Time-dependent effect of antipsychotic discontinuation and dose reduction on social functioning and subjective quality of life-a multilevel meta-analysis.

Background: Meta-analyses indicate superiority of antipsychotic maintenance treatment over discontinuation within up to 24 months after treatment initiation for patients with schizophrenia-spectrum disorders. In terms of functional recovery, long-term trials show improved functioning after discontinuation, suggesting a time-dependent effect of antipsychotic maintenance. However, these trials were not included in previous meta-analyses. We therefore investigated whether the effect of antipsychotic maintenance treatment vs. discontinuation on social functioning and quality of life varies by trial length. Methods: The study was preregistered with PROSPERO (CRD42021248933). PubMed, PsycINFO, Web of Science, Embase and trial registers were systematically searched on 8th November 2021 and updated on 25th June, 2023 and 10th August, 2023 for studies that compared antipsychotic maintenance to discontinuation and reported data on social functioning or subjective quality of life in patients with schizophrenia-spectrum disorders. Risk of bias was assessed with the RoB 2, the ROBINS-I and the RoB-ME tools. Quality of evidence was rated using the Grading of Recommendations Assessment, Development, and Evaluation approach. Findings: We included k = 35 studies (N = 5924) with follow-ups between one month and 15 years. Overall, maintenance and discontinuation did not differ on social functioning (k = 32; n = 5330; SMD = 0.204; p = 0.65; 95% CI [-0.69, 1.10]) or quality of life (k = 10; n = 943; SMD = -0.004; p = 0.97; 95% CI [-0.22, 0.21]), whilst subgroup analyses of middle- (2-5 years; k = 7; n = 1032; SMD = 0.68; 95% CI [0.06, 1.28]) and long-term follow-ups (>5 years; k = 2; n = 356; SMD = 1.04; 95% CI [0.82, 1.27]) significantly favoured discontinuation. However, the quality of evidence was rated as very low. Interpretation: Although our findings suggest a time-dependent decrease in the effect of maintenance treatment on social functioning, interpretation of these findings is limited by the serious risk of bias in middle- and long-term trials. Therefore, any conclusions regarding the long-term benefits of antipsychotic treatment or discontinuation for functional recovery are premature and more high-quality trials tailored to comparing state of the art maintenance treatment vs. discontinuation are needed. Funding: None.

Mindfulness, psychological flexibility and their relationship with psychopathology in persons with schizophrenia-spectrum-disorders and healthy controls - A multicenter cross-sectional study.

The precise nature of the relationship between mindfulness, psychological flexibility (PF) and psychopathology in schizophrenia spectrum disorders (SSD) remains largely unclear and warrants further investigation. We recruited 43 persons with SSD and 43 controls. Our findings revealed that SSD showed lower mindfulness and PF than controls. Mindfulness was associated with higher PS, anticipatory pleasure, behavioral activation, and lower depressive and negative symptoms. PS was associated with lower depressive and negative symptoms and higher anticipatory pleasure and behavioral activation. The outcomes imply that targeting mindfulness and PF may prove beneficial in alleviating the amotivational psychopathology exhibited in SSD.

"Goals in Focus"-a targeted CBT approach for motivational negative symptoms of psychosis: study protocol for a randomized-controlled feasibility trial.

BACKGROUND: The reduction of goal-directed behavior is the main characteristic in motivational negative symptoms of psychosis as it accounts for the long-term decline in psychological well-being and psychosocial functioning. However, the available treatment options are largely unspecific and show only small effects on motivational negative symptoms. Interventions that directly target the relevant psychological mechanisms are likely to be more effective. For "Goals in Focus", we translated findings from basic clinical research on mechanisms underlying motivational negative symptoms into a tailored and comprehensive novel psychological outpatient treatment program. With this study, we will test the feasibility of the therapy manual and the trial procedures. We also aim to examine first estimates of the effect size that can be expected from "Goals in Focus" to inform the sample size calculation of a subsequent fully powered trial. METHODS: Thirty participants diagnosed with a schizophrenia spectrum disorder and at least moderate motivational negative symptoms will be randomly assigned to either 24 sessions of "Goals in Focus" over the course of 6 months (n = 15) or to a 6-month wait-list control group (n = 15). Single-blind assessments will be conducted at baseline (t0) and 6 months after baseline completion (t1). Feasibility outcomes include patient recruitment, retention, and attendance rates. Acceptability will be rated by trial therapists and by participants at end of treatment. Primary outcome for effect size estimation is the motivational negative symptom subscale sum score of the Brief Negative Symptom Scale at t1 corrected for baseline values. Secondary outcomes include psychosocial functioning, psychological well-being, depressive symptoms, expressive negative symptoms, negative symptom factor scores, and goal pursuit in everyday life. DISCUSSION: The feasibility and acceptability data will be used to improve trial procedures and the "Goals in Focus" intervention where necessary. The treatment effect on the primary outcome will provide the basis for the sample size calculation for a fully powered RCT. TRIAL REGISTRATION: 1) ClinicalTrials.gov, NCT05252039 . Registered on 23 February 2022. 2) Deutsches Register Klinischer Studien, DRKS00018083 . Registered on 28 August 2019.

Psychosocial and behavioural interventions for the negative symptoms of schizophrenia: a systematic review of efficacy meta-analyses.

BACKGROUND: Currently there is no first-line treatment recommended for the negative symptoms of schizophrenia. Psychosocial and behavioural interventions are widely used to reduce the burden of negative symptoms. Meta-analytic studies have summarised the evidence for specific approaches but not compared evidence quality and benefit. AIM: To review and evaluate the evidence from meta-analytic studies of psychosocial and behavioural interventions for the negative symptoms of schizophrenia. METHOD: A systematic literature search was undertaken to identify all meta-analyses evaluating psychosocial and behavioural interventions reporting on negative symptom outcomes in people with schizophrenia. Data on intervention, study characteristics, acceptability and outcome were extracted. Risk of bias was evaluated. Results were summarised descriptively, and evidence ranked on methodological quality. RESULTS: In total, 31 systematic reviews met the inclusion criteria evaluating the efficacy of negative symptom interventions on 33 141 participants. Exercise interventions showed effect sizes (reduction in negative symptoms) ranging from -0.59 to -0.24 and psychological interventions ranging from -0.65 to -0.04. Attrition ranged between 12% to 32%. Across the studies considered heterogeneity varied substantially (range 0-100). Most of the reviews were of very low to low methodological quality. Methodological quality ranking suggested that the effect size for cognitive remediation and exercise therapy may be more robust compared with other approaches. CONCLUSIONS: Most of the interventions considered had a small-to-moderate effect size, good acceptability levels but very few had negative symptoms as the primary intervention target. To improve the confidence of these effect sizes being replicated in clinical settings future studies should minimise risk of bias.

In the eyes of the beholders: Subjective experiences of positive symptoms among patients with symptoms of psychosis seeking psychotherapy.

BACKGROUND: Reduction of positive symptoms is often the focus of psychiatric treatment for patients with psychosis; however, it is becoming increasingly clear that some patients experience ambivalence towards positive symptoms or may even experience them as pleasant. The present study extends upon work from online studies of patients without verified diagnoses. The first aim was to examine the frequency with which patients report negative, neutral or even positive appraisals of positive symptoms. A second aim was to identify whether these appraisals were associated with medication adherence. METHODS: One-hundred twelve treatment-seeking patients with current symptoms of psychosis completed the Subjective Perception of Positive Symptoms-Revised (SUPPOSY-R), a scale assessing appraisals of positive symptoms (e.g., gain from illness, impact on daily life), as well as questions regarding medication adherence. RESULTS: Although most patients reported experiencing positive symptoms as predominantly unpleasant, appraisals differed between symptom clusters and up to 54.4 % reported that they would miss at least some aspects of positive symptoms should they disappear. Patients particularly welcomed the disappearance of auditory hallucinations (71.2 %). Symptom appraisal was not significantly associated with medication compliance (p > .17); however, more patients with low medication adherence reported they would feel at least some regret if their symptoms were to completely disappear (48.9 %, n = 23) versus patients with high adherence (41.7 %, n = 20). DISCUSSION: Ambivalent or positive appraisals of positive symptoms are lower among treatment-seeking patients compared to patients recruited for online studies, who may not be actively seeking treatment. Auditory hallucinations may cause most distress among treatment-seeking patients. A collaborative approach including assessment of possible positive appraisals of symptoms is important when identifying treatment goals.

Expanding the positivity offset theory of anhedonia to the psychosis continuum.

People with schizophrenia and negative symptoms show diminished net positive emotion in low-arousing contexts (diminished positivity offset) and co-activate positive and negative emotion more frequently (increased ambivalence). Here, we investigated whether diminished positivity offset and increased ambivalence covary with negative symptoms along the continuum of psychotic symptoms. We conducted an online-study in an ad-hoc community sample (N = 261). Participants self-reported on psychotic symptoms (negative symptoms, depression, positive symptoms, anhedonia) and rated positivity, negativity, and arousal elicited by pleasant, unpleasant, and neutral stimuli. The data were analyzed with multilevel linear models. Increasing levels of all assessed symptom areas showed significant associations with diminished positivity offset. Increased ambivalence was related only to positive symptoms. Our results show that the diminished positivity offset is associated with psychotic symptoms in a community sample, including, but not limited to, negative symptoms. Ecological validity and symptom specificity require further investigation.

From Memories of Past Experiences to Present Motivation? A Meta-analysis on the Association Between Episodic Memory and Negative Symptoms in People With Psychosis.

Based on findings from cognitive science, it has been theorized that the reductions in motivation and goal-directed behavior in people with psychosis could stem from impaired episodic memory. In the current meta-analysis, we investigated this putative functional link between episodic memory deficits and negative symptoms. We hypothesized that episodic memory deficits in psychosis would be related to negative symptoms in general but would be more strongly related to amotivation than to reduced expressivity. We included 103 eligible studies (13,622 participants) in the analyses. Results revealed significant, moderate negative associations of episodic memory with negative symptoms in general (k = 103; r = -.23; z = -13.40; P ≤ .001; 95% CI [-.26; -.20]), with amotivation (k = 16; r = -.18; z = -6.6; P ≤ .001; 95% CI [-.23; -.13]) and with reduced expressivity (k = 15; r = -.18; z = -3.30; P ≤.001; 95% CI[-.29; -.07]). These associations were not moderated by sociodemographic characteristics, positive symptoms, depression, antipsychotic medication or type of negative symptom scale. Although these findings provide sound evidence for the association between episodic memory deficits and amotivation, the rather small magnitude and the unspecific pattern of this relationship also indicate that episodic memory deficits are unlikely to be the only factor relevant to amotivation. This implicates that future research should investigate episodic memory in conjunction with other factors that could account for the association of episodic memory deficits and amotivation in psychosis.

Increasing motivation in effort-based decision-making tasks: effects of salience and reward expectancy manipulations.

BACKGROUND: A significant proportion of patients with affective and psychotic disorders show a marked reduction in goal-directed behaviour, which is also reflected in the behavioural outcomes of effort-based decision-making paradigms. The factors underlying this reduction are not yet fully understood. Reward salience and reward expectancy have been discussed as factors that potentially influence approach behaviour. The aim of this study was thus to test their effects on behaviour in an effort-based decision-making paradigm. METHODS: In two studies with community samples we applied a modified version of the Balloon Task. In study 1, we manipulated reward salience in a within-subject design (N = 32) by highlighting the monetary rewards. In study 2, we manipulated reward expectancy in a between-subject design (N = 72) by adding five practice trials with either positive or negative feedback prior to the task. RESULTS: The salience of rewards manipulation significantly increased effort expenditure and the allocation of effort to the level of rewards whereas the reward expectancy manipulation did not. CONCLUSIONS: The finding that increasing the salience of rewards increases motivated behaviour in an effort-based decision-making paradigm offers promising possibilities for intervention in disorders characterised by motivational deficits, such asaffective and psychotic disorders.

Does social defeat cause negative symptoms? A prospective study in a multi-national community sample.

Psychological models of the consequences of ostracism (i.e. being socially excluded and ignored) and negative symptoms in schizophrenia suggest that repeatedly experiencing ostracism can lead to elevated levels of amotivation, anhedonia, and asociality (i.e. negative symptoms). We tested this assumption in a prospective study, following up a large multi-national community sample from Germany, Indonesia, and the United States (N = 962) every four months over one year. At each of the four assessment points (T0 - T3), participants rated their recent ostracism experiences and negative symptoms. Using cross-lagged panel analyses we found a) that negative symptoms and experiences of ostracism were significantly associated in each of the four assessment points, b) that ostracism predicted negative symptoms over time (T2 to T3), and c) that negative symptoms increased ostracism (T0 to T1). The results are in line with the social defeat model of negative symptoms and suggest a bi-directional longitudinal relationship between ostracism and negative symptoms. Moving forward, it will therefore be important to gain an understanding of potential moderators involved in the mechanism.

RELATE-a randomised controlled feasibility trial of a Relating Therapy module for distressing auditory verbal hallucinations: a study protocol.

INTRODUCTION: Auditory verbal hallucinations (AVHs) are associated with distress and reduced functioning. Research suggests that distress is associated with the voice hearer's responding to AVH in a passive and subordinate manner. A novel approach focuses on relating to AVH and teaches assertive responses to AVH using experiential role-plays. A small pilot study found a large effect of this approach on AVH distress but an independent multicentre study is required to ascertain effectiveness across different settings. We aim to estimate the expected effect for a subsequent trial to demonstrate that adding a module of Relating Therapy (RT) to treatment as usual (TAU) is superior to TAU alone in reducing AVH distress. We also test the feasibility of patient recruitment, therapist training, and therapy monitoring in different psychological and psychiatric outpatient facilities in Germany. METHODS AND ANALYSIS: We will recruit 75 patients diagnosed with a schizophrenia spectrum disorder and persistent distressing AVH across four sites. Patients will be randomised to receive either 16 sessions of RT plus TAU or TAU alone within a 5-month period. Randomisation will be stratified by sites. Single-blind assessments will take place at baseline, at 5 months (T1) and at 9 months (T2). The primary outcome is the distress factor score of the AVH subscale of the Psychotic Symptoms Rating Scale at T2 adjusted for the baseline value. Secondary outcomes are change in depressive symptoms, quality of life, time spent in structured activities as well as negative relating to voices and to other people. ETHICS AND DISSEMINATION: The trial has received ethical approval from the German Psychological Society Ethics Committee. The trial results will be disseminated through conference presentations, peer-reviewed publications and social media. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Registry (NCT04578314).

Ebola Virus Disease Survivors Show More Efficient Antibody Immunity than Vaccinees Despite Similar Levels of Circulating Immunoglobulins.

The last seven years have seen the greatest surge of Ebola virus disease (EVD) cases in equatorial Africa, including the 2013-2016 epidemic in West Africa and the recent epidemics in the Democratic Republic of Congo (DRC). The vaccine clinical trials that took place in West Africa and the DRC, as well as follow-up studies in collaboration with EVD survivor communities, have for the first time allowed researchers to compare immune memory induced by natural infection and vaccination. These comparisons may be relevant to evaluate the putative effectiveness of vaccines and candidate medical countermeasures such as convalescent plasma transfer. In this study, we compared the long-term functionality of anti-EBOV glycoprotein (GP) antibodies from EVD survivors with that from volunteers who received the recombinant vesicular stomatitis virus vectored vaccine (rVSV-ZEBOV) during the Phase I clinical trial in Hamburg. Our study highlights important differences between EBOV vaccination and natural infection and provides a framework for comparison with other vaccine candidates.

"I just don't look forward to anything". How anticipatory pleasure and negative beliefs contribute to goal-directed activity in patients with negative symptoms of psychosis.

Anticipatory pleasure refers to a state of positive affect in anticipation of future events that has been found to motivate goal-directed behavior. Previous research has indicated that patients with negative symptoms of psychosis show reduced goal-directed behavior because 'demotivating beliefs' impede anticipatory pleasure. This study aims to link demotivating beliefs and anticipatory pleasure to patients' motivation in everyday life. Using the Experience Sampling Method, we examined the motivational process of goal-directed activity in the daily lives of 35 patients with negative symptoms and 36 healthy controls. We tested whether the mechanism underlying goal-directed behavior differs between patients and healthy controls and whether demotivating beliefs interfere with goal-directed behavior by impeding anticipatory pleasure. Multilevel analyses revealed that anticipatory pleasure mediated the association between goal-intentions and goal-directed activity in both groups (indirect effects: 24-30%). In the patient group, however, the association between social goal-intentions and anticipatory pleasure was weaker (b = -0.09, SE = 0.05, p ≤ .01, [-0.17;-0.04]) than in the controls, but this was not found for goal-intentions related self-care or recreational activites. Also, demotivating beliefs were more pronounced in the patient sample. (F(1,70) = 72.11, p ≤ .001) and moderated the effect of goal-intentions on anticipatory pleasure for social activities in the whole sample (b = -0.12, SE = 0.05, p ≤ .01, [-0.20;-0.08]). Our results support the assumption that a set of demotivating beliefs prevents patients with negative symptoms from looking forward to social activities and thus provide a possible psychological explanation for the social withdrawal of patients with negative symptoms.

Efficacy of Psychological Treatments for Patients With Schizophrenia and Relevant Negative Symptoms: A Meta-Analysis.

Background: Recent meta-analyses on the efficacy of psychological treatments for the negative symptoms of schizophrenia included mostly trials that had not specifically targeted negative symptoms. To gauge the efficacy of such treatments in the target patient population - namely people with schizophrenia who experience negative symptoms - we conducted a meta-analysis of controlled trials that had established an inclusion criterion for relevant negative symptom severity. Method: We conducted a systematic literature search and calculated random-effects meta-analyses for controlled post-treatment effects and for pre-post changes within treatment arms. Separate analyses were conducted for different therapeutic approaches. Our primary outcome was reduction in negative symptoms; secondary outcomes were amotivation, reduced expression, and functioning. Results: Twelve studies matched our inclusion criteria, testing Cognitive Behavioral Therapy (CBT) vs. treatment-as-usual (k = 6), Cognitive Remediation (CR) vs. treatment-as-usual (k = 2), CBT vs. CR (k = 2), and Body-oriented Psychotherapy (BPT) vs. supportive group counseling and vs. Pilates (k = 1 each). Accordingly, meta-analyses were performed for CBT vs. treatment-as-usual, CR vs. treatment-as-usual, and CBT vs. CR. CBT and CR both outperformed treatment-as-usual in reducing negative symptoms (CBT: Hedges' g = -0.46; CR: g = -0.59). There was no difference between CBT and CR (g = 0.12). Significant pre-post changes were found for CBT, CR, and to a lesser extent for treatment-as-usual, but not for BPT. Conclusion: Although effects for some approaches are promising, more high-quality trials testing psychological treatments for negative symptoms in their target population are needed to place treatment recommendations on a sufficiently firm foundation.

[Modern cognitive behavior therapy of psychotic disorders]. / Moderne kognitive Verhaltenstherapie bei psychotischen Störungen.

The current treatment guidelines recommend several effective psychotherapeutic approaches for different indications or aims in the therapy of patients with psychotic disorders. In particular, cognitive behavior therapy (CBTp) is recommended for the treatment of positive and general symptoms in all phases of the disorder without any restriction. Although CBTp could be easily implemented in routine care, very few of the affected patients have access to this evidence-based procedure in inpatient or outpatient settings. The interventions in CBTp directly address the psychotic symptoms themselves as well as the factors involved in the development and maintenance of symptoms. The core features of CBTp are a normalizing attitude of the therapist towards symptoms, an individualized approach and cognitive interventions. Recent developments include symptom-specific, metacognitive as well as mindfulness and acceptance-based approaches. Moreover, the reduction of comorbid symptoms can add to the benefit of the treatment. This article provides an overview of the basic CBTp techniques and of some of the latest developments in this field. It is hoped that this will contribute to the training of therapists and to the better implementation of evidence-based and guideline-based psychotherapy in the care of patients with psychotic disorders.

The demotivating effect of social exclusion: An experimental test of a psychosocial model on the development of negative symptoms in psychosis.

The impairment in social functioning of patients with psychotic disorders is mainly driven by motivational negative symptoms with a widely unknown etiology. Building on the well-confirmed link between specific social risk factors and psychosis, the current study tested the postulated effect of immediate social exclusion on the development of motivational negative symptoms and the association of repeated social exclusion experiences with demotivating beliefs in a community sample (N = 84). Repeated social exclusion experiences and demotivating beliefs were assessed at baseline. We randomized the participants to either an exclusion or an inclusion condition of a virtual ball tossing game. Motivation and anticipatory pleasure were measured before and after the manipulation via self-report and via a behavioral effort paradigm. We found a significant multivariate effect of social exclusion on self-reported motivation (F(4,79) = 4.25, p < .01, η2 = .18), but not on behavioral effort (F(1,82) = 1.24, p = .27, η2 = .02). Repeated social exclusion was significantly associated with demotivating beliefs (r = .58, p < .01) and negative symptoms (r = .43, p < .001). Our findings support the notion that reduced motivation, anticipatory anhedonia and demotivating beliefs can be understood as motivational and cognitive consequences of social exclusion. We also discuss the implications for psychological interventions and for further research on the etiology of negative symptoms.

Using Functional Analysis as a Framework to Guide Individualized Treatment for Negative Symptoms.

Although numerous interventions are available for negative symptoms, outcomes have been unsatisfactory with pharmacological and psychological interventions producing changes of only limited clinical significance. Here, we argue that because negative symptoms occur as a complex syndrome caused and maintained by numerous factors that vary between individuals they are unlikely to be treated effectively by the present "one size fits all" approaches. Instead, a well-founded selection of those interventions relevant to each individual is needed to optimize both the efficiency and the efficacy of existing approaches. The concept of functional analysis (FA) can be used to structure existing knowledge so that it can guide individualized treatment planning. FA is based on stimulus-response learning mechanisms taking into account the characteristics of the organism that contribute to the responses, their consequences and the contingency with which consequences are tied to the response. FA can thus be flexibly applied to the level of individual patients to understand the factors causing and maintaining negative symptoms and derive suitable interventions. In this article we will briefly introduce the concept of FA and demonstrate-exemplarily-how known psychological and biological correlates of negative symptoms can be incorporated into its framework. We then outline the framework's implications for individual assessment and treatment. Following the logic of FA, we argue that a detailed assessment is needed to identify the key factors causing or maintaining negative symptoms for each individual patient. Interventions can then be selected according to their likelihood of changing these key factors and need to take interactions between different factors into account. Supplementary case vignettes exemplify the usefulness of functional analysis for individual treatment planning. Finally, we discuss and point to avenues for future research guided by this model.

Predictors of improved functioning in patients with psychosis: The role of amotivation and defeatist performance beliefs.

Defeatist performance beliefs (DPBs) are associated with the severe impairments in functioning of patients with negative symptoms of schizophrenia. This association has been found to be mediated by amotivation, a core aspect of negative symptoms. Although causality is assumed, longitudinal evidence for this is lacking. The current study aimed to extend previous findings by investigating both cross-sectional and longitudinal associations between DPBs, motivational impairments and functioning in a sample of patients with psychotic disorders (N=58). We hypothesized, that DPBs would be related to functioning in cross-sectional and longitudinal analyses and that this link would be mediated by motivational impairments. Data was assessed at baseline and post-treatment in a trial on the effects of cognitive behavior therapy for psychosis. At baseline, amotivation mediated the association between DPBs and functioning. From baseline to post-treatment, reduction of amotivation was associated with improvement of functioning significantly, whereas reduction of DPBs was unrelated to improvements in functioning or amotivation. The findings suggest that improvement in amotivation accounts for favorable treatment outcomes in regard to functioning but question the causal role of DPBs in negative symptoms and functioning.