Positive And Negative Syndrome Scale Negative Subscale Scores Research Articles

Statins as an adjuvant therapy for patients with schizophrenia: An up-to-date systematic review and meta-analysis

BackgroundEvidence suggests that inflammatory processes play a role in the pathophysiology of schizophrenia. Statins exert anti-inflammatory and antioxidant effects and may be effective in improving the symptoms of schizophrenia. This study explored whether statins, as an adjunctive therapy, can alleviate the symptoms of schizophrenia. MethodsPubMed, EMBASE, and the Cochrane Library were searched for articles published up to March 2023. The risk-of-bias tool for randomized trials was used to assess study quality. Two researchers independently assessed the risks of bias and extracted data. Pooled data on Positive and Negative Syndrome Scale (PANSS) scores were analyzed. A random-effects model was employed to calculate pooled effect sizes. Statistical heterogeneity across studies was assessed using the I2 statistic. All analyses were performed using RevMan5 and Comprehensive Meta-Analysis software. ResultsNine trials enrolling 533 patients in total were included. Add-on statin therapy was found to be associated with a significantly better total PANSS score [standardized mean difference (SMD) = −0.42, 95% confidence interval (CI) −0.75 to −0.09, I2 = 72%; P = 0.01] and PANSS negative subscale score (SMD = −0.26, 95% CI −0.45 to −0.07, I2 = 0%; P = 0.009) in comparison with placebo. However, add-on statin therapy did not appear to improve scores for the PANSS positive and general subscales at the study-defined endpoint (6–24 weeks). ConclusionsOur meta-analysis indicates that adjunctive statin therapy may confer benefits in ameliorating PANSS negative and total scores. It needs more solid data to confirm the results are related to clinical improvement and functioning.

Efficacy and Safety of Xanomeline-Trospium Chloride in Schizophrenia

A significant need exists for new antipsychotic medications with different mechanisms of action, greater efficacy, and better tolerability than existing agents. Xanomeline is a dual M1/M4 preferring muscarinic receptor agonist with no direct D2 dopamine receptor blocking activity. KarXT combines xanomeline with the peripheral muscarinic receptor antagonist trospium chloride with the goal of reducing adverse events due to xanomeline-related peripheral muscarinic receptor activation. In prior trials, xanomeline-trospium chloride was effective in reducing symptoms of psychosis and generally well tolerated in people with schizophrenia. To evaluate the efficacy and safety of xanomeline-trospium vs placebo in adults with schizophrenia. EMERGENT-3 (NCT04738123) was a phase 3, multicenter, randomized, double-blind, placebo-controlled, 5-week trial of xanomeline-trospium in people with schizophrenia experiencing acute psychosis, conducted between April 1, 2021, and December 7, 2022, at 30 inpatient sites in the US and Ukraine. Data were analyzed from February to June 2023. Participants were randomized 1:1 to receive xanomeline-trospium chloride (maximum dose xanomeline 125 mg/trospium 30 mg) or placebo for 5 weeks. The prespecified primary end point was change from baseline to week 5 in Positive and Negative Syndrome Scale (PANSS) total score. Secondary outcome measures were change from baseline to week 5 in PANSS positive subscale score, PANSS negative subscale score, PANSS Marder negative factor score, Clinical Global Impression-Severity score, and proportion of participants with at least a 30% reduction in PANSS total score. Safety and tolerability were also evaluated. A total of 256 participants (mean [SD] age, 43.1 [11.8] years; 191 men [74.6%]; 156 of 256 participants [60.9%] were Black or African American, 98 [38.3%] were White, and 1 [0.4%] was Asian) were randomized (125 in xanomeline-trospium group and 131 in placebo group). At week 5, xanomeline-trospium significantly reduced PANSS total score compared with placebo (xanomeline-trospium , -20.6; placebo, -12.2; least squares mean difference, -8.4; 95% CI, -12.4 to -4.3; P < .001; Cohen d effect size, 0.60). Discontinuation rates due to treatment-emergent adverse events (TEAEs) were similar between the xanomeline-trospium (8 participants [6.4%]) and placebo (7 participants [5.5%]) groups. The most common TEAEs in the xanomeline-trospium vs placebo group were nausea (24 participants [19.2%] vs 2 participants [1.6%]), dyspepsia (20 participants [16.0%] vs 2 participants [1.6%]), vomiting (20 participants [16.0%] vs 1 participant [0.8%]), and constipation (16 participants [12.8%] vs 5 participants [3.9%]). Measures of extrapyramidal symptoms, weight gain, and somnolence were similar between treatment groups. Xanomeline-trospium was efficacious and well tolerated in people with schizophrenia experiencing acute psychosis. These findings, together with the previously reported and consistent results from the EMERGENT-1 and EMERGENT-2 trials, support the potential of xanomeline-trospium to be the first in a putative new class of antipsychotic medications without D2 dopamine receptor blocking activity. ClinicalTrials.gov Identifier: NCT04738123.

Relationship between plasma risperidone concentrations and clinical features in chronic schizophrenic patients in China.

Prior studies have noted great variability in the plasma levels of risperidone (RIS). Plasma concentrations of RIS and its active moiety are highly variable and depend on absorption, metabolism, and other predictors of metabolic dysregulation; however, these factors are poorly understood and the association between metabolic change and change in psychopathology is uncertain. To ascertain the characteristics of chronic schizophrenic patients treated with RIS, and to assess their relationship with plasma RIS levels. This was a descriptive cross-sectional study of 50 patients with a diagnosis of schizophrenic psychosis treated with RIS in a psychiatric service. The plasma concentrations of RIS and its metabolite 9-hydroxyrisperidone were determined by high performance liquid chromatography. The patients' demographic and clinical characteristics, and psychopathologies were assessed, and the associations between clinical variables and plasma levels of RIS were explored. Male patients received higher doses of RIS than female ones, but plasma concentrations of RIS and risperidone + 9-hydroxyrisperidone (active moiety) were higher in female patients. Age and the mean scores of the general psychopathology subscale of the Positive and Negative Syndrome Scale (PANSS) were significantly positively correlated with plasma concentrations of risperidone + 9-hydroxyrisperidone adjusted for weight and dose in all 50 subjects. In male subjects, we found a statistically significant positive correlation between the concentrations of risperidone + 9-hydroxyrisperidone in plasma/(dose × kg) and age, mean PANSS negative subscale scores, mean PANSS general psychopathology subscale scores, and mean PANSS total scores. Long-term use of RIS should be closely monitored in older patients and females to minimize the risk of high concentrations which could induce side effects.

The association of SOD and HsCRP with the efficacy of sulforaphane in schizophrenia patients with residual negative symptoms

ObjectivesEmerging evidence indicates a connection between oxidative stress, immune-inflammatory processes, and the negative symptoms of schizophrenia. In addition to possessing potent antioxidant and anti-inflammatory properties, sulforaphane (SFN) has shown promise in enhancing cognitive function among individuals with schizophrenia. This study aims to investigate the efficacy of combined treatment with SFN in patients with schizophrenia who experience negative symptoms and its effect on the levels of superoxide dismutase (SOD) and the inflammatory marker, high-sensitivity C-reactive protein (HsCRP).DesignForty-five patients with schizophrenia were recruited, who mainly experienced negative symptoms during a stable period. In addition to the original treatments, the patients received SFN tablets at a daily dose of 90 mg for 24 weeks. At baseline, 12 weeks, and 24 weeks, the participants were interviewed and evaluated. The reduction rate of the Positive and Negative Syndrome Scale (PANSS) was used to assess each participant. The side effects scale of Treatment Emergent Symptom Scale (TESS) was applied to assess the adverse reactions. Additionally, the levels of the SOD, HsCRP, and other indicators were examined.ResultsThe study findings revealed a significant decrease in PANSS negative subscale scores (P < 0.001). Furthermore, there was a significant increase in SOD activity and HsCRP levels (P < 0.001 and P < 0.05). Notably, the group of participants who exhibited a reduction in PANSS negative subscale scores demonstrated a significant improvement in HsCRP levels (P < 0.05).ConclusionsOur study suggests that SFN may potentially serve as a safe adjunctive intervention to improve the negative symptoms of schizophrenia. The potential mechanism by which SFN improves negative symptoms in schizophrenia patients may involve its anti-inflammatory properties, specifically its ability to reduce HsCRP levels.Trial registrationClinicalTrial.gov (ID: NCT03451734).

Sex difference in association between tardive dyskinesia and cognitive deficits in patients with chronic schizophrenia.

Tardive dyskinesia (TD), a side effect due to long-term use of antipsychotic medication, is associated with cognitive impairment. Several studies have found sex differences in cognitive impairment in schizophrenia patients, while whether there are sex differences in cognitive performance in schizophrenia patients with TD has not been reported. A total of 496 schizophrenia inpatients and 362 healthy controls were recruited for this study. We used the Positive and Negative Syndrome Scale (PANSS) to assess patients' psychopathological symptoms and the Abnormal Involuntary Movement Scale (AIMS) to assess the severity of TD. Cognitive function was measured in 313 of these inpatients and 310 of healthy controls using the Repeatable Battery for Assessment of Neuropsychological Status (RBANS). Patients with schizophrenia performed worse in all cognitive domains than healthy controls(all p<0.001). Compared to patients without TD, patients with TD had higher PANSS total, PANSS negative symptom subscale and AIMS scores (all p<0.001), while RBANS total, visuospatial/constructional and attention subscale scores were significantly lower (all p<0.05). In addition, the visuospatial/constructional and attention indices remained significantly lower in male patients with TD than those without TD (both p<0.05), but these results were not observed in female patients. Moreover, visuospatial/constructional and attention indices were negatively correlated with total AIMS scores only in male patients (both p<0.05). Our results suggest that there may be sex differences in cognitive impairment in schizophrenia patients with comorbid TD, indicating that female gender may have a protective effect on cognitive impairment in schizophrenia patients caused by TD.

Safety and efficacy of KarXT (Xanomeline Trospium) in Schizophrenia in the Phase 3, Randomized, Double-Blind, Placebo-Controlled EMERGENT-2 Trial

AbstractIntroductionKarXT combines the M1/M4 preferring muscarinic receptor agonist xanomeline and the peripherally restricted anticholinergic trospium. In the phase 2 EMERGENT-1 study, KarXT met the primary endpoint of a significant reduction in Positive and Negative Syndrome Scale (PANSS) total score through week 5 vs placebo, improved other key secondary efficacy measures, and was generally well tolerated.MethodsEMERGENT-2 was a phase 3, randomized, double-blind, placebo-controlled, 5-week trial of KarXT in acutely psychotic patients with schizophrenia in the inpatient setting. Eligible patients were randomized 1:1 to KarXT or matched placebo. Dosing of KarXT (mg xanomeline/mg trospium) started at 50 mg/20 mg BID and increased to a maximum of 125 mg/30 mg BID. The primary efficacy endpoint was change from baseline to week 5 in PANSS total score. Key secondary endpoints included change from baseline to week 5 in PANSS positive subscale, PANSS negative subscale, and PANSS negative Marder factor scores compared with placebo. Efficacy analyses were performed using the modified intent-to-treat population (patients with ≥1 dose of study medication, a baseline PANSS assessment, and ≥1 postbaseline PANSS assessment). All patients receiving ≥1 dose of study drug were included in safety analyses.Results252 US patients were enrolled. KarXT demonstrated a statistically significant and clinically meaningful 9.6-point reduction from baseline to week 5 (effect size=0.61) in PANSS total score vs placebo (p&lt;0.0001); a significant improvement in PANSS total score was demonstrated starting at week 2 (first postbaseline rating) and continued through the study end. KarXT also met key secondary endpoints. Results at week 5 included a 2.9-point reduction in PANSS positive subscale score with KarXT vs placebo (p&lt;0.0001), a 1.8-point reduction in PANSS negative subscale score with KarXT vs placebo (p=0.0055), and a 2.2-point reduction in PANSS negative Marder factor score with KarXT vs placebo (p=0.0022). KarXT was generally well tolerated. Overall discontinuation rates were similar with KarXT (25%) and placebo (21%). The overall treatment-emergent adverse events (TEAEs) rate for KarXT and placebo was 75% and 58%, respectively. Discontinuation rates related to TEAEs were similar between KarXT (7%) and placebo (6%). Rates of serious TEAEs were similar with KarXT and placebo (2%, each group); no serious TEAEs were determined to be drug related. The most common TEAEs (≥5%) with KarXT were all mild to moderate in severity and included constipation, dyspepsia, nausea, vomiting, headache, blood pressure increases, dizziness, gastroesophageal reflux disease, abdominal discomfort, and diarrhea. KarXT was not associated with sedation/somnolence, weight gain, and extrapyramidal symptoms.ConclusionsKarXT has the potential to be the first in a new class of treatments for patients with schizophrenia and a promising alternative to postsynaptic dopamine D2 receptor antagonists.FundingKaruna Therapeutics, Inc.

Diminished Auditory Cortex Dynamic Range and its Clinical Correlates in First Episode Psychosis.

There is growing appreciation for the contribution of sensory disruptions to disease morbidity in psychosis. The present study examined auditory cortex (AC) dynamic range: the scaling of neurophysiological responses to stimulus intensity, among individuals with a schizophrenia spectrum illness (FESz) and its relationship to clinical outcomes at disease onset. Magnetoencephalography (MEG) was recorded from 35 FESz and 40 healthy controls (HC) during binaural presentation of tones at three intensities (75 dB, 80 dB, and 85 dB). MRIs were obtained to enhance cortical localization of MEG sensor-level activity. All participants completed the MATRICS cognitive battery (MCCB) and Global Functioning: Role and Social scales (GFR/GFS). Patients were administered the Positive and Negative Syndrome Scale (PANSS). FESz exhibited reduced AC response relative to HC. Enhancement of AC activity to tones of increasing intensity was blunted in FESz relative to HC. Reduced dynamic range (85-75 dB AC response) was associated with lower GFS (r = .58) and GFR (r = .45) scores, worse MCCB performance (r = .45), and increased PANSS Negative symptom subscale scores (r = -.55) among FESz, relationships not observed with AC responses to individual tones. Beyond an impaired AC response to pure tones, FESz exhibit reduced dynamic range relative to HC. This impairment was correlated with markers of disease morbidity including poorer community functioning as well as cognitive and negative symptoms. The relationship with impaired social functioning may reflect the role of AC dynamic range in decoding the emotional content of language and highlights its importance to future therapeutic sensory remediation protocols.

Gender differences in empathy and clinical symptoms in chronic schizophrenia patients: a large sample study based on a Chinese Han population

Background Empathy is social cognition and reduced empathy in schizophrenia (SCZ) has been noted; however, whether there are gender differences in empathy remains unclear. Therefore, the purpose of this study was to explore this issue by examining a large sample of the population with SCZ. Methods We recruited 987 SCZ patients (M/F = 638/349). The empathy was assessed by The Interpersonal Reactivity Index (IRI). The Positive and Negative Syndrome Scale (PANSS) was adopted to assess their clinical psychiatric symptoms and their ability to recognise the facial emotions of others was assessed by the Pictures Of Facial Affect (POFA). Results Female SCZ patients had higher IRI total score than male patients. In male patients, Pearson correlation analysis showed that empathy was negatively correlated with PANSS total score and negative symptom subscale scores, but positively correlated with anger identification. In female patients, IRI total score was negatively correlated with PANSS total score as well as its positive and negative symptom subscale scores (all p < 0.05). Conclusion There are gender differences in the empathy of SCZ patients, with female patients having greater empathy and a correlation with their clinical symptoms. This gender difference may provide potential clinical value for the treatment of SCZ. KEY POINTS Female SCZ were more likely to empathise than males; Female patients had more severe clinical symptoms than males; There were gender differences in the association between certain specific clinical presentations and empathy. In future studies, it may be useful to investigate gender differences in schizophrenia empathy for the diagnosis and treatment of the disorder.

Effect of Vitamin D Supplementation on Cardiometabolic Indices and the Severity of Symptoms in Male Patients With Chronic Schizophrenia

Objectives: Hypovitaminosis D is suggested to be related to the high risk of metabolic disorders and symptoms of schizophrenia. Therefore, this study aimed to evaluate the effect of vitamin D supplementation on cardio-metabolic indices and the severity of symptoms in schizophrenic patients. Materials and Methods: Patients with schizophrenia (N=42) were randomly assigned to 2 groups, i.e., intervention (2000 IU of vitamin D daily; n=21) and placebo groups (n=21). The intervention was administered for 8 weeks. Anthropometric, clinical, and laboratory measures were assessed at both baseline and end of the trial. The Positive and Negative Syndrome Scale (PANSS) was performed to assess the schizophrenia symptoms. Results: Vitamin D supplementation leads to a significant decrease in low-density lipoprotein cholesterol (LDL-C) levels (P=0.006). In addition, a significant improvement was found in the PANSS negative subscale score (PANSS-NSS) and PANSS total score (PANSS-TS; P=0.005 and P=0.015, respectively). At the baseline, there was a significant negative correlation between PANSS-NSS, PANSS positive subscale score (PANSS-PSS), and PANSS-TS with serum levels of vitamin D (r=-0.42, P=0.010; r=-0.34, P=0.041; and r=-0.47, P=0.004, respectively). Conclusions: Vitamin D supplementation may have helpful efficacy on some cardio-metabolic indices and schizophrenia severity.

Add-On Pramipexole for the Treatment of Schizophrenia and Schizoaffective Disorder: A Randomized Controlled Trial.

Objective: Several small clinical trials have reported that the dopamine agonist pramipexole was beneficial in treating patients with schizophrenia. A confirmatory trial was conducted to test this hypothesis.Methods: This 16-week, multicenter, double-blind, randomized, placebo-controlled study included 200 subjects meeting DSM-IV-TR criteria for schizophrenia or schizoaffective disorder. Patients were randomized to receive either pramipexole (0.75 mg twice daily, n = 100) or placebo (n = 100) as an add-on to their regular antipsychotic treatment. The primary outcome measure was the total score on the Positive and Negative Syndrome Scale (PANSS); secondary outcome measures included PANSS subscale and cognitive functioning scores. Recruitment was performed in 30 sites in Romania and 1 site in the Republic of Moldova between January and June 2011.Results: Analysis of covariance models showed no significant difference between pramipexole and placebo for total PANSS (P > .99) and PANSS positive (P > .99), negative (P = .73), and general psychopathology (P = .99) subscale scores. Changes in Clinical Global Impressions-Severity of Illness scale and Brief Assessment of Cognition in Schizophrenia scores showed no significant difference between pramipexole and placebo.Conclusions: The results of this large randomized controlled trial indicated that pramipexole was not efficacious as an add-on to antipsychotic medications for schizophrenia.Trial Registration: ClinicalTrials.gov identifier NCT01320982.

Efficacy of Spironolactone as an Adjunctive Therapy to Risperidone to Improve Symptoms of Schizophrenia: A Double-Blind, Randomized, Placebo-Controlled, Clinical Trial.

Objective: Spironolactone (C24H32O4S), a potent mineralocorticoid receptor (MR) inhibitor, is a potassium-sparing diuretic that is traditionally used to treat fluid build-up in the body or for its anti-androgenic properties. This study is a double-blind, placebo-controlled, randomized clinical trial assessing the beneficial effects of spironolactone in addition to risperidone in improving negative symptoms of schizophrenia. Method: 40 patients with chronic schizophrenia, aged 18–60 years, were assigned to two groups: risperidone + spironolactone or risperidone + placebo. Risperidone was administered to both the spironolactone and placebo groups with a dose up to 6 mg/day throughout the trial. Spironolactone (C24H32O4S) was ordered 100 mg/day for the full 8-week course of the study. Patients were rated on the Positive and Negative Syndrome Scale (PANSS) at four time points: baseline, weeks two, four, and eight. The PANSS negative subscale score was the main objective. Results: PANSS negative, positive, and total scores showed significantly greater improvements in the spironolactone relative to the placebo group from baseline to the trial endpoint (P (Cohen’s d): 0.004 (0.96), 0.007 (0.90), and 0.042 (0.66), respectively). Similarly, ANOVA also presented significant time × treatment interaction effect for spironolactone on PANSS negative (F = 9.04; ηp2 = 0.19; df = 1.38; P = 0.002), positive (F = 3.43; ηp2 = 0.08; df = 2.72; P = 0.023), and total (F = 3.94; ηp2 = 0.09; df = 2.05; P = 0.022) scores. However, spironolactone did not cause significant decrease in the general psychiatric pathology score of PANSS. Conclusion: Our findings suggest the efficacy and safety of spironolactone as an adjunctive therapy to risperidone in improving the symptoms of schizophrenia.

Online Left-Hemispheric In-Phase Frontoparietal Theta tACS for the Treatment of Negative Symptoms of Schizophrenia

Negative symptoms represent an unmet need for schizophrenia treatment. The effect of theta frequency transcranial alternating current stimulation (theta-tACS) applied during working memory (WM) tasks on negative symptoms has not been demonstrated as of yet. We conducted a randomized, double-blind, sham-controlled trial of 36 stabilized schizophrenia patients, randomized to receive either twice daily, 6 Hz 2 mA, 20 min sessions of in-phase frontoparietal tACS or sham for five consecutive weekdays. Participants were concurrently engaged in WM tasks during stimulation. The primary outcome measure was the change over time in the Positive and Negative Syndrome Scale (PANSS) negative subscale score measured from baseline through to the 1-month follow-up. Secondary outcome measures were other symptom clusters, neurocognitive performance, and relevant outcomes. The intention-to-treat analysis demonstrated greater reductions in PANSS negative subscale scores at the end of stimulation in the active (−13.84%) than the sham (−3.78%) condition, with a large effect size (Cohen’s d = 0.96, p = 0.006). The positive effect endured for at least one month. Theta-tACS also showed efficacies for cognitive symptoms, WM capacity, and psychosocial functions. Online theta-tACS offers a novel approach to modulate frontoparietal networks to treat negative symptoms of schizophrenia. The promising results require large-scale replication studies in patients with predominantly negative symptoms.

M184. SOCIAL SKILLS TRAINING FOR TREATMENT-RESISTANT SCHIZOPHRENIA WITH PREDOMINANTLY NEGATIVE SYMPTOMS

BackgroundPoor social skills are a core characteristic of schizophrenia and are highly associated with the progression of negative symptoms. While positive symptoms have a good response to antipsychotics, the treatment of negative symptoms remains an unmet need.MethodsA randomized controlled trial to assess the efficacy of a 20-week social skills training (SST) program for the improvement of negative symptoms in patients with treatment-resistant schizophrenia (TRS) with predominantly negative persistent symptoms, with a score > 4 (moderate) in at least 3 items of the Negative Symptom Factor Score (NSFS) (blunted affect, emotional withdrawal, poor rapport, passive social withdrawal, lack of spontaneity, motor retardation and active social avoidance).Each session lasted 60 minutes and included 6 to 9 participants. The SST sessions were conducted by trained psychologists, following topics previously outlined in a manual, and role-playing activities. The non-directive control group was conducted by nurses specialists in mental health, with the same duration but without role-playing activities. Control groups’ therapists were instructed not to give directions to the patients but to listen and redirect questions to the group.TRS was defined as the persistence of psychotic symptoms after at least two adequate trials with two different antipsychotics, All patients were taking clozapine. Blinded raters evaluated the patients at baseline, 20 weeks and after 6 months follow-up by the Positive and Negative Syndrome Scale (PANSS), Clinical Global Impression (CGI) and the Social Skills Inventory (SSI). Longitudinal comparisons between groups were carried out using a linear mixed-effects model at pre, post and follow-up to assess differences between groups. Cohen’s d effect size was computed at each time point. Primary outcome measure was the PANSS negative subscale score.Social skill were assessed with the Social Skills Inventory.Results62 patients were randomized to SST (N=29) and control group (N=33). Subjects were predominantly male (70.96%) and single (88.70%). At baseline, groups showed no differences in terms of demographic variables and illness duration. Patients were moderately ill, with mean CGI = 4.10 (SD 0.78) in SST group and 4.34 (0.90) in the control group, and had a high baseline PANSS score, with a mean total PANSS 71.90 (10.83) in the SST group and 70.4 (13.8) in the control group. The mean PANSS negative subscale score was 25.48 (4.56) in SST group and 25.13 (6.34) in control group; in the SST group 28 patients completed the 20-week intervention and 24 were assessed after 6 months; in the control group, 18 completed the treatment and 16 were assessed at the follow-up. After the 20-week intervention period, the PANSS negative scores were 24.57 (4.92) in the SST group and 22.67 (6.59) in the control group. At the follow-up, the negative score was 23.92 (5.85) in the SST group and 22.97 (5.32) in the control. There was no improvement at any timepoint (p= 0.162) or any difference between groups (p= 0.864). Patients remained clinically stable during the study. The only symptom which showed a significant improvement was the control of aggressiveness (Cohen’s d at week 20 = 0.445 [IC 95% -0.140; 1.030]), which was maintained at follow-up (Cohen’s d = 0.682 [IC 95% 0.037; 1.327]).DiscussionThe study has limitations: the SSI was not designed to assess social skills in patients with psychosis, and we have not assessed the adherence to pharmacological treatment. Our findings suggest that SST is not effective to improve negative symptoms in patients with TRS with predominantly negative symptoms, but may be potentially useful for the control of aggressiveness in situations such as criticism and mockery, which frequently occur in social interactions.

138 Efficacy and Safety of SEP-363856, a Novel Psychotropic Agent with a Non-D2 Mechanism of Action, in the Treatment of Schizophrenia

SEP-363856 is a novel psychotropic agent that has shown broad efficacy in animal models of schizophrenia and depression. Its antipsychotic effects appear to be mediated by agonist activity at both trace amine-associated receptor 1 (TAAR1) and 5-HT1A receptors. Notably, SEP-363856 does not bind to any dopaminergic, serotonergic (except 5-HT1A), glutamatergic, or other neuroreceptors thought to mediate the effects of currently available antipsychotics. The aim of this study was to evaluate the efficacy and safety of SEP-363856 in acutely symptomatic patients with schizophrenia. Patients aged 18-40 years meeting DSM-5 criteria for schizophrenia (PANSS total score ≥80) were randomized, double-blind, to 4-weeks of flexible-dose SEP-363856 (50 or 75 mg/d) or placebo. Efficacy measures included the Positive and Negative Syndrome Scale (PANSS) total score (primary), PANSS subscale scores, and the Clinical Global Impressions-Severity (CGI-S) score. Change from baseline in primary and secondary measures were analyzed using a mixed model for repeated measures (MMRM) analysis. Study treatment groups were similar at baseline: SEP-363856 (N=120; male, 64.2%; mean age, 30.0 years; PANSS total score, 101.4) and placebo (N=125; male, 63.2%; mean age, 30.6 years; PANSS total score, 99.7). Least-squares (LS) mean reduction from baseline to week 4 was significantly greater for SEP-363856 vs. placebo on the PANSS total score (-17.2 vs. -9.7; P=0.001; effect size, 0.45), PANSS positive subscale score (-5.5 vs. -3.9; P=0.019; effect size, 0.32), PANSS negative subscale score (-3.1 vs. -1.6; P=0.008; effect size, 0.37), PANSS general psychopathology subscale score (-9.0 vs. -4.7; P<0.001; effect size, 0.51), and the CGI-Severity score (-1.0 vs. -0.5; P<0.001; effect size, 0.52). Discontinuation rates for SEP-363856 vs. placebo were similar overall (21.7% vs. 20.8%) and due to an adverse event (8.3% vs. 6.4%). Change in weight, lipids, glucose and prolactin was similar in SEP-363856 and placebo groups. Adverse events occurring with an incidence ≥2% on SEP-363856 or placebo (with SEP-363856 incidence higher than placebo) were: somnolence (6.7% vs. 4.8%), agitation (5.0% vs. 4.8%), nausea (5.0% vs. 3.2%), diarrhea (2.5% vs. 0.8%), and dyspepsia (2.5% vs. 0%). The proportion of patients who reported any extrapyramidal symptom was 3.3% on SEP-363856 and 3.2% on placebo. In this placebo-controlled study, treatment with SEP-363856, a novel psychotropic agent, was associated with statistically significant and clinically meaningful improvement in schizophrenia symptoms as demonstrated by endpoint change in PANSS total and subscale scores, and CGI-Severity scores. Safety and tolerability findings for SEP-363856 were in general similar to placebo. In particular, SEP-363856 was not associated with extrapyramidal symptoms, akathisia, or hyperprolactinemia, consistent with its non-D2 mechanism of action. NCT02969382. Supported by funding from Sunovion Pharmaceuticals Inc.

Improvement of Negative Symptoms in Schizophrenia with Paliperidone Palmitate 1-Month and 3-Month Long-Acting Injectables: Results from a Phase 3 Non-Inferiority Study.

BackgroundNegative symptoms in schizophrenia are associated with impairments in social and cognitive functioning leading to substantial long-term disability. Available antipsychotic treatments have demonstrated only modest benefit in the improvement of negative symptoms.ObjectiveTo compare improvements in negative symptoms among patients treated with paliperidone palmitate 3-month (PP3M) or paliperidone palmitate 1-month (PP1M) long-acting injectable (LAI) formulations.MethodsData from a randomized double-blind (DB), phase-3, non-inferiority study in patients with schizophrenia were analyzed. Following screening, patients entered a 17-week open-label (OL) phase to receive flexibly dosed PP1M followed by a 48-week DB phase where patients were randomized (1:1) to receive either PP1M or PP3M. Positive and Negative Syndrome Scale (PANSS) total scores with emphasis on 7-item negative subscale scores for PP1M vs PP3M were assessed.ResultsOf 1429 patients enrolled, 1016 were randomized to receive PP3M (n=504) or PP1M (n=512). At baseline, mean (SD) PANSS negative subscale was 23.2 (4.60) and negative symptom factor score was 22.3 (4.87), indicating moderate-to-severe negative symptoms. Negative subscale and symptoms factor scores showed continuous improvements throughout OL (15.9 [4.99]) and DB (14.9 [4.81]) phases. Mean (SD) changes from DB baseline in the PANSS negative subscale score were comparable between PP1M (–1.4 [3.67]) and PP3M (–1.4 [3.63]) treatment groups.ConclusionTreatment with PP3M or PP1M demonstrated comparable improvement in negative symptoms in patients with moderate-to-severe negative symptoms and in patients with prominent negative symptoms. Long-term treatment with PP3M demonstrated benefit, suggesting that continuous antipsychotic medication treatment for >1 year is needed to achieve greater benefit for negative symptoms.Trial RegistrationClinicalTrials.gov Identifier: NCT01515423.

Sodium Nitroprusside Infusion for the Treatment of Schizophrenia

Abstract One previous small single-center clinical trial showed that a single intravenous administration of sodium nitroprusside added-on to antipsychotics improved a wide spectrum of schizophrenia (SCZ) symptoms more than placebo, and the improvement persisted for 4 weeks after infusion even though no additional drug was given. Our study attempted to replicate these data in a 4-week, add-on, double-blind, randomized, placebo-controlled trial on 20 patients performed in a site in Romania and a site in Moldova. This study’s sample size and protocol were identical to the previous trial, including patients with a diagnosis of SCZ, within the first 5 years after diagnosis. Patients recruited needed to have a baseline total positive and negative syndrome scale (PANSS) score of 60 or above. Ten participants received a single dose of 0.5 µg/kg/min intravenous sodium nitroprusside over 4 hours, and 10 participants received matching placebo infusion, added-on to antipsychotics. The primary outcomes were the PANSS total score and the PANSS negative subscale. There were no significant between-group differences in PANSS total scores or negative subscale scores during the infusion on daily evaluations for the next 7 days nor on weekly evaluations at weeks 2, 3, and 4. No significant differences were found between the 2 study groups in adverse events. Meta-analyses including all 5 published randomized controlled trials on the topic, representing 155 subjects, do not show a statistically significant benefit of sodium nitroprusside. We conclude that the current evidence does not support the efficacy of sodium nitroprusside in the treatment of SCZ.

Efficacy and Safety of Transcranial Direct Current Stimulation for Treating Negative Symptoms in Schizophrenia

Negative symptoms represent a substantial burden in schizophrenia. Although preliminary studies have suggested that transcranial direct current stimulation (tDCS) is effective for some clusters of symptoms, the clinical benefits for negative symptoms are unclear. To determine the efficacy and safety of tDCS vs sham as an add-on treatment for patients with schizophrenia and predominant negative symptoms. The double-blind Schizophrenia Treatment With Electric Transcranial Stimulation (STARTS) randomized clinical trial was conducted from September 2014 to March 2018 in 2 outpatient clinics in the state of São Paulo, Brazil. Patients with schizophrenia with stable negative and positive symptoms and a minimum score of 20 points in the negative symptoms subscale of the Positive and Negative Syndrome Scale (PANSS) were included. Ten sessions of tDCS performed twice a day for 5 days or a sham procedure. The anode and the cathode were positioned over the left prefrontal cortex and the left temporoparietal junction, respectively. Change in the PANSS negative symptoms subscale score at week 6 was the primary outcome. Patients were followed-up for an additional 6 weeks. Of the 100 included patients, 20 (20.0%) were female, and the mean (SD) age was 35.3 (9.3) years. A total of 95 patients (95.0%) finished the trial. In the intention-to-treat analysis, patients receiving active tDCS showed a significantly greater improvement in PANSS score compared with those receiving the sham procedure (difference, 2.65; 95% CI, 1.51-3.79; number needed to treat, 3.18; 95% CI, 2.12-6.99; P < .001). Response rates for negative symptoms (20% improvement or greater) were also higher in the active group (20 of 50 [40%]) vs the sham group (2 of 50 [4%]) (P < .001). These effects persisted at follow-up. Transcranial direct current stimulation was well tolerated, and adverse effects did not differ between groups, except for burning sensation over the scalp in the active group (43.8%) vs the sham group (14.3%) (P = .003). Transcranial direct current stimulation was effective and safe in ameliorating negative symptoms in patients with schizophrenia. ClinicalTrials.gov identifier: NCT02535676.

Open Trial of the Addition of Divalproex Sodium for Improving the Symptoms of Batak and Non-Batak Males with Schizophrenia in North Sumatra, Indonesia

Background: Ethnicity is one of many intrinsic factors influencing the drug response and its severity in patients with schizophrenia. In North Sumatera, Indonesia, information is very limited on the effect of divalproex sodium in Batak and non-Batak tribes. Objectives: The study aimed to investigate differences in positive and negative syndrome scale (PANSS) scores between Batak and non-Batak males with schizophrenia receiving risperidone treatment alone or in combination with divalproex sodium. Methods: This open trial experimental study was conducted on 60 Batak and non-Batak male subjects with schizophrenia. The doses of divalproex sodium and risperidone were 1500 mg and 6 mg, respectively. The sample was obtained from Prof. Dr. M. Ildrem Psychiatric Hospital, North Sumatra, Indonesia, in a span of six months from September 2017 to February 2018. The mini international statistical classification of diseases-10 (Mini ICD-10) structured interviews were used for diagnosis. Results: There were no differences between the Batak and Non-Batak groups in the PANSS positive subscale score (P = 0.766), PANSS negative subscale score (P = 0.789), and PANSS total score (P = 0.673) in six weeks of observation. Conclusions: There were no significant differences in the PANSS scores between males with schizophrenia from Batak and non-Batak tribes who received risperidone monotherapy or combined with divalproex sodium.

Assessing negative symptoms in schizophrenia: Validity of the clinical assessment interview for negative symptoms in Singapore

This study aimed to examine the validity of the Clinical Assessment Interview for Negative Symptoms (CAINS) in Singapore. 274 participants with schizophrenia were assessed on the CAINS, Scale for the Assessment of Negative Symptoms (SANS), Positive and Negative Syndrome Scale (PANSS), Calgary Depression Scale for Schizophrenia (CDSS), Social and Occupational Functioning Assessment Scale (SOFAS) and the Simpson-Angus Extrapyramidal Side Effects Scale (SES). Factor analyses were conducted and Cronbach's coefficient alpha was calculated. Spearman's correlation coefficient was used to assess correlations. The 2-factor model of the CAINS failed to fit our data. Exploratory factor analysis of a randomly selected split-half of the sample yielded four factors: motivation-pleasure (MAP) social, MAP vocational, MAP recreational and expression (EXP), accounting for 73.94% of the total variance. Confirmatory factor analysis on the remaining sample supported this factor structure. Cronbach's alpha for the CAINS was 0.770. Significant correlations were observed between the CAINS total and the SANS total and PANSS negative subscale scores. Good divergent validity was shown by insignificant correlations with PANSS positive subscale score and CDSS total score. The MAP social and recreational factor scores had moderate correlations with the SANS anhedonia-asociality subscale scores, whereas the MAP vocational factor had the highest correlation with the avolition-apathy subscale of the SANS. EXP factor score correlated strongly with the SANS affective flattening and alogia subscales scores. In conclusion, the CAINS has good psychometric properties and can be used by clinicians to assess negative symptoms in individuals with schizophrenia in the local population.

Prevalence and Clinical Correlates of and Cognitive Function at the Time of Suicide Attempts in First-Episode and Drug-Naive Patients With Schizophrenia.

It is well established that patients with chronic schizophrenia have a substantially higher rate of attempted and completed suicide than the general population. However, the actual prevalence of suicide attempts at first-episode psychosis is relatively unknown. Previous studies showed that suicidal schizophrenia patients demonstrate higher cognitive function than nonsuicidal patients, though with inconsistent results. The aims of the study were to examine the prevalence of suicide attempts and the association of this prevalence with demographic and clinical variables and cognitive function in Chinese first-episode, drug-naive (FEDN) schizophrenia patients using a cross-sectional and case-control design. A total of 357 FEDN inpatients meeting DSM-IV criteria for schizophrenia and 380 healthy controls were enrolled and completed a detailed in-house questionnaire. The suicide attempt data were collected from medical records and interviews with the patients and their family members. The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) was administered to measure cognition in the 28 patients with and 95 patients without a history of suicide attempt and 151 healthy controls. Also, patients were rated on the Positive and Negative Syndrome Scale (PANSS). This study was conducted from June 2013 to December 2015. A suicide attempt rate of 12.0% was found in inpatients with first-episode schizophrenia. The attempters were more likely to smoke (34.4% vs 17.9%; χ² = 5.49, P = .019) and had lower severity of negative symptoms (F₁,₃₅₄ = 4.12, P = .043) as compared to FEDN patients without a suicide attempt. All 5 RBANS subscales (all P < .001) except for the Visuospatial/Constructional index (P > .05) showed significantly lower cognitive performance for FEDN patients than for healthy controls. Among the FEDN patients, the suicide attempters performed better than nonattempters on attention (F₁,₁₂₁ = 5.12, P = .025), with an effect size of 0.49. The following variables were independently associated with suicide attempt as shown by multivariate regression analysis: PANSS negative symptom subscale score (Wald χ²₁ = 7.90 P = .005; adjusted OR = 0.807, 95% CI, 0.696-0.936) and Attention (Wald χ²₁ = 4.69, P = .03; adjusted OR = 0.957, 95% CI, 0.918-0.997). FEDN patients with schizophrenia attempt suicide more often than the general population. The suicidal patients were more likely to smoke, had lower severity of negative symptoms, and showed better attention than nonsuicidal patients.