Does relapse cause illness progression in first-episode psychosis? A review.

BACKGROUND: It is widely believed that relapse in first-episode psychosis (FEP) causes illness progression, with previous reviews suggesting that treatment non-response develops in one in six patients who relapse. This belief contributes to the primary treatment goal in FEP being relapse-prevention, often in favor of other recovery-oriented goals. However, previous reviews primarily reported on naturalistic studies in chronic schizophrenia and predated multiple major studies with higher-quality designs. METHODS: We conducted a narrative review of studies of any design that examine the impact of relapse on medication response and other symptomatic and functional outcomes in FEP. RESULTS: We identified eight relevant studies, five of these published since the last major review on this topic. Observational studies show a clear association between relapses and worse response to medication, but poorly control for confounding. Three higher-quality studies (two randomized) generally do not find worse symptomatic or functional outcomes among medication reduction/discontinuation arms compared to maintenance controls, despite significantly higher initial rates of relapse. CONCLUSION: While the social and psychological consequences of a relapse should not be dismissed, clinicians should demand high-quality evidence about the risks of relapse on long-term outcomes. The conventional notion that relapse leads to treatment non-response or worse long-term outcomes is generally not supported by the highest quality studies. These findings can help clinicians and patients weigh the risks and benefits of competing treatment strategies in FEP.

Effects of PDE10A inhibitor MK-8189 in people with an acute episode of schizophrenia: A randomized proof-of-concept clinical trial.

BACKGROUND: PDE10A inhibition represents a potential mechanism for treating schizophrenia. PDE10A inhibitors increase cyclic nucleotides in striatal neurons, thereby mimicking the effects of dopamine receptor D2 antagonists and D1 agonists. We evaluated the PDE10A inhibitor MK-8189 for treating schizophrenia. METHODS: Randomized, double-blind, placebo and active-controlled, phase 2a, multicenter, inpatient trial in adults experiencing an acute episode of schizophrenia. Participants were randomized 2:2:1 to once-daily MK-8189 12 mg, placebo, or risperidone 6 mg (active control) for 4-weeks. The primary outcome was change-from-baseline in total score on the Positive and Negative Syndrome Scale (PANSS) at 4 weeks. RESULTS: The number of treated participants was 90 for MK-8189, 89 for placebo, and 45 for risperidone. MK-8189 demonstrated a trend towards improvement versus placebo for change-from-baseline in PANSS total score after 4 weeks (difference = -4.7 [95 % CI: -9.8,0.5], P = 0.074). The active control risperidone was superior to placebo on PANNS total score (difference = -7.3 [95 % CI: -14.0,-0.6], P = 0.033), demonstrating assay sensitivity, while MK-8189 and risperidone did not significantly differ (difference = 2.6 [95 % CI: -4.0,9.2], P = 0.440). MK-8189 had a nominally significant effect on PANSS positive subscale score compared to placebo (difference = -2.2 [95 % CI: -3.8,-0.5], P = 0.011). Discontinuation of MK-8189 treatment due to an adverse event was low (<10 %). Extrapyramidal symptoms occurred with MK-8189 but were mostly mild and transient. Compared with placebo, MK-8189 reduced body weight while risperidone increased weight. CONCLUSIONS: These findings suggest that PDE10A inhibition may produce antipsychotic effects and associated weight loss and that further trials with PDE10A inhibitors are warranted. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT03055338.

Sustained Treatment Response and Global Improvements With Long-term Valbenazine in Patients With Tardive Dyskinesia.

PURPOSE/BACKGROUND: Using data from KINECT® 4, a phase 3, 48-week study of valbenazine, post hoc analyses were conducted to assess long-term outcomes that are relevant to the real-world management of tardive dyskinesia (TD). METHODS/PROCEDURES: Post hoc analyses of the participants of the KINECT 4 study who completed 48 weeks of open-label valbenazine (40 or 80 mg) treatment were conducted. Valbenazine effects on TD were evaluated using the Abnormal Involuntary Movement Scale (AIMS), Clinical Global Impression of Change-TD (CGI-TD), and Patient Global Impression of Change (PGIC). FINDINGS/RESULTS: Of 103 participants completing 48 weeks of treatment, 55% experienced clinically meaningful improvement (defined as ≥2-point reduction in AIMS total score [sum of items 1 - 7, evaluated by site raters]) by week 4; at week 48, 97% met this threshold. The percentage of completers who achieved AIMS total score response thresholds of ≥10% to ≥90% increased over time, with 86% of completers reaching ≥50% improvement. Of the 40 (39%) completers with AIMS ≥50% response at week 8, 38 (95%) sustained this response at week 48; 81% of those who did not meet this threshold at week 8 had achieved it by week 48. At week 48, more than 85% of completers achieved CGI-TD and PGIC ratings of "much improved" or "very much improved." IMPLICATIONS/CONCLUSIONS: The majority of participants who completed 48 weeks of treatment with once-daily valbenazine experienced substantial clinically meaningful and sustained TD improvements. These findings indicate that valbenazine can be a highly effective long-term treatment in patients with TD.

Implementation of Cognitive Behavioral Therapy for psychosis via telehealth: An expert consultation and clinical service model.

Individuals living with psychosis are often underserved in the United States, partly due to the dearth of providers trained in evidence-based practices for this population. One such practice is Cognitive Behavioral Therapy for psychosis, which the Substance Abuse and Mental Health Services Administration has identified as a standard of care for this population. The explosion of telehealth, in large part due to the COVID-19 pandemic, has led to increased opportunities for virtual psychotherapy. Telehealth offers a number of benefits, such as the ability to address service inequities, including lack of access to a local provider well-trained in the modality of therapy needed. The current article describes the National Psychosis Telehealth Program within the National Expert Consultation and Specialized Services (formerly VA National Telemental Health Center) program, U.S. Department of Veterans Affairs. The goal of this telehealth program is to utilize an expert consultation model and offer a remote individual, time-limited Cognitive Behavioral Therapy for psychosis protocol to Veterans across the nation in order to decrease access disparities to this relatively scarce service. We share our initiation activities and lessons learned as we developed this program in hopes of encouraging others to consider similar efforts at their sites. We also include a typical, complex case that serves to illustrate the challenges and benefits of this approach. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Relapse in clinically stable adult patients with schizophrenia or schizoaffective disorder: evidence-based criteria derived by equipercentile linking and diagnostic test accuracy meta-analysis.

BACKGROUND: There is no consensus on defining relapse in schizophrenia, and scale-derived criteria with unclear clinical relevance are widely used. We aimed to develop an evidence-based scale-derived set of criteria to define relapse in patients with schizophrenia or schizoaffective disorder. METHODS: We searched the Yale University Open Data Access (YODA) for randomised controlled trials (RCTs) in clinically stable adults with schizophrenia or schizoaffective disorder, and obtained individual participant data on Positive and Negative Syndrome Scale (PANSS), Clinical Global Impression Severity (CGI-S), Personal and Social Performance (PSP), and Social and Occupational Functioning Assessment Scale (SOFAS). Our main outcomes were PANSS-derived criteria based on worsening in PANSS total score. We examined their relevance using equipercentile linking with CGI-S and functioning scales, and their test-performance in defining relapse with diagnostic test accuracy meta-analysis against CGI-S worsening (≥1-point increase together with a score ≥4 points) and psychiatric hospitalisation. FINDINGS: Based on data from seven RCTs (2354 participants; 1348 men [57·3%] and 1006 women [42·7%], mean age of 39·5 years [SD 12·0, range 17-89]; 303 Asian [12.9%], 255 Black [10.8%], 1665 White [70.7%], and other or unspecified 131 [5.6%]), an increase of 12 points or more in PANSS total (range 30-210 points) corresponded to clinically important deterioration in global severity of illness (≥1 point increase in CGI-S, range 1-7) and functioning (≥10 points decline in PSP or SOFAS, range 1-100). The interpretation of percentage changes varied importantly across different baseline scores. An increase of 12 points or more in PANSS total had good sensitivity and specificity using CGI-S as reference standard (sensitivity 82·1% [95% CI 77·1-86·4], specificity 86·9% [82·9-90·3]), as well as good sensitivity but lower specificity compared to hospitalisation (sensitivity 81·7% [74·1-87·7], specificity 69·2% [60·5-76·9]). Requiring either an increase in PANSS total or in specific items for positive and disorganization symptoms further improved test-performance. Cutoffs for situations where high sensitivity or specificity is needed are presented. INTERPRETATION: An increase of either 12 points or more in the PANSS total score, or worsening of specific positive and disorganisation symptom items could be a reasonable evidence-based definition of relapse in schizophrenia, potentially linking symptoms used to define remission and relapse. Percentage changes should not be used to define relapse because their interpretation depends on baseline scores. FUNDING: German Research Foundation (grant number: 428509362).

Negative symptoms in schizophrenia: Newly emerging measurements, pathways, and treatments.

The negative symptoms of schizophrenia, which often appear earlier than any other symptom, are prominent and clinically relevant in the majority of patients. As a result, interest in their treatment has increased. Patients who exhibit significant negative symptoms have worse functional outcomes than those without, resulting in impairments in occupational, household, and recreational functioning, as well as difficulties in relationships. Yet treatment with currently available medications does not lead to any significant improvements in this core component of schizophrenia. An increased understanding of the pathophysiology underlying negative symptoms and the discovery of novel treatments that do not directly target dopamine offer the potential to develop therapies that may reduce negative symptoms and increase quality of life for patients. The current article will discuss the impact of negative symptoms, outline current measurement tools for the assessment of negative symptoms, and examine how these measures may be improved. Insights into the neural circuitry underlying negative symptoms will be discussed, and promising targets for the development of effective treatments for these symptoms will be identified. As more prospective, large-scale, randomized studies focus on the effects of treatments on negative symptoms, progress in this area is foreseeable. However, improvements in clinical assessment instruments, a better understanding of the underlying neural mechanisms, development of novel treatments with varied targets, and a greater focus on personalized treatment are all important to produce significant benefits for patients with negative symptoms of schizophrenia.

Psychosis among individuals with methamphetamine use disorder is associated with elevated rates of hospitalizations and emergency department visits across an academic health care system.

INTRODUCTION: Methamphetamine (MA) is increasingly available in the United States and manufactured with increasing potency. Although psychosis is a known harm related to MA use, we know little about the clinical outcomes and prognosis of individuals who use MA and experience psychosis. Some evidence exists that psychosis among people who use methamphetamine leads to a high utilization of emergency and acute inpatient services, but the extent of this use is unclear. METHODS: Using an electronic health record (EHR) database, this study assessed acute care visits of individuals receiving diagnostic codes of the following disorders: methamphetamine use disorder with undifferentiated psychosis (MUDp), schizophrenia (MUDs) and no history of psychosis (MUD) in addition to individuals without MUD diagnosis but with diagnoses of either undifferentiated psychosis (Psy) or schizophrenia (Scz) from 2006 to 2019. The study explored potential clinical risk factors associated with rate of acute care visits. RESULTS: Receiving diagnoses of psychotic disorders and MUD were both associated with high rates of acute care utilization. The incidence rate ratio (IRR) was highest in the MUDp group 6.30 (95% CI: 5.73, 6.93) followed by the MUDs group 4.03 (95% CI: 3.87, 4.20), the Psy group 3.77 (95% CI: 3.45, 4.11), the Scz group 3.11 (95% CI: 2.99, 3.23), and the MUD group 2.17 (95% CI: 2.09, 2.25). Receiving another SUD diagnosis was identified as a risk factor for acute care visits in the MUDp group, and mood and anxiety disorder diagnoses were a risk factor in the MUDs group. CONCLUSIONS: In a general health care system, individuals receiving diagnoses of MUD and co-occurring psychotic disorders were observed to have particularly high rates of acute care service utilization, suggesting a high degree of disease burden and the need for development of targeted treatment interventions with both MUD and psychosis.

Remote Assessment of Negative Symptoms of Schizophrenia.

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.

N-Acetylcysteine effects on glutathione and glutamate in schizophrenia: A preliminary MRS study.

N-acetylcysteine (NAC) is a commonly used antioxidant that may have beneficial effects for schizophrenia. In this double-blind, randomized, placebo-controlled preliminary study, 40 patients with schizophrenia or schizoaffective disorder were randomized to receive 2400 mg NAC daily or placebo over eight weeks to examine the effects of NAC on prefrontal magnetic resonance spectroscopy levels of glutathione and glutamate. Secondary outcomes included negative symptoms, cognition, and plasma glutathione levels. We found that NAC treatment was associated with increased glutathione (statistically significant) and decreased glutamate (trend-level) compared with placebo in medial prefrontal cortex but not dorsolateral prefrontal cortex. We also observed a baseline association between medial prefrontal cortex levels of glutathione and plasma reduced / oxidized glutathione ratios. No treatment effects on symptoms or cognition were observed. Taken together, these findings indicate that treatment with N-acetylcysteine may increase medial prefrontal cortical levels of glutathione after eight weeks of treatment. These changes in cortical levels of glutathione may serve as an early biomarker of later clinical change and may underlie the cognitive and symptomatic improvements reported in longer-term treatment studies.

Comparative risks of all-cause mortality for Veterans with schizophrenia with ongoing receipt of clozapine and other antipsychotic medications.

To guide care for patients with schizophrenia, the Veterans Health Administration (VHA) evaluated the associations between current or recent use of clozapine and all-cause mortality and explored associations for other antipsychotic medications. Using a case-control design, patients with schizophrenia who died in fiscal years 2014-2018 were matched on age, sex, race, and VHA facility to up to 10 controls who were alive on the case's date of death (index date). Medication coverage during the 91 days before the index date was classified as none, partial (1-44 days), and consistent (45-91 days). Medication coverage patterns during the index period were compared to coverage patterns during the period of 92-182 days prior to index date with each medication coverage classified as no change, no coverage, increased, or decreased. Conditional logistic regression analyses controlling for patient characteristics identified no associations of consistent or increasing clozapine coverage with mortality; partial and decreasing coverage were associated with greater mortality and these effects did not differ from those of other the medications considered. Exploratory analyses considering non-clozapine antipsychotic agents suggest that consistent coverage by olanzapine may be associated with increased mortality, that mortality associated with olanzapine may be greater than aripiprazole, and that this effect can be attributed primarily to patients with diabetes. Further study of this topic is needed.

Examining racial differences in community integration between black and white homeless veterans.

Black Americans are overrepresented in Veteran and non-Veteran homeless populations. Community integration remains a problem for many Veterans after they obtain housing, and Black Veterans may encounter additional difficulties due to systemic racism. However, no prior study has specifically examined whether there are racial differences in community integration; similarly, no study has considered racial differences in psychosocial correlates of community integration in homeless Veterans. Knowledge of these factors could inform the development of culturally congruent rehabilitative interventions for Black Veterans. Semi-structured clinical interviews were administered to Black (N = 99) and White (N = 49) homeless Veterans to examine relations among psychiatric symptoms, motivation, and community integration domains (e.g., social integration, work productivity, and independent living). There were no significant racial differences in independent living or work productivity. Black Veterans had better social integration with family compared to White Veterans. In addition, psychiatric symptoms were more strongly correlated with social integration for Black than White Veterans. The association between motivation and work productivity was also stronger for Black Veterans. Recovery-oriented interventions could harness family connections and better target psychiatric symptoms to improve community integration for Black Veterans. Work productivity may improve from interventions aimed at enhancing motivation for Black Veterans.

Motivational and cognitive factors linked to community integration in homeless veterans: study 1 - individuals with psychotic disorders.

BACKGROUND: Little is known about the determinants of community integration (i.e. recovery) for individuals with a history of homelessness, yet such information is essential to develop targeted interventions. METHODS: We recruited homeless Veterans with a history of psychotic disorders and evaluated four domains of correlates of community integration: perception, non-social cognition, social cognition, and motivation. Baseline assessments occurred after participants were engaged in supported housing services but before they received housing, and again after 12 months. Ninety-five homeless Veterans with a history of psychosis were assessed at baseline and 53 returned after 12 months. We examined both cross-sectional and longitudinal relationships with 12-month community integration. RESULTS: The strongest longitudinal association was between a baseline motivational measure and social integration at 12 months. We also observed cross-sectional associations at baseline between motivational measures and community integration, including social, work, and independent living. Cross-lagged panel analyses did not suggest causal associations for the motivational measures. Correlations with perception and non-social cognition were weak. One social cognition measure showed a significant longitudinal correlation with independent living at 12 months that was significant for cross-lagged analysis, consistent with a causal relationship and potential treatment target. CONCLUSIONS: The relatively selective associations for motivational measures differ from what is typically seen in psychosis, in which all domains are associated with community integration. These findings are presented along with a partner paper (Study 2) to compare findings from this study to an independent sample without a history of psychotic disorders to evaluate the consistency in findings regarding community integration across projects.

Assessment of Negative Symptoms in Clinical Trials of Acute Schizophrenia: Test of a Novel Enrichment Strategy.

Drug trials for negative symptoms in schizophrenia select patients based on the severity and stability of negative symptoms, using criteria that are not suitable for trials of acute exacerbation of schizophrenia. Here we present a method to prognostically enrich subjects having a predefined factor structure in PANSS and apply it to the measurement of negative symptoms specifically in trials of acute schizophrenia. A vector of 1335 elements based on between- and within-item variances, covariances, and differences of PANSS items was created to calculate an index of heterogeneity and to enrich for a predetermined symptom construct in PANSS. Using prerandomization PANSS scores across N = 4876 subjects in 13 trials of acute schizophrenia, we demonstrate an ability to select for a subpopulation having the greatest amount of variance explained across the 7-items of the Marder PANSS negative symptom (MPNS) construct. Network analyses on subjects enriched for MPNS construct confirm that negative symptoms were most influential in overall psychopathology, distinct from subjects without the MPNS construct. As expected for D2 antagonists, drug-placebo differences on negative symptoms with lurasidone were not specific to the subpopulation having the MPNS construct. In contrast, the novel TAAR1 agonist ulotaront demonstrated specific improvements in negative symptoms which were greatest in the MPNS subpopulation. These results demonstrate the utility of a novel prognostic enrichment strategy that can address heterogeneity in clinical trials, where patients can be selected on the basis of a greater likelihood of having the measured symptom construct (negative symptoms) related to the disorder (schizophrenia). ClinicalTrials.gov Identifiers: NCT0296938, NCT00088634, NCT00549718, NCT00615433, NCT00790192.

Effects of Brexpiprazole Across Symptom Domains in Patients With Schizophrenia: Post Hoc Analysis of Short- and Long-Term Studies.

The successful treatment of schizophrenia entails improvement across a spectrum of symptoms. The aim of this post hoc analysis was to characterize the short- and long-term effects of brexpiprazole on Positive and Negative Syndrome Scale (PANSS) 'Marder factors.' Data were included from three 6-week, randomized, double-blind, placebo-controlled studies; a 52-week, randomized, double-blind, placebo-controlled maintenance treatment study; and two 52-week open-label extension (OLEx) studies-all in schizophrenia (DSM-IV-TR criteria). Patients receiving oral brexpiprazole were dosed at 2-4 mg/day (short-term studies) or 1-4 mg/day (long-term studies). At Week 6, least squares mean differences (LSMDs, with 95% confidence limits [CLs]) for brexpiprazole (n = 868) vs placebo (n = 517) were: Positive symptoms: -1.55 (-2.30, -0.80), P < .0001, Cohen's d effect size (ES) = 0.27; Negative symptoms: -1.12 (-1.63, -0.61), P < .0001, ES = 0.29; Disorganized thought: -1.26 (-1.78, -0.74), P < .0001, ES = 0.32; Uncontrolled hostility/excitement: -0.76 (-1.15, -0.37), P = .0002, ES = 0.26; Anxiety/ depression: -0.56 (-0.91, -0.22), P = .0014, ES = 0.22. At last visit of the maintenance study, LSMDs (95% CLs) for brexpiprazole (n = 96) vs placebo (n = 104) were: Positive symptoms: -3.44 (-4.99, -1.89), P < .0001, ES = 0.62; Negative symptoms: -1.23 (-2.52, 0.07), P = .063, ES = 0.27; Disorganized thought: -1.69 (-2.81, -0.56), P = .0035, ES = 0.42; Uncontrolled hostility/excitement: -1.26 (-2.12, -0.39), P = .0046, ES = 0.41; Anxiety/depression: -0.72 (-1.47, 0.03), P = .061, ES = 0.27. In the OLEx studies, improvements were maintained over 58 (6 + 52) weeks of brexpiprazole treatment. In conclusion, these data suggest that brexpiprazole treats the continuum of schizophrenia symptoms, in the short- and long-term. Trial Registration: Data used in this post hoc analysis came from ClinicalTrials.gov identifiers: NCT01396421, NCT01393613, NCT01810380, NCT01668797, NCT01397786, NCT01810783.

PANSS Individual Item and Marder Dimension Analyses From a Pivotal Trial of RBP-7000 (Monthly Extended-Release Risperidone) in Schizophrenia Patients.

Background: Positive and Negative Syndrome Scale (PANSS) data from a pivotal phase 3 study in participants with schizophrenia of RBP-7000, a recently marketed long-acting subcutaneous injectable risperidone formulation, were examined to determine if dose-response relationships existed for different items of the PANSS.Methods: Changes in the 30 PANSS items were analyzed individually and using the 5 factor-analysis-derived dimensions defined by Marder and colleagues. Subgroups of patients who could benefit from the RBP-7000 120 mg dose were investigated.Results: 337 participants were randomized and received study medication (RBP-7000 90 mg n = 111, RBP-7000 120 mg n = 114, placebo n = 112). Dose-dependent responses were observed in items from the study-specified PANSS positive and general psychopathology exploratory subscales. Dose-dependent responses were observed across all 5 Marder dimensions, with the largest effect sizes observed with the 120 mg dose in the uncontrolled hostility/excitement (UHE) and anxiety/depression dimensions. Participants with baseline UHE dimension scores ≥ 9 demonstrated greater improvement in PANSS total score at the 120 mg dose compared to the 90 mg dose.Conclusions: RBP-7000 demonstrated efficacy across both the primary and exploratory PANSS study endpoints and the post hoc Marder dimensions. Schizophrenia patients with higher baseline Marder UHE scores may benefit from initiation of treatment at the 120 mg dose.Trial Registration: ClinicalTrials.gov identifier: NCT02109562.