRICS Consensus Cognitive Battery: A different perspective.

Objective: Persons with schizophrenia exhibit greater neurocognitive test score dispersion. Here, we seek to characterize dispersion on the Neurocognitive Composite subtests of the Measurement of Treatment Research to Improve Cognition in Schizophrena Consensus Cognitive Battery (MCCB) and determine the relative effects of different antipsychotic formulations on dispersion and mean performance. Method: In this post hoc analysis of the DREaM study (NCT02431702), which compared treatment with paliperidone palmitate (PP) long-acting injectable with oral antipsychotic (OAP) treatment over 18 months, dispersion in MCCB neurocognitive subtest performance was calculated for each participant by visit (test occasion). Results: Over 18 months, mean neurocognitive performance improved in a manner consistent with the expected effects of practice in both groups (p < 0.05); this improvement was observed during the first 9 months (PP: p < 0.05, OAP: p < 0.001), followed by stable performance over the second 9 months (PP: p = 0.821, OAP: p = 0.375). Rates of change did not differ between groups (treatment-by-visit interaction: p = 0.548). In contrast, analyses of dispersion focusing on contrasts between baselines and end points of the first and second 9 months revealed different patterns. Over the first 9 months, dispersion in both groups lessened to a similar extent. However, over the second 9 months, dispersion remained stable in the PP group, whereas neurocognitive performance became significantly more variable in the OAP group (p < 0.01). Conclusion: Dispersion of neurocognitive test scores provides a different index of cognitive change than that provided by composite scores. Long-term maintenance of therapeutic levels provided by PP over time may limit (relative to oral AP) the extent to which cognitive performance becomes more variable.

SIBAT-A Computerized Assessment Tool for Suicide Ideation and Behavior: Development and Psychometric Properties.

Objective: Most assessments of suicidal ideation and behavior (SIB) are limited by reliance on a single assessor, typically a clinician or patient, with scant detail on patient-related drivers of SIB and inability to detect rapid change in SIB. Furthermore, many techniques do not include a semistructured interview, increasing rater variability. The Suicide Ideation and Behavior Assessment Tool (SIBAT) addresses these limitations. Design: More than 30 experts in scale development, statistics, and clinical management of suicidal patients collaborated over a greater than four-year period to develop the SIBAT. Input for content and validity was received from patients, clinicians, and regulatory authorities in the United States (US) and Europe. Psychometric properties of the SIBAT were evaluated in validation studies. Results: The SIBAT is organized into eight independent patient- or clinician-rated modules with branching logic and scoring algorithms, which necessitates computerization. Patient-reported information is first captured in Modules 1 to 5. Thereafter, an experienced clinician reviews the patient's report, conducts a semistructured interview (Module 6), and assesses the patient's suicide risk (Module 7) and optimal antisuicide management (Module 8). Input from cognitive interviews of diverse adult, adolescent, and clinician participants was incorporated into the final version of the SIBAT. Psychometric testing demonstrated good inter-rater reliability (intraclass coefficient range: 0.68-0.82), intra-rater reliability (weighted-kappa range: 0.64-0.76), and concurrent validity with other instruments for assessing SIB. Conclusion: Patient- and clinician-based assessments and the psychometric studies summarized in this report support the validity and reliability of the SIBAT for capturing critical information related to assessment of SIB in adolescents and adults at risk for suicide.

Evaluation of major treatment failure in patients with recent-onset schizophrenia or schizophreniform disorder: A post hoc analysis from the Disease Recovery Evaluation and Modification (DREaM) study.

OBJECTIVE: A post hoc analysis of the Disease Recovery Evaluation and Modification (DREaM) study was conducted to evaluate time to first major treatment failure (ie, arrest/incarceration or psychiatric hospitalization) in participants with recent-onset schizophrenia or schizophreniform disorder treated with paliperidone palmitate (PP) versus oral antipsychotics (OAPs). METHODS: DREaM was an open-label, delayed-start, randomized, multipart trial consisting of: Part I, 2-month oral run-in; Part II, 9-month disease progression phase (PP or OAP); and Part III, 9 months of additional treatment (PP/PP; OAP re-randomized: OAP/OAP or OAP/PP). PP/PP and OAP/OAP comprised the 18-month extended disease progression (EDP) analysis. RESULTS: In Part II (PP, n = 78; OAP, n = 157), similar proportions of participants experienced a major treatment failure across groups (PP: 12.8 %; OAP: 13.4 %); no difference in time to first major treatment failure was identified (P = 0.918). Significant differences favoring PP emerged after 9 months; in Part III, no participants in the PP/PP group, 3.5 % of participants in the OAP/PP group, and 15.9 % in the OAP/OAP group experienced a major treatment failure (P = 0.002). In the EDP analysis, 10.2 % (PP/PP) and 25.4 % (OAP/OAP) of participants experienced a major treatment failure (P = 0.045; number needed to treat = 6). Safety results were similar between groups and consistent with the known safety profile of PP in adults with schizophrenia. CONCLUSIONS: Initiation of PP during the early stages of schizophrenia spectrum disorders significantly delayed time to hospitalization and arrest/incarceration, outcomes with important personal and economic consequences, compared with OAP during this 18-month study. CLINICALTRIALS: gov identifier: NCT02431702.

Using Artificial Intelligence-based Methods to Address the Placebo Response in Clinical Trials.

The placebo response is a highly complex psychosocial-biological phenomenon that has challenged drug development for decades, particularly in neurological and psychiatric disease. While decades of research have aimed to understand clinical trial factors that contribute to the placebo response, a comprehensive solution to manage the placebo response in drug development has yet to emerge. Advanced data analytic techniques, such as artificial intelligence (AI), might be needed to take the next leap forward in mitigating the negative consequences of high placebo-response rates. The objective of this review was to explore the use of techniques such as AI and the sub-discipline of machine learning (ML) to address placebo response in practical ways that can positively impact drug development. This examination focused on the critical factors that should be considered in applying AI and ML to the placebo response issue, examples of how these techniques can be used, and the regulatory considerations for integrating these approaches into clinical trials.

The Disease Recovery Evaluation and Modification (DREaM) study: Effectiveness of paliperidone palmitate versus oral antipsychotics in patients with recent-onset schizophrenia or schizophreniform disorder.

We report primary results of the Disease Recovery Evaluation and Modification (DREaM) study, a randomized, open-label, delayed-start trial designed to compare the effectiveness of paliperidone palmitate (PP) versus oral antipsychotics (OAP) in delaying time to first treatment failure (TtFTF) in participants with recent-onset schizophrenia or schizophreniform disorder. DREaM included: Part I, 2-month oral run-in; Part II, 9-month disease progression phase (PP or OAP); Part III, 9 months of additional treatment (PP/PP; OAP rerandomized: OAP/OAP or OAP/PP). PP/PP and OAP/OAP comprised the 18-month extended disease progression (EDP) analysis. A total of 235 participants were randomized to PP (n = 78) or OAP (n = 157) in Part II. No statistically significant differences in TF between treatment groups were identified during Part II (PP 29.5%, OAP 24.8%; P = 0.377), Part III (PP/PP 14.3%, OAP/PP 15.8%, OAP/OAP 28.6%; P = 0.067) or the EDP analysis (PP/PP 28.6%, OAP/OAP 44.4%; NNT = 6; P = 0.080). Using a modified definition of TF excluding treatment supplementation with another antipsychotic, a common approach to managing dose adjustments, significant differences were observed between treatment groups in Part III (PP/PP 4.1%, OAP/PP 14.0%, OAP/OAP 27.0%; P = 0.002) and EDP (PP/PP 14.3%, OAP/OAP 42.9%; P = 0.001). Safety results were consistent with the known safety profile of PP. Although significant treatment differences were not observed during the first 9 months of DREaM, numerical differences favoring PP emerged in the last 9 months and significant differences were observed when TF criteria were limited to their most impactful components. These results highlight the potential benefit of initiating PP early in the course of schizophrenia and provide valuable insights for future clinical trials in recent-onset schizophrenia or schizophreniform disorder. Clinicaltrials.gov identifier: NCT02431702.

The Health-Related Quality of Life, Work Productivity, Healthcare Resource Utilization, and Economic Burden Associated with Levels of Suicidal Ideation Among Patients Self-Reporting Moderately Severe or Severe Major Depressive Disorder in a National Survey.

BACKGROUND: Suicidal ideation (SI) is a cardinal aspect of major depressive disorder (MDD); however, patient-reported outcomes data from large-scale surveys are limited concerning SI in the context of MDD. This study aims to understand the association between varying levels of SI and health-related quality of life (HRQoL), work productivity, healthcare resource utilization (HRU), and associated costs in patients with moderately severe/severe MDD. METHODS: This was a retrospective, cross-sectional analysis of 2013 national survey data. Patients who self-reported moderately severe or severe MDD and completed the Short Form Survey Version 2 (SF-36v2), Work Productivity Loss and Activity Impairment questionnaire (WPAI), and questions related to HRU were analyzed. Direct and indirect costs were calculated. Patients were categorized and analyzed by the level of SI (no SI, low, moderate, and high) based on their response to Item 9 of the Patient Health Questionnaire-9. RESULTS: Among 75,000 respondents, 15.3% self-reported receiving a physician diagnosis of moderately severe or severe MDD and 2.8% of the total sample endorsed some level of SI. Patients with high SI showed a higher burden than patients with no SI, reporting lower mean SF-36v2 mental component summary scores (p<0.001), higher work productivity loss (p=0.039), and higher numbers of per patient per month hospitalizations (p=0.002) and emergency room visits (p=0.011). High SI was associated with greater per patient per month direct costs ($1220 vs $796; p=0.002) and indirect costs ($1449 vs $1058; p=0.001) compared with no SI. When patients with low or moderate SI were compared with patients with no SI, the results were mixed. CONCLUSION: Higher levels of SI were associated with lower HRQoL, greater HRU, and more work impairment resulting in higher direct and indirect costs compared with patients with MDD but no SI. These results highlight the need to implement effective treatment models and interventions in the employed population.

Clinically meaningful changes on depressive symptom measures and patient-reported outcomes in patients with treatment-resistant depression.

OBJECTIVE: To use the Clinical Global Impression-Severity (CGI-S) scale to estimate clinically meaningful and clinically substantial changes as measured using the Montgomery-Åsberg Depression Rating Scale (MADRS), the Sheehan Disability Scale (SDS), and the Patient Health Questionnaire-9 (PHQ-9) in patients with treatment-resistant depression (TRD). METHODS: Pooled data were derived from two 4-week, randomized, active-controlled studies evaluating esketamine nasal spray (ESK) plus oral antidepressant (OAD) or OAD plus placebo nasal spray (PBO) in adults with TRD (N = 565). CGI-S, MADRS, SDS, and PHQ-9 scores were obtained at baseline and over 4 weeks of treatment. In this post hoc analysis, change scores on the MADRS, SDS, and PHQ-9 that corresponded to a clinically meaningful (1-point) or clinically substantial (2-point) change on the CGI-S scale were identified. RESULTS: Clinically meaningful changes in CGI-S scores after 28 days corresponded to 6-, 4-, and 3-point changes from baseline on the MADRS, SDS, and PHQ-9, respectively. Similarly, a 2-point CGI-S score change (clinically substantial change) corresponded to a 12-, 8-, and 6-point change on the MADRS, SDS, and PHQ-9, respectively. The proportion of patients showing substantial clinical improvement in the ESK plus OAD group versus the OAD plus PBO group after 28 days of treatment favored ESK plus OAD: 69.0% vs 55.3% (MADRS), 64.5% vs 48.9% (SDS), and 77.1% vs 64.7% (PHQ-9). CONCLUSION: We provide a basis for identifying clinically meaningful and clinically substantial changes as assessed with commonly used outcome measures for depression to facilitate the translation of clinical trial results into clinical practice.

Suicide Ideation and Behavior Assessment Tool (SIBAT): Evaluation of Intra- and Inter-Rater Reliability, Validity, and Mapping to Columbia Classification Algorithm of Suicide Assessment.

The psychometric properties of the Suicide Ideation and Behavior Assessment Tool (SIBAT) were evaluated in 130 participants with varying levels of suicidality. Inter- and intra-rater reliability were assessed for clinician-rated outcomes, including the revised Clinical Global Impressions (CGI) of severity of suicidality (CGI-SS-r). Concurrent validity of patient-reported modules with Patient-reported Outcomes Measurement Information System (PROMIS) depression scale and Sheehan-Suicidality Tracking Scale Clinically Meaningful Change Measure (S-STS CMCM), and concordance between Columbia Classification Algorithm of Suicide Assessment (C-CASA) mappings for SIBAT, S-STS CMCM and Columbia-Suicide Severity Rating Scale (C-SSRS) were assessed. 52/130 participants (mean [SD] age: 38.3 [17.77] years) consented for multiple interviews (C-CASA mappings: n=52; rater-reliability: n=25/52). SIBAT demonstrated good intra-rater reliability (weighted-kappa range:0.64-0.76; CGI-SS-r, 0.75) and adequate inter-rater reliability (ICC range:0.68-0.82; CGI-SS-r, 0.81). There were strong correlations between PROMIS depression scores and SIBAT Module 5 ratings (Spearman correlations, r=0.64-0.74) and moderate correlations (r=0.29-0.72) between S-STS CMCM and SIBAT Modules 2, 3 and 5 ratings. Moderate agreement was noted between SIBAT C-CASA mappings and corresponding mappings from S-STS CMCM (weighted kappa: 0.54) and C-SSRS (weighted kappa: 0.56). Thus, the SIBAT provided valid assessment of suicidal ideation and behavior that could be reliably rated and adequately mapped to the C-CASA.

Descriptive analysis of the economic burden of treatment resistance in a major depressive episode.

Objectives: To assess characteristics and healthcare costs associated with pharmacologically treated episodes of treatment-resistant depression (TRD) in patients with major depressive disorder (MDD).Methods: Patients aged ≥18 years with continuous health plan enrollment for ≥12 months before and after a newly observed MDD diagnosis (observed between 1 January 2010 and 31 December 2015) were included in this retrospective claims-based analysis. A pharmacologically treated episode was defined as beginning at the date of the first MDD diagnosis and ending when a gap of 180 days occurred between MDD diagnoses, or when a gap of 180 days occurred following the end of the antidepressant (AD)/antipsychotic (AP) drug supply. When such a gap occurred, the episode end date was determined to be either the date of the last MDD diagnosis or date of the end of AD/AP drug supply, whichever was later. An episode was considered TRD if ≥3 AD regimens occurred. Episode duration, medication regimens used, and relapse hospitalization were reported for TRD and non-TRD MDD episodes. Total all-cause and per-patient-per-month (PPPM) healthcare costs (in 2016 $) were estimated.Results: Of 48,440 patients identified with ≥1 AD-treated MDD episode, the mean (SD) age was 39 (15) years, and 62% were female. Of all episodes, 7% were TRD, with a mean duration of 571 (285) days vs. 200 (198) days for non-TRD MDD episodes. Mean total all-cause costs were $19,626 ($44,160) for TRD and $7440 ($25,150) for non-TRD MDD episodes.Conclusions: Results show TRD episodes are longer and costlier than non-TRD MDD episodes, and that higher costs are driven by episode duration. Longer episodes imply protracted suffering for patients with TRD and increased burden on caregivers. Effective intervention to shorten TRD episodes may lessen disease burden and reduce costs.

An Evaluation of the Clinical and Economic Burden Among Older Adult Medicare-Covered Beneficiaries With Treatment-Resistant Depression.

OBJECTIVE: To compare the clinical and economic burden of treatment-resistant depression (TRD) among older adult patients with major depressive disorder (MDD) to non-TRD MDD and non-MDD patients. METHODS: Retrospective cohort study using 5% Medicare data (January 1, 2012-December 31, 2015) for MDD patients aged ≥65 years who were defined as TRD if they received ≥2 antidepressant treatments in the current episode. MDD patients not meeting TRD criteria were deemed non-TRD MDD; those without an MDD diagnosis were categorized as non-MDD. All were required to have continuous health plan enrollment for ≥6 months pre- and ≥12 months postindex date (index: first antidepressant claim/random [non-MDD]). Three cohorts were matched, and generalized linear and Cox proportional hazards models were used to compare medication use, healthcare resource utilization, costs, and risks of initial hospitalization and readmission ≤30 days postdischarge from initial hospitalization. RESULTS: After matching, 178 patients from each cohort were analyzed. During 12 months of follow-up, TRD patients had higher use of different antidepressants and antipsychotics, higher inpatient and emergency room visits, longer inpatient stays, and higher total healthcare costs ($24,543 versus $16,059, $8,058) than non-TRD MDD and non-MDD cohorts, respectively (all p <0.05). Risk of initial hospitalization was higher in the TRD (hazard ratio [HR] = 3.60, 95% confidence interval [CI] = 2.08-6.23) and non-TRD MDD cohorts (HR = 1.82, 95% CI = 1.02-3.25) than the non-MDD cohort. CONCLUSIONS: The burden of MDD among older adult Medicare beneficiaries is substantial, and even greater among those with TRD compared to non-TRD MDD, demonstrating the need for more effective treatments than those currently available.

Clinical utility of the Negative Symptom Assessment-16 in individuals with schizophrenia.

This study examined the clinical utility of the Negative Symptom Assessment-16 (NSA-16) in schizophrenia. 274 individuals with schizophrenia were assessed on the NSA-16, Positive and Negative Syndrome Scale (PANSS), Clinical Assessment for Negative Symptoms (CAINS), Calgary Depression Scale for Schizophrenia (CDSS), Social and Occupational Functioning Assessment Scale (SOFAS) and the Simpson-Angus Extrapyramidal Side Effects Scale (SAS). Factor analyses were conducted and Cronbach's alpha was computed. Correlations were assessed using Spearman's correlation coefficient. The 5-factor model of the NSA-16 did not give good fit statistics from our sample. Exploratory factor analysis on a randomly selected split-half of the sample followed by confirmatory factor analysis on the remaining sample supported a 4-factor structure with 12 items. The factors were: Restricted speech, Poor quality of speech, Affective blunting and Amotivation. The NSA-16 with the 12 items was termed as the NSA-12. The NSA-12 showed good internal reliability. The NSA-12 total score and global negative symptom rating had strong correlations with CAINS total and PANSS negative factor scores, suggesting good convergent validity. Weak correlations of the NSA-12 total score and global negative symptom rating with PANSS positive, CDSS and SAS scores suggested good divergent validity. The NSA-12 total score and global negative symptom rating were strongly and inversely associated with SOFAS and positively associated with NSA-12 global level of functioning. In conclusion, the NSA-12 is useful to evaluate negative symptoms in clinical and research settings in individuals with schizophrenia. Our study results also support a 4-factor structure of the NSA-12 in outpatients with schizophrenia.

An episode level evaluation of the treatment journey of patients with major depressive disorder and treatment-resistant depression.

BACKGROUND: Many patients with major depressive disorder (MDD) fail to respond to antidepressant (AD) pharmacotherapy. The objectives of this study were to characterize MDD and treatment-resistant depression (TRD) at the level of pharmacologically treated episodes and to describe the sequential treatment patterns by lines of therapy (LOT) in the first two episodes. METHODS: Adults (≥18 years of age) with continuous enrollment ≥12 months before and after the first MDD diagnosis and treated with an AD, with or without an MDD-indicated antipsychotic (AP), were identified (1/1/2010-12/31/2015). The MDD episode started on the date of MDD diagnosis that was preceded by a clean period without any MDD diagnosis. The MDD episode ended on the last MDD diagnosis or the end of the days' supply of AD/AP medication, whichever came last. TRD was defined as an MDD episode with ≥3 AD/AP regimens. Measured outcomes included episode duration, number of LOT, relapse hospitalization, and sequential treatment patterns of MDD episode stratified by TRD and non-TRD episodes. RESULTS: Of 48,440 patients who received AD/AP in the 1st MDD episode, 3,317 (6.8%) of episodes were considered TRD. Mean duration of 1st TRD episodes was 571 days, mean number of AD/AP LOTs was 3.47, and 13.7% involved relapse hospitalization. Mean duration of 1st non-TRD episodes was 200 days, mean number of AD/AP LOTs was 1.21, and 9.6% involved relapse hospitalization. Among 1st MDD episodes, 25.5% had a second LOT; 7.3% had a third LOT. Most patients received selective serotonin reuptake inhibitors (SSRIs) as the first LOT (63.0%), and the plurality of regimens were SSRIs in second (44.9%) and third LOT (41.1%). CONCLUSIONS: Compared to non-TRD episodes, TRD episodes were longer and more often involved relapse hospitalizations. SSRIs were the most common treatment; treatment changes and potential treatment unresponsiveness were frequent among MDD patients.

Application of Bayesian analyses to doubly randomized delayed start, matched control designs to demonstrate disease modification.

Disease modification is a primary therapeutic aim when developing treatments for most chronic progressive diseases. The best treatments do not simply affect disease symptoms but fundamentally improve disease course by slowing, halting, or reversing disease progression. One of many challenges for establishing disease modification relates to the identification of adequate analytic tools to show differences in a disease course following intervention. Traditional approaches rely on the comparisons of slopes or noninferiority margins. However, it has proven difficult to conclusively demonstrate disease modification using such approaches. To address these challenges, we propose a novel adaptation of the delayed start study design that incorporates posterior probabilities identified by hierarchical Bayesian inference approaches to establish evidence for disease modification. Our models compare the size of treatment differences at the end of the delayed start period with those at the end of the early start period. Simulations that compare several models are provided. These include general linear models, repeated measures models, spline models, and model averaging. Our work supports the superiority of model averaging for accurately characterizing complex data that arise in real world applications. This novel approach has been applied to the design of an ongoing, doubly randomized, matched control study that aims to show disease modification in young persons with schizophrenia (the Disease Recovery Evaluation and Modification (DREaM) study). The application of this Bayesian methodology to the DREaM study highlights the value of this approach and demonstrates many practical challenges that must be addressed when implementing this methodology in a real world trial.

Economic Burden of Treatment-Resistant Depression Among Patients Hospitalized for Major Depressive Disorder in the United States.

Objectives: This study aimed to evaluate hospital length of stay (LOS) and cost as well as readmission risk and the associated economic burden among patients hospitalized for treatment-resistant and non-treatment-resistant major depressive disorder. Methods: Adult patients with a primary hospital discharge diagnosis of major depressive disorder were identified from the Premier Hospital Database (January 1, 2012-September 30, 2015). Patients were stratified into two cohorts: those whose hospital treatment was suggestive of treatment-resistant depression and those with non-treatment-resistant depression. Hospital LOS and cost during the initial admission and readmissions rates, LOS, and cost within the 6-month follow-up were compared between cohorts with a propensity score-matched sample. Results: After matching, 45,066 patients were included in each cohort. For index hospitalizations, mean hospital LOS was longer (7.4 vs. 5.9 days, p<0.001) and mean hospital cost higher ($8,681 vs. $6,632, p<0.001) for patients with treatment-resistant depression vs. non-treatment-resistant depression. Rates for all-cause (24.4% vs. 20.0%, p<0.001), major depressive disorder-related (17.0% vs. 13.3%, p<0.001), and suicidal ideation/suicide attempt-related (12.8% vs. 9.5%, p<0.001) readmissions were higher for patients with treatment-resistant depression. Mean LOS and total hospital costs per patient for readmissions were also greater for patients with treatment-resistant depression vs. non-treatment-resistant depression. Correspondingly, the combined hospital cost (index hospitalization+all-cause readmissions) was greater for patients with treatment-resistant depression ($12,370 vs. $9,429, p<0.001). Conclusions: Treatment-resistant depression was associated with substantial economic burden among patients hospitalized for major depressive disorder. More-effective treatment and care for this patient population may reduce the hospital burden of patients with treatment-resistant depression.

Efficacy and Safety of Intranasal Esketamine for the Rapid Reduction of Symptoms of Depression and Suicidality in Patients at Imminent Risk for Suicide: Results of a Double-Blind, Randomized, Placebo-Controlled Study.

(Reprinted with permission from AmJ Psychiatry 2018; 175:620-630).