Formin Binding Protein 1 (FNBP1) regulates non-canonical Wnt signaling and vertebrate gastrulation (12 words).

The Formin protein Daam1 is required for Wnt-induced cytoskeletal changes during gastrulation, though how it accomplishes this remains unresolved. Here we report the characterization of Formin Binding Protein 1 (FNBP1) as a binding partner of Daam1. The interaction of Daam1 with FNBP1 and its domains required for this interaction were delineated. Immunofluorescence studies showed FNBP1 co-localizes with Daam1 and is an integral component of the actin cytoskeletal complex that is responsive to Wnt stimulation. Specifically, FNBP1 can induce intracellular tubule-like structures and localize to focal adhesions suggesting a role for FNBP1 in cell migration. Functional FNBP1 studies in Xenopus embryos uncover a critical role for FNBP1 in regulating vertebrate gastrulation. Additionally, suboptimal doses of Daam1 and FNBP1 synergize to produce severe gastrulation defects, indicating FNBP1 and Daam1 may function within the same signaling pathway. These results together show FNBP1 is an integral component of Daam1-regulated non-canonical Wnt signaling required for vertebrate gastrulation.

Real-world predictors of relapse in patients with schizophrenia and schizoaffective disorder in a large health system.

Schizophrenia is often characterized by recurring relapses, which are associated with a substantial clinical and economic burden. Early identification of individuals at the highest risk for relapse in real-world treatment settings could help improve outcomes and reduce healthcare costs. Prior work has identified a few consistent predictors of relapse in schizophrenia, however, studies to date have been limited to insurance claims data or small patient populations. Thus, this study used a large sample of health systems electronic health record (EHR) data to analyze relationships between patient-level factors and relapse and model a set of factors that can be used to identify the increased prevalence of relapse, a severe and preventable reality of schizophrenia. This retrospective, observational cohort study utilized EHR data extracted from the largest Midwestern U.S. non-profit healthcare system to identify predictors of relapse. The study included patients with a diagnosis of schizophrenia (ICD-10 F20) or schizoaffective disorder (ICD-10 F25) who were treated within the system between October 15, 2016, and December 31, 2021, and received care for at least 12 months. A relapse episode was defined as an emergency room or inpatient encounter with a pre-determined behavioral health-related ICD code. Patients' baseline characteristics, comorbidities and healthcare utilization were described. Modified log-Poisson regression (i.e. log Poisson regression with a robust variance estimation) analyses were utilized to estimate the prevalence of relapse across patient characteristics, comorbidities and healthcare utilization and to ultimately identify an adjusted model predicting relapse. Among the 8119 unique patients included in the study, 2478 (30.52%) experienced relapse and 5641 (69.48%) experienced no relapse. Patients were primarily male (54.72%), White Non-Hispanic or Latino (54.23%), with Medicare insurance (51.40%), and had baseline diagnoses of substance use (19.24%), overweight/obesity/weight gain (13.06%), extrapyramidal symptoms (48.00%), lipid metabolism disorder (30.66%), hypertension (26.85%), and diabetes (19.08%). Many differences in patient characteristics, baseline comorbidities, and utilization were revealed between patients who relapsed and patients who did not relapse. Through model building, the final adjusted model with all significant predictors of relapse included the following variables: insurance, age, race/ethnicity, substance use diagnosis, extrapyramidal symptoms, number of emergency room encounters, behavioral health inpatient encounters, prior relapses episodes, and long-acting injectable prescriptions written. Prevention of relapse is a priority in schizophrenia care. Challenges related to historical health record data have limited the knowledge of real-world predictors of relapse. This study offers a set of variables that could conceivably be used to construct algorithms or models to proactively monitor demographic, comorbidity, medication, and healthcare utilization parameters which place patients at risk for relapse and to modify approaches to care to avoid future relapse.

Ulotaront: review of preliminary evidence for the efficacy and safety of a TAAR1 agonist in schizophrenia.

Ulotaront is a trace amine-associated receptor 1 (TAAR1) agonist in Phase 3 clinical development for the treatment of schizophrenia. Ulotaront was discovered through a unique, target-agnostic approach optimized to identify drug candidates lacking D2 and 5-HT2A receptor antagonism, while demonstrating an antipsychotic-like phenotypic profile in vivo. The mechanism of action (MOA) of ulotaront is thought to be mediated by agonism at TAAR1 and serotonin 5-HT1A receptors. Ulotaront has completed two Phase 2 trials (4-week acute study and 26-week open-label extension) which led to Breakthrough Therapy Designation from the US Food and Drug Administration for the treatment of schizophrenia. In the double-blind, placebo-controlled, acute study, ulotaront was associated with significant (p < 0.001) improvement in Positive and Negative Syndrome Scale (PANSS) total score (effect size [ES]: 0.45), with improvements vs. placebo also observed across secondary endpoints. Post-hoc analyses of the acute trial revealed additional evidence to support the effect of ulotaront on negative symptoms. In the 4-week study, ulotaront was well-tolerated, with an incidence of adverse events (AEs) numerically lower compared to placebo (45.8% vs. 50.4%; with a number needed to harm [NNH] for individual ulotaront AEs all > 40). The open-label extension demonstrated further improvement across schizophrenia symptoms and confirmed the tolerability of ulotaront, with a 6-month completion rate of 67%. Based on current data, ulotaront shows potential to be a first-in-class TAAR1 agonist for the treatment of schizophrenia with a safety and efficacy profile distinct from current antipsychotics.

Challenges in the clinical development of non-D2 compounds for schizophrenia.

Schizophrenia is a chronic, heterogeneous, severe psychiatric disorder characterized by a spectrum of symptomology and is associated with substantial morbidity and mortality. For the last 70 years, available treatments have shared blockade of dopamine D2 receptors as their primary mechanism of action (MOA), the efficacy of which has been limited by incomplete resolution of all symptoms as well as treatment non-response in a select subset of patients. In addition, antipsychotics are associated with class-related side effects attributed to this primary MOA, including extrapyramidal symptoms (EPS). The need for non-D2 treatment options for patients which offer a novel risk/benefit profile is therefore apparent. There has been substantial investment in the research and development of non-D2 drug candidates. However, none of these programs have received successful regulatory approval by the FDA (as of Oct 2022). In this article, the scale of industry-sponsored clinical trials for D2-based investigational pharmacological treatments in schizophrenia was quantified and compared with investigational compounds with non-D2 MOAs. In a dataset of 545 clinical trials identified in ClinicalTrials.gov from January 2002 to July 2022, total enrollments in trials of non-D2-based compounds for the treatment of schizophrenia summed to approximately 34,000 patients, compared with 27,144 patients for D2-based compounds. These data indicate that there remains substantial and ongoing investment in the development of novel non-D2 options for schizophrenia, with a success rate measured by regulatory approval that is well-below recent benchmarks for the broader category of CNS drugs. Improved trial design, conduct, endpoints, and analyses/methods may influence signal detection and reliability to support development and registration of non-D2 compounds.

Depicting Risperidone Safety Profiles in Clinical Trials Across Different Diagnoses Using a Dopamine D2-Based Pharmacological Class Effect Query Defined by FAERS.

BACKGROUND AND OBJECTIVE: Current methods are not designed to relate the incidence of individual adverse events reported in clinical trials to the plurality of adverse events accumulated in spontaneous reporting databases during real-world use. We have previously reported on a pharmacological class-effect query of clinical trial data defined by a disproportionality analysis of the US Food and Drug Administration Adverse Event Reporting System (FAERS) post-marketing data. The aim of the current analysis was to apply a dopamine D2-based pharmacological class-effect query to clinical trial safety data of an atypical antipsychotic tested across different patient populations. METHODS: Patient-level adverse event data (n = 4400) from controlled clinical trials of the antipsychotic risperidone in schizophrenia, bipolar disorder, Alzheimer's disease psychosis, and autism were obtained through the Yale University Open Data Access (YODA) project. An Empirical Bayes Geometric Mean analysis was performed, and a three-fold threshold incidence level was applied to determine if a preferred term met criteria for being an antipsychotic class-related adverse event. RESULTS: In pooled data from seven trials of adult schizophrenia, class-specific adverse events were identified in 49% of patients treated with risperidone; in 49% of risperidone-treated patients in two trials in adolescent schizophrenia; in 65% of risperidone-treated patients in four trials in adult bipolar disorder; in 50% of risperidone-treated patients in two trials in adolescent schizophrenia; in 36% of risperidone-treated patients in one trial in Alzheimer's disease; and in 94% of risperidone-treated patients in one trial in autism. CONCLUSIONS: The cumulative curves of class-specific adverse events in risperidone clinical trials of schizophrenia were similar to those first reported for other atypical antipsychotic drugs. However, the class-specific adverse event curves were notably lower for Alzheimer's disease and higher for autism, suggesting that the diagnostic indication may have an important effect on the cumulative class-specific side-effect burden.

Therapeutic Potential of TAAR1 Agonists in Schizophrenia: Evidence from Preclinical Models and Clinical Studies.

Trace amine-associated receptor 1 (TAAR1) has emerged as a promising therapeutic target for neuropsychiatric disorders due to its ability to modulate monoaminergic and glutamatergic neurotransmission. In particular, agonist compounds have generated interest as potential treatments for schizophrenia and other psychoses due to TAAR1-mediated regulation of dopaminergic tone. Here, we review unmet needs in schizophrenia, the current state of knowledge in TAAR1 circuit biology and neuropharmacology, including preclinical behavioral, imaging, and cellular evidence in glutamatergic, dopaminergic and genetic models linked to the pathophysiology of psychotic, negative and cognitive symptoms. Clinical trial data for TAAR1 drug candidates are reviewed and contrasted with antipsychotics. The identification of endogenous TAAR1 ligands and subsequent development of small-molecule agonists has revealed antipsychotic-, anxiolytic-, and antidepressant-like properties, as well as pro-cognitive and REM-sleep suppressing effects of TAAR1 activation in rodents and non-human primates. Ulotaront, the first TAAR1 agonist to progress to randomized controlled clinical trials, has demonstrated efficacy in the treatment of schizophrenia, while another, ralmitaront, is currently being evaluated in clinical trials in schizophrenia. Coupled with the preclinical findings, this provides a rationale for further investigation and development of this new pharmacological class for the treatment of schizophrenia and other psychiatric disorders.

Efficacy and Safety of HP-3070, an Asenapine Transdermal System, in Patients With Schizophrenia: A Phase 3, Randomized, Placebo-Controlled Study.

OBJECTIVE: Asenapine is a second-generation antipsychotic used to treat individuals with schizophrenia. This phase 3 study assessed efficacy and safety of HP-3070, an asenapine transdermal system (patch), in adults with schizophrenia. METHODS: In this inpatient study, a 3- to 14-day screening/single-blind run-in washout period was followed by a 6-week double-blind period wherein patients with acutely exacerbated schizophrenia (DSM-5 criteria) were randomized 1:1:1 and received HP-3070 7.6 mg/24 h (n = 204), HP-3070 3.8 mg/24 h (n = 204), or placebo (n = 206). Primary endpoint was change from baseline (CFB) in week 6 Positive and Negative Syndrome Scale (PANSS) total score versus placebo; key secondary endpoint was CFB in week 6 Clinical Global Impression-Severity of Illness score versus placebo. Safety endpoints included treatment-emergent adverse events (TEAEs) and dermal assessments. RESULTS: Each of the HP-3070 doses demonstrated significant improvement versus placebo at week 6 for the primary and key secondary endpoints. Differences in the least-squares mean (LSM) (95% CI; adjusted P) of CFB for PANSS total scores were -4.8 (-8.06 to -1.64; adjusted P = .003) and -6.6 (-9.81 to -3.40; adjusted P < .001) for 7.6 mg/24 h and 3.8 mg/24 h, respectively. HP-3070 was well tolerated, with a systemic safety profile consistent with sublingual asenapine. Incidence of application site TEAEs was higher for HP-3070 (14.2%, 7.6 mg/24 h; 15.2%, 3.8 mg/24 h) versus placebo (4.4%). Discontinuations due to application site reactions or skin disorders (urticaria, pruritus) were infrequent (≤ 0.5% per treatment group). CONCLUSIONS: HP-3070 7.6 mg/24 h and 3.8 mg/24 h doses were efficacious and well tolerated. As the first transdermal antipsychotic patch available in the US, HP-3070 offers a novel treatment option for people with schizophrenia. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02876900; EudraCT number: 2015-005134-21.

Patches: Established and Emerging Transdermal Treatments in Psychiatry.

Transdermal delivery is an alternative to oral routes of drug administration and has made considerable contributions to the treatment of various medical diseases. With the advent of new transdermal delivery technologies, higher numbers of medications are being approved for use as transdermal formulations. This route of administration has several innate advantages that have the potential to benefit various patient populations, including those with central nervous system disorders. The current review briefly outlines the history of transdermal medications, discusses the advantages and disadvantages of transdermal formulations, and examines the challenges and opportunities present for the use of transdermal treatments in psychiatry. Patients with psychiatric illnesses have many unmet needs that may be filled through the benefits gained from transdermal treatments, such as reduced dosing frequency, effective control of plasma medication concentrations, improved tolerability, ability to check compliance visually, and avoidance of first-pass hepatic metabolism. Established transdermal treatments for various psychiatric diseases are discussed followed by an introduction to therapies that are being developed as the first patch formulations for the treatment of schizophrenia. Hypothetical schizophrenia patient profiles are also outlined to aid providers in considering how transdermal treatments for this disease may fill unmet needs for specific patients. The evidence demonstrating the potential benefits of transdermal treatments in psychiatry presented in the current review should both encourage health care providers to consider how patients may benefit from transdermal alternatives and promote future innovation in the area of transdermal drug delivery for psychiatric disorders.