Positive And Negative Syndrome Scale Negative Symptom Scores Research Articles

Association between angiotensin-converting enzyme gene insertion/deletion polymorphism and cognition impairment in patients with schizophrenia.

Several lines of evidence indicate that an insertion/deletion (I/D) polymorphism in the angiotensin-converting enzyme gene (ACE) gene may be involved in the pathogenesis of schizophrenia and cognitive impairment. However, the relationship between ACE I/D polymorphism and cognitive impairment in patients with schizophrenia remains unclear. The aim of this study was to examine whether ACE gene I/D polymorphism contributed to cognitive impairment in Chinese patients with schizophrenia, and whether the association between clinical symptoms and cognitive impairment depended on different ACE genotypes. The ACE I/D polymorphism was genotyped in 928 schizophrenia patients and 325 healthy controls using a case-control design. The severity of psychopathological symptoms was assessed using the Positive and Negative Syndrome Scale (PANSS). Cognitive functioning was assessed by the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). There were significant differences in genotype and allele frequencies of the ACE I/D polymorphism between patients and healthy controls (both P < 0.01). After controlling for demographic characteristics, patients who are homozygous carriers of D and I performed worse on the RBANS attention index than heterozygous carriers (P = 0.009). In addition, attention index score was negatively correlated with PANSS negative symptom score in patients of all genotypes (all P < 0.05), and positively correlated with positive symptom score only in the I/I genotype (P = 0.005). These findings suggest that ACE I/D gene variants play a role in susceptibility to schizophrenia, specific cognitive impairment and the association between clinical symptoms and cognitive impairment in schizophrenia patients.

A comparison of clinical characteristics and course predictors in early- and childhood-onset schizophrenia.

The aim of this study was to compare the clinical characteristics of childhood-onset schizophrenia (COS) and early-onset schizophrenia (EOS) during the first- episode psychosis and the stable period, to examine psychopharmacological treatment approaches, and to investigate potential predictive factors for prognosis. Demographic, clinical, and psychopharmacological therapy data for 31 patients diagnosed with COS and 66 with EOS were retrieved from the file records in this multicenter study. Symptom distribution and disease severity and course were evaluated twice, in the acute psychotic stage and in the latest stable phase, during follow-up using the positive and negative syndrome scale (PANSS) and clinical global impression (CGI) scales. A statistically significant difference was observed between the groups' CGI improvement rates and median last stable stage PANSS positive, negative, and general psychopathology symptom scores (p = .005, p = .031, p = .005, and p = .012, respectively). Premorbid neurodevelopmental disorder and obsessive-compulsive disorder and comorbidities were more common in the COS group (p = .025 and p = .030, respectively), and treatment required greater multiple antipsychotic use in that group (p = .013). When the independent variables affecting the difference between pre- and post-treatment PANSS scores were examined using linear regression analysis, the model established was found to be statistically significant (F = 5.393; p = .001), and the group variable (p = .024), initial disease severity (p = .001), and socioeconomic level (p = .022; p = .007) emerged as predictive factors for the disease course. Although early diagnosis and treatment is an important factor in improving prognosis in schizophrenia, more specific predictors for schizophrenia need to be identified. Additionally, preventive programs and pharmacological methods need to be developed in children with neurodevelopmental problems, particularly those from low socioeconomic status families.

Association of empathy with clinical symptoms and cognitive function in Chinese chronic schizophrenia patients with and without deficit syndrome

BackgroundPatients with deficit syndrome (DS) are known to experience cognitive impairment. However, there is no consistent conclusion on the impairment of neurocognitive features in DS patients, and no studies have examined their empathy. The purpose of this study was to compare neurocognition and empathy in patients with DS and non-DS schizophrenia. MethodsTotally, 665 patients with chronic schizophrenia were enrolled. DS patients were identified by the Proxy Scale for Deficit Syndrome (PDS). Neurocognition and social cognition were assessed by Repeatable Battery for the measurement of Neuropsychological Status (RBANS) and the Interpersonal Reactivity Index (IRI), respectively. In addition, psychopathological symptom severity was assessed by the Positive and Negative Syndrome Scale (PANSS). ResultsParticipants included 150 patients with DS and 140 patients with non-DS. DS patients performed significantly worse on the all RBANS domain (except for visuospatial) and total scores as well as IRI scores. Regression analysis showed that PANSS general psychopathology and education were associated with RBANS total score in the DS group (adjusted R2 = 0.29), while education and PANSS negative symptoms were correlated with RBANS total score in non-DS patients (adjusted R2 = 0.33). In the non-DS group, suicide attempts and PANSS negative symptom score were independently associated with IRI total score (adjusted R2 = 0.06), whereas in the DS group, no variable was associated with IRI total score. ConclusionsOur findings suggest that patients with DS may have poor neurocognitive and empathy performance. In chronic schizophrenia patients, negative symptoms may play a different role in cognition between DS and non-DS groups.

Association between clinical symptoms and apolipoprotein A1 or apolipoprotein B levels is regulated by apolipoprotein E variant rs429358 in patients with chronic schizophrenia

BackgroundThe apolipoprotein E (ApoE) gene polymorphisms are correlated with blood lipid levels and several neuropsychiatric symptoms. Therefore, this study aimed to examine whether the ApoE rs429358 affected the development and clinical symptoms of schizophrenia and to explore the relationship between apolipoproteins levels and clinical symptoms.MethodsThe ApoE rs429358 was genotyped using a case–control design. The Positive and Negative Syndrome Scale (PANSS) was employed to evaluate the psychopathology of all patients.ResultsA total of 637 patients with schizophrenia and 467 healthy controls were recruited. We found no significant differences in the genotype and allele distribution between the patient and control groups. A significant correlation between PANSS negative symptoms and ApoA1 levels (p = 0.048) or ApoB levels (p = 0.001) was found in patients with schizophrenia, which was also confirmed by linear regression analyses (p = 0.048 vs. p = 0.001). Interestingly, only in the T homozygote group, ApoA1 and ApoB levels were predictors of the PANSS negative symptom score (p = 0.008 vs. p = 0.012), while in the C allele carrier group, no correlation was observed.ConclusionsThis study found that the levels of ApoA1 and ApoB were negatively associated with negative symptoms of patients with schizophrenia. Furthermore, the association between ApoA1 or ApoB levels and psychopathology of schizophrenia was regulated by ApoE rs429358.

Ketamine Alters Functional Gamma and Theta Resting-State Connectivity in Healthy Humans: Implications for Schizophrenia Treatment Targeting the Glutamate System.

Disturbed functional connectivity is assumed to cause neurocognitive deficits in patients suffering from schizophrenia. A Glutamate N-methyl-D-aspartate receptor (NMDAR) dysfunction has been suggested as a possible mechanism underlying altered connectivity in schizophrenia, especially in the gamma- and theta-frequency range. The present study aimed to investigate the effects of the NMDAR-antagonist ketamine on resting-state power, functional connectivity, and schizophrenia-like psychopathological changes in healthy volunteers. In a placebo-controlled crossover design, 25 healthy subjects were recorded using resting-state 64-channel-electroencephalography (EEG) (eyes closed). The imaginary coherence-based Multivariate Interaction Measure (MIM) was used to measure gamma and theta connectivity across 80 cortical regions. The network-based statistic was applied to identify involved networks under ketamine. Psychopathology was assessed with the Positive and Negative Syndrome Scale (PANSS) and the 5-Dimensional Altered States of Consciousness Rating Scale (5D-ASC). Ketamine caused an increase in all PANSS (p < 0.001) as well as 5D-ASC scores (p < 0.01). Significant increases in resting-state gamma and theta power were observed under ketamine compared to placebo (p < 0.05). The source-space analysis revealed two distinct networks with an increased mean functional gamma- or theta-band connectivity during the ketamine session. The gamma-network consisted of midline regions, the cuneus, the precuneus, and the bilateral posterior cingulate cortices, while the theta-band network involved the Heschl gyrus, midline regions, the insula, and the middle cingulate cortex. The current source density (CSD) within the gamma-band correlated negatively with the PANSS negative symptom score, and the activity within the gamma-band network correlated negatively with the subjective changed meaning of percepts subscale of the 5D-ASC. These results are in line with resting-state patterns seen in people who have schizophrenia and argue for a crucial role of the glutamate system in mediating dysfunctional gamma- and theta-band-connectivity in schizophrenia. Resting-state networks could serve as biomarkers for the response to glutamatergic drugs or drug development efforts within the glutamate system.

Sex differences in P50 inhibition defects with psychopathology and cognition in patients with first-episode schizophrenia

BackgroundA large number of studies have shown that the pathophysiology of schizophrenia may be involved in sensory gating that appears to be P50 inhibition. However, few studies have investigated the relationship between clinical symptoms, cognitive impairment and sensory gating disorders in patients with first-episode schizophrenia. The purpose of this study was to explore the sex differences in the relationship between clinical symptoms, cognitive impairment and P50 inhibition defects in patients with first-episode schizophrenia, which has not been reported. Methods130 patients with first-episode schizophrenia (53 males and 77 females) and 189 healthy controls (87 males and 102 females) participated in the study. Positive and Negative Syndrome Scale (PANSS) was used to evaluate the patients' psychopathological symptoms, and the 64-channel electroencephalogram (EEG) system was used to record the P50 inhibition. ResultsMale patients had higher PANSS negative symptom, general psychopathology, cognitive factor and total scores than female patients (all p < 0.01). The S1 amplitude was smaller in male than female patients (all p < 0.05). Multiple regression analysis showed that in male patients, S1 latency was contributor to negative symptoms, while S1 latency, S2 latency, age, and smoking status were contributors to cognitive factor (all p < 0.05). In female patients, no P50 component was found to be an independent contributor to PANSS scores (all p > 0.05). ConclusionsOur results indicate that there is a sex difference in the relationship between clinical symptoms, cognitive impairment and P50 inhibition defects in Chinese Han patients with first-episode schizophrenia.

Low-Dose Ziprasidone in Combination with Sertraline for First-Episode Drug-Naïve Patients with Schizophrenia: A Randomized Controlled Trial

Background: Many patients with SCZ discontinue antipsychotics, frequently due to dose related multiple and severe adverse effects. This clinical trial was designed to investigate the efficacy, safety, and tolerability of adding sertraline to ziprasidone in order to substantially reduce its dose and potential side effects in first-episode and drug-naive (FEDN) patients with SCZ. Methods: This 24-week randomized, double-blinded controlled clinical trial randomly allocated 452 FEDN SCZ patients to receive a usual dose of ziprasidone (control group) or half the dose of ziprasidone in combination with sertraline (ZS group). Treatment outcome included the Positive and Negative Syndrome Scale (PANSS), the Hamilton Depression Rating Scale (HAMD), CGI-Severity (CGI-S) and the Personal and Social Performance Scale (PSP) at baseline and weeks 2, 4, 8, 12 and 24. Findings: Repeated measures ANCOVA showed significant treatment by time interactions on the PANSS negative symptom, general psychopathology and total scores, as well as CGI-S, HAMD and PSP scores (all p<0.05). Furthermore, the ZS group had greater reductions in PANSS negative symptoms, general psychopathology and total scores (all p<0.05) and greater increases in the PSP total score (p<0.01) than the control group. Importantly, adverse effects were lower in the ZS than control group. The reduction in PANSS, CGI-S or HAMD scores was not correlated with the increase in PSP. Sex and duration of disease predicted PSP improvement from baseline to week 24 in the ZS group. Interpretation: Our FEND patients with SCZ were effectively treated for their psychotic and depressive symptoms while experiencing significantly fewer adverse effects using half the usual ziprasidone dose when combined with sertraline. The implications for long term improved retention and compliance with treatment using this combination therapy are substantial for introducing them to life saving chronic care that will be optimally effective and minimally aversive due to antipsychotic side effects including cardiac problems. Trial Registration: The clinical trial was registered with ClinicalTrials.gov (ClinicalTrials.gov Identifier NCT04076371). Funding: Funding for this study was provided by the CAS Pioneer Hundred Talents Program. Declaration of Interest: None to declare. Ethical Approval: The study protocol was approved by the Institutional Review Board of First Hospital of Shanxi Medical University

S40. COMBINING PHARMACOTHERAPY OF BI 425809 WITH COMPUTERISED COGNITIVE TRAINING IN PATIENTS WITH SCHIZOPHRENIA: INITIAL EXPERIENCE OF A LARGE-SCALE MULTICENTRE RANDOMISED CLINICAL TRIAL

BackgroundThere are currently no approved medications for cognition in patients with schizophrenia. BI 425809, a glycine transporter 1 inhibitor, increases glycine in the synaptic cleft and may improve glutamatergic neurotransmission, synaptic neuroplasticity, and cognition. Pharmacotherapies targeting neuroplasticity may require concurrent cognitive stimulation, and often the surroundings of patients with schizophrenia provide only a low level of cognitive demand. At-home computerised cognitive training (CCT) should increase the level of cognitive stimulation for these patients. Combining CCT with pharmacotherapy could therefore improve cognition in patients with schizophrenia. CCT studies are currently limited in scale and are associated with challenges, such as patient compliance.This ongoing study explores whether at-home CCT combined with BI 425809 could improve cognition, as compared with patients on at-home CCT and placebo, in patients with schizophrenia. Here, we provide an initial reflection on the experiences and challenges associated with setting up this large-scale clinical trial, in addition to an update on recruitment trajectories.MethodsThis is a Phase II, double-blind, placebo-controlled, parallel group trial in patients with schizophrenia on stable antipsychotic therapy, across ~50 centres in 6 countries. Recruitment commenced in June 2019. Patients (aged 18–50 years) must demonstrate compliance with CCT during a 2-week run-in period; this means completing at least 2 hours/week (i.e. 4 hours total during screening). Only CCT-compliant patients are randomised (1:1) to BI 425809 or placebo once daily on top of CCT for 12 weeks. The target duration for at-home CCT is ~30 hours, across 3–5 sessions (2.5 hours total) per week. The primary endpoint is change from baseline in neurocognitive composite score of the Measurement and Treatment Research to Improve Cognition in Schizophrenia Consensus Cognitive Battery after 12 weeks of treatment. Novel exploratory endpoints include the Virtual Reality Functional Capacity Assessment Tool to assess daily functioning and the Balloon Effort Task to assess motivation in cognitive performance and, its association with patients’ willingness to comply with at-home CCT.ResultsTo date, 32 patients have been screened and 11 randomised (21 patients failed screening, primarily due to non-compliance with CCT run-in). The last patient out is planned for December 2020 and results are expected in Q1 2021. Patients randomised so far (n=11; 82% male) have a mean age of 33 years; those who failed screening (n=21; 67% male) have a mean age of 36 years. Mean MCCB total scores for the two groups are 30.9 and 22.3; Positive and Negative Syndrome Scale (PANNS) total scores: 71.3 vs 77.9; and PANNS negative symptom scores: 20.5 vs 20.3, for the randomised and screen failure patients, respectively.DiscussionIt is expected that the results of this trial will help to: indicate if there is an enhanced benefit of combining pharmacotherapy with cognitive stimulation through at-home CCT; and determine the role of motivation in CCT compliance and performance in patients with schizophrenia. The main reason for screen failures was non-compliance with CCT run-in, underscoring the relevance of coaching and motivational accompaniment to promote adherence to CCT. The results will indicate if large-scale implementation of at-home CCT across multiple centres and several countries is feasible.

Obesity in Chinese patients with chronic schizophrenia: Prevalence, clinical correlates and relationship with cognitive deficits

The prevalence of obesity in schizophrenia patients is high, especially in chronic and medicated patients. Few studies have explored the relationships between obesity, cognition and clinical correlates in patients with schizophrenia. This study was designed to assess the prevalence and clinical correlates of obesity and its relationship to cognitive impairment in Chinese patients with schizophrenia. We recruited 633 inpatients and collected clinical, demographic data and lipid parameters. The Positive and Negative Syndrome Scale (PANSS) and its five-factor model were adopted for psychopathological symptoms. The prevalence of comorbid obesity in schizophrenia patients was 16.4%. The plasma levels of glucose, triglyceride, low density lipoprotein (LDL), apolipoprotein B, and cholesterol were higher, but high density lipoprotein (HDL) levels were lower in obese patients than those in non-obese patients (all p < 0.05). Furthermore, obese patients had lower PANSS negative symptom, cognitive factor and total scores than non-obese patients (all p < 0.05). Correlation analysis showed a significant correlation between BMI and the following variables: age, marriage, gender, negative symptoms, general psychopathological symptoms, cognitive factor, PANSS total score, glucose, triglycerides, HDL, LDL, cholesterol and apolipoprotein B (all p < 0.05). Further multiple regression showed that PANSS cognitive factor, PANSS total score, and triglyceride were important independent predictors of obesity. Our results indicate a high prevalence of obesity in Chinese patients with chronic schizophrenia. Multiple demographics, clinical variables, and lipid parameters are associated with obesity in schizophrenia. Moreover, obesity appears to be a protective factor for psychological symptoms. However, not having objective assessments for cognition in this study is a limitation.

Metabolic profiling identifies TC and LDL as potential serum biomarkers for depressive symptoms in schizophrenia

This study aimed to explore the relationship between serum levels of cardiometabolic biomarkers and depressive symptoms in schizophrenia patients treated with atypical antipsychotics. A total of 210 patients with schizophrenia and 70 healthy controls were recruited in our present study. All patients were rated on the 17-item Hamilton Depression Rating Scale (HAMD-17) to measure depressive symptoms and the Positive and Negative Syndrome Scale (PANSS) for psychopathology. Serum cardiometabolic biomarkers (HDL, LDL, TC, TG, GLU) in all participants were measured. Our results showed that schizophrenia patients had higher levels of serum GLU, TG, TC, LDL and BMI, but lower levels of HDL than controls (all P < 0.05). Compared to patients without depressive symptoms, those with depressive symptoms showed higher PANSS total, general psychopathology, positive and negative symptom scores (all p < 0.05), as well as higher serum levels of LDL (p < 0.001) and TC (p = 0.011). In addition, our correlation analysis showed that serum LDL (P < 0.001) and TC (P = 0.045) levels were positively associated with HAMD total scores in schizophrenia patients after age, sex and education levels were controlled. Our results suggest the appearance of depression in schizophrenia patients may be associated with high levels of metabolic parameters, especially TC and LDL.

Linking PANSS negative symptom scores with the Clinical Global Impressions Scale: understanding negative symptom scores in schizophrenia

Understanding how rating scale improvement corresponds to a clinical impression in patients with negative symptoms of schizophrenia may help define the clinical relevance of change in this patient population. We conducted post hoc equipercentile linking analyses of Positive and Negative Syndrome Scale (PANSS) outcomes (e.g., PANSS-Factor Score for Negative Symptoms [FSNS]) with Clinical Global Impressions-Improvement (CGI-I) and -Severity (CGI-S) ratings on data from patients treated with cariprazine (n = 227) or risperidone (n = 229) in a clinical study evaluating negative symptoms in schizophrenia. Patients were prospectively selected for persistent, predominant negative symptoms of schizophrenia (PNS), and minimal positive/depressive/extrapyramidal symptoms. Linking results demonstrated that greater improvement on PANSS-derived measures corresponded to clinical impressions of greater improvement, as measured by the CGI-I, and less severe disease states, as measured by the CGI-S. For example, CGI-S scores of 1 (normal), 2, 3, 4, 5, and 6 (severely ill) corresponded to PANSS-FSNS scores of 7, 13, 19, 24, 29, and 35, respectively. Likewise, CGI-I scores of minimally improved, much improved, and very much improved corresponded to a change from baseline in PANSS-FSNS scores of −27%, −49%, and −100%, respectively. These are important findings for the interpretation of the results of trials in patients with persistent negative symptoms.

Efficacy and Safety of MIN-101: A 12-Week Randomized, Double-Blind, Placebo-Controlled Trial of a New Drug in Development for the Treatment of Negative Symptoms in Schizophrenia.

The authors assessed the efficacy, safety, and tolerability of MIN-101, a compound with affinities for sigma-2 and 5-HT2A receptors and no direct dopamine affinities, in comparison with placebo in treating negative symptoms in stabilized patients with schizophrenia. The trial enrolled 244 patients who had been symptomatically stable for at least 3 months and had scores of at least 20 on the negative subscale of the Positive and Negative Syndrome Scale (PANSS). After at least 5 days' withdrawal from all antipsychotic medication, patients were randomly assigned to receive placebo or 32 mg/day or 64 mg/day of MIN-101 for 12 weeks. The primary outcome measure was the PANSS negative factor score (pentagonal structure model). Secondary outcome measures were PANSS total score and scores on the Clinical Global Impressions Scale (CGI), the Brief Negative Symptom Scale, the Brief Assessment of Cognition in Schizophrenia, and the Calgary Depression Scale for Schizophrenia. A statistically significant difference in PANSS negative factor score was observed, with lower scores for the MIN-101 32 mg/day and 64 mg/day groups compared with the placebo group (effect sizes, d=0.45 and d=0.57, respectively). Supporting these findings were similar effects on several of the secondary outcome measures, such as the PANSS negative symptom, total, and activation factor scores, the CGI severity item, and the Brief Negative Symptom Scale. There were no statistically significant differences in PANSS positive scale score between the MIN-101 and placebo groups. No clinically significant changes were observed in vital signs, routine laboratory values, weight, metabolic indices, and Abnormal Involuntary Movement Scale score. MIN-101 demonstrated statistically significant efficacy in reducing negative symptoms and good tolerability in stable schizophrenia patients.

Prevalence, demographic and clinical features of comorbid depressive symptoms in drug naïve patients with schizophrenia presenting with first episode psychosis

Depressive symptoms are common in first episode schizophrenia. However, the prevalence and its associations of comorbid depressive symptoms with clinical variables are less well characterized in Chinese Han patients with schizophrenia. In this cross-sectional study, we recruited 240 first-episode and drug naïve (FEDN) inpatients with schizophrenia. All patients were rated on the 17-item Hamilton Depression Rating Scale (HAMD-17) to measure depressive symptoms, and also on the Positive and Negative Syndrome Scale (PANSS) for psychopathology. Our results showed that 131 patients had a total score of 8 or more points on HAMD-17, making the prevalence of comorbid depressive symptoms 54.6%. Fewer women (48.1%, 62 of 129) than men (62.2%, 69 of 111) had comorbid depressive symptoms. Compared to those patients without depressive symptoms, those with depressive symptoms showed higher PANSS total, general psychopathology, cognitive factor and negative symptom scores (all p<0.05). Further stepwise multiple logistic regression analysis indicated that the PANSS general psychopathology, the PANSS total score and gender (all p<0.05) remained significantly associated with depressive symptoms. In addition, correlation analysis showed significant correlations between HAMD total score and the following parameters: the PANSS general psychopathology, total score, and cognitive factor (Bonferroni corrected p's<0.05). Our results suggest that depressive symptoms occur with high prevalence in FEND schizophrenia in a Chinese Han population, and show association with general psychopathology, as well as with cognitive impairment.

Effectiveness of amisulpride in Chinese patients with predominantly negative symptoms of schizophrenia: a subanalysis of the ESCAPE study.

BackgroundEffective management strategies for the negative symptoms of schizophrenia remain an unmet need, and data on the use of antipsychotics in this population are scarce, particularly in Chinese patients. Therefore, we investigated amisulpride for the treatment of Chinese patients with predominantly negative symptoms of schizophrenia.MethodsThis post hoc subanalysis of the prospective Effectiveness and Safety of Amisulpride in Chinese Patients with Schizophrenia (ESCAPE) study included adult Chinese patients with an International Classification of Diseases-10 diagnosis of schizophrenia and predominantly negative symptoms, who received amisulpride for 8 weeks. Effectiveness outcomes included ≥50% decrease in Positive and Negative Syndrome Scale (PANSS) negative score, and a reduction in PANSS negative symptom score and Clinical Global Impression Severity Scale (CGI-S). The study was registered at ClinicalTrials.gov (NCT01795183).ResultsIn total, 26 patients were included in the analysis. A ≥50% decrease in PANSS negative score from baseline to week 8 was achieved by 34.6% of patients. From baseline to week 8, the mean PANSS negative symptom score decreased by 45.2% (31.9 to 20.7) and CGI-S decreased 1.9 points (5.2 to 3.3). The mean week 8 dose of amisulpride was lower for patients who achieved a ≥50% decrease in PANSS negative score at week 8 versus those who did not (481.2 vs 704.1 mg/day). The most common treatment-related adverse events included blood prolactin increase (19.2%) and extrapyramidal disorder (19.2%). Weight gain was reported by one patient.ConclusionAmisulpride effectively reduced PANSS negative symptom score and CGI-S for Chinese patients with predominantly negative symptoms of schizophrenia. No unexpected adverse events were reported.

111. Efficacy and Safety of MIN-101: A New Drug for the Treatment of Negative Symptoms in Schizophrenia. A 12-Week Randomized, Double-Blind, Placebo-Controlled Trial

Background: To compare the efficacy, safety, and tolerability of MIN-101, a compound with high affinities for sigma 2 and 5-HT2A receptors, to placebo in treating negative symptoms, in stabilized patients with schizophrenia. Methods: This multi-national Phase 2b trial enrolled 244 patients diagnosed with schizophrenia who were symptomatically stable for ≥3 months prior to entering the trial and had scores ≥20 on the three factors negative subscale of the Positive and Negative Syndrome Scale (PANSS). Patients were randomized to monotherapy with MIN 101 32 mg/day, MIN-101 64 mg/day or placebo in a 1:1:1 ratio. The primary endpoint was the PANSS negative symptom score based on the five factors (pentagonal) model. Secondary outcomes were the three factors PANSS negative symptom subscale score, the PANSS total score, the PANSS positive symptom score, the Clinical Global Impression (CGI), the Brief Negative Symptoms Scale (BNSS), the Brief Assessment of Cognition in Schizophrenia (BACS), the Calgary Depression Scale for Schizophrenia (CDSS), and the Personal and Social Performance (PSP) scale. Safety parameters included treatment-emergent adverse events (TEAE), clinical laboratory, vital signs, electrocardiograms, Sheehan-suicidality tracking scale (S-STS), and the Abnormal Involuntary Movement Scale (AIMS). The Mixed-Effect Model Repeated Measure (MMRM) was used for analyzing the efficacy data. Results: The three treatment groups were balanced on all demographic and illness-related baseline characteristics. Statistically significant reduction in the primary endpoint score was demonstrated for MIN-101 32 mg and 64 mg compared to placebo (P ≤ .022, ES 0.45 and ≤ .003, ES 0.58, respectively). This was supported by similar effects on most of the secondary measurements including: the PANSS three factors negative symptoms subscale, PANSS total score, CGI, BACS, CDSS, and PSP. There were no statistically significant differences in PANSS positive subscale scores between MIN 101 and placebo. No weight gain or clinically significant changes in vital sings, prolactin levels, routine laboratory values, metabolic indices and extrapyramidal symptom scores (EPS) were observed. One patient on 64 mg MIN-101 was discontinued from the trial based on a-priori established QT interval prolongation criteria and a second one following an episode of syncope. Conclusion: MIN-101 at dosages of 32 and 64 mg/day demonstrated statistically significant efficacy of medium ES in reducing negative symptoms and good tolerability in stable schizophrenia patients. Since positive symptoms and EPS did not change, the improvement in negative symptoms was not secondary to improvement in positive symptoms or EPS, suggesting that MIN-101 might be the first specific treatment to have a direct effect on negative symptoms.

Elevated copper, hs C-reactive protein and dyslipidemia in drug free schizophrenia: Relation with psychopathology score.

Inflammation, dyslipidemia and altered copper levels have been reported in several psychiatric disorders, including schizophrenia. However, their association with the severity of psychopathology in schizophrenia is yet to be established. The present study was designed to assess the serum levels of copper, highly sensitive C-reactive protein (hs-CRP) and lipid profile and to explore their association with psychopathology scores in schizophrenia. 40 cases and 40 controls were included in the study. Serum copper, hs-CRP and lipid profile were estimated in all the subjects. Disease severity was assessed using Positive and Negative Syndrome Scale (PANSS). Copper, hs-CRP, total cholesterol and LDL-Cholesterol were significantly increased and HDL-Cholesterol was significantly reduced in schizophrenia cases when compared with controls. Copper was positively correlated with hs-CRP (r=0.338, p=0.003). Total cholesterol was significantly correlated with PANSS total (r=0.452, p=0.003) and negative symptom scores (r=0.337, p=0.033). Triacylglycerol was positively correlated with general psychopathology symptom score (r=0.416, p=0.008). Copper and hs-CRP were increased and correlated well with each other in schizophrenia cases. Though total cholesterol and triacylglycerol showed positive association with severity of the psychopathology, copper and hs-CRP were not associated with the disease severity.

Neural Correlates of RTMS Treatment of Negative Symptoms

Repetitive Transcranial Magnetic Stimulation (rTMS) of the frontal cortex has been shown to improve negative symptoms in schizophrenia in a number of small studies, although inconsistent results have also been reported. Neuroimaging has shown bilateral hypofrontality in schizophrenia, and rTMS may improve brain activation. We therefore aimed to investigate whether 10 Hz stimulation of the bilateral dorsolateral prefrontal cortex during 3 weeks would yield substantial treatment effects and would improvement of frontal activation. Methods This study concerned a multicenter double-blind randomized controlled trial in 32 patients with schizophrenia or schizoaffective disorder. All had moderate to severe negative symptoms (Positive and Negative Syndrome Scale (PANSS) negative subscale ≥ 15). Patients were randomized to a 3-week course of active or sham rTMS. Primary outcome was severity of negative symptoms as measured with the Scale for the Assessment of Negative Symptoms (SANS) and the PANSS negative symptom score. Twenty-four patients participated in the pre- and posttreatment fMRI measurement. Analyses concerned changes in brain activation as measured with functional magnetic resonance imaging (fMRI) during the Tower of London (ToL) task from pre-treatment to post-treatment. Results Brain activation increased more in the active group in the right DLPFC and the right medial frontal gyrus as compared to the sham group. Different activation change was also found in the left posterior cingulate, with decreased activation in the active and increased activation in the sham group. The changes in brain activation were accompanied by a significant improvement of negative symptoms in the treatment group ( p =0.04). Conclusions Our findings suggest that treatment with rTMS over the DLPFC may potentially increase task-related activation in frontal areas and improve negative symptoms in patients with schizophrenia.

Efficacy of bilateral repetitive transcranial magnetic stimulation for negative symptoms of schizophrenia: results of a multicenter double-blind randomized controlled trial.

Few studies have investigated the efficacy of repetitive transcranial magnetic stimulation (rTMS) treatment for negative symptoms of schizophrenia, reporting inconsistent results. We aimed to investigate whether 10Hz stimulation of the bilateral dorsolateral prefrontal cortex during 3 weeks enhances treatment effects. A multicenter double-blind randomized controlled trial was performed in 32 patients with schizophrenia or schizo-affective disorder, and moderate to severe negative symptoms [Positive and Negative Syndrome Scale (PANSS) negative subscale ⩾15]. Patients were randomized to a 3-week course of active or sham rTMS. Primary outcome was severity of negative symptoms as measured with the Scale for the Assessment of Negative Symptoms (SANS) and the PANSS negative symptom score. Secondary outcome measures included cognition, insight, quality of life and mood. Subjects were followed up at 4 weeks and at 3 months. For analysis of the data a mixed-effects linear model was used. A significant improvement of the SANS in the active group compared with sham up to 3 months follow-up (p = 0.03) was found. The PANSS negative symptom scores did not show a significant change (p=0.19). Of the cognitive tests, only one showed a significant improvement after rTMS as compared with sham. Finally, a significant change of insight was found with better scores in the treatment group. Bilateral 10Hz prefrontal rTMS reduced negative symptoms, as measured with the SANS. More studies are needed to investigate optimal parameters for rTMS, the cognitive effects and the neural basis.

Smoking and BDNF Val66Met polymorphism in male schizophrenia: A case-control study

Some recent studies show an association between a functional polymorphism of BDNF gene (Val66Met) and the susceptibility to nicotine dependence and we hypothesized that this polymorphism was associated with smoking in both schizophrenia patients and healthy controls. The BDNF Val66Met gene polymorphism was genotyped in 690 chronic male schizophrenia patients (smoker/nonsmoker = 522/169) and 628 male controls (smoker/nonsmoker = 322/306) using a case-control design. Nicotine dependence (ND) was assessed by the cigarettes smoked per day (CPD), the Heaviness of Smoking Index (HSI), and the Fagerstrom Test for ND (FTND). Patients also were rated on the Positive and Negative Syndrome Scale (PANSS). The results showed no significant differences in BDNF Val66Met genotype and allele distributions between the patients and healthy controls or between smokers and nonsmokers in either patients or healthy controls alone. In patient groups, however, the smokers with the Met allele had significantly higher HSI scores (Met/Met: 2.8 ± 1.7 vs. Met/Val: 2.2 ± 1.7 vs. Val/Val: 2.0 ± 1.6, p < 0.01) and a trend toward a significantly higher FTND score (p = 0.09) than those with the Val/Val genotype. In addition, the smokers showed significantly lower PANSS negative symptom and total scores, longer duration of illness and more hospitalizations (all p < 0.05). In the control group, the smokers with the Met allele started smoking significantly earlier than those with the Val/Val genotype (both p < 0.05). These results suggest that the BDNF Val66Met polymorphism may affect a smoker's response to nicotine in both schizophrenia and healthy controls from a Chinese Han population, but with differential effects in different aspects of smoking behaviors.

An Exploratory, Open-Label, Randomized Trial Comparing Risperidone Long-Acting Injectable with Oral Antipsychotic Medication in the Treatment of Early Psychosis

Few studies have examined effectiveness and tolerability of risperidone long-acting injections (RLAI) in the early phase of a schizophrenia spectrum (SS) disorder using a randomized controlled trial (RCT) design. Eighty-five patients in early phase of an SS disorder were randomized to receive either oral second-generation antipsychotics (SGAs; n=41) or RLAI (n=44) over two years. Analyses were conducted on eligible participants (n=77) for the stabilization (maximum 18 weeks) and maintenance phases (up to Week 104) on primary outcome measures of time to stabilization and relapse, change in symptoms and safety, and comparisons made across the two groups. Both groups showed improvement on Positive and Negative Syndrome Scale (PANSS) scores and Clinical Global Impression-Severity (CGI-S) scores. There were no time X group interactions on any of the primary outcome measures. Post hoc examination revealed that the RLAI group showed greater change on CGI-S and PANSS negative symptom scores during the stabilization phase, while the oral group reached the same level of improvement during the maintenance phase. The current exploratory study suggests that-within an RCT design-RLAI and oral SGAs are equally effective and have similar safety profiles in patients in the early phase of SS disorders. Thus, RLAI offers no advantage to patients in early phase of SS disorders, but is likely to be effective and safe for those who may have problems with adherence and may either choose to take it or be prescribed under conditions of external control such as community treatment orders.