Improvement In Negative Symptoms Research Articles

A Randomized, Placebo-Controlled Study Investigating the Nicotinic α7 Agonist, RG3487, for Cognitive Deficits in Schizophrenia

Effective treatments for cognitive impairment associated with schizophrenia (CIAS) remain an unmet need. Nicotinic α7 receptor agonists may be effective in CIAS. This 8-week (week 1, inpatient; weeks 2-8, outpatient), double-blind, randomized study used Measurement And Treatment Research to Improve Cognition in Schizophrenia (MATRICS) guidelines to investigate the nicotinic α7 partial agonist RG3487 (formerly MEM3454) in CIAS; 215 patients with chronic stable schizophrenia received placebo or RG3487 (5, 15, or 50 mg) added to ongoing treatment with risperidone, paliperidone, or aripiprazole. Primary end point was baseline to week 8 change in MATRICS Consensus Cognitive Battery (MCCB) composite t-score. Secondary outcomes were change in MCCB domain and negative symptom assessment (NSA) scores. The study did not allow for evaluation of nonsmokers. Each RG3487 dose was evaluated using a mixed-effects model repeated measures approach. Mean (SD) baseline MCCB composite t-score was 28.3 (12.0). No significant effect on MCCB composite t-scores was observed with RG3487 (adjusted mean difference (SE) vs placebo: 5 mg: 0.11 (1.39); 15 mg: -1.95 (1.39); 50 mg: -1.13 (1.37); p = 0.2-0.9). RG3487 did not improve MCCB domain scores. In a post hoc analysis of patients with moderate negative symptoms, 5 and 50 mg RG3487 vs placebo significantly improved NSA total (-4.45 (p = 0.04) and -4.75 (p = 0.02), respectively) and global (-0.39 (p = 0.04) and -0.55 (p = 0.003), respectively) scores. The MCCB did not lead to higher than expected patient withdrawal. RG3487 was generally well tolerated. In patients with stable schizophrenia, RG3487 did not improve cognitive deficits, as assessed by the MCCB; however, in patients with moderate negative symptoms, a post hoc analysis revealed significant improvement of negative symptoms.

Efficacy of amisulpride and olanzapine for negative symptoms and cognitive impairments: An open-label clinical study.

Background:Negative symptoms and diminished cognitive ability are also considered as core features of schizophrenia. There are many studies in which negative symptoms and cognitive impairments are individually treated with atypical antipsychotic in comparison with either a placebo or a typical antipsychotic. There is paucity of studies comparing the efficacy of olanzapine and amisulpride on improvement of negative symptoms and cognitive impairments.Aim:To examine the effectiveness of amisulpride and olanzapine in treatment of negative symptoms and cognitive impairments in schizophrenia.Materials and Methods:Total 40 adult inpatients diagnosed as schizophrenia fulfilling inclusion/exclusion criteria were included in the study with their informed consent. These patients were recruited consecutively to one of the two drug regimen group, i.e. tab Amisulpride (100-300 mg/day) and tab Olanzapine (10-20 mg). Patients were evaluated on day 0 and day 60 with various rating scales like Scale for the Assessment of Negative Symptoms (SANS), Scale for the Assessment of Positive Symptoms (SAPS), Schizophrenia Cognition Rating Scale (SCoRS), Brief Psychiatric Rating Scale (BPRS), Calgary Depression Scale for Schizophrenia (CDSS), and three different scales to measure drug side effects.Results:The mean SANS score in amisulpride and olanzapine group at day 0 and day 60 were 83.89 (±12.67) and 21.00 (±11.82) and 84.40 (±13.22) and 26.75 (±12.41), respectively. The mean rank of SCoRS global in amisulpride and olanzapine group at day 0 and day 60 were 4.78 (±1.13) and 2.78 (±0.63) and 4.85 (±1.18) and 3.30 (±1.12), respectively. The percentage improvement in SANS, SAPS, SCoRS interviewer, and SCoRS global in amisulpride group are 74.96%, 13.36%, 54.14%, and 42.00%, respectively. Similarly in olanzapine group percentage improvement in SANS, SAPS, SCoRS interviewer, and SCoRS global are 68.30%, 30.28%, 35.22%, and 31.95%, respectively. There is significant improvement in SANS, SCoRS, SAS, BPRS, and PANSS (Insight) in both amisulpride and olanzapine groups at the two time points. However, there is no significant difference between amisulpride and olanzapine group of patients.Conclusion:Both amisulpride and olanzapine group patients showed significant improvement in negative and cognitive symptoms from baseline to endpoint, but there was no significant difference between amisulpride and olanzapine group of patients.

EPA-1454 - TMS and negative symptoms

In schizophrenia negative symptoms often persist and determine an unfavourable course. Reviews including studies with small sample sizes indicate improvement of negative symptoms in schizophrenia patients by repetitive transcranial magnetic stimulation (rTMS), but provide heterogenous results. To prove the clinical efficacy of rTMS on negative symptoms trials with larger samples of patients are needed. In a multicentre randomized, sham-controlled, rater- and patient-blind clinical trial including 197 patients we investigated the efficacy and tolerability of a 3 week 10 Hertz (Hz) rTMS add-on to antipsychotic therapy (in total 15000 stimuli, stimulation intensity 110 % of the individual motor threshold) over the left dorso-lateral prefrontal cortex (LDLPFC) immediately after treatment and during a 12 weeks follow-up. According to our primary outcome parameter we observed a significant decline in negative symptoms (negative sum score of the PANSS) in the verum and sham group (N = 124), but could not find a significant superior reduction in the verum group at day 21. At day 28 significant more patients in the verum compared to the sham group showed a clinical meaningful reduction of PANSS negative subscore (= 20 %) (N = 89; 57.5 % vs. 32.7 %, p = 0.033), however this effect did not persist at further follow-up. High-frequency (10 Hz) rTMS of LDLPFC over 3 weeks provided only a small benefit in the reduction of negative symptoms, however HF-rTMS was well tolerated. We discuss our results in comparison to current meta-analyses and previous studies. ClinicalTrials.gov NCT00783120.

EPA-1149 – Assessment of negative and affective symptoms in a group of women with schizophrenia who are in treatment with paliperidone long acting injection

Evaluate the psychopathological changes in a group of women who suffer schizophrenia, before and after beginning treatment with paliperidone long acting injection. We focus on affective and negative symptons. We recruit the women from Vallecas Villa Mental Health Centre who initiate paliperidone long acting injection, from 1st of January of 2013. We use for the assessment: Positive and Negative Syndrome Scale (PANSS), Hamilton Depression Rating Scales (HDRS), Clinical Global Impression-Schizophrenia (CG-ISCH), Global Assessment Scale (GAF), Subjective Wellbeing under Neuroleptics (SWN-K) before beginning the treatment and 2 months later. Our sample was formed by 20 women, only one left the treatment for secondary effects. In baseline all women were severely ill to moderate ill in Clinical Global Impression Scale. The results in baseline and two months after treatment can be read in table 1. The patients improve in all the scales: in GAF scale the functionality of the patients change from 48 to 62. This recovery seems related with the improvement in affective and negative symptoms, but not with positive symptoms (in fact in baseline mild-moderate). Schizophrenia is more than positive symptoms, sometimes the lack of functionality is related with other group of symptoms that initially are considered secondary: affective and negative. TABLE 1 Baseline After AGE A 40,23 (9,4) PANSS-P 21,92 (8,9) 13,84 (5,9) PANSS-N 25,23 (8,1) 18,76 (6,5) PANSS-PG 50 (10,5) 36,53 (12,26) PANSS-Total 97,15 (20,02) 69,15 (22,13) EAAG 48,07 (11,99) 62,3 (10,53) HAMILTON 18,15 (6,3) 10,38 (8,3) SWN-K 58,76 (11,27) 74,15 (18,14)

EPA-1551 - Paliperidone palmitate – impact on negative, disorganized and depressive symptoms, subjective well-being and patient satisfaction in patients with schizophrenia previously unsuccessfully treated with oral antipsychotics

Negative, disorganized and depressive symptoms are among the major unmet needs in the treatment of patients with schizophrenia. The objective of this analysis was to explore the impact of flexibly dosed paliperidone palmitate (PP) on negative and depressive symptoms, disorganized thoughts, subjective well-being and treatment satisfaction in adult non-acute but symptomatic patients with schizophrenia previously unsuccessfully treated with oral antipsychotics. International, prospective 6-month open-label multicenter study. Outcomes analyzed were changes from baseline to endpoint in negative symptoms, disorganized thoughts and anxiety/depression Marder factors of the Positive and Negative Syndrome Scale (PANSS), patient well-being (Subjective Well-Being with Neuroleptics, short version), and patient treatment satisfaction. 593 patients (intent-to-treat population), 63.1% male, mean age 38.4±11.8 years, 78.6% paranoid schizophrenia, were analyzed. 74.5% of patients completed the study. Mean baseline PANSS negative subscale scores (20.2±5.4) improved significantly by -3.5±5.4 points from baseline to endpoint (95% confidence interval [CI] -3.9;-3.0), the PANSS negative symptoms Marder factor score improved from 19.6±5.6 to 16.1±5.7 (95%CI of change -3.9;-3.1), and the disorganized thoughts Marder factor score improved from 16.2±4.4 to 13.9±4.6 (95%CI -2.6;-1.9). Similarly, the anxiety/depression Marder factor score improved from 9.3±3.1 to 7.6±3.1 (95%CI -2.0;-1.5, all p<0.0001). Subjective well-being (SWN-S) increased from 80.1±17.2 at baseline to 85.5±17.3 at endpoint (95%CI 4.0;6.7), and treatment satisfaction improved significantly from 55.3±19.6 to 63.9±22.8 (95%CI 6.4;11.0, both p<0.0001). Paliperidone palmitate treatment of non-acute but symptomatic patients with schizophrenia showed significant and clinically relevant improvements in negative and depressive symptoms, disorganized thoughts, subjective well-being and patient treatment satisfaction.

Randomized clinical trial of cognitive behavioral social skills training for schizophrenia: improvement in functioning and experiential negative symptoms.

Identifying treatments to improve functioning and reduce negative symptoms in consumers with schizophrenia is of high public health significance. In this randomized clinical trial, participants with schizophrenia or schizoaffective disorder (N = 149) were randomly assigned to cognitive behavioral social skills training (CBSST) or an active goal-focused supportive contact (GFSC) control condition. CBSST combined cognitive behavior therapy with social skills training and problem-solving training to improve functioning and negative symptoms. GFSC was weekly supportive group therapy focused on setting and achieving functioning goals. Blind raters assessed functioning (primary outcome: Independent Living Skills Survey [ILSS]), CBSST skill knowledge, positive and negative symptoms, depression, and defeatist performance attitudes. In mixed-effects regression models in intent-to-treat analyses, CBSST skill knowledge, functioning, amotivation/asociality negative symptoms, and defeatist performance attitudes improved significantly more in CBSST relative to GFSC. In both treatment groups, comparable improvements were also found for positive symptoms and a performance-based measure of social competence. The results suggest CBSST is an effective treatment to improve functioning and experiential negative symptoms in consumers with schizophrenia, and both CBSST and supportive group therapy actively focused on setting and achieving functioning goals can improve social competence and reduce positive symptoms.

The longitudinal interplay between negative and positive symptom trajectories in patients under antipsychotic treatment: a post hoc analysis of data from a randomized, 1-year pragmatic trial

BackgroundSchizophrenia is a highly heterogeneous disorder with positive and negative symptoms being characteristic manifestations of the disease. While these two symptom domains are usually construed as distinct and orthogonal, little is known about the longitudinal pattern of negative symptoms and their linkage with the positive symptoms. This study assessed the temporal interplay between these two symptom domains and evaluated whether the improvements in these symptoms were inversely correlated or independent with each other.MethodsThis post hoc analysis used data from a multicenter, randomized, open-label, 1-year pragmatic trial of patients with schizophrenia spectrum disorder who were treated with first- and second-generation antipsychotics in the usual clinical settings. Data from all treatment groups were pooled resulting in 399 patients with complete data on both the negative and positive subscale scores from the Positive and Negative Syndrome Scale (PANSS). Individual-based growth mixture modeling combined with interplay matrix was used to identify the latent trajectory patterns in terms of both the negative and positive symptoms. Pearson correlation coefficients were calculated to examine the relationship between the changes of these two symptom domains within each combined trajectory pattern.ResultsWe identified four distinct negative symptom trajectories and three positive symptom trajectories. The trajectory matrix formed 11 combined trajectory patterns, which evidenced that negative and positive symptom trajectories moved generally in parallel. Correlation coefficients for changes in negative and positive symptom subscale scores were positive and statistically significant (P < 0.05). Overall, the combined trajectories indicated three major distinct patterns: 1) dramatic and sustained early improvement in both negative and positive symptoms (n = 70, 18%), 2) mild and sustained improvement in negative and positive symptoms (n = 237, 59%), and 3) no improvement in either negative or positive symptoms (n = 82, 21%).ConclusionsThis study of symptom trajectories over 1 year shows that changes in negative and positive symptoms were neither inversely nor independently related with each other. The positive association between these two symptom domains supports the notion that different symptom domains in schizophrenia may depend on each other through a unified upstream pathological disease process.

D2receptor occupancy following lurasidone treatment in patients with schizophrenia or schizoaffective disorder

OBJECTIVE/INTRODUCTION: Lurasidone is an atypical antipsychotic medication approved for the treatment of schizophrenia over a dose range of 40-160 mg/day. This study examined D2 receptor occupancy and its association with clinical improvement and side effects in patients with schizophrenia or schizoaffective disorder following repeated doses of 80, 120, or 160 mg/day of lurasidone. Twenty-five patients with The Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV) diagnoses of schizophrenia or schizoaffective disorder were washed out of their antipsychotic medications (5 half-lives) and randomly assigned to 80, 120, or 160 mg/day of lurasidone. Subjects were imaged with 18F-fallypride at baseline and at steady-state lurasidone treatment to determine D2 receptor occupancy. Blood lurasidone concentration (plus major metabolite), but not dose, significantly correlated with D2 receptor occupancy. D2 receptor occupancy in several subcortical structures is associated with positive but not negative symptom improvement or the presence of movement symptoms. Blood concentrations greater than 70 ng/mL may be required to achieve a 65% occupancy level in subcortical areas. Intersubject blood concentrations at fixed dose were highly variable and may account for the lack of dose correlations. Positron emission tomography (PET) occupancy data suggest that greater than 65% occupancy can be achieved across the dose range of 80-160 mg/day and that some patients require higher doses to achieve antipsychotic efficacy; this finding supports prior randomized clinical trial results.

A virtual reality-integrated program for improving social skills in patients with schizophrenia: A pilot study

Background and objectivesSocial skills training (SST) intervention has shown its efficacy to improve social dysfunction in patients with psychosis; however the implementation of new skills into patients' everyday functioning is difficult to achieve. In this study, we report results from the application of a virtual reality (VR) integrated program as an adjunct technique to a brief social skills intervention for patients with schizophrenia. It was predicted that the intervention would improve social cognition and performance of patients as well as generalisation of the learned responses into patient's daily life. MethodsTwelve patients with schizophrenia or schizoaffective disorder completed the study. They attended sixteen individual one-hour sessions, and outcome assessments were conducted at pre-treatment, post-treatment and four-month follow-up. ResultsThe results of a series of repeated measures ANOVA revealed significant improvement in negative symptoms, psychopathology, social anxiety and discomfort, avoidance and social functioning. Objective scores obtained through the use of the VR program showed a pattern of learning in emotion perception, assertive behaviours and time spent in a conversation. Most of these gains were maintained at four-month follow-up. LimitationsThe reported results are based on a small, uncontrolled pilot study. Although there was an independent rater for the self-reported and informant questionnaires, assessments were not blinded. ConclusionsThe results showed that the intervention may be effective for improving social dysfunction. The use of the VR program contributed to the generalisation of new skills into the patient's everyday functioning.

Converging Evidence for the Association of Functional Genetic Variation in the Serotonin Receptor 2a Gene With Prefrontal Function and Olanzapine Treatment

Serotonin (5-hydroxytryptamine) receptor 2a (5-HT2AR) signaling is important for modulation of corticostriatal pathways and prefrontal activity during cognition. Furthermore, newer antipsychotic drugs target 5-HT2AR. A single-nucleotide polymorphism in the 5-HT2AR gene (HTR2A rs6314, C>T; OMIM 182135) has been weakly associated with differential 5-HT2AR signaling and with physiologic as well as behavioral effects. To use a hierarchical approach to determine the functional effects of this single-nucleotide polymorphism on 5-HT2AR messenger RNA and protein expression, on prefrontal phenotypes linked with genetic risk for schizophrenia, and on treatment with olanzapine. In silico predictions, in vitro, and case-control investigations. Academic and clinical facilities. The postmortem study included 112 brains from healthy individuals; the in vivo investigation included a total sample of 371 healthy individuals and patients with schizophrenia. EXPOSURES Patients received olanzapine monotherapy for 8 weeks. In silico predictions, messenger RNA, and protein expression in postmortem human prefrontal cortex and HeLa cells, functional magnetic resonance imaging prefrontal activity and behavior during working memory and attention in healthy individuals, and response to an 8-week trial of olanzapine treatment in patients with schizophrenia. Bioinformatic analysis predicted that rs6314 alters patterns of splicing, with possible effects on HTR2A expression. Moreover, the T allele was associated with reduced prefrontal messenger RNA expression in postmortem prefrontal cortex, with reduced protein expression in vitro, inefficient prefrontal blood oxygen level-dependent functional magnetic resonance imaging response during working memory and attentional control processing, and impaired working memory and attention behavior, as well as with attenuated improvement in negative symptoms after olanzapine treatment. Our results suggest that HTR2A rs6314 affects 5-HT2AR expression and functionally contributes to genetic modulation of known endophenotypes of schizophrenia-like higher-level cognitive behaviors and related prefrontal activity, as well as response to treatment with olanzapine.

Addition of amoxapine improves positive and negative symptoms in a patient with schizophrenia

Amoxapine is a tricyclic antidepressant of the dibenzoxazepine class with a heterogeneous receptor binding profile, mainly monoamine reuptake inhibition plus antagonism of 5-HT 2a and D4/D2 receptors [Kapur et al. 1999]. It is an inhibitor of both norepinephrine (NE) and serotonin (5-HT) reuptake with Kd values of 16 and 58 nM, respectively [Tatsumi et al. 1997]. It also blocks 5-HT and dopamine (DA) receptors: at a dose of 150 mg/day amoxapine displayed 98% 5-HT2 occupancy and 63% D2 receptor occupancy by brain positron emission tomography (PET) in normal volunteers [Kapur et al. 1999]. In addition to its effects on monoamines, amoxapine acts on other neurotransmitter systems. It is a potent inhibitor of glycine transporters GLYT1b and GLYT2a [Nunez et al. 2000], and it activates delta-opioid receptors in human frontal cortex in vitro [Onali et al. 2010]. In addition, amoxapine has been shown to inhibit several K+ channels including the voltage-gated K+ [He et al. 2010] and the G protein-activated inwardly rectifying K+ (GIRK) channels [Kobayashi et al. 2011] at micromolar concentrations, the same range as the brain concentration of the drug during treatment (5–67 μM); this effect seems to be mediated through serotonin and dopamine D1/D5 receptors [Yang et al. 2011]. Amoxapine is metabolized in vivo via CYP2D6 to 7-hydroxyamoxapine, which has affinity for 5-HT2a and D2 receptors. It is also metabolized to 8-hydroxyamoxapine via CYP1A2 [Wong et al. 2012]. These various sites of action on neurotransmitters and ion channels give amoxapine a unique pharmacological profile that may be relevant for its therapeutic activity and side effects. Tardive dyskinesia and neuroleptic malignant syndrome have been described with amoxapine and attributed to its blockade of DA receptors, while seizures may be related to its activity on ion channels. Amoxapine has demonstrated efficacy in major depressive disorder, with and without psychotic features [Gelenberg et al. 1984; Anton and Burch, 1990]. Its use in schizophrenia is not as well documented. Although one small randomized placebo-controlled study of 10 schizophrenia patients did not find improvement after amoxapine [Fitzgerald et al. 2004], an open-label [Apiquian et al. 2003] and two double-blind trials demonstrated efficacy similar to risperidone and haloperidol in the treatment of psychosis, with additional improvement in negative symptoms [Chaudhry et al. 2007; Apiquian et al. 2005]. Here, we report the improvement, following amoxapine initiation, of positive and negative symptoms in a patient with schizophrenia who had shown lack of clinical response to a robust antipsychotic regimen. This case highlights the use of amoxapine for augmentation with potential to improve positive and negative symptoms of schizophrenia.

Neural markers of negative symptom outcomes in distributed working memory brain activity of antipsychotic-naive schizophrenia patients

Since working memory deficits in schizophrenia have been linked to negative symptoms, we tested whether features of the one could predict the treatment outcome in the other. Specifically, we hypothesized that working memory-related functional connectivity at pre-treatment can predict improvement of negative symptoms in antipsychotic-treated patients. Fourteen antipsychotic-naive patients with first-episode schizophrenia were clinically assessed before and after 7 months of quetiapine monotherapy. At baseline, patients underwent functional magnetic resonance imaging while performing a verbal n-back task. Spatial independent component analysis identified task-modulated brain networks. A linear support vector machine was trained with these components to discriminate six patients who showed improvement in negative symptoms from eight non-improvers. Classification accuracy and significance was estimated by leave-one-out cross-validation and permutation tests, respectively. Two frontoparietal and one default mode network components predicted negative symptom improvement with a classification accuracy of 79% (p=0.003). Discriminating features were found in the frontoparietal networks but not the default mode network. These preliminary data suggest that functional patterns at baseline can predict negative symptom treatment-response in schizophrenia. This information may be used to stratify patients into subgroups thereby facilitating personalized treatment.

A long-term, phase 2, multicenter, randomized, open-label, comparative safety study of pomaglumetad methionil (LY2140023 monohydrate) versus atypical antipsychotic standard of care in patients with schizophrenia

BackgroundWe compared the time to discontinuation due to lack of tolerability over 24 weeks in patients suffering from schizophrenia treated with pomaglumetad methionil (LY2140023 monohydrate, the prodrug of metabotropic glutamate 2/3 receptor agonist, LY404039) or standard of care (SOC: olanzapine, risperidone, or aripiprazole).MethodsStudy HBBR was a multicenter, randomized, open-label study comparing the long-term safety and tolerability of LY2140023 with SOC for schizophrenia. Patients had moderate symptomatology with prominent negative symptoms and evidence of functional impairment. Those who met entry criteria were randomized to open-label treatment with either LY2140023 (target dose: 40 mg twice daily [BID]; n = 130) or SOC (n = 131).ResultsThere was no statistically significant difference between LY2140023 and SOC for time to discontinuation due to lack of tolerability (primary objective; P = .184). The Kaplan-Meier estimates revealed comparable time to event profiles. Only 27% of LY2140023 and 45% of SOC patients completed the 24-week open-label, active treatment phase. Twenty-seven patients (20.8%) in the LY2140023 group and 15 patients (11.5%) in the SOC group discontinued due to lack of efficacy (P = .044). Twenty-three patients (17.7%) in the LY2140023 group and 19 patients (14.5%) in the SOC group discontinued due to adverse events (physician and subject decision combined, P = .505). The incidence of serious adverse events was comparable between groups. LY2140023-treated patients reported significantly more treatment-emergent adverse events of vomiting, agitation, and dyspepsia, while SOC-treated patients reported significantly more akathisia and weight gain. The incidence of treatment-emergent parkinsonism (P = .011) and akathisia (P = .029) was significantly greater in SOC group. Improvement in PANSS total score over the initial 6 to 8 weeks of treatment was similar between groups, but improvement was significantly greater in the SOC group at 24-week endpoint (P = .004). LY2140023 and SOC groups had comparable negative symptom improvement at 24-week endpoint (P = .444).ConclusionThese data provide further evidence that the potential antipsychotic LY2140023 monohydrate, with a glutamatergic mechanism of action, may have a unique tolerability profile characterized by a low association with some adverse events such as extrapyramidal symptoms and weight gain that may characterize currently available dopaminergic antipsychotics.Trials registrationA Long-term, Phase 2, Multicenter, Randomized, Open-label, Comparative Safety Study of LY2140023 Versus Atypical Antipsychotic Standard of Care in Patients with DSM-IV-TR SchizophreniaClinicalTrials.gov identifier: NCT00845026.

Improvements in Negative Symptoms and Functional Outcome After a New Generation Cognitive Remediation Program: A Randomized Controlled Trial

Cognitive remediation improves cognition in patients with schizophrenia, but its effect on other relevant factors such as negative symptoms and functional outcome has not been extensively studied. In this hospital-based study, 84 inpatients with chronic schizophrenia were recruited from Alava Hospital (Spain). All of the subjects underwent a baseline and a 3-month assessment that examined neurocognition, clinical symptoms, insight, and functional outcome according to the Global Assessment of Functioning (GAF) scale and Disability Assessment Schedule from World Health Organization (DAS-WHO). In addition to receiving standard treatment, patients were randomly assigned either to receive neuropsychological rehabilitation (REHACOP) or to a control group. REHACOP is an integrative program that taps all basic cognitive functions. The program included experts' latest suggestions about positive feedback and activities of daily living in the patients' environment. The REHACOP group showed significantly greater improvements at 3 months in the areas of neurocognition, negative symptoms, disorganization, and emotional distress compared with the control group (Cohen's effect size for these changes ranged from d = 0.47 for emotional distress to d = 0.58 for disorganization symptoms). The REHACOP group also improved significantly in both the GAF (d = 0.61) and DAS-WHO total scores (d = 0.57). Specifically, the patients showed significant improvement in vocational outcomes (d = 0.47), family contact (d = 0.50), and social competence (d = 0.56). In conclusion, neuropsychological rehabilitation may be useful for the reduction of negative symptoms and functional disability in schizophrenia. These findings support the integration of neuropsychological rehabilitation into standard treatment programs for patients with schizophrenia.

Adjunctive Lisdexamfetamine Dimesylate Therapy in Adult Outpatients With Predominant Negative Symptoms of Schizophrenia: Open-Label and Randomized-Withdrawal Phases

Negative symptoms of schizophrenia (NSS), related to hypodopaminergic activity in the mesocortical pathway and prefrontal cortex, are predictive of poor outcomes and have no effective treatment. Use of dopamine-enhancing drugs (eg, psychostimulants) has been limited by potential adverse effects. This multicenter study examined lisdexamfetamine dimesylate (LDX), a d-amphetamine prodrug, as adjunctive therapy to antipsychotics in adults with clinically stable schizophrenia and predominant NSS. Outpatients with stable schizophrenia, predominant NSS, limited positive symptoms, and maintained on stable atypical antipsychotic therapy underwent a 3-week screening, 10-week open-label adjunctive LDX (20-70 mg/day), and 4-week, double-blind, randomized, placebo-controlled withdrawal. Efficacy measures included a modified Scale for the Assessment of Negative Symptoms (SANS-18) and Positive and Negative Syndrome Scale (PANSS) total and subscale scores. Ninety-two participants received open-label LDX; 69 received double-blind therapy with placebo (n=35) or LDX (n=34). At week 10 (last observation carried forward; last open-label visit), mean (95% confidence interval) change in SANS-18 scores was -12.9 (-15.0, -10.8; P<0.0001). At week 10, 52.9% of participants demonstrated a minimum of 20% reduction from baseline in SANS-18 score. Open-label LDX was also associated with significant improvement in PANSS total and subscale scores. During the double-blind/randomized-withdrawal phase, no significant differences (change from randomization baseline) were found between placebo and LDX in SANS-18 or PANSS subscale scores. In adults with clinically stable schizophrenia, open-label LDX appeared to be associated with significant improvements in negative symptoms without positive symptom worsening. Abrupt LDX discontinuation was not associated with positive or negative symptom worsening. Confirmation with larger controlled trials is warranted.

Negative symptom improvement during cognitive rehabilitation: Results from a 2-year trial of Cognitive Enhancement Therapy

Cognitive rehabilitation has shown beneficial effects on cognition in patients with schizophrenia, which may also help to improve negative symptoms due to overlapping pathophysiology between these two domains. To better understand the possible relationship between these areas, we conducted an exploratory analysis of the effects of Cognitive Enhancement Therapy (CET) on negative symptoms. Early course schizophrenia outpatients (n=58) were randomized to 2 years of CET or an Enriched Supportive Therapy (EST) control condition. Results revealed significant and medium-sized (d=0.61) differential improvements favoring CET in overall negative symptoms, particularly social withdrawal, affective flattening, and motor retardation. Neurocognitive improvement was associated with reduced negative symptoms in CET, but not EST patients. No relationships were observed between improvements in emotion processing aspects of social cognition, as measured by the Mayer–Salovey–Caruso Emotional Intelligence Test, and negative symptoms. CET represents an effective cognitive rehabilitation intervention for schizophrenia that may also have benefits to negative symptoms. Future studies specifically designed to examine negative symptoms during the course of cognitive rehabilitation are needed.

Meta-Analysis of Efficacy of Mirtazapine as an Adjunctive Treatment of Negative Symptoms in Schizophrenia

Despite advances made in treating the positive symptoms of schizophrenia, treatment of negative symptoms remains an unmet therapeutic need. Adjunctive mirtazapine has shown promise for treatment of negative symptoms in several small clinical trials. To assess the efficacy of mirtazapine as an adjunctive treatment of negative symptoms in patients with chronic schizophrenia via meta-analysis. A systematic literature review of articles in English and Spanish was conducted in November 2011 by searching PubMed, the Cochrane Library, the Clinical Trial Registry of the NIH, and SIGLE (System for Grey Literature in Europe). Free text search terms for PubMed were "schizophrenia," "negative symptoms" and "mirtazapine." Publication date was not a limitation. Studies of people with schizophrenia/schizoaffective disorder were included in the meta-analysis if they were randomized, double-blind, and used the Positive and Negative Syndrome Scale (PANSS) as an outcome measure. Nine studies were initially identified. Five studies were included in the meta-analysis; 1 study was excluded for not using the PANSS, 3 were excluded as representing duplicate publications and open-label phases of one of the selected randomized control trials. Studies varied in the quality of their selection for participants with primary negative symptoms. Three of the 5 studies showed significant improvement in negative symptoms individually. The overall analysis showed improvement in negative symptoms with an effect size of 1.00 (0.084-1.918), which was statistically significant (p=0.032). Data from the negative symptoms subscale of the PANSS from 169 subjects was used in a forest plot to illustrate the relative strength of treatment effects. The variation in standard median deviation (SMD) attributable to heterogeneity was 27.35 %, indicating a high degree of heterogeneity. This meta-analysis supports the hypothesis that adding mirtazapine to treatment with antipsychotics can improve negative symptoms in schizophrenia. However, additional studies with more stringent negative symptom selection criteria and homogeneous use of antipsychotics are needed.

A Mixed-Methods Evaluation of a Pilot Psychosocial Intervention Group for Older People with Schizophrenia

There is a strong evidence base for psychological treatments in younger adults with schizophrenia, but limited work has been done on adapting these interventions for older people. We describe a study of a pilot psychosocial intervention group specifically designed to meet the needs of older people with schizophrenia in NHS settings. We used a mixed-methods approach to evaluate the group. We assessed feasibility and acceptability by monitoring uptake and retention in the study. We used a within groups design comparing participants on a range of potentially relevant outcomes at baseline and posttreatment. Treatment acceptability was also assessed by semi-structured interviews conducted at the end of treatment. We recruited 11 participants to the study and 7 of these completed the majority of the group sessions. At a group level participants made improvements in self-esteem and negative symptoms that were statistically significant even in this small sample. Feedback interviews suggested that participants valued the social contact provided by the group and made actual changes in their day-to-day lives as a result of attending. The intervention could offer help with some of the secondary disability associated with the diagnosis of schizophrenia and is acceptable to older adults. Further evaluation is, however, warranted.

Ondansetron and simvastatin added to treatment as usual in patients with schizophrenia: study protocol for a randomized controlled trial

BackgroundNegative symptoms and cognitive deficits are two partially-related features of schizophrenia which have a major negative impact on social function and objective quality of life. Standard drug treatments have little impact on either. There is some evidence that anti-inflammatory treatment may have beneficial effects in schizophrenia and major depression. Statins are cholesterol-lowering agents that have been found to be anti-inflammatory agents and are also known to decrease C-reactive protein (CRP). Ondansetron is a serotonin (5-HT3) receptor antagonist widely used to prevent nausea and vomiting in patients receiving chemotherapy for cancer. Small studies have suggested that ondansetron is effective as an adjunct drug in improving the symptoms of schizophrenia.Methods/designThis is a two center, six-month, double-blind placebo controlled, factorial design study of ondansetron and/or simvastatin added to treatment as usual for patients suffering from schizophrenia, schizoaffective disorder, psychosis not otherwise specified or schizophreniform disorder. This will be a 2 × 2 design, with 54 patients in each cell, giving a total of 216 patients over three years. There will be a screening, a randomization and seven follow-up visits. Full clinical and neurocognitive assessments will be carried out at baseline (randomization), 14 weeks and at 26 weeks, while the positive and negative syndrome scale (PANSS), pill count and side effects checklist will be carried out at every visit. Simvastatin will be started at 20 mg once daily (OD), this will be increased to 40 mg after four weeks. Ondansetron will be administered in an 8 mg dose.DiscussionAnti-inflammatory treatments have been shown to have some beneficial effects in schizophrenia. Both simvastatin and ondansetron provide some evidence of a reduction in symptoms compared to treatment as usual. The aim of this study is to establish the degree of improvement in negative symptoms with the addition of ondansetron and/or simvastatin to treatment as usual.Trail registrationClinicalTrails.gov NCT01602029

Reduced serum paraoxonase 1 (PON1) activity in patients with schizophrenia treated with olanzapine but not quetiapine

BackgroundSecond generation antipsychotics (SGAs) are currently the most prescribed drugs in the treatment of schizophrenia. Despite their advantages, which include greater improvement in negative symptoms, cognitive function, prevention of deterioration, quality of life, and fewer extrapyramidal symptoms, the concern regarding metabolic abnormalities which might cause cardiovascular diseases during treatment with SGAs have been rising. Paraoxonase 1 (PON1) is an enzyme mostly located on high-density lipoprotein particles, and has been shown to protect or inhibit lipoprotein oxidation. Growing evidence suggests that PON1 plays a key role in the pathophysiology of atherosclerosis.MethodsIn the present study, we measured serum PON1 activity and serum levels of total cholesterol (TC), triglyceride, high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) in patients with schizophrenia, who had been treated with either olanzapine or quetiapine, and in healthy controls. Thirty five patients who had been treated with olanzapine, 29 patients who had been treated with quetiapine, and 32 age, sex, and smoking status-matched healthy control (HC) participants were enrolled. Serum PON1 activity and serum levels of TC, triglyceride, HDL-C, and LDL-C were measured.ResultsSerum PON1 activity in the olanzapine group was significantly lower than that of HC and quetiapine groups. Furthermore, serum levels of TC and LDL-C in the olanzapine group were significantly higher than those of quetiapine and HC groups. Interestingly, there was a positive correlation between PON1 activity and HDL-C levels in the olanzapine group.ConclusionThese findings suggest that serum PON1 activity in patients treated with olanzapine was lower than that of HC and quetiapine groups, and that PON1 may play a role in the metabolic side effects associated with olanzapine treatment. A further study to examine the relationship between serum PON1 activity and cardiovascular and metabolic side effects during treatment with SGAs will be of great interest.