Change In Negative Symptoms Research Articles

Efficacy of adjunctive D-Cycloserine for the treatment of schizophrenia: a systematic review and meta-analysis of randomized controlled trials.

D-Cycloserine is a partial agonist at the glycine site of the N-methyl-D-aspartate (NMDA) receptor. Results have been inconsistent in trials on the efficacy of D-Cycloserine in patients with schizophrenia. We examined the efficacy of D-Cycloserine against negative and cognitive symptoms (primary and co-primary outcomes). Secondary outcomes were efficacy of D-Cycloserine against positive symptoms and the examination of early treatment outcomes. A systematic literature search was carried out using following selection criteria: Population = Patients with Schizophrenia; Intervention = Trials using D-Cycloserine either as monotherapy or adjuvant therapy; Comparison = Placebo or active comparator; Outcome = Change in negative symptoms, cognitive symptoms and positive symptoms; Study design = Randomized controlled trials with parallel design. We used the Cochrane Collaboration tool for risk of bias for study quality appraisal. Effect sizes for trials were calculated separately for negative, positive and cognitive symptom dimensions using the DerSimonian-Laird random effects model. Seven studies (pooled N = 413) provided data for meta-analysis. The pooled Standardized Mean Difference (SMD) for negative, cognitive, and positive symptom change scores were -0.32 (95% CI, -0.75 to 0.11), -0.05 (95% CI, -0.91 to 0.81), and -0.08 (95% CI, -0.37 to 0.20), respectively. No significant improvement was noted with regard to early outcome. I2 values for heterogeneity were 61%, 67%, and 0% for studies assessing negative, cognitive, and positive symptom ratings, respectively. D-Cycloserine did not exhibit significant efficacy in treating negative, cognitive, or positive symptoms of schizophrenia at either study-defined endpoint (4-36weeks) or at four weeks (early outcome).

Impact of changes in social anxiety on social functioning and quality of life in outpatients with schizophrenia: A naturalistic longitudinal study

The prevalence of comorbid social anxiety disorder among patients with schizophrenia is currently attracting attention, and symptoms of social anxiety are reportedly associated with various clinical features. However, the contribution of social anxiety to social functioning and quality of life (QOL) over time remains obscure. The aim of this study was to examine the impact of changes in social anxiety symptoms on social functioning and QOL among outpatients with schizophrenia. Of the 207 outpatients who were eligible at baseline, 118 patients agreed with and completed a follow-up investigation at least 1 year (695.8 days on average) after the baseline study. Stepwise multiple regressions examining the change in social functioning using demographic data and changes in clinical variables as explanatory variables demonstrated that the changes in social anxiety and general psychopathology contributed to the change in the Social Functioning Scale, while the changes in clinical severity and negative symptoms contributed to the change in the Global Assessment of Functioning scale. Stepwise multiple regressions for the change in QOL demonstrated that the changes in social anxiety and depression contributed to the change in the World Health Organization QOL scale, Brief version, and the changes in social anxiety and positive symptoms contributed to the Subjective Well-being Under Neuroleptic Drug Treatment, Short Form. The results revealed that the changes in social anxiety symptoms were significantly associated with the change in functional outcome among patients with schizophrenia. Treatments targeting social anxiety seem to be key to achieving a full recovery in patients with schizophrenia.

Anti-inflammatory Combination Therapy for the Treatment of Schizophrenia

Despite adequate antipsychotic treatment, most people with schizophrenia continue to exhibit persistent positive and negative symptoms and cognitive impairments. The current study was designed to examine the efficacy and safety of adjunctive anti-inflammatory combination therapy for these illness manifestations. Thirty-nine people with either Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision, schizophrenia or schizoaffective disorder were entered into a 12-week double-blind, 2-arm, triple-dummy, placebo-controlled, randomized clinical trial: 19 were randomized to anti-inflammatory combination therapy and 20 were randomized to placebo. The Brief Psychiatric Rating Scale positive symptom item total score was used to assess positive symptom change, the Scale for the Assessment of Negative Symptoms total score was used to assess negative symptom change, the Calgary Depression Scale total score was used to assess depressive symptom change, and the MATRICS Consensus Cognitive Battery was used to assess neuropsychological test performance. There was a significant time effect for Brief Psychiatric Rating Scale positive symptom item score (t226 = -2.66, P = 0.008), but the treatment (t54=1.52, P = 0.13) and treatment × time (t223 = 0.47, P = 0.64) effects were not significant. There were no significant time (t144 = 0.53, P = 0.72), treatment (t58=0.48, P = 0.63), or treatment × time (t143 = -0.20, P = 0.84) effects for the Scale for the Assessment of Negative Symptoms total score; or for any of the other symptom measures. There were no significant group differences in the change in the MATRICS Consensus Cognitive Battery composite score over the course of the study (F1,26=2.20, P = 0.15). The study results suggest that there is no significant benefit of combined anti-inflammatory treatment for persistent positive symptoms or negative symptoms or cognitive impairments (clinicaltrials.gov trial number: NCT01514682).

Psychological interventions for people with psychotic experiences: A systematic review and meta-analysis of controlled and uncontrolled effectiveness and economic studies.

Objective:Many people with psychotic experiences do not develop psychotic disorders, yet those who seek help demonstrate high clinical complexity and poor outcomes. In this systematic review and meta-analysis, we evaluated the effectiveness and cost-effectiveness of psychological interventions for people with psychotic experiences.Method:We searched 13 databases for studies of psychological interventions for adults with psychotic experiences, but not psychotic disorders. Our outcomes were the proportion of participants remitting from psychotic experiences (primary); changes in positive and negative psychotic symptoms, depression, anxiety, functioning, distress, and quality of life; and economic outcomes (secondary). We analysed results using multilevel random-effects meta-analysis and narrative synthesis.Results:A total of 27 reports met inclusion criteria. In general, there was no strong evidence for the superiority of any one intervention. Five studies reported on our primary outcome, though only two reports provided randomised controlled trial evidence that psychological intervention (specifically, cognitive behavioural therapy) promoted remission from psychotic experiences. For secondary outcomes, we could only meta-analyse trials of cognitive behavioural therapy. We found that cognitive behavioural therapy was more effective than treatment as usual for reducing distress (pooled standardised mean difference: −0.24; 95% confidence interval = [−0.37, −0.10]), but no more effective than the control treatment for improving any other outcome. Individual reports indicated that cognitive behavioural therapy, mindfulness-based cognitive therapy, sleep cognitive behavioural therapy, systemic therapy, cognitive remediation therapy, and supportive treatments improved at least one clinical or functional outcome. Four reports included economic evaluations, which suggested cognitive behavioural therapy may be cost-effective compared with treatment as usual.Conclusion:Our meta-analytic findings were primarily null, with the exception that cognitive behavioural therapy may reduce the distress associated with psychotic experiences. Our analyses were limited by scarcity of studies, small samples and variable study quality. Several intervention frameworks showed preliminary evidence of positive outcomes; however, the paucity of consistent evidence for clinical and functional improvement highlights a need for further research into psychological treatments for psychotic experiences.PROSPERO protocol registration number:CRD42016033869

T45. THE EFFICACY AND HETEROGENEITY OF ANTIPSYCHOTIC RESPONSE IN SCHIZOPHRENIA: A META-ANALYSIS

BackgroundAntipsychotics are more effective than placebo in reducing symptoms in schizophrenia. However, response to treatment appears to vary, and as such it has been proposed that different subtypes of schizophrenia exist, defined by treatment-response. This has not been formally examined using meta-analysis.MethodsRandomised controlled trials comparing placebo and antipsychotics for the acute treatment of schizophrenia published between January 1 1950 and November 30, 2018 were examined. Mean change and variance of change in symptoms were extracted from each study, alongside publication year, participant age and gender, baseline symptom severity, antipsychotic dose, and use of placebo lead-in. Relative variability of symptomatic improvement in antipsychotic-treated individuals compared to placebo-treated individuals was quantified using coefficient of variation ratio (CVR). Mean difference in symptom change was quantified using Hedges’ g. The significance of potential moderating factors was assessed using meta-regression and sensitivity analyses. In addition, individual patient data from two clinical trials (N=522) was examined in terms of both the distribution of total symptom change, and the variability of individual symptoms and symptom factors.Results11,006 articles were identified. 66 met inclusion criteria, reporting on 17,202 participants. Compared with placebo, antipsychotic-treated patients demonstrated both greater symptomatic improvement (g=0.47, p<0.001) and reduced variability in symptomatic improvement (CVR=0.86, p<0.001). Lower variability in antipsychotic-response was associated with studies including younger patients (z=3.07, p=0.002), those published earlier (z=3.98, p<0.001), with higher dose treatments (z=-2.62, p=0.009), and greater mean-difference in symptom-change (z=-5.70, p<0.001). In the individual patient data antipsychotic treated patients did not show significantly increased variability for any individual symptom, and there was no evidence of a bimodal distribution of response.DiscussionCompared to placebo, in addition to a greater mean change, antipsychotic treatment shows lower variability of change in total, positive, and negative symptoms. This is contrary to the hypothesis that there exists a subtype of antipsychotic non-responsive schizophrenia, instead providing evidence for a relatively homogeneous effect of antipsychotic treatment in improving symptoms of schizophrenia.

T41. SAFETY PROFILE OF ADJUNCTIVE PIMAVANSERIN IN THE ENHANCE STUDY, A PHASE 3 TRIAL FOR THE POTENTIAL TREATMENT OF SCHIZOPHRENIA IN PATIENTS WITH AN INADEQUATE RESPONSE TO ANTIPSYCHOTIC TREATMENT

BackgroundMany patients with schizophrenia (SCZ) do not fully respond to antipsychotic (AP) treatment despite adherence and require augmentation, often with an AP with similar mode of action. Evidence supporting polypharmacy is limited and adding another AP increases associated risks of adverse effects, including extrapyramidal symptoms and cardiometabolic disturbances. Pimavanserin (PIM) is a highly selective serotonin 5-HT2A inverse agonist/antagonist approved for the treatment of Parkinson’s disease psychosis. The phase 3 ENHANCE study evaluated adjunctive PIM in patients with SCZ and inadequate response to their current AP. As previously reported (ACNP 2019), the primary efficacy endpoint of ENHANCE (change in Positive and Negative Syndrome Scale [PANSS] total score) did not achieve statistical significance. Other prespecified analyses did yield nominal statistical separation from placebo, including changes in PANSS Negative Symptoms subscale, and in PANSS total score for the subgroup of European patients. Here we describe key safety results.MethodsENHANCE was a 6-week, randomized, double-blind, placebo (PBO)-controlled study of adjunctive PIM in patients with SCZ and inadequate response to their prescribed AP (aripiprazole, olanzapine, risperidone, and others). Patients included were age 18–55 years with PANSS total score of ≥65 and ≤110, and scores of ≥4 on ≥2 items including delusions, hallucinatory behavior, and/or suspiciousness/persecution; Clinical Global Impression-Severity scale score ≥4 was also required. The starting dose of PIM or PBO was 20 mg daily and could be adjusted up to 34 mg or down to 10 mg daily after 1 week based on investigator discretion. Safety was evaluated in all randomized patients who received ≥1 dose of study drug.ResultsAll 396 randomized patients (PIM, n=198; PBO, n=198) were included in the safety analysis set. Treatment-emergent adverse events (TEAEs) were reported in 39.9% and 36.4% of patients in the PIM and PBO groups, respectively; most frequent TEAEs were headache (PIM 6.6%, PBO 9.1%), somnolence (PIM 6.6%, PBO 3.5%), and insomnia (PIM 5.1%, PBO 3.5%). Changes from baseline in Abnormal Involuntary Movement Scale (AIMS), Barnes Akathisia Scale global clinical assessment of akathisia (GCAA), and Simpson–Angus Scale (SAS) scores were similar in the PIM and PBO groups. No patient developed dyskinesia (defined as a score ≥3 on any, or ≥2 on 2 of the first 7 AIMS items). Akathisia (GCAA score ≥2) in patients without baseline akathisia occurred in 4/186 (2.2%) patients receiving PIM and 1/189 (0.5%) receiving PBO. Parkinsonism (SAS total score >3) in patients without Parkinsonism at baseline occurred in 3/181 (1.7%) patients receiving PIM and 4/182 (2.2%) receiving PBO. No patient in either treatment arm had QTcF prolongation >500 msec or Torsades de Pointes during the study period; 2 (1.1%) patients in the PIM arm and 0 in the PBO arm had post-baseline QTcF prolongation >60 msec. Hypotension was reported in 1 patient in each treatment group; no patient had clinically important changes from baseline in blood pressure during treatment. Weight increase ≥7% from baseline was reported in 5/189 (2.6%) patients in the PIM group and 3/191 (1.6%) in the PBO group. Mean changes from baseline in PIM and PBO groups for fasting glucose were 0.07 mmol/L and 0.01 mmol/L; for triglycerides were -0.007 mmol/L and -0.136 mmoL/L, and for cholesterol were -0.10 mmol/L and -0.03 mmol/L, respectively.DiscussionResults of ENHANCE provide evidence that the addition of PIM to frequently used APs is well tolerated in patients with SCZ.

Understanding How Virtual Reality Can Support Mindfulness Practice: Mixed Methods Study.

BackgroundRegular mindfulness practice has been demonstrated to be beneficial for mental health, but mindfulness can be challenging to adopt, with environmental and personal distractors often cited as challenges. Virtual reality (VR) may address these challenges by providing an immersive environment for practicing mindfulness and by supporting the user to orient attention to the present moment within a tailored virtual setting. However, there is currently a limited understanding of the ways in which VR can support or hinder mindfulness practice. Such an understanding is required to design effective VR apps while ensuring that VR-supported mindfulness is acceptable to end users.ObjectiveThis study aimed to explore how VR can support mindfulness practice and to understand user experience issues that may affect the acceptability and efficacy of VR mindfulness for users in the general population.MethodsA sample of 37 participants from the general population trialed a VR mindfulness app in a controlled laboratory setting. The VR app presented users with an omnidirectional video of a peaceful forest environment with a guided mindfulness voiceover that was delivered by a male narrator. Scores on the State Mindfulness Scale, Simulator Sickness Questionnaire, and single-item measures of positive and negative emotion and arousal were measured pre- and post-VR for all participants. Qualitative feedback was collected through interviews with a subset of 19 participants. The interviews sought to understand the user experience of mindfulness practice in VR.ResultsState mindfulness (P<.001; Cohen d=1.80) and positive affect (P=.006; r=.45) significantly increased after using the VR mindfulness app. No notable changes in negative emotion, subjective arousal, or symptoms of simulator sickness were observed across the sample. Participants described the user experience as relaxing, calming, and peaceful. Participants suggested that the use of VR helped them to focus on the present moment by using visual and auditory elements of VR as attentional anchors. The sense of presence in the virtual environment (VE) was identified by participants as being helpful to practicing mindfulness. Interruptions to presence acted as distractors. Some uncomfortable experiences were discussed, primarily in relation to video fidelity and the weight of the VR headset, although these were infrequent and minor.ConclusionsThis study suggests that an appropriately designed VR app can support mindfulness practice by enhancing state mindfulness and inducing positive affect. VR may help address the challenges of practicing mindfulness by creating a sense of presence in a tailored VE; by allowing users to attend to visual and auditory anchors of their choice; and by reducing the scope of the content in users’ mind-wandering. VR has the unique capability to combine guided mindfulness practice with tailored VEs that lend themselves to support individuals to focus attention on the present moment.

Clinical implications of oxidative stress in schizophrenia: Acute relapse and chronic stable phase

Several studies have suggested a higher oxidative stress in schizophrenia. However, the implications of oxidative stress on clinical symptoms remain unclear. This study aimed to investigate the platelet oxidative stress in different stages of schizophrenia (i.e., chronic stable and acute relapse) in order to clarify the clinical implications of oxidative stress and the treatment effects. We recruited 43 chronic stable patients with schizophrenia and 48 non-psychiatric controls. Platelets were collected for measuring the levels of nitric oxide (NO), lipid peroxidation (LPO), and glutathione (GSH) and the activity of GSH peroxidase (GPx) and superoxide dismutase (SOD). The levels and activity were compared between patients and controls and were examined for their relationship with clinical severity. Further, we evaluated the changes of levels and activity before and after treatment in an independent sample with acute relapse (N = 19). Patients with chronic stable schizophrenia had lower SOD activity compared to non-psychiatric controls. In chronic stable patients, NO level was positively correlated with positive and disorganized symptoms, while the GPx activity were negatively correlated with excitement. In patients with acute relapse, the levels and activity were not different before and after four weeks of antipsychotic treatment, but LPO level was negatively correlated with pretreatment disorganized symptoms. The change of LPO can also predict the change of disorganized symptoms and negative symptoms. Our findings suggest that platelet SOD was lower in chronic stable schizophrenia. Platelet LPO may be associated with less disorganized symptoms in acute relapse patients and better treatment response.

Psychosocial treatments for relapse prevention in schizophrenia: study protocol for a systematic review and network meta-analysis of randomised evidence

IntroductionThere is evidence that different psychosocial interventions could reduce the risk of relapse in schizophrenia, but a comprehensive evidence based on their relative efficacy is lacking. We will conduct a...

Heterogeneity and efficacy of antipsychotic treatment for schizophrenia with or without treatment resistance: a meta-analysis

Two important clinical questions are whether there is a subtype of schizophrenia which responds differently to clozapine relative to other antipsychotics, and whether greater efficacy of clozapine is dependent on the degree of treatment-resistance. The authors address this by examining both variability and magnitude of response in patients treated with clozapine and other antipsychotics for both treatment-resistant schizophrenia (TRS) and non-resistant schizophrenia. Double-blind randomised controlled trials comparing clozapine with other antipsychotics in patients with schizophrenia were identified using five databases. Standard deviations and means of change in total, positive, and negative symptoms were extracted. Variability ratio (VR) and coefficient of variation ratio (CVR) were used to quantify relative variability in symptom change. Hedges’ g was used to quantify mean differences. Ten TRS studies (n = 822) and 29 non-TRS studies (n = 2566) were meta-analysed. Relative variability in change of total symptoms did not differ significantly between clozapine and other antipsychotics in TRS studies (VR = 1.84; 95%CI, 0.85–4.02). These findings were similar with CVR, and for positive and negative symptoms. Clozapine was superior to other antipsychotics in improving total symptoms in both TRS (g = 0.34; 95%CI, 0.13–0.56) and non-TRS (g = 0.20; 95%CI, 0.08–0.32) studies. Furthermore, clozapine was superior in improving positive symptoms in both study groups, but not for negative symptoms. Pooled effect sizes showed no significant difference between TRS and non-TRS studies. These findings do not support a subtype of schizophrenia which responds specifically to clozapine. Clozapine is more effective than other antipsychotics irrespective of treatment-resistance, arguing for its use more generally in schizophrenia. PROSPERO CRD42018086507

The relationship between childhood trauma, dopamine release and dexamphetamine-induced positive psychotic symptoms: a [11C]-(+)-PHNO PET study

Childhood trauma is a risk factor for psychosis. Amphetamine increases synaptic striatal dopamine levels and can induce positive psychotic symptoms in healthy individuals and patients with schizophrenia. Socio-developmental hypotheses of psychosis propose that childhood trauma and other environmental risk factors sensitize the dopamine system to increase the risk of psychotic symptoms, but this remains to be tested in humans. We used [11C]-(+)-PHNO positron emission tomography to measure striatal dopamine-2/3 receptor (D2/3R) availability and ventral striatal dexamphetamine-induced dopamine release in healthy participants (n = 24). The relationships between dexamphetamine-induced dopamine release, dexamphetamine-induced positive psychotic symptoms using the Positive and Negative Syndrome Scale (PANSS), and childhood trauma using the Childhood Trauma Questionnaire (CTQ) were assessed using linear regression and mediation analyses, with childhood trauma as the independent variable, dexamphetamine-induced dopamine release as the mediator variable, and dexamphetamine-induced symptoms as the dependent variable. There was a significant interaction between childhood trauma and ventral striatal dopamine release in predicting dexamphetamine-induced positive psychotic symptoms (standardized β = 1.83, p = 0.003), but a mediation analysis was not significant (standardized β = −0.18, p = 0.158). There were no significant effects of dopamine release and childhood trauma on change in negative (p = 0.280) or general PANSS symptoms (p = 0.061), and there was no relationship between ventral striatal baseline D2/3R availability and positive symptoms (p = 0.368). This indicates childhood trauma and dopamine release interact to influence the induction of positive psychotic symptoms. This is not consistent with a simple sensitization hypothesis, but suggests that childhood trauma moderates the cognitive response to dopamine release to make psychotic experiences more likely.

The longitudinal course of schizophrenia: testosterone and progression of the negative symptoms

Background: The longitudinal course of schizophrenia shows a high level of heterogeneity with testosterone as a possible factor in the variety of clinical outcomes.Aim: Evaluation of the course of schizophrenia in male patients over an eight-year period and of the possible testosterone effects on changes in clinical features.Subjects and methods: The initial study population consisted of 120 male schizophrenic patients (aged 18–40) hospitalized in the University Psychiatric Hospital Vrapce in 2009. Patients were classified into nonaggressive (control, n = 60) and aggressive (n = 60) groups. In 2017, we reassessed 85 patients (67,5%) from the initial sample. Symptoms of schizophrenia were determined using the Positive and Negative Syndrome Scale (PANSS) and compared with the total serum testosterone level taken at the inclusion in the study. The distribution of values for individual variables was determined using the Smirnov–Kolmogorov test; for all further analyses, the appropriate non-parametric test was used.Results: The control group showed a statistically significant negative correlation between testosterone and negative PANSS. The initial PANSS scores, compared to those at the follow-up, showed a statistically significant reduction in positive and general symptoms in all groups, with the greatest reduction in the control group.Conclusion: We found a reduction in positive and general symptoms of schizophrenia among all patients and no changes in negative symptoms. Inverse correlation between testosterone and negative symptoms was found only in the control group, but there was no testosterone influence on the progression of any PANSS subscales.

The efficacy and heterogeneity of antipsychotic response in schizophrenia: A meta-analysis.

SummaryThe response to antipsychotic treatment in schizophrenia appears to vary, and as such it has been proposed that different subtypes of schizophrenia exist, defined by treatment-response. This has not been formally examined using meta-analysis. Randomised controlled trials comparing placebo and antipsychotics in acute treatment of schizophrenia listed in PubMed, EMBASE and PsycINFO from inception until November 30, 2018 were examined. Relative variability of symptomatic improvement in antipsychotic-treated individuals compared to placebo-treated individuals was quantified using coefficient of variation ratio (CVR). Mean difference in symptom change was quantified using Hedges’ g. In addition, individual patient data from two clinical trials was examined in terms of both the distribution of total symptom change, and the variability of individual symptoms and symptom factors. 11,006 articles were identified. 66 met inclusion criteria, reporting on 17,202 patients. Compared with placebo, antipsychotic-treated patients demonstrated greater total symptom improvement (g=0.47, p<0.001) and reduced variability in symptomatic improvement for total (CVR=0.86, p<0.001), positive (CVR=0.89, p<0.001), and negative symptoms (CVR=0.86, p=0.001). Lower variability in antipsychotic-response was associated with studies published earlier (z=3.98, p<0.001), younger patients (z=3.07, p=0.002), higher dose treatments (z=-2.62, p=0.009), and greater mean-difference in symptom-change (z=-5.70, p<0.001). In the individual patient dataset (N=522 patients), antipsychotic treated patients did not show significantly increased variability for any individual symptom, and there was no evidence of a bimodal distribution of response. Compared to placebo, antipsychotic treatment shows greater improvement and lower variability of change in total, positive and negative symptoms. This is contrary to the hypothesis that there is a subtype of antipsychotic non-responsive schizophrenia. Instead our findings, provide evidence for a relatively homogeneous effect of antipsychotic treatment in improving symptoms of schizophrenia.

Thérapie comportementale et cognitive des symptômes négatifs de la schizophrénie. Revue de la question : pratiques actuelles et directions futures

Negative symptoms, such as a lack of motivation, anhedonia or poverty of speech, constitute a major difficulty in schizophrenia. Indeed, these symptoms have deleterious effects on quality of life and functional outcome of individuals with schizophrenia. However, although multiple interventions have been the subject of investigation, to date, including pharmacological strategies, brain stimulation, physical activity and psychosocial interventions, none reached the threshold for clinically significant improvement. Therefore the treatment of negative symptoms represents a major challenge for mental health care in schizophrenia. If recent advances in CBT have clearly shown their efficiency on positive symptom and are now recommended as first line treatment for schizophrenia, CBT trials mainly focused on positive symptoms and investigated change in negative symptoms only as a secondary outcome. The aim of this article is to describe and to provide a brief description of the different CBT interventions targeting negative symptoms, the theoretical models on which they are based and empirical evidence highlighting their effectiveness. Of the interventions reviewed, cognitive interventions, behavioral activations and social skills training appear to have the most empirical support. The cognitive approach suggests the role of negative cognitions, or dysfunctional attitudes in the maintenance and exacerbation of behaviors is associated with negative symptoms in schizophrenia (Rector et. al., 2005 ; Beck et. al., 2009). Consequently, cognitive therapy interventions focus primarily on changing generalized beliefs that prevent patients with prominent negative symptoms from goal attainment. Clinical trials showed improvements on apathy, avolition, and functioning but not on anhedonia, blunted affects, and alogia suggesting that cognitive models of negative symptoms would be valid for the dimension avolition but less for the dimension diminished expression. Regarding behavioral interventions, there is now clear evidence that social skills training should be routinely recommended in treatment guidelines for psychological intervention targeting negative symptoms as a whole (Turner et al., 2018). However, its distinct impact on the two main dimensions of negative symptoms is still unknown. Behavioral activation appears particularly promising in the treatment of negative symptoms secondary to depression. Although psychosocial treatments show promise for the treatment of negative symptoms, certain limitations exist, particularly regarding the conceptualization of the different negative symptoms and the lack of integrative psychological models proposed in the literature. However, cognitive and behavioral therapy offer interesting possibilities for the improvement of negative symptomatology, particularly recovery-oriented cognitive therapy, focusing on dysfunctional beliefs, and adaptations to circumvent neurocognitive and engagement difficulties. As recommendations, we emphasize the need for a detailed and integrative functional analysis of each negative symptom before any interventions in order to understand the influence of the different environmental factors and psychological processes. Specific CBT interventions have utility in ameliorating negative symptoms in psychosis but validated and integrative psychological models need to be developed to increase their effectiveness.

Role of coping with negative emotions in cognitive behavioral therapy for persistent somatoform pain disorder: Is it more important than pain catastrophizing?

Cognitive behavioral therapy (CBT) is known to be effective for patients with persistent somatoform pain disorder (PSPD). Improvement of negative emotions in interpersonal stressful situations has been reported to reduce PSPD-related clinical pain. However, these associations in CBT remain unclear. Therefore, we examined the relation between changes in negative emotions and clinical pain symptoms after CBT by using a multiple regression analysis that included pain catastrophizing. We analyzed negative emotional intensity scores in stressful situations of 38 patients with PSPD who had completed CBT treatment and all the daily worksheets. Negative emotional intensity scores were recorded in daily worksheets during 12 weekly CBT sessions. Scores for the Pain Catastrophizing Scale (PCS), Visual Analogue Scale (VAS) as clinical pain intensity, Beck Depression Inventory - Second Edition (BDI-II), and State-Trait Anxiety Inventory (STAI) were also obtained at pre- and post-treatment. A multiple regression analysis was conducted using changes in VAS scores after CBT as the dependent variable, and changes in negative emotional intensity, PCS, BDI-II, and STAI scores after CBT, age, and sex as independent variables. Negative emotional intensity scores decreased after CBT. In a multiple regression analysis, the emotional changes resulting from CBT depicted a modest positive relation with changes in VAS scores (β = 0.37; P < 0.05); however, there was no relation between changes in PCS scores after CBT and changes in VAS scores after CBT (β = 0.03). The results show that negative emotions play an important role in the treatment effects of CBT for PSPD.

Psychological Interventions for People with Psychotic Experiences: A Systematic Review and Meta-Analysis of Effectiveness and Economic Studies

Background: Many people with psychotic experiences who seek help do not develop psychotic disorders, yet still demonstrate higher clinical complexity, suboptimal treatment response, and poor clinical and functional outcomes. Methods: We searched thirteen databases for studies concerning psychological interventions for adults with psychotic experiences, but not psychotic disorders. Our outcomes were the proportion of participants remitting/recovering from psychotic experiences (primary); changes in positive and negative psychotic symptoms, depression, anxiety, functioning, distress, or quality of life; and economic outcomes (secondary). We analysed results using random-effects meta-analysis and narrative synthesis. Findings: Twenty-seven reports from 21 studies met inclusion criteria. Five reported the proportion of participants remitting from psychotic experiences. Non-meta-analytic evidence suggested that cognitive behavioural therapy (CBT) may promote symptomatic recovery. For secondary outcomes, CBT demonstrated effectiveness over treatment as usual (TAU) and supportive treatments (ST) in improving distress (pooled standardised mean difference: -0.23 [-0.36 to -0.10]), but no other outcome. Individual reports indicated that CBT, mindfulness, sleep CBT, systemic therapy, cognitive remediation therapy, and supportive treatments improved some clinical and/or functional outcomes. Only four reports, using data from two studies, included economic evaluations, which suggested CBT may be cost-effective compared with TAU. Interpretation: Initial evidence suggests that CBT may promote recovery from psychotic experiences and reduce associated distress, although scarcity of studies, small sample sizes, and variable study quality limit our ability to make definitive conclusions. The paucity of consistent evidence for improving other non-psychotic clinical and functional outcomes highlights a need for further research into psychological treatments for this population. Funding: This paper presents independent research funded by the National Institute for Health Research (NIHR) under its Programme Grants for Applied Research Programme (Reference Number RP-PG-0616-20003). Declaration of Interest: The authors declare no competing interests. Ethical Approval: Not applicable.

Cerebellar-Prefrontal Network Connectivity and Negative Symptoms in Schizophrenia.

The interpretability of results in psychiatric neuroimaging is significantly limited by an overreliance on correlational relationships. Purely correlational studies cannot alone determine whether behavior-imaging relationships are causal to illness, functionally compensatory processes, or purely epiphenomena. Negative symptoms (e.g., anhedonia, amotivation, and expressive deficits) are refractory to current medications and are among the foremost causes of disability in schizophrenia. The authors used a two-step approach in identifying and then empirically testing a brain network model of schizophrenia symptoms. In the first cohort (N=44), a data-driven resting-state functional connectivity analysis was used to identify a network with connectivity that corresponds to negative symptom severity. In the second cohort (N=11), this network connectivity was modulated with 5 days of twice-daily transcranial magnetic stimulation (TMS) to the cerebellar midline. A breakdown of connectivity in a specific dorsolateral prefrontal cortex-to-cerebellum network directly corresponded to negative symptom severity. Restoration of network connectivity with TMS corresponded to amelioration of negative symptoms, showing a statistically significant strong relationship of negative symptom change in response to functional connectivity change. These results demonstrate that a connectivity breakdown between the cerebellum and the right dorsolateral prefrontal cortex is associated with negative symptom severity and that correction of this breakdown ameliorates negative symptom severity, supporting a novel network hypothesis for medication-refractory negative symptoms and suggesting that network manipulation may establish causal relationships between network markers and clinical phenomena.

The contribution of employment duration to 18-month neurocognitive outcomes in first-episode psychosis.

Increased employment duration has been associated with change in performance on specific neurocognitive domains in populations with schizophrenia, but not in first-episode psychosis. The aim of this exploratory study was to examine whether employment duration over 18 months is associated with neurocognitive outcomes over 18 months among individuals with first-episode psychosis. Eighty-eight young people with first-episode psychosis completed a neurocognitive battery at baseline and 18 months. Setwise (hierarchical) multivariate linear regressions were used to examine predictors of change in neurocognitive performance over 18 months. Total hours employed over 18 months were entered after accounting for age, gender, premorbid IQ, and negative symptom change scores. Total hours employed was significantly associated with change in Symbol Digit Modalities Test raw score (p = .020), Letter-Number Sequencing scaled score (p = .016), Digit Span total scaled score (p = .047) and Rey Complex Figure Test delayed recall raw score (p = .016) over 18 months, after controlling demographic characteristics, premorbid IQ, and changes in negative psychotic symptoms. Total hours worked over 18 months was associated with small improvements on one test of processing speed and one test of working memory. However, total hours worked over 18 months was also associated with decline on one test of attention and working memory and visual organization and memory. The findings implicate that work alone may not be entirely effective in changing neurocognitive functioning for young people with first-episode psychosis. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

Efficacy, acceptability and tolerability of antipsychotics in patients with schizophrenia and comorbid substance use. A systematic review and meta-analysis

Patients with schizophrenia and substance related comorbidity or substance induced psychotic disorder are difficult to treat. Although the prevalence of a comorbid substance use is approximately 40% in schizophrenia, such patients are usually excluded from clinical trials. We therefore performed a random-effects meta-analysis of all randomized controlled antipsychotic drug trials in this patient subgroup. We searched multiple databases up to May, 2018. The primary outcome was the reduction of substance user; secondary outcomes were craving, mean reduction of substance use, overall change in schizophrenia symptoms, positive and negative symptoms, response, dropouts, quality of life, social functioning, weight gain, sedation, prolactin, extrapyramidal side effects and use of antiparkinsonian medication. We identified 27 references from 19 RCTs published from 1999 to March 2017 including 1742 participants. The most frequent types of substance abuse were cannabis (8 studies) and cocaine (6 studies) use/dependence. Clozapine was superior to other antipsychotics for reduction of substance use and risperidone to olanzapine for craving. Olanzapine, clozapine and risperidone showed superiority for symptom reduction compared to some other drugs. When reported, results of side-effects followed known patterns. The evidence-base is considerable (19 RCTs), however, firm conclusions cannot be drawn due to small sample sizes of individual studies and insufficient reporting.

Chlorpromazine versus piperacetazine for schizophrenia.

Schizophrenia is a severe mental disorder with a prevalence of about 1% among the general population. It is listed among the top 10 causes of disability-adjusted life years (DALYs) worldwide. Antipsychotics are the mainstay treatment. Piperacetazine has been reported to be as clinically effective as chlorpromazine, a well established 'benchmark' antipsychotic, for people with schizophrenia. However, the side effect profiles of these antipsychotics differ and it is important that an evidence base is available comparing the benefits, and potential harms of these two antipsychotics. To assess the clinical and side effects of chlorpromazine for people with schizophrenia and schizophrenia-like psychoses in comparison with piperacetazine. We searched the Cochrane Schizophrenia Group's Trials Register (6 June 2015 and 8 October 2018) which is based on regular searches of CINAHL, CENTRAL, BIOSIS, AMED, Embase, PubMed, MEDLINE, PsycINFO and registries of clinical trials. There are no language, date, document type, or publication status limitations for inclusion of records in the register. We included randomised controlled trials (RCTs) focusing on chlorpromazine versus piperacetazine for people with schizophrenia, reporting useable data. We extracted data independently. For binary outcomes, we calculated risk ratio (RR) and its 95% confidence interval (CI), on an intention-to-treat basis. For continuous data, we estimated the mean difference (MD) between groups and its 95% CI. We employed a fixed-effect model for analyses. We assessed risk of bias for included studies and created 'Summary of findings' tables using GRADE. We found 12 records referring to six trials. We included five trials, all from the 1970s, randomising 343 participants. We excluded one trial. The overall methodology and data reporting by the trials was poor. Only short-term data were available.Results from the included trials found that, in terms of global state improvement, when rated by a psychiatrist, there was no clear difference between chlorpromazine and piperacetazine (RR 0.90, 95% CI 0.80 to 1.02; participants = 208; studies = 2; very low-quality evidence). One trial reported change scores on the mental state scale Brief Psychiatric Rating Scale (BPRS); no clear difference was observed (MD -0.40, 95% CI -1.41 to 0.61; participants = 182; studies = 1; very low-quality evidence). Chlorpromazine appears no worse or better than piperacetazine regarding adverse effects. In both treatment groups, around 60% of participants experienced some sort of adverse effect (RR 1.00, 95% CI 0.75 to 1.33; participants = 74; studies = 3; very low-quality evidence), with approximately 40% of these participants experiencing some parkinsonism-type movement disorder (RR 0.95, CI 0.61 to 1.49; participants = 106; studies = 3; very low-quality evidence). No clear difference in numbers of participants leaving the study early for any reason was observed (RR 0.50, 95% CI 0.10 to 2.56; participants = 256; studies = 4; very low-quality evidence). No trial reported data for change in negative symptoms or economic costs. The results of this review show chlorpromazine and piperacetazine may have similar clinical efficacy, but data are based on very small numbers of participants and the evidence is very low quality. We can not make firm conclusions based on such data. Currently, should clinicians and people with schizophrenia need to choose between chlorpromazine and piperacetazine they should be aware there is no good quality evidence to base decisions. More high quality research is needed.