Exacerbation Of Schizophrenia Research Articles

Comparing the latent state-trait structure of the PANSS in cariprazine-medicated and placebo-controlled patients with acute schizophrenia.

After over a hundred years of research, the question whether the symptoms of schizophrenia are rather trait-like (being a relatively stable quality of individuals) or state-like (being substance to change) is still unanswered. To assess the trait and the state component in patients with acute schizophrenia, one group receiving antipsychotic treatment, the other not. Data from four phase II/III, 6-week, randomized, double-blind, placebo-controlled trials of similar design that included patients with acute exacerbation of schizophrenia were pooled. In every trial, one treatment group received a third-generation antipsychotic, cariprazine, and the other group placebo. To assess symptoms of schizophrenia, the Positive and Negative Symptom Scale (PANSS) was applied. Further analyses were conducted using the five subscales as proposed by Wallwork and colleagues. A latent state-trait (LST) model was developed to estimate the trait and state components of the total variance of the observed scores. All symptom dimensions behaved more in a trait-like manner. The proportions of all sources of variability changed over the course of the observational period, with a bent around weeks 3 and 4. Visually inspected, no major differences were found between the two treatment groups regarding the LST structure of symptom dimensions. This high proportion of inter-individual stability may represent an inherent part of symptomatology that behaves independently from treatment status.

The relationship between hot temperatures and hospital admissions for psychosis in adults diagnosed with schizophrenia: A case-crossover study in Quebec, Canada

IntroductionSome studies have found hot temperatures to be associated with exacerbations of schizophrenia, namely psychoses. As climate changes faster in Northern countries, our understanding of the association between temperature and hospital admissions (HA) for psychosis needs to be deepened. Objectives1) Among adults diagnosed with schizophrenia, measure the relationship between mean temperatures and HAs for psychosis during summer. 2) Determine the influence of individual and ecological characteristics on this relationship. MethodsA cohort of adults diagnosed with schizophrenia (n = 30,649) was assembled using Quebec's Integrated Chronic Disease Surveillance System (QICDSS). The follow-up spanned summers from 2001 to 2019, using hospital data from the QICDSS and meteorological data from the National Aeronautics and Space Administration's (NASA) Daymet database. In four geographic regions of the province of Quebec, a conditional logistic regression was used for the case-crossover analysis of the relationship between mean temperatures (at lags up to 6 days) and HAs for psychosis using a distributed lag non-linear model (DLNM). The analyses were adjusted for relative humidity, stratified according to individual (age, sex, and comorbidities) and ecological (material and social deprivation index and exposure to green space) factors, and then pooled through a meta-regression. ResultsThe statistical analyses revealed a statistically significant increase in HAs three days (lag 3) after elevated mean temperatures corresponding to the 90th percentile relative to a minimum morbidity temperature (MMT) (OR 1.040; 95% CI 1.008–1.074), while the cumulative effect over six days was not statistically significant (OR 1.052; 95% IC 0.993–1.114). Stratified analyses revealed non statistically significant gradients of increasing HAs relative to increasing material deprivation and decreasing green space levels. ConclusionsThe statistical analyses conducted in this project showed the pattern of admissions for psychosis after hot days. This finding could be useful to better plan health services in a rapidly changing climate.

Guideline for the use of therapeutic drug monitoring of antipsychotics to individualize the selection of therapy in the treatment of exacerbation of schizophrenia

Significant individual variability in the concentration of antipsychotics (AP) and its impact on both the efficacy and safety of therapy has been shown in many studies. In this regard, the use of therapeutic drug monitoring (TDM) of AP seems to be a clinically relevant method for the individualization of psychopharmacotherapy in the treatment of exacerbations of schizophrenia. The purpose of this work was to develop recommendations on the use of TDM AP for the individualization of therapy for exacerbation of schizophrenia. Materials and methods. To develop recommendations, a literature search was performed on the Medline, Google Scolar and Elibrary databases and the materials of the dissertation of Potanin S.S. "The role of therapeutic drug monitoring of antipsychotics in the individualization of therapy for exacerbations of paroxysmal-progredient schizophrenia" were used. Results. The conducted literature search made it possible to classify AP according to the degree of expediency of TDM, to determine the optimal therapeutic concentrations for each drug, indications for TDM, and to develop a structured decision-making algorithm depending on the results obtained. The main indications for TDM AP in the treatment of exacerbation of schizophrenia are signs of impaired drug compliance, insufficient efficacy of therapy, pronounced dose-dependent side effects, and the addition of concomitant therapy that can significantly affect the concentration of AP. According to the results obtained, TDM is strongly recommended for clozapine, olanzapine and amisulpride, recommended for risperidone, paliperidone, aripiprazole, quetiapine, haloperidol, ziprasidone, perphenazine, sertindole, trifluoperazine, sulpiride and chlorpromazine, for other antipsychotics TDM may be useful in selected cases. A detailed decision-making algorithm is presented in the form of a table and is based on both the clinical situation and the results of TDM AP. Conclusion. Thus, TDM AP seems to be one of the most relevant and potentially close to the introduction into everyday practice methods of individualization of therapy for exacerbation of schizophrenia.

Thiol-disulphide Homeostasis in Patients with Schizophrenia: The Potential Biomarkers of Oxidative Stress in Acute Exacerbation of Schizophrenia.

: Recent evidence suggests that oxidative stress contributes to the pathophysiology of schizophrenia. This study aimed to compare thiol-disulphide homeostasis in acute and stable phases of schizophrenia for the first time. : Among the patients with schizophrenia, 61 in the acute-phase and 61 in the stable phase of their illness were enrolled in the study. Native thiol (NT), total thiol (TT), disulphide (SS), disulphide/native thiol, disulphide/total thiol, and native thiol/total thiol for thiol-disulphide homeostasis were compared between the groups. The Brief Psychiatric Rating Scale (BPRS), Scale for the Assessment of Positive/Negative Symptoms (SAPS/SANS), Clinical Global Impression-Severity Scale (CGI-S), Barnes Akathisia Rating Scale, and Simpson-Angus Scale were used to assess symptoms. : After controlling for age, sex, body mass index, and smoking status there were significant differences in NT, TT, SS/NT, SS/TT, and NT/TT, but not SS. Thiol/disulphide homeostasis has shifted in favour of the oxidative side in patients with acute-phase compared to that in stable schizophrenia. BPRS, SAPS, and CGI-S scores were significantly correlated with all six thiol-disulphide parameters, but not SANS, when controlling for age and sex. Significant receiver operating characteristic (ROC) curves were obtained for all thiol-disulphide homeostasis parameters. Discriminant analysis was found to be statistically significant in discriminating between groups. : These results show that oxidative status increases thiol-disulphide homeostasis in patients with acute-phase schizophrenia compared to those with stable schizophrenia. These findings suggest that thiol-disulphide parameters can be used as biomarkers for the acute exacerbation of schizophrenia.

Antipsychotic dose, dopamine D2 receptor occupancy and extrapyramidal side-effects: a systematic review and dose-response meta-analysis.

Antipsychotic drugs differ in their propensity to cause extrapyramidal side-effects (EPS), but their dose-effects are unclear. Therefore, we conducted a systematic review and dose-response meta-analysis. We searched multiple electronic databases up to 20.02.2023 for fixed-dose studies investigating 16 second-generation antipsychotics and haloperidol (all formulations and administration routes) in adults with acute exacerbations of schizophrenia. The primary outcome was the number of participants receiving antiparkinsonian medication, and if not available, the number of participants with extrapyramidal side-effects (EPS) and the mean scores of EPS rating scales were used as proxies. The effect-size was odds ratio (ORs) compared with placebo. One-stage random-effects dose-response meta-analyses with restricted cubic splines were conducted to estimate the dose-response curves. We also examined the relationship between dopamine D2 receptor (D2R) occupancy and ORs by estimating occupancies from administrated doses. We included data from 110 studies with 382 dose arms (37193 participants). Most studies were short-term with median duration of 6 weeks (range 3-26 weeks). Almost all antipsychotics were associated with dose-dependent EPS with varied degrees and the maximum ORs ranged from OR = 1.57 95%CI [0.97, 2.56] for aripiprazole to OR = 7.56 95%CI [3.16, 18.08] for haloperidol at 30 mg/d. Exceptions were quetiapine and sertindole with negligible risks across all doses. There was very low quality of findings for cariprazine, iloperidone, and zotepine, and no data for clozapine. The D2R occupancy curves showed that the risk increased substantially when D2R occupancy exceeded 75-85%, except for D2R partial agonists that had smaller ORs albeit high D2R occupancies. In conclusion, we found that the risk of EPS increases with rising doses and differs substantially in magnitude among antipsychotics, yet exceptions were quetiapine and sertindole with negligible risks. Our data provided additional insights into the current D2R therapeutic window for EPS.

Effects of low-dose combined olanzapine and sertraline on negative and depressive symptoms in treatment-resistant outpatients with acute exacerbated schizophrenia.

Background: Treatment-resistant schizophrenia (TRS) is a major clinical challenge. Current antipsychotic medications do not adequately address negative and depressive symptoms in patients with TRS, and novel treatments are thus needed. This study examines the efficacy of low-dose combined olanzapine (OLA) and sertraline on depressive and negative symptoms in patients with TRS. Methods: A total of 34 TRS outpatients with acutely exacerbated schizophrenia were randomly assigned to OLA monotherapy (12.5-20mg/day) (control group) or low-dose combined OLA (7.5-10mg/day) and sertraline (50-100mg/day) (OS group). Clinical symptoms were assessed using the Positive and Negative Syndrome Scale (PANSS) at baseline and at the end of treatment in weeks 4, 8, 12, and 24. Depressive symptoms and social functioning were also assessed. Results: Compared to the control group, the OS group showed significant improvements in depressive and negative symptoms over time. In addition, the low-dose combination of OLA and sertraline significantly improved social functioning compared with OLA monotherapy. There were no significant between-group differences in psychotic symptom improvement. However, the reduction in Hamilton Depression Rating Scale total score and PANSS negative subscore were not associated with improvements in social functioning, suggesting that these effects of combined treatment are independent. Conclusion: Low-dose combined OLA and sertraline may be effective in the treatment of negative and depressive symptoms compared with standard OLA monotherapy in patients with TRS who are experiencing an acute exacerbation of schizophrenia. Clinical Trial Registration: [ClinicalTrials.gov], identifier [NCT04076371].

Review of the Trace Amine-Associated Receptor 1 (TAAR1) Agonist Ulotaront: Part II—Summary of Initial Clinical Efficacy/Safety Results

AbstractIntroductionUlotaront is a trace amine-associated receptor 1 (TAAR1) agonist with serotonin 5-HT1A agonist activity that has received FDA Breakthrough Therapy Designation for the treatment of schizophrenia. Here we summarize ongoing clinical research characterizing the efficacy and safety of ulotaront as a member of the novel trace amine-associated receptor 1 (TAAR1) agonist class.MethodsSummarized are results from a double-blind, placebo-controlled study to evaluate the efficacy and safety of ulotaront (50 mg or 75 mg) in an acute exacerbation of schizophrenia, and a 6-month, open-label follow-up study. Also summarized are post-hoc analyses evaluating negative symptom efficacy, and key safety and adverse event (AE) outcomes.ResultsIn the short-term study, treatment with ulotaront was associated with significant (p<0.001) endpoint improvement in the PANSS total score (effect size [ES]: 0.45), the CGI-Severity score (ES: 0.52) and the Brief Negative Symptom Scale total score (ES: 0.48). The incidence of any AE was lower on ulotaront versus placebo (45.8% vs. 50.4%), and the number needed to harm (NNH) for individual AEs on ulotaront were all >40. Ulotaront was associated with lower risk for antipsychotic class-related AEs (extrapyramidal symptoms, akathisia, somnolence, nausea/vomiting, increased weight/metabolic labs, prolactinemia). The 6-month study demonstrated further improvement, with a completion rate (67%) that was higher than reported for current dopamine D2 antipsychotics.ConclusionsThe emerging profile of ulotaront is characterized by significant improvement in positive and negative symptoms of schizophrenia. The safety and tolerability profile of ulotaront is markedly different with respect to antipsychotic class-related AEs. The benefit-risk profile of ulotaront, as a member of a novel TAAR1 agonist class, is distinguished from antipsychotics by lack of AEs related to D2 and serotonin 5-HT2A receptor blockade.FundingSunovion Pharmaceuticals, Inc., and Otsuka Pharmaceutical Development & Commercialization, Inc.

Factor Analysis Investigating the Efficacy of HP-3070 Transdermal System in Positive and Negative Syndrome Scale Five Adults With Schizophrenia

AbstractIntroductionHP-3070, a once-daily asenapine transdermal system, is FDA-approved for adults with schizophrenia. In a pivotal phase 3 randomized controlled study, patients with schizophrenia who were treated once daily with HP-3070 demonstrated significant improvement in Positive and Negative Syndrome Scale (PANSS) total scores compared with placebo. The PANSS score’s five-factor structure can also assess treatment efficacy across different domains. This post-hoc analysis of the pivotal study evaluated the efficacy of HP-3070 by examining these domains.MethodsIn the pivotal phase 3 study, adults with acute exacerbations of schizophrenia were randomized to 6 weeks of treatment with HP-3070 3.8mg/24h, 7.6mg/24h, or placebo. Factor analysis of PANSS scores was performed using five domains (negative symptoms, positive symptoms, disorganized thought, uncontrolled hostility/excitement, anxiety/depression). Mixed-model repeated-measures (MMRM) analysis included change from baseline in PANSS factor score as the repeated dependent variable, with country, treatment, visit, treatment by visit interaction, and baseline PANSS score as covariates.ResultsThe analysis included 607 patients. Least-squares mean estimates (standard error) of the difference from placebo in change from baseline to Week 6 for each factor were as follows: negative symptoms, 3.8mg/24h, -0.9 (0.43), P=0.045, and 7.6mg/24h, -0.4 (0.43), P=0.41; positive symptoms, 3.8mg/24h, -2.3 (0.57), P<0.001, and 7.6mg/24h, -2.0 (0.57), P<0.001; disorganized thought, 3.8mg/24h, -1.5 (0.38), P<0.001, and 7.6mg/24h, -0.9 (0.38), P=0.03; uncontrolled hostility/excitement: 3.8mg/24h, -1.1 (0.30), P<0.001, and 7.6mg/24h -0.9 (0.30), P=0.002; anxiety/depression, 3.8mg/24h, -0.5 (0.31), P=0.14, and 7.6mg/24h, -0.6 (0.31), P=0.07.ConclusionsHP-3070 demonstrated treatment effects on a PANSS five-factor model, with the results indicating impact on negative symptoms, positive symptoms, disorganized thought, uncontrolled hostility/excitement, and anxiety/depression. These findings suggest that HP-3070 may address a broad range of symptoms in schizophrenia.FundingNoven Pharmaceuticals, Inc., a wholly-owned subsidiary of Hisamitsu Pharmaceutical, Co.

Does short-term antipsychotic discontinuation of up to 3 weeks worsen symptoms in acute schizophrenia? A pooled analysis of placebo washout data.

This study aimed to examine symptom changes during short-term discontinuation of antipsychotics up to 3 weeks including the placebo washout phase in acute schizophrenia. The data from three double-blind, randomized, controlled trials comparing lurasidone versus placebo in patients with acute exacerbation of schizophrenia were analyzed. Symptom severity was assessed using the Positive and Negative Syndrome Scale (PANSS) total and the Clinical Global Impression-Severity scale (CGI-S) scores. The scores before and after the antipsychotic discontinuation phase were compared, and factors associated with score changes were explored. Among 2154 patients participating in the trials, 600 who received antipsychotic monotherapy and completed the antipsychotic discontinuation phase were included in the analysis. No patients received clozapine. The mean duration of the discontinuation phase was 5.9 ± 2.5 days. The PANSS total and CGI-S scores significantly changed from 94.0 ± 9.5 to 95.4 ± 10.5 (P < 0.001) and from 4.9 ± 0.6 to 4.9 ± 0.7 (P=0.041), respectively, during this phase; however, the absolute difference was minimal. The score changes were not associated with the type or dose of prior antipsychotics, or the duration or strategy (abrupt vs gradual) of antipsychotic discontinuation. Symptoms may not worsen to a clinically meaningful degree after short-term discontinuation of non-clozapine antipsychotics up to 3 weeks in patients with acute exacerbation of schizophrenia, suggesting that antipsychotic efficacy persists at least several days after discontinuation. This finding supports once-daily dosing regimen of antipsychotics and abrupt antipsychotic discontinuation when switching to another antipsychotic.

Changes in inflammatory parameters and their impact on clinical symptoms in patients suffering from schizophrenia

IntroductionOne of the factors influencing the symptoms of schizophrenia, which may indicate changes in the cognitive functioning of patients, is the fluctuating level of inflammatory cytokines.ObjectivesThe aim of the review was to analyze the available literature on the importance of selected inflammatory factors [interleukin-1β (IL-1β), interleukin-6 (IL-6), interleukin-8 (IL-8), interleukin-10 (IL-10), of tumor necrosis α (TNF-α)] in schizophrenia and the assessment of the impact of changes in cytokine levels on the occurrence of schizophrenia symptoms.MethodsFor this purpose, available scientific publications from following databases: PubMed, Scopus, Google Scholar were used to prove that the levels of selected inflammatory parameters changed in people suffering from schizophrenia. Moreover, fluctuations in cytokine concentrations influenced the occurrence of negative symptoms of schizophrenia, including cognitive disorders, as well as psychotic symptoms.ResultsAn increase in the concentration of IL-1β in the cerebrospinal fluid of patients with the first episode of schizophrenia has been described, which may indicate the involvement of the cytokine in the inflammatory process involving the CNS. The increased level of IL-6 is associated with the occurrence of psychotic disorders, it is also noted in stressful conditions. IL-6 is qualified as an indicator of exacerbation of schizophrenia, which normalizes after antipsychotic treatment. In the blood of patients with paranoid schizophrenia, elevated levels of IL-8 and IL-6 were detected compared to healthy individuals, which indicates the development of an inflammatory process in schizophrenia. The relationship between the level of IL-8 in women in the second trimester of pregnancy and the risk of developing schizophrenia spectrum disorder in children has been proven. Untreated patients with acute psychotic symptoms showed an increase in the level of TNF-α in the blood serum (compared to healthy subjects). An increase in the level of TNF-α in the blood serum of patients with an acute relapse of schizophrenia or the first episode of psychosis was also demonstrated. In conclusion, the relationship of IL-6 and TNF-α with the occurrence of psychotic disorders, the relationship of IL-1β with the appearance of changes in mood, behavior, including cognitive dysfunction, the relationship of IL-8 with the risk of developing schizophrenia spectrum disorder in children, the relationship of reduced concentrations of IL-10 with the intensification of negative symptoms, including cognitive deficits.ConclusionsIn conclusion, the analysis showed that patients with schizophrenia fluctuate in the concentration of inflammatory cytokines, which affects the occurrence of clinical symptoms.Disclosure of InterestNone Declared

Effects of lurasidone on hostility in patients with an acute exacerbation of schizophrenia: a pooled analysis of short-term studies

Effects of lurasidone on hostility in patients with an acute exacerbation of schizophrenia: a pooled analysis of short-term studies

Blood Viscosity and Inflammation in First-Episode and Acute Exacerbations of Schizophrenia: A Case-Control Study with Healthy Controls.

Elevated proinflammatory status and alterations in blood flow, both of which are associated with the pathophysiology of schizophrenia, may be linked with an increased risk of cardiovascular diseases. However, such a relationship at different acute stages of schizophrenia has not been evaluated. We aimed to examine whether blood viscosity and systemic inflammatory status varied between first-episode schizophrenia (FES) and acute exacerbations of schizophrenia. Fifty-two patients with FES, 69 schizophrenia patients with acute exacerbation (S-AE) and 56 healthy controls (HC) were included in the study. Whole blood viscosity (WBV) was calculated according to de Simone's formula at low and high shear rates (LSR and HSR). Systemic immune-inflammation index (SII) and systemic inflammatory response index (SIRI) were calculated from hemogram screening data at admission. When adjusted for age, WBV at both LSR and HSR were significantly decreased in both FES and S-AE groups compared to HCs. Systemic inflammatory response index was significantly higher in FES patients than in the S-AE and HC groups. Total cholesterol (TC) and WBV at HSR were correlated in patients. Total cholesterol predicted WBV at LSR in patients with FES whereas other independent variables including age and SIRI did not. Both first and subsequent episodes of schizophrenia are associated with reduced blood viscosity. Increased inflammatory status may not fully explain such a relationship. Extrapolation of hemorheological characteristics in schizophrenia may help to stratify cardiovascular risk and reflect the pathophysiological process in the early and later stages of schizophrenia.

Ulotaront: a TAAR1/5-HT1A agonist in clinical development for the treatment of schizophrenia

ABSTRACT Introduction Current antipsychotics are postsynaptic dopamine-2(D2) receptor blockers, which often, but not always, effectively improve acute psychotic symptoms and prevent relapse in schizophrenia and other severe mental disorders, but are associated with various side effects, including parkinsonism, akathisia, sedation/somnolence, and cardiometabolic alterations. Furthermore, the efficacy of current antipsychotics for negative and cognitive symptoms in schizophrenia is limited. Ulotaront is a novel trace-amine-associated receptor-1(TAAR1) agonist with serotonin-1A receptor agonist activity, and without postsynaptic D2-receptor antagonism. Phase 2 clinical data for ulotaront in patients with acutely exacerbated schizophrenia are promising regarding the potential improvement in positive, negative, and depressive symptoms. Areas covered An overview of the pharmacokinetic and pharmacodynamic properties of ulotaront is given. Summary of clinical efficacy and safety/tolerability from Phase 1/2-trials, and of ongoing Phase 3-trials, is also given. Expert opinion Ulotaront is a promising agent for the treatment of schizophrenia with an apparent benign safety profile, which might provide a much-needed new and different treatment option for various domains of schizophrenia. Data from larger Phase 3-trials, including for relapse prevention, schizophrenia subdomains, and in adolescents, are awaited. If ongoing Phase 3-trials in adults are successful, further research on combination regimens with existing antipsychotics, and in treatment-resistant schizophrenia as well as in mood disorders would be desirable.

Effectiveness of Lurasidone 80 mg in Patients with Schizophrenia: Results of an Open-Label, 12-Week Extension Study.

To evaluate the effectiveness and safety of lurasidone 80 mg/day (versus the 40 mg/day dose) during a 12-week, open-label extension study in patients with an acute exacerbation of schizophrenia who had completed a 6-week double-blind study of lurasidone. A total of 289 adult patients with schizophrenia completed the double-blind study and enrolled in the 12-week extension study. Lurasidone was flexibly dosed at 40 or 80 mg/day. Effectiveness measures included the Positive and Negative Syndrome Scale (PANSS) subscale scores, Clinical Global Impression-Severity Scale (CGI-S), and Calgary Depression Scale for Schizophrenia (CDSS), analyzed based on last observation carried forward (LOCF-endpoint). Safety/tolerability assessments included adverse events, body weight, laboratory tests, and discontinuation due to adverse events. Mean endpoint change was greater for lurasidone in modal doses of 80 mg/d (N=136) vs 40 mg/d (N=153) on the PANSS positive subscale (-3.0 vs -2.3), PANSS negative subscale (-1.9 vs -1.7), PANSS General Psychopathology subscale (-5.1 vs -3.8), the CGI-S score (-0.5 vs -0.4), and the CDSS score (-0.7 vs -0.1). Discontinuation rates due to adverse events on lurasidone modal 80 mg/d vs 40 mg/d were 4.4% vs 7.2%; and the most common adverse events in the modal 80 mg/d group were nasopharyngitis, 7.4% (vs 4.6% on modal 40 mg/d), constipation, 5.9% (vs 2.0%), and headache, 5.9% (vs 2.0%). In patients with acute schizophrenia treated with lurasidone 40 mg/d, increasing the dose to 80 mg/d was well tolerated, and was associated with greater improvement in PANSS subscale scores compared to continued treatment with a dose of 40 mg/d.

Clinical Effectiveness of Lurasidone Monotherapy in Patients with Acute Episodes of Schizophrenia and Associated Symptoms of Depression

AIM: We endeavored to evaluate the efficacy of Lurasidone at doses of 40160 mg per day on symptoms of schizophrenia associated with symptoms of depression in real clinical practice in a Russian patient population.&#x0D; METHODS: One hundred sixty eight patients aged 1865 years old, who at the time of the start of the observation were being treated in a hospital or day hospital due to an exacerbation of paranoid schizophrenia accompanied by symptoms of depression, were prescribed lurasidone. Treatment with lurasidone and other concomitant drugs, their prescription, withdrawal, selection, and dose modifications were determined based on the indications for the use of those drugs and the recommended doses in the instructions, clinical need, and patient interests, rather than by the goals of the study. During the observation period, the severity of depressive symptoms according to the Calgary Depression Scale (CDSS) and that of psychotic symptoms according to the Positive and Negative Syndrome Scale (PANSS) were assessed six times (before the start of treatment and then on the 4th, 7th, 14th, 28th, and 42nd days).&#x0D; RESULTS: A statistically significant reduction in the severity of the symptoms was observed with the use of lurasidone in doses ranging from 40 mg to 160 mg per day. The fastest and most significant (p 0.001) reductions in the total PANSS and CDSS scores were observed with lurasidone 120 mg. A somewhat lower efficacy of lurasidone was observed at a dose of 160 mg. The largest reductions in the total PANSS and CDSS scores with lurasidone 120 mg were associated with the highest survival rate and the longest median time from treatment initiation to discontinuation or follow-up. The most commonly reported side effects with lurasidone in this study (nausea, akathisia, tremor and drowsiness) were consistent with the known safety profile of the drug. Adverse events in most cases were assessed as mild, or occasionally moderate.&#x0D; CONCLUSION: A six-week prospective observational study of the real-world clinical effectiveness of lurasidone in doses ranging from 40 mg to 160 mg per day established statistically and clinically significant improvements in both psychotic and depressive symptoms in patients with acute exacerbation of schizophrenia and associated symptoms of depression.

Distal sacral nerve roots severed by a fragility fracture of the sacrum: a case report

BackgroundOwing to the aging population, fragility fractures of the pelvis are occurring more frequently. Fixation of the fracture and stabilization of the pelvic ring usually provide good clinical results. A case of distal sacral nerve roots severed by a fragility fracture of the sacrum is presented.Case presentationA 62-year-old Japanese woman with schizophrenia with low back pain, gait disorder, dysuria, and fecal incontinence presented to an emergency department, and plain X-rays showed no findings. She also complained of dysuria, and neurogenic bladder and cystitis were diagnosed. One month later, she was admitted to a psychiatric hospital for exacerbation of schizophrenia. In hospital, she had a urethral catheter inserted and spent 3 months in bed. She was referred to our orthopedic department because a gait disorder was discovered after her mental condition improved and she was permitted to walk. On examination, she could not walk and had decreased sensation from the buttocks to both posterior thighs and around the anus and perineum. Manual muscle testing of her lower limbs showed mild weakness of about 4 in bilateral flexor hallucis longus and gastrocnemius, and bilateral Achilles tendon reflexes were lost. Her anal sphincter did not contract, and urinary retention continued after urethral catheter removal. Imaging examinations showed an H-shaped sacral fracture consisting of a transverse fracture with displacement of the third sacral vertebra and vertical fractures of the bilateral sacral wings, with severe stenosis of the spinal canal at the site of the transverse fracture. The patient was diagnosed as having bladder and rectal dysfunction due to a displaced, unstable sacral fracture. First to third sacral laminectomy and alar–iliac fixation using percutaneous pedicle screws and sacral alar–iliac screws were then performed. The bilateral distal sacral nerve roots (S3, S4, S5) were completely severed at the second to third sacral levels, but bilateral second sacral nerve roots were not compressed from the bifurcation to the sacral foramen. Postoperatively, bladder and rectal dysfunction remained, but the low back pain was alleviated. Two weeks postoperatively, she could walk with a walker and was discharged. Three months after the operation, bone fusion of the fracture was observed.ConclusionsIn cases of bladder–rectal dysfunction with low back pain, the possibility of sacral fracture should be considered, and computed tomography, magnetic resonance imaging, and X-ray examinations should be performed. Even sacral fractures without displacement require attention because they can cause serious injury in the event of a nerve root being severed if not diagnosed early and given appropriate treatment.

Trace Amine-Associated Receptor 1 Agonists for Schizophrenia

TAAR1 agonists are an emerging drug class in the treatment of schizophrenia as they may offer a novel mechanism of action for symptom management without blocking dopamine D2 receptors, unlike currently available antipsychotic medications that act primarily via D2 binding. Two TAAR1 agonists are currently in clinical development for schizophrenia. The first is ulotaront, a TAAR1 full agonist with 5-hydroxytryptamine 1A agonist activity that is administered orally once daily, and the other is ralmitaront, a TAAR1 partial agonist that is also administered orally once daily. The published clinical trial evidence on TAAR1 agonists currently only pertains to ulotaront, which includes a 4-week, phase II, placebo-controlled randomized trial on patients with acute exacerbation of schizophrenia and a 26-week, open-label extension study of this same trial. These studies demonstrated improvements across disease-specific and global impression scales following treatment with ulotaront, with statistically significant differences compared to placebo, and no increased risk of the side effects (extrapyramidal symptoms and metabolic changes) associated with traditional D2-binding antipsychotic therapies. There is currently no cost information available for TAAR1 agonists. Ulotaront is currently undergoing phase III trials and, though it is not currently approved in any country and the date of Health Canada licensing and marketing in Canada is not yet known, it is expected to be the first TAAR1 agonist for schizophrenia in the Canadian market. Ulotaront received Breakthrough Therapy designation from the FDA in 2019 to expedite its development and the drug’s manufacturer is planning to file a New Drug Application with the FDA in 2023. Ralmitaront is currently in phase II trials, which are expected to be completed in 2023.

The efficacy of cariprazine in chronic schizophrenia – post hoc analyses of phase II/III clinical trials

IntroductionChronic schizophrenia patients are experiencing persistent and severe illness for more than 15-20 years and are usually suffering from long-term negative symptoms. Cariprazine, a novel D3-D2 partial agonist has been proven to be effective in the treatment of acute schizophrenia, however its ability to treat chronic patients has not been assessed yet.ObjectivesThe primary aim of the present post-hoc analysis is to assess the efficacy of cariprazine in treating patients with chronic schizophrenia (late-stage and residual schizophrenia patients).MethodsData from 3 phase II/III 6-week, randomized, double-blind, placebo-controlled trials with similar design in patients with acute exacerbation of schizophrenia were pooled and patients with more than 15 years of schizophrenia were analysed (late-stage patients). Furthermore, schizophrenia patients experiencing predominantly negative symptoms from a 26-week, randomized, double-blind, active-controlled, fixed-flexible-dose trial with an ICD-10 code of F20.5 were analysed post-hoc (residual patients).ResultsAltogether, 414 late stage (286 cariprazine and 128 placebo) and 35 residual (23 cariprazine and 12 risperidone) patients were identified. The pooled analysis evaluating mean change from baseline to week 6 in the PANSS total score indicated statistically significant difference in favour of cariprazine in the late stage (LSMD -6.7, p&lt;0.01) subpopulation compared to placebo. The mean change from baseline in patients with residual schizophrenia in the cariprazine arm was -9.6 on the PANSS-FSNS scale, while -7.9 in the risperidone arm.ConclusionsBased on the results, it seems that cariprazine might be a good treatment option for patients with chronic schizophrenia. Nonetheless, further studies are needed to confirm this.DisclosureI am an employee of Gedeon Richter Plc.

A Smartphone-Based Intervention as an Adjunct to Standard-of-Care Treatment for Schizophrenia: Randomized Controlled Trial.

BackgroundAntipsychotic medications have limited benefits in schizophrenia, and cognitive behavioral therapy may be beneficial as an adjunct. There may be potential for implementing mobile cognitive behavioral therapy–based treatment for schizophrenia in addition to standard antipsychotic medications.ObjectiveThis study aims to determine whether PEAR-004, a smartphone-based investigational digital therapeutic, improves the symptoms of an acute psychotic exacerbation of schizophrenia when it is added to standard treatments.MethodsThis was a 12-week, multicenter, randomized, sham-controlled, rater-blinded, parallel group proof‑of‑concept study of 112 participants with moderate acute psychotic exacerbation in schizophrenia. This study was conducted in 6 clinical trial research sites in the United States from December 2018 to September 2019. The primary outcome, change in Positive and Negative Syndrome Scale (PANSS) from baseline to week 12 or the last available visit, was analyzed using the mixed-effects regression model for repeated measures, applied to an intent-to-treat sample.ResultsThe total PANSS scores slightly decreased from baseline over the study period in both groups; the treatment difference at day 85 between PEAR-004 and sham was 2.7 points, in favor of the sham (2-sided P=.09). The secondary scales found no benefit, except for transient improvement in depressive symptoms with PEAR-004. Application engagement was good, and patient and clinical investigator satisfaction was high. No safety concerns were observed. There was some evidence of study site heterogeneity for the onboarding processes and directions on PEAR-004 product use at baseline and throughout the study. However, these differences did not affect the efficacy results.ConclusionsIn the largest-to-date randomized, sham-controlled study of a digital therapeutic in schizophrenia, PEAR-004 did not demonstrate an effect on the primary outcome—total PANSS scores—when compared with a nonspecific digital sham control. The secondary and exploratory results also did not demonstrate any notable benefits, except for possible temporary improvement in depressive symptoms. This study provided many useful scientific and operational insights that can be used in the further clinical development of PEAR-004 and other investigational digital therapeutics.Trial RegistrationClinicalTrials.gov NCT03751280; https://clinicaltrials.gov/ct2/show/NCT03751280

Emerging Treatments in Schizophrenia.

Although antipsychotics have been available for almost 70 years and greatly improved outcomes for individuals with schizophrenia, all currently available options derive their efficacy from blockade of dopaminergic receptors. However, this mechanism of action leaves many symptoms unresolved and is associated with a significant side effect burden. The mechanisms underlying schizophrenia, which were initially thought to be related to excessive presynaptic dopamine in specific areas of the brain, are now understood to be much more complex and involve structural and molecular changes throughout brain circuits. Consequently, drug discovery efforts have sought new targets in the search for safer and more effective medications that can improve symptoms of schizophrenia and psychosis, including trace amine-associated receptors (TAARs), muscarinic receptors, and serotonergic receptors. Positive phase 2 trial results indicating efficacy and safety of the TAAR1 agonist ulotaront (SEP-363856) and of the muscarinic M1/M4 agonist KarXT (xanomeline plus trospium) for total, positive, and negative symptoms in patients with acute exacerbation of schizophrenia, and of the serotonin 5-HT2A agonist/antagonist pimavanserin in patients with schizophrenia and predominant negative symptoms for negative symptom control are encouraging. Taken together, these data indicate in the context of ongoing phase 3 trial programs that patients with schizophrenia may soon have access to the first non-D2 blocking medication, which could drastically change the treatment landscape and improve outcomes for many of the individuals with schizophrenia who do not fully respond to or cannot tolerate currently available antipsychotic agents that currently all act via postsynaptic dopamine D2 receptor blockade.