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Objective: Negative symptoms of schizophrenia are substantially disabling and treatment resistant. Novel treatments like repetitive transcranial magnetic stimulation (TMS) need to be examined for the same using the experimental medicine approach that incorporates tests of mechanism of action in addition to clinical efficacy in trials.Methods: Study was a double-blind, parallel, randomized, sham-controlled trial recruiting schizophrenia with at least a moderate severity of negative symptoms. Participants were randomized to real or sham intermittent theta burst stimulation (iTBS) under MRI-guided neuro-navigation, targeting the cerebellar vermis area VII-B, at a stimulus intensity of 100% active motor threshold, two sessions/day for five days (total = 6000 pulses). Assessments were conducted at baseline (T0), day-6 (T1) and week-6 (T2) after initiation of intervention. Main outcomes were, a) Scale for the Assessment of Negative Symptoms (SANS) score (T0, T1, T2), b) fronto-cerebellar resting state functional connectivity (RSFC) (T0, T1).Results: Thirty participants were recruited in each arm. Negative symptoms improved in both arms (p < 0.001) but was not significantly different between the two arms (p = 0.602). RSFC significantly increased between the cerebellar vermis and the right inferior frontal gyrus (pcluster-FWER = 0.033), right pallidum (pcluster-FWER = 0.042) and right frontal pole (pcluster-FWER = 0.047) in the real arm with no change in the sham arm.Conclusion: Cerebellar vermal iTBS engaged a target belonging to the class of cerebello-subcortical-cortical networks, implicated in negative symptoms of schizophrenia. However, this did not translate to a superior clinical efficacy. Future trials should employ enhanced midline cerebellar TMS stimulation parameters for longer durations that can potentiate and translate biological changes into clinical effects. [ABSTRACT FROM AUTHOR]

Background: A Growing body of literature indicates therapeutic effectiveness of mindfulness for mental disorders. Only few trials have been conducted with schizophrenia spectrum disorders (SSD), mostly in outpatient settings. Primary objective was to assess feasibility, acceptability, and preliminary outcomes of mindfulness-based group therapy (MBGT) for in-patients with SSD.Methods: A pre-registered randomized controlled trial was conducted to assess feasibility and acceptability of the MBGT. The primary outcome was mindfulness measured with the Southampton Mindfulness Questionnaire (SMQ). Secondary outcomes were rater-blinded positive- and negative symptoms, depression, social functioning, and self-reported mindfulness, depression, anxiety, psychological flexibility, quality of life, and medication regime at baseline, post-intervention, and follow-up (Clinical Trails NCT03671005).Results: 40 participants received either treatment-as-usual (TAU; n=19) or (MBGT+TAU; n = 21) for four weeks. At post-intervention, protocol adherence was 95.2%, and retention rate was 95%. ANCOVA revealed significant improvements in the MBGT+TAU for the primary outcome SMQ as well as negative symptoms at post-intervention between groups. In exploratory analyses, secondary outcomes showed medium-to-large pre-to-post-intervention effects on mindfulness, positive-, negative-, and depressive symptoms, psychological flexibility, quality of life, and social functioning for MBGT+TAU and small-to-moderate changes on positive symptoms and social functioning for TAU. No serious adverse effects were reported.Conclusions: MBGT appears feasible and acceptable for in-patient settings, with high protocol adherence and retention rates. Preliminary findings highlight a proof of concept of MBGT and various improvements in clinical- and process dimensions. A fully powered trial is warranted to determine efficacy, cost-efficiency, and longitudinal changes based on these promising outcomes. [ABSTRACT FROM AUTHOR]

The merging of evidence-based interventions with supported employment programs are being increasingly studied, with encouraging results. The current study is aimed at determining the impact of a brief cognitive behaviour therapy group intervention adapted for supported employment programs (called CBT-SE) on the work outcomes of: obtaining a competitive job, number of weeks worked, and number of hours worked per week. Participants were randomized to either receive the 8-session CBT-SE group on top of their supported employment program, or to only receive their support employment program. The results show that those who received CBT-SE were significantly more likely to obtain a job (75% vs 58%), and worked a significantly greater number of hours (24 vs 18 hours per week). No differences were found in terms of number of weeks worked. Those in the CBT-SE condition also experienced a significant decrease in their negative symptoms over time, compared to the control condition. Although replication is needed, these results suggest that a brief cognitive-behavioural intervention specifically tailored to work-related issues can be greatly beneficial. [ABSTRACT FROM AUTHOR]

This study investigated the efficacy of 10-module metacognitive training (MCT) among Japanese patients with schizophrenia by conducting a multicenter randomized controlled trial to test the influence of the most recent and extended version of MCT on positive symptoms. A six-center, randomized, assessor-blind, controlled trial between "treatment as usual" (TAU) and TAU + MCT was conducted. Fifty inpatients and outpatients with schizophrenia, schizotypal, and delusional disorders (ICD 10) were enrolled, then randomly assigned to TAU (n = 26) or TAU + MCT (n = 24). Assessments were made at baseline, after six weeks, immediately posttreatment, and 1-month post-treatment. The primary outcome was positive symptom score, as measured by the Positive and Negative Syndrome Scale (PANSS). General assessment of functioning (GAF) and measures of cognitive biases were secondary outcomes. Completion at post-treatment (10 weeks later) and 1-month follow-up was high-TAU + MCT, n = 22 (91.67%) and TAU, n = 23 (88.46%). The severity of PANSS positive symptoms declined significantly in the TAU + MCT treatment group compared with the TAU group. GAF also showed significantly greater improvement in the TAU + MCT group compared with the TAU group. There was also a trend for greater efficacy of MCT on cognitive biases. In conclusion, this study provides support for the efficacy of 10 module MCT concerning positive symptomatology (especially, delusion) and general functioning. [ABSTRACT FROM AUTHOR]

The aim of the study was to assess changes in cortical thickness related to the use of n-3 polyunsaturated fatty acids (PUFA) as add-on therapy in patients with first episode schizophrenia. A double-blind randomized controlled study was conducted using a 26-week intervention composed of concentrated fish oil containing 2.2g/d of eicosapentaenoic (EPA) and docosahexaenoic acid (DHA) or placebo (olive oil). Participants underwent MRI scanning twice to assess changes in cortical thickness: at the beginning and at the end of intervention. Data of suitable quality was obtained from 29 participants. The T1-weighted images for each participant were analyzed using FreeSurfer methodology for longitudinal pipeline. Significant differences in cortical thickness loss were observed between the groups in the parieto-occipital regions of Brodmann areas 7 and 19 of the left hemisphere, dysfunctions in which may be involved in schizophrenia symptomatology. The results of the study support the previous observations carried out in older individuals and patients with mild cognitive impairment, indicating that n-3 PUFA may have neuroprotective properties, especially at early stages of neurodegenerative diseases, such as schizophrenia. If replicated, the results of the present study may encourage clinicians to consider n-3 PUFA as a promising addition to antipsychotics for long-term treatment of schizophrenia. [ABSTRACT FROM AUTHOR]

Auditory hallucinations (AH) are a common and distressing experience and patients report distress reduction to be a priority. Relating Therapy adopts a symptom-specific and mechanism focused approach to the reduction of AH distress. We conducted this single-blind, pragmatic, parallel groups, superiority pilot RCT within a single mental health centre in the UK. Patients (18+years) with persistent and distressing AH, irrespective of diagnosis were randomly allocated to receive either Relating Therapy and Treatment-as-usual (RT) or Treatment as-usual alone (TAU). Assessment of outcome was completed pre-randomisation (T0), 16weeks post-randomisation (T1) and 36weeks post-randomisation (T2). The primary outcome was the 5-item Distress scale of the Psychotic Symptoms Rating Scale - Auditory Hallucinations (PSYRATS-AHRS) at T1. We randomly assigned 29 patients to receive RT (n=14) or TAU (n=15). Twenty-five patients (86%) provided complete datasets. Compared with TAU, RT led to reductions in AH distress in the large effect size range across T1 and T2. Our findings suggest that Relating Therapy might be effective for reducing AH distress. A larger, suitably powered phase 3 study is needed to provide a precise estimate of the effects of Relating Therapy for AH distress. [ABSTRACT FROM AUTHOR]

Cariprazine, a dopamine D3/D2 receptor partial agonist with preference for D3 receptors, has demonstrated efficacy in randomized controlled trials in schizophrenia. This multinational, randomized, double-blind, placebo-controlled, parallel-group study evaluated the efficacy, safety, and tolerability of cariprazine for relapse prevention in adults with schizophrenia; total study duration was up to 97weeks. Schizophrenia symptoms were treated/stabilized with cariprazine 3-9mg/d during 20-week open-label treatment consisting of an 8-week, flexible-dose run-in phase and a 12-week fixed-dose stabilization phase. Stable patients who completed open-label treatment could be randomized to continued cariprazine (3, 6, or 9mg/d) or placebo for double-blind treatment (up to 72weeks). The primary efficacy parameter was time to relapse (worsening of symptom scores, psychiatric hospitalization, aggressive/violent behavior, or suicidal risk); clinical measures were implemented to ensure safety in case of impending relapse. A total of 264/765 patients completed open-label treatment; 200 eligible patients were randomized to double-blind placebo (n=99) or cariprazine (n=101). Time to relapse was significantly longer in cariprazine- versus placebo-treated patients (P=.0010, log-rank test). Relapse occurred in 24.8% of cariprazine- and 47.5% of placebo-treated patients (hazard ratio [95% CI]=0.45 [0.28, 0.73]). Akathisia (19.2%), insomnia (14.4%), and headache (12.0%) were reported in ≥10% of patients during open-label treatment; there were no cariprazine adverse events ≥10% during double-blind treatment. Long-term cariprazine treatment was significantly more effective than placebo for relapse prevention in patients with schizophrenia. The long-term safety profile in this study was consistent with the safety profile observed in previous cariprazine clinical trials. ClincalTrials.gov identifier: NCT01412060. [ABSTRACT FROM AUTHOR]

The chronic and prevalent natures of schizophrenia result in long-term institutionalization for the patients. Conventional treatment of anti-psychotic medication on management of psychotic symptoms often brings on severe side effects and reduces patients' well-being. Tai-chi is a mind-body exercise that underscores motor coordination and relaxation. This 3-arm randomized controlled trial investigated the psychophysiological benefits of Tai-chi on 153 chronic schizophrenia patients, who were recruited from a mental health rehab complex and randomized into Tai-chi, exercise, or waitlist control groups. Both intervention groups received 12weeks of specific intervention plus standard medication received by the controls. All participants completed psychiatric interviews, self-report questionnaires, performance tasks, and salivary cortisol measures at baseline, 3-month, and 6-month follow-up on psychotic symptoms, motor coordination, memory, daily living function, and stress. Multigroup latent growth modeling was used to evaluate the intervention effects on the outcomes. Compared to controls, the Tai-chi group showed significant decreases in motor deficits and increases in backward digit span and mean cortisol, while the exercise group displayed significant decreases in motor deficits, negative and depression symptoms and increases in forward digit span, daily living function, and mean cortisol. The two interventions did not show significantly different therapeutic effects, except for fewer symptom manifestations in the exercise group. These results suggest psychophysiological benefits for Tai-chi on chronic schizophrenia patients in terms of motor coordination and memory. Though both Tai-chi and exercise groups tended to manifest fewer symptoms than the control group, the exercise group showed better symptoms management than the Tai-chi group. [ABSTRACT FROM AUTHOR]

Objective: Relapse and acute exacerbation are common in schizophrenia and may impact treatment response and outcome. Evidence is conflicting in respect to superiority of long-acting injectable antipsychotic therapies versus oral antipsychotics in relapse prevention. This randomized controlled study assessed the efficacy of paliperidone palmitate versus oral antipsychotics for relapse prevention.Method: Eligible patients with a recent diagnosis of schizophrenia (within 1-5 years) were randomized 1:1 to paliperidone palmitate (n=376) or oral antipsychotic monotherapy (n=388) and entered a 2-week initial acute oral treatment phase. Patients who met predefined response criteria were eligible to enter the 24-month rater-blinded core treatment phase. Patients were evaluated for relapse, symptoms, functioning, quality of life, treatment satisfaction, and tolerability.Results: In the core treatment phase, time to relapse was significantly longer in the paliperidone palmitate (n=352) compared with the oral antipsychotics arm (n=363): 85% of patients were relapse-free at 469 versus 249 days (P=0.019). Significantly fewer patients receiving paliperidone palmitate met the relapse criteria (52 [14.8%] versus 76 [20.9%, oral antipsychotics]; P=0.032), representing a 29.4% relative risk reduction. For paliperidone palmitate, a significantly greater improvement in Positive and Negative Syndrome Scale total score on Day 8 (P=0.021) and a trend at endpoint (P=0.075) were observed. Functioning improvements were comparable between treatment arms. No new safety signals were identified.Conclusion: The observed time to relapse superiority of paliperidone palmitate over oral antipsychotics provides further evidence for the value of long-acting injectable antipsychotic therapies in the treatment of schizophrenia, including during the early stages of illness. [ABSTRACT FROM AUTHOR]

Background: Schizophrenia with an onset in adolescence is known to be associated with a poorer outcome and cognitive difficulties. These impairments have an impact on quality of life and represent treatment targets. Cognitive remediation therapy (CRT) attempts to improve cognitive deficits by teaching information processing strategies through guided mental exercises. The objective of this study is to evaluate the efficacy of CRT in alleviating cognitive deficits compared to treatment as usual and explore the mediating and moderating effects of cognitive improvement. Method: Single-blind randomized controlled trial with two groups, one receiving CRT (N21) and the other standard care (N19) assessed at baseline, 3 months (post therapy) and follow-up (3 months post therapy). Participants were recruited from specialist inpatient and community mental health services and were young patients with recent onset schizophrenia (average age of 18) and evidence of cognitive and social behavioural difficulties. The intervention was individual cognitive remediation therapy delivered over a period of 3 months with at least three sessions per week. The main outcome measures were cognition (memory, cognitive flexibility and planning) and secondary outcomes (symptoms, social contacts and self-esteem). Results: Compared to standard care, CRT produced significant additional improvements in cognitive flexibility as measured by the Wisconsin Card Sort Test (WCST). Therapy moderated the effects of improved planning ability on symptoms such that improvements only had a beneficial effect when they were achieved in the context of CRT. Improvements in cognition in all domains had a direct effect on social functioning and improvements in WCST had a direct effect on overall symptom improvement. Conclusions: Cognitive remediation therapy can contribute to the improvement in WCST even in adolescents. The changes in cognitive outcomes also contributed to improvements in functioning either directly or solely in the context of CRT. Evidence of the mediator and moderator effects of cognitive changes should lead to more effective therapy development. [ABSTRACT FROM AUTHOR]

Abstract: An emerging body of research has shown that computer-assisted cognitive remediation, consisting of training in attention, memory, language and/or problem-solving, produces improvement in neurocognitive function that generalizes to untrained neurocognitive tests and may also impact symptoms and work functioning in patients with schizophrenia. The active ingredient of these interventions, however, remains unknown as control groups in these studies have typically included few, if any, of the elements of these complex behavioral treatments. This study compared the effects of an extended (12-month), standardized, computer-assisted cognitive remediation intervention with those of a computer-skills training control condition that consisted of many of the elements of the experimental intervention, including hours spent on a computer, interaction with a clinician and non-specific cognitive stimulation. Forty-two patients with schizophrenia were randomly assigned to one of two conditions and were assessed with a comprehensive neuropsychological test battery before and after treatment. Results revealed that cognitive-remediation training produced a significant improvement in working memory, relative to the computers-skills training control condition, but that there was overall improvement in both groups on measures of working memory, reasoning/executive-function, verbal and spatial episodic memory, and processing speed. Taken together, these findings suggest that specific practice in neurocognitive exercises targeted at attention, memory and language, produce improvements in neurocognitive function that are not solely attributable to non-specific stimulation associated with working with a computer, interacting with a clinician or cognitive challenge, but that non-specific stimulation has a salutary effect on neurocognition as well. [Copyright &y& Elsevier]

Objective: Worldwide, conventional antipsychotic medication continues to be used extensively, and tardive dyskinesia (TD) remains a serious complication. The primary objective of the present study was to compare the efficacy of EPA versus placebo in reducing symptoms of TD.Method: This was a 12-week, double-blinded, randomized study of ethyl-EPA 2g/day versus placebo as supplemental medication, in patients with schizophrenia or schizoaffective disorder, with established TD.Results: Eighty-four subjects were randomized, of whom 77 were included in the analysis. Both the EPA and placebo groups displayed significant baseline to endpoint improvements in Extrapyramidal Symptom Rating Scale dyskinesia scores, but there were no significant between-group differences (p=0.4). Response rates (>or=30% improvement in TD symptoms) also did not differ significantly between EPA-treated subjects (45%) and placebo-treated subjects (32%) (p=0.6). However, a post-hoc linear mixed model repeated measures analysis of variance indicated an effect for treatment group and duration of TD. The EPA-treated patients had significantly greater mean reductions in dyskinesia scores initially, although this was not sustained beyond 6 weeks.Conclusions: This trial failed to demonstrate an anti-dyskinetic effect for ethyl-EPA 2g/day on the primary efficacy measure. However, a modest and transient benefit is suggested in patients with more recent onset of TD. The lack of clear-cut efficacy could be explained on the basis of the dose of EPA being too low, the study being underpowered, TD being too chronic in the majority of cases, differences in dietary fatty acid intake, or that EPA lacks an anti-dyskinetic action. [ABSTRACT FROM AUTHOR]