Negative symptoms in schizophrenia: reconsidering evidence and focus in clinical trials.

Negative symptoms of schizophrenia have been documented in the literature for over a century. Nevertheless, research has not convincingly produced effective interventions for their treatment. We propose to re-analyse currently published evidence on treatment of negative symptoms, using narrower definitions for symptom dimensions, to better understand what works for whom.

Negative symptoms in drug-naive patients with a first-episode psychosis (FEP).

INTRODUCTION: Negative symptoms are nuclear features of schizophrenia that may be present from the onset of the disease. In recent years, it has been described 2 subdomains of negative symptoms: experiential and expressive deficits. The aim of the study is to examine the relationship between negative symptoms and demographic and clinical variables in patients with first-episode psychosis. Also, to explore whether there are differences in the association among these variables and negative symptoms when divided into both subdomains. MATERIAL AND METHODS: A cross-sectional study was performed in 160 patients (52 females and 108 males) with a diagnosis of a first episode psychosis. A questionnaire was administered to collect demographic and clinical variables. RESULTS: A backward stepwise linear regressions analysis was performed in order to observe potential associations between demographic and clinical variables and the presence of negative symptoms. All three models are predicted by worse PSP score, a higher CDSS, a higher disorganized factor score and a lower excited factor score. A longer duration of untreated psychosis (DUP) is associated to a higher score in the experiential deficit subdomain only. CONCLUSIONS: Our work highlights some clinical and phenomenological differences between experiential and expressive deficits. We think that taking into account both subdomains in future studies may lead to more accurate clinical assessment and interventions.

Modifiable predictors of self-reported and performance-based functioning in individuals with schizophrenia-spectrum disorders and high levels of negative symptoms.

Individuals with schizophrenia who have high negative symptoms are at high risk for poor functional outcomes. However, the determinants of psychosocial functioning in this group are not well understood. We aimed to examine modifiable predictors of both objective, performance-based functional capacity and social skills, and self-reported functioning in individuals with schizophrenia and schizoaffective disorder and high negative symptoms. Fifty-five adults with moderate-to-severe negative symptoms were administered measures of neuropsychological performance, performance-based functional capacity and social competence, self-reported functioning, psychiatric symptom severity, defeatist/asocial beliefs, and intrinsic motivation. In the context of multiple significant predictor variables identified through bivariate correlations, multiple regression models showed that neuropsychological performance was the only significant predictor of performance-based functional capacity; neuropsychological performance and motivation/pleasure negative symptoms were significant predictors of performance-based social competence. For two different measures of self-reported functioning, intrinsic motivation, asocial beliefs, and diminished expression emerged as significant predictors. Neurocognitive ability was a better predictor of performance-based functional skills whereas motivation and beliefs more strongly predicted self-reported real-world functioning. The findings of this study suggest a complex picture of predictors of performance-based functional capacity (objective neuropsychological functioning) and self-reported functioning (motivation and beliefs), underscoring the clinical and scientific utility of including both self-reported and objective measures of functioning to identify treatment approach. Individuals with high negative symptoms and a cognitive/functional skills deficit may benefit from interventions such as cognitive remediation or skills training, whereas individuals with motivational difficulties may benefit from treatments such as cognitive behavioral therapy.

Impact of Negative Symptoms on Functioning and Quality of Life in First Psychotic Episodes of Schizophrenia.

Negative symptoms are not considered a unitary construct encompassing two different domains, diminished expression, and avolition-apathy. The aim of this study was to explore the relationships between each domain and psychosocial functioning and quality of life in people with a first psychotic episode of schizophrenia. In total, 61 outpatients were assessed with the Clinical Assessment Interview for Negative Symptoms (CAINS), The Functioning Assesment Short Test (FAST) and The Quality of Life Scale (QLS). The mean global score for CAINS was 21.5 (SD: 15.6), with a CAINS Avolition-Apathy (MAP) score of 17.0 (SD: 11.8), and CAINS Diminished Expression (EXP) score of 4.5 (SD: 5.0). The mean FAST score was 31.9 (SD: 18.9), and 41.1 (SD: 17.9) for QLS. Linear regression analysis revealed a significant (F(4,53) = 15.65, p < 0.001) relationship between MAP and EXP CAINS' score and FAST score. CAINS-MAP was more predictive of FAST scores (ß = 0.44, p = 0.001) than CAINS-EXP (ß = 0.37, p = 0.007). Linear regression analysis for QLS revealed a significant model (F(4,56) = 29.29, p < 0.001). The standardized regression weight for the CAINS-MAP was around three times greater (ß = -0.63, p < 0.001) than for CAINS-EXP (ß = -0.24, p = 0.024). The two different domains are associated differently with functionality and quality of life.

Compensatory Cognitive Training for psychosis: Effects on negative symptom subdomains.

Research identifying the effects of cognitive training on negative symptoms of psychosis is limited. We examined the effects of Compensatory Cognitive Training (CCT) on expressive deficits and social amotivation in a randomized controlled trial comparing CCT to standard pharmacotherapy alone in 43 individuals with psychosis. ANCOVA analyses demonstrated significant CCT-associated effects on both expressive deficits and social amotivation. Moreover, improvements in both sub-domains were associated with improvements in global life satisfaction, with improvements in social amotivation also related to increased social contact. CCT appears to be a beneficial treatment approach for improving multiple aspects of negative symptoms.

Long-term course of negative symptom subdomains and relationship with outcome in patients with a psychotic disorder.

BACKGROUND: The longitudinal course of the negative symptoms subdomains social amotivation (SA) and expressive deficits (ED) remains largely unknown. We investigated i) the longitudinal course of SA and ED subdomain scores, ii) whether subgroups based on the course of SA and ED subdomain scores could be identified, iii) whether baseline SA and ED subdomain scores were related to functioning and quality of life six years later and iv) the longitudinal relationship between subgroups and outcomes. METHODS: Measurements at baseline, three and six years from 1067 patients participating in the Genetic Risk and Outcome of Psychosis (GROUP) project were used. We applied mixed models analysis, regression analysis and trajectory analyses. RESULTS: SA and ED subdomain scores decreased over time. Within both subdomains, four subgroups were identified: for both SA and ED a steady low course (±60%), increased (±15%) and decreased course (±15%). Within SA only, a higher level decreased course (±6%) and within ED only, a course with relatively stable high ED scores (±6%) was found. Lower symptom levels at baseline were related to better functioning (SA & ED) and quality of life (SA) at six years. Overall, low SA and low ED subgroups showed better outcomes than the other subgroups. CONCLUSION: In many patients the course of negative symptoms is unstable and related to the course of outcome. Patients who do show steady low negative symptom levels (60%) may complicate the interpretation of treatment evaluation studies, as they may average out possible effects in subgroups with fluctuating symptom levels.

Negative Symptom Dimensions of the Positive and Negative Syndrome Scale Across Geographical Regions: Implications for Social, Linguistic, and Cultural Consistency.

Objective: Recognizing the discrete dimensions that underlie negative symptoms in schizophrenia and how these dimensions are understood across localities might result in better understanding and treatment of these symptoms. To this end, the objectives of this study were to 1) identify the Positive and Negative Syndrome Scale negative symptom dimensions of expressive deficits and experiential deficits and 2) analyze performance on these dimensions over 15 geographical regions to determine whether the items defining them manifest similar reliability across these regions. Design: Data were obtained for the baseline Positive and Negative Syndrome Scale visits of 6,889 subjects across 15 geographical regions. Using confirmatory factor analysis, we examined whether a two-factor negative symptom structure that is found in schizophrenia (experiential deficits and expressive deficits) would be replicated in our sample, and using differential item functioning, we tested the degree to which specific items from each negative symptom subfactor performed across geographical regions in comparison with the United States. Results: The two-factor negative symptom solution was replicated in this sample. Most geographical regions showed moderate-to-large differential item functioning for Positive and Negative Syndrome Scale expressive deficit items, especially N3 Poor Rapport, as compared with Positive and Negative Syndrome Scale experiential deficit items, showing that these items might be interpreted or scored differently in different regions. Across countries, except for India, the differential item functioning values did not favor raters in the United States. Conclusion: These results suggest that the Positive and Negative Syndrome Scale negative symptom factor can be better represented by a two-factor model than by a single-factor model. Additionally, the results show significant differences in responses to items representing the Positive and Negative Syndrome Scale expressive factors, but not the experiential factors, across regions. This could be due to a lack of equivalence between the original and translated versions, cultural differences with the interpretation of items, dissimilarities in rater training, or diversity in the understanding of scoring anchors. Knowing which items are challenging for raters across regions can help to guide Positive and Negative Syndrome Scale training and improve the results of international clinical trials aimed at negative symptoms.

The relationship between experiential deficits of negative symptoms and subjective quality of life in schizophrenia.

Understanding the link between quality of life and symptoms in schizophrenia is important in enhancing the prospect of patient recovery. Only weak associations have been found between subjective quality of life (SQOL) and negative symptoms. However, this may be because many existing symptom assessment scales inadequately assess the experiential deficits of negative symptoms. This study aimed to re-evaluate these findings using the Clinical Assessment Interview for Negative Symptoms (CAINS), which as been designed to capture both the expressive and experiential subdomains of negative symptoms as separate constructs. In this observational study 275 participants with at least moderate negative symptoms were assessed three times over nine months using the CAINS, the Positive and Negative Syndrome Scale (PANSS), and the Manchester Short Assessment of Quality of Life (MANSA). A significant negative association between SQOL and the CAINS experiential subscale was found in the cross-sectional analysis (adj. B=-0.28, 95% CI=-0.44 to -0.12, P=0.001), and in the change scores (adj. B=-0.13, 95% CI=-0.26 to -0.01, P=0.032). No associations between SQOL and expressive symptoms, or negative symptoms measured using the PANSS were detected in the multivariable models. These findings suggest that the association between negative symptoms and SQOL is related primarily to experiential deficits, and highlights the importance of measuring the separate subdomains of negative symptoms as distinct constructs. The findings also highlight the impact of negative symptoms and experiential deficits in particular on social outcomes, further emphasising the need to develop new treatments for these symptoms.

A Two-Factor Model Better Explains Heterogeneity in Negative Symptoms: Evidence from the Positive and Negative Syndrome Scale.

Acknowledging separable factors underlying negative symptoms may lead to better understanding and treatment of negative symptoms in individuals with schizophrenia. The current study aimed to test whether the negative symptoms factor (NSF) of the Positive and Negative Syndrome Scale (PANSS) would be better represented by expressive and experiential deficit factors, rather than by a single factor model, using confirmatory factor analysis (CFA). Two hundred and twenty individuals with schizophrenia spectrum disorders completed the PANSS; subsamples additionally completed the Brief Negative Symptom Scale (BNSS) and the Motivation and Pleasure Scale-Self-Report (MAP-SR). CFA results indicated that the two-factor model fit the data better than the one-factor model; however, latent variables were closely correlated. The two-factor model's fit was significantly improved by accounting for correlated residuals between N2 (emotional withdrawal) and N6 (lack of spontaneity and flow of conversation), and between N4 (passive social withdrawal) and G16 (active social avoidance), possibly reflecting common method variance. The two NSF factors exhibited differential patterns of correlation with subdomains of the BNSS and MAP-SR. These results suggest that the PANSS NSF would be better represented by a two-factor model than by a single-factor one, and support the two-factor model's adequate criterion-related validity. Common method variance among several items may be a potential source of measurement error under a two-factor model of the PANSS NSF.

Dissecting negative symptoms in schizophrenia: opportunities for translation into new treatments.

Among the constellation of symptoms that characterize schizophrenia, negative symptoms have emerged as a critical feature linked to the functional impairment experienced by affected individuals. Despite advances in our understanding of the role of negative symptoms in the illness, effective treatments for these debilitating symptoms have remained elusive. In this review we explore the contemporary conceptualization of negative symptoms in schizophrenia, including the identification of two key subdomains of diminished expression and amotivation, and clarifications around hedonic capacity. We then explore strategies for clinical assessments of negative symptoms, followed by findings using objective paradigms for evaluating discrete aspects of these negative symptoms in clinical populations and animal models, both for symptoms of diminished expression and within the multifaceted motivation system. We conclude with a consideration of current strategies for drug development for these negative symptoms, the role of heterogeneity in the clinical presentation of symptoms in schizophrenia and opportunities for personalized assessment and treatment approaches, as well as a commentary on current clinical drug trial design and the role of environmental opportunities for novel treatments to effect change and improve outcomes for affected individuals.

Negative symptoms and everyday functioning in schizophrenia: a cross-sectional study in a real world-setting.

Negative symptoms have been suggested to have a greater impact on real-world functioning in schizophrenia than other symptoms. We aimed to examine the relationship of specific negative symptoms components ("expressive deficits" - DE - which include alogia and blunted affect, and "avolition" - AA - which includes amotivation, anhedonia, and asociality), with separate domains of real-world outcomes (the Personal and Social Performance Scale - PSP - and selected items of the Heinrichs Quality of Life Scale - QLS - that did not overlap with negative symptoms) and two functional milestones (recent employment and marriage). Regression analyses were performed to identify the determinants of QLS and PSP scores and of the two milestones, in 92 consecutive outpatients with stable schizophrenia. AA was the strongest predictor of QLS interpersonal relations and social network (IRSN), PSP total score and the first three PSP domains. The variance explained ranged from 36% for PSP self care to 54% for the PSP personal and social relationships. Moreover, higher scores in AA were significant predictors of the single status. DE does not appear to have an impact at real-world functional performance. Taken together, our analysis indicates a relatively specific set of relationships between the AA subdomain and aspects of real-world functioning in schizophrenia. These findings, if confirmed, could have important implications for research, diagnostics and treatment: in fact our results would suggest that AA and DE should be analyzed as separate and distinct domains to be rated and treated individually.