Electrophysiological Correlates of Reward Anticipation in Subjects with Schizophrenia: An ERP Microstate Study.

The current study aimed to investigate alterations of event-related potentials (ERPs) microstate during reward anticipation in subjects with schizophrenia (SCZ), and their association with hedonic experience and negative symptoms. EEG data were recorded in thirty SCZ and twenty-three healthy controls (HC) during the monetary incentive delay task in which reward, loss and neutral cues were presented. Microstate analysis and standardized low-resolution electromagnetic tomography (sLORETA) were applied to EEG data. Furthermore, analyses correlating a topographic index (the ERPs score), calculated to quantify brain activation in relationship to the microstate maps, and scales assessing hedonic experience and negative symptoms were performed. Alterations in the first (125.0-187.5 ms) and second (261.7-414.1 ms) anticipatory cue-related microstate classes were observed. In SCZ, reward cues were associated to shorter duration and earlier offset of the first microstate class as compared to the neutral condition. In the second microstate class, the area under the curve was smaller for both reward and loss anticipation cues in SCZ as compared to HC. Furthermore, significant correlations between ERPs scores and the anticipation of pleasure scores were detected, while no significant association was found with negative symptoms. sLORETA analysis showed that hypo-activation of the cingulate cortex, insula, orbitofrontal and parietal cortex was detected in SCZ as compared to HC. Abnormalities in ERPs could be traced already during the early stages of reward processing and were associated with the anticipation of pleasure, suggesting that these dysfunctions might impair effective evaluation of incoming pleasant experiences. Negative symptoms and anhedonia are partially independent results.

EPA guidance on treatment of negative symptoms in schizophrenia.

Negative symptoms of schizophrenia remain a major therapeutic challenge. The progress in the conceptualization and assessment is not yet fully reflected by treatment research. Nevertheless, there is a growing evidence base regarding the effects of biological and psychosocial interventions on negative symptoms. The importance of the distinction between primary and secondary negative symptoms for treatment selection might seem evident, but the currently available evidence remains limited. Good clinical practice is recommended for the treatment of secondary negative symptoms. Antipsychotic treatment should be optimized to avoid secondary negative symptoms due to side effects and due to positive symptoms. For most available interventions, further evidence is needed to formulate sound recommendations for primary, persistent, or predominant negative symptoms.However, based on currently available evidence recommendations for the treatment of undifferentiated negative symptoms (including both primary and secondary negative symptoms) are provided. Although it has proven difficult to formulate an evidence-based recommendation for the choice of an antipsychotic, a switch to a second-generation antipsychotic should be considered for patients who are treated with a first-generation antipsychotic. Antidepressant add-on to antipsychotic treatment is an option. Social skills training is recommended as well as cognitive remediation for patients who also show cognitive impairment. Exercise interventions also have shown promise. Finally, access to treatment and to psychosocial rehabilitation should be ensured for patients with negative symptoms. Overall, there is definitive progress in the field, but further research is clearly needed to develop specific treatments for negative symptoms.

EPA guidance on assessment of negative symptoms in schizophrenia.

BACKGROUND: During the last decades, a renewed interest for negative symptoms (NS) was brought about by the increased awareness that they interfere severely with real-life functioning, particularly when they are primary and persistent. METHODS: In this guidance paper, we provide a systematic review of the evidence and elaborate several recommendations for the conceptualization and assessment of NS in clinical trials and practice. RESULTS: Expert consensus and systematic reviews have provided guidance for the optimal assessment of primary and persistent negative symptoms; second-generation rating scales, which provide a better assessment of the experiential domains, are available; however, NS are still poorly assessed both in research and clinical settings.This European Psychiatric Association (EPA) guidance recommends the use of persistent negative symptoms (PNS) construct in the context of clinical trials and highlights the need for further efforts to make the definition of PNS consistent across studies in order to exclude as much as possible secondary negative symptoms. We also encourage clinicians to use second-generation scales, at least to complement first-generation ones.The EPA guidance further recommends the evidence-based exclusion of several items included in first-generation scales from any NS summary or factor score to improve NS measurement in research and clinical settings. Self-rated instruments are suggested to further complement observer-rated scales in NS assessment.Several recommendations are provided for the identification of secondary negative symptoms in clinical settings. CONCLUSIONS: The dissemination of this guidance paper may promote the development of national guidelines on negative symptom assessment and ultimately improve the care of people with schizophrenia.

Premorbid academic and social functioning in patients with schizophrenia and its associations with negative symptoms and cognition.

OBJECTIVE: The study aimed to explore premorbid academic and social functioning in patients with schizophrenia, and its associations with the severity of negative symptoms and neurocognitive impairment. METHOD: Premorbid adjustment (PA) in patients with schizophrenia was compared to early adjustment in unaffected first-degree relatives and healthy controls. Its associations with psychopathology, cognition, and real-life functioning were investigated. The associations of PA with primary negative symptoms and their two factors were explored. RESULTS: We found an impairment of academic and social PA in patients (P ≤ 0.000001) and an impairment of academic aspects of early adjustment in relatives (P ≤ 0.01). Patients with poor PA showed greater severity of negative symptoms (limited to avolition after excluding the effect of depression/parkinsonism), working memory, social cognition, and real-life functioning (P ≤ 0.01 to ≤0.000001). Worse academic and social PA were associated with greater severity of psychopathology, cognitive impairment, and real-life functioning impairment (P ≤ 0.000001). Regression analyses showed that worse PA in the academic domain was mainly associated to the impairment of working memory, whereas worse PA in the social domain to avolition (P ≤ 0.000001). CONCLUSION: Our findings suggest that poor early adjustment may represent a marker of vulnerability to schizophrenia and highlight the need for preventive/early interventions based on psychosocial and/or cognitive programs.

Disorganization and real-world functioning in schizophrenia: Results from the multicenter study of the Italian Network for Research on Psychoses.

BACKGROUND: A general consensus has not yet been reached regarding the role of disorganization symptoms in real-world functioning in schizophrenia. METHODS: We used structural equations modeling (SEM) to analyze the direct and indirect associations between disorganization and real-world functioning assessed through the Specific Levels of Functioning Scale (SLOF) in 880 subjects with schizophrenia. RESULTS: We found that: 1) conceptual disorganization was directly and strongly connected with SLOF daily activities; difficulty in abstract thinking was associated with moderate strength to all SLOF domains, and poor attention was connected with SLOF work skills; 2) grandiosity was only related with poor work skills, and delusions were associated with poor functioning in all SLOF domains; interpersonal relationships were weakly indirectly influenced by hallucinatory behavior, delusions and unusual thought contents through the mediation of social cognition (SC); 3) among the negative symptoms, avolition had only direct links with SLOF work skills and SLOF activities; anhedonia had direct links with SLOF work skills and SLOF interpersonal and indirect link with SLOF work skills through functional capacity (FC); asociality with SLOF interpersonal; blunted affect had direct links with SLOF activities and indirect links with SLOF interpersonal relationships mediated by SC. Lastly, alogia had only indirect links mediated by SC, FC, and neurocognition (NC). CONCLUSIONS: Overall conceptual disorganization is the symptom that contributed more (both directly and indirectly) to the activities of community living in real-world. Thus, it should be considered as a treatment target in intervention programs for patients with schizophrenia.

Familial aggregation of MATRICS Consensus Cognitive Battery scores in a large sample of outpatients with schizophrenia and their unaffected relatives.

BACKGROUND: The increased use of the MATRICS Consensus Cognitive Battery (MCCB) to investigate cognitive dysfunctions in schizophrenia fostered interest in its sensitivity in the context of family studies. As various measures of the same cognitive domains may have different power to distinguish between unaffected relatives of patients and controls, the relative sensitivity of MCCB tests for relative-control differences has to be established. We compared MCCB scores of 852 outpatients with schizophrenia (SCZ) with those of 342 unaffected relatives (REL) and a normative Italian sample of 774 healthy subjects (HCS). We examined familial aggregation of cognitive impairment by investigating within-family prediction of MCCB scores based on probands' scores. METHODS: Multivariate analysis of variance was used to analyze group differences in adjusted MCCB scores. Weighted least-squares analysis was used to investigate whether probands' MCCB scores predicted REL neurocognitive performance. RESULTS: SCZ were significantly impaired on all MCCB domains. REL had intermediate scores between SCZ and HCS, showing a similar pattern of impairment, except for social cognition. Proband's scores significantly predicted REL MCCB scores on all domains except for visual learning. CONCLUSIONS: In a large sample of stable patients with schizophrenia, living in the community, and in their unaffected relatives, MCCB demonstrated sensitivity to cognitive deficits in both groups. Our findings of significant within-family prediction of MCCB scores might reflect disease-related genetic or environmental factors.

Deconstructing vulnerability for psychosis: Meta-analysis of environmental risk factors for psychosis in subjects at ultra high-risk.

BACKGROUND: Subjects at ultra high-risk (UHR) for psychosis have an enhanced vulnerability to develop the disorder but the risk factors accounting for this accrued risk are undetermined. METHOD: Systematic review of associations between genetic or environmental risk factors for psychosis that are widely established in the literature and UHR state, based on comparisons to controls. RESULTS: Forty-four studies encompassing 170 independent datasets and 54 risk factors were included. There were no studies on association between genetic or epigenetic risk factors and the UHR state that met the inclusion criteria. UHR subjects were more likely to show obstetric complications, tobacco use, physical inactivity, childhood trauma/emotional abuse/physical neglect, high perceived stress, childhood and adolescent low functioning, affective comorbidities, male gender, single status, unemployment and low educational level as compared to controls. CONCLUSIONS: The increased vulnerability of UHR subjects can be related to environmental risk factors like childhood trauma, adverse life events and affective dysfunction. The role of genetic and epigenetic risk factors awaits clarification.

Social cognition in people with schizophrenia: a cluster-analytic approach.

BACKGROUND: The study aimed to subtype patients with schizophrenia on the basis of social cognition (SC), and to identify cut-offs that best discriminate among subtypes in 809 out-patients recruited in the context of the Italian Network for Research on Psychoses. METHOD: A two-step cluster analysis of The Awareness of Social Inference Test (TASIT), the Facial Emotion Identification Test and Mayer-Salovey-Caruso Emotional Intelligence Test scores was performed. Classification and regression tree analysis was used to identify the cut-offs of variables that best discriminated among clusters. RESULTS: We identified three clusters, characterized by unimpaired (42%), impaired (50.4%) and very impaired (7.5%) SC. Three theory-of-mind domains were more important for the cluster definition as compared with emotion perception and emotional intelligence. Patients more able to understand simple sarcasm (⩾14 for TASIT-SS) were very likely to belong to the unimpaired SC cluster. Compared with patients in the impaired SC cluster, those in the very impaired SC cluster performed significantly worse in lie scenes (TASIT-LI <10), but not in simple sarcasm. Moreover, functioning, neurocognition, disorganization and SC had a linear relationship across the three clusters, while positive symptoms were significantly lower in patients with unimpaired SC as compared with patients with impaired and very impaired SC. On the other hand, negative symptoms were highest in patients with impaired levels of SC. CONCLUSIONS: If replicated, the identification of such subtypes in clinical practice may help in tailoring rehabilitation efforts to the person's strengths to gain more benefit to the person.

Shall we really say goodbye to first rank symptoms?

BACKGROUND: First rank symptoms (FRS) of schizophrenia have been used for decades for diagnostic purposes. In the new version of the DSM-5, the American Psychiatric Association (APA) has abolished any further reference to FRS of schizophrenia and treats them like any other "criterion A" symptom (e.g. any kind of hallucination or delusion) with regard to their diagnostic implication. The ICD-10 is currently under revision and may follow suit. In this review, we discuss central points of criticism that are directed against the continuous use of first rank symptoms (FRS) to diagnose schizophrenia. METHODS: We describe the specific circumstances in which Schneider articulated his approach to schizophrenia diagnosis and discuss the relevance of his approach today. Further, we discuss anthropological and phenomenological aspects of FRS and highlight the importance of self-disorder (as part of FRS) for the diagnosis of schizophrenia. Finally, we will conclude by suggesting that the theory and rationale behind the definition of FRS is still important for psychopathological as well as neurobiological approaches today. RESULTS: Results of a pivotal meta-analysis and other studies show relatively poor sensitivity, yet relatively high specificity for FRS as diagnostic marker for schizophrenia. Several methodological issues impede a systematic assessment of the usefulness of FRS in the diagnosis of schizophrenia. However, there is good evidence that FRS may still be useful to differentiate schizophrenia from somatic causes of psychotic states. This may be particularly important in countries or situations with little access to other diagnostic tests. FRS may thus still represent a useful aid for clinicians in the diagnostic process. CONCLUSION: In conclusion, we suggest to continue a tradition of careful clinical observation and fine-grained psychopathological assessment, including a focus on symptoms regarding self-disorders, which reflects a key aspect of psychosis. We suggest that the importance of FRS may indeed be scaled down to a degree that the occurrence of a single FRS alone should not suffice to diagnose schizophrenia, but, on the other hand, absence of FRS should be regarded as a warning sign that the diagnosis of schizophrenia or schizoaffective disorder is not warranted and requires specific care to rule out other causes, particularly neurological and other somatic disorders. With respect to the current stage of the development of ICD-11, we appreciate the fact that self-disorders are explicitly mentioned (and distinguished from delusions) in the list of mandatory symptoms but still feel that delusional perceptions and complex hallucinations as defined by Schneider should be distinguished from delusions or hallucinations of "any kind". Finally, we encourage future research to explore the psychopathological context and the neurobiological correlates of self-disorders as a potential phenotypic trait marker of schizophrenia.

Reward anticipation and trait anhedonia: An electrophysiological investigation in subjects with schizophrenia.

OBJECTIVE: Investigate impairment of reward anticipation in subjects with schizophrenia (SCZ) and its association with negative symptom dimensions and hedonic experience. METHODS: Event-related potentials (ERPs) were recorded, in thirty SCZ and twenty-three matched healthy controls (HC), during a "Monetary Incentive Delay" task in which reward and loss cues (incentive cues of positive and negative value) of different magnitude, as well as neutral cues were presented. ASSESSMENTS: anticipatory and consummatory pleasure, trait anhedonia and motivation in all subjects; avolition and expressive deficit in SCZ. RESULTS: SCZ had lower motivation but comparable hedonic experience with respect to HC. In HC, during reward anticipation, the early P3 was larger for large magnitude incentives, irrespective of their valence, while the late P3 was larger for large reward. In SCZ, early P3 did not discriminate the incentive magnitude and the late P3 was larger for large loss. Early P3 amplitude for large magnitude incentives was inversely related to trait social anhedonia but not to negative symptoms dimensions. CONCLUSIONS: SCZ are unable to integrate the incentive magnitude and reward value of future events in the context of their ongoing task. P3 abnormalities are associated with trait anhedonia, but not with negative symptoms dimensions. SIGNIFICANCE: In line with recent studies, our findings indicate that anhedonia and avolition are partially independent constructs.

The Brief Negative Symptom Scale (BNSS): Independent validation in a large sample of Italian patients with schizophrenia.

BACKGROUND: The Brief Negative Symptom Scale (BNSS) was developed to address the main limitations of the existing scales for the assessment of negative symptoms of schizophrenia. The initial validation of the scale by the group involved in its development demonstrated good convergent and discriminant validity, and a factor structure confirming the two domains of negative symptoms (reduced emotional/verbal expression and anhedonia/asociality/avolition). However, only relatively small samples of patients with schizophrenia were investigated. Further independent validation in large clinical samples might be instrumental to the broad diffusion of the scale in clinical research. METHODS: The present study aimed to examine the BNSS inter-rater reliability, convergent/discriminant validity and factor structure in a large Italian sample of outpatients with schizophrenia. RESULTS: Our results confirmed the excellent inter-rater reliability of the BNSS (the intraclass correlation coefficient ranged from 0.81 to 0.98 for individual items and was 0.98 for the total score). The convergent validity measures had r values from 0.62 to 0.77, while the divergent validity measures had r values from 0.20 to 0.28 in the main sample (n=912) and in a subsample without clinically significant levels of depression and extrapyramidal symptoms (n=496). The BNSS factor structure was supported in both groups. CONCLUSIONS: The study confirms that the BNSS is a promising measure for quantifying negative symptoms of schizophrenia in large multicenter clinical studies.

Is avolition in schizophrenia associated with a deficit of dorsal caudate activity? A functional magnetic resonance imaging study during reward anticipation and feedback.

BACKGROUND: The neurobiological underpinnings of avolition in schizophrenia remain unclear. Most brain imaging research has focused on reward prediction deficit and on ventral striatum dysfunction, but findings are not consistent. In the light of accumulating evidence that both ventral striatum and dorsal caudate play a key role in motivation, we investigated ventral striatum and dorsal caudate activation during processing of reward or loss in patients with schizophrenia. METHOD: We used functional magnetic resonance imaging to study brain activation during a Monetary Incentive Delay task in patients with schizophrenia, treated with second-generation antipsychotics only, and in healthy controls (HC). We also assessed the relationships of ventral striatum and dorsal caudate activation with measures of hedonic experience and motivation. RESULTS: The whole patient group had lower motivation but comparable hedonic experience and striatal activation than HC. Patients with high avolition scores showed lower dorsal caudate activation than both HC and patients with low avolition scores. A lower dorsal caudate activation was also observed in patients with deficit schizophrenia compared to HC and patients with non-deficit schizophrenia. Dorsal caudate activity during reward anticipation was significantly associated with avolition, but not with anhedonia in the patient group. CONCLUSIONS: These findings suggest that avolition in schizophrenia is linked to dorsal caudate hypoactivation.

Comorbid substance abuse in first-episode schizophrenia: effects on cognition and psychopathology in the EUFEST study.

UNLABELLED: Studies and meta-analyses investigating the influence of substance use disorder (SUD) (substance abuse or dependence) on psychopathology and neurocognitive function in schizophrenia patients have revealed controversial results. Most studies did only have small samples and did not focus exclusively on first-episode schizophrenia patients. METHOD: In a post-hoc analysis of the European First Episode Schizophrenia Trial (EUFEST) psychopathology and cognitive performances of patients with (FE-SUD, N=119, consisting of N=88 patients with persisting SUD at baseline and N=31 patients with previous SUD) and without SUD (FE-non-SUD, N=204) were compared at baseline and 6 months follow-up. Neurocognitive assessment included the Rey Auditory Verbal Learning Test (RAVLT); Trail Making Tests A and B (TMT), Purdue Pegboard and Digit-Symbol Coding. RESULTS: In total 31.1% of patients reported SUD, and 22.2% of patients used cannabis. There were no significant differences between patients with and without SUD concerning PANSS scores, extrapyramidal motor symptoms or neurocognitive measures except better performance in psychomotor speed (TMT-A, p=0.033, Cohen's d=0.26) in patients with SUD at 6 months follow-up. Interestingly, SUD patients with ongoing substance use at follow-up showed elevated positive symptoms (PANSS positive score, p=0.008, Cohen's d=0.84) compared to those who abstained. PANSS scores at baseline were increased in patients with an onset of SUD before the age of 16 years. In addition we found a correlation between longer duration of cannabis use and higher cognitive performance as well as reduced symptom improvement and more extrapyramidal motor symptoms in patients with higher frequency of cannabis consumption. CONCLUSIONS: FE-SUD and FE-non-SUD show similar psychopathology and neuropsychological performances at baseline and during the first 6 months of antipsychotic treatment.

Familial sinistrality and handedness in patients with first episode schizophrenia: the EUFEST study.

The population with schizophrenia is characterised by a leftward shift in handedness-sinistrality. However, findings are inconsistent in chronic patients, and familial sinistrality (FS), defined as the presence of left-handed close relatives, might contribute to the discrepancies. Therefore the aim of this study was to investigate the strength of manual lateralisation in patients with first episode schizophrenia, taking into account familial sinistrality. The Edinburgh Inventory (EI) allowed us to categorise 179 patients from the EUFEST study and 189 controls presenting "strong handedness" (SH: EI absolute value between ∣81∣ and ∣100∣) or "weak-handedness" (WH: EI value between -80 and +80). The nominal logistic regression did not show an FS effect, but a nearly significant interaction between illness and FS (p =.07). There were fewer participants without FS presenting SH among patients (99/151: 65.6%) than among controls (134/164: 81.7%, p =.001). In contrast, the number of participants with FS presenting SH was similar between controls (68%) and patients (75%, p =.57). The presence of left-handed relatives (FS + ) tended to reduce manual lateralisation, but only in controls. This supports the notion that reduced manual lateralisation in schizophrenia is related to the illness rather than to familial left-handedness.

No gender differences in social outcome in patients suffering from schizophrenia.

Differences between female and male patients with schizophrenia in psychopathology and course of illness have frequently been reported. However, the influence of sex on symptomatic and social remission is still an open issue. In the present study, differences between males and females in both clinical and social remission rates and in scores on several scales assessing social functioning were evaluated in 295 stabilized patients with schizophrenia, schizoaffective or delusional disorder. Female patients, as compared with males, showed a later onset of the illness, less negative symptoms and less frequent alcohol abuse. No significant difference was found between females and males in the rate of symptomatic and functional remission. No significant effect of sex was observed on any index of social functioning.

A functional comparison of patients with schizophrenia between the North and South of Europe.

INTRODUCTION: The main objective of this study was to compare clinical and functional outcomes of patients with schizophrenia in Italy and Sweden with a special focus on daily functioning performance and real life milestones. Also, to study if outcome is to be regarded as a consequence of premorbid function, the level of symptom control and functional capacity or if other influences, such as cultural differences, must parallel be considered. METHOD: Ninety-five patients from three centres, Milan and Naples in Italy and Trollhattan in Sweden were investigated. The Positive and Negative Syndrome Scale and the UCSD Performance-Based Skills Assessment - Brief version were used together with patients' school history and their status of accommodation and occupation. RESULTS: Patients in Trollhattan were more likely to live independently and patients in Naples to have a work or take part in education. Differences in symptoms and the performance test were present but subtle. DISCUSSION: Differences in real life milestones were not explained by corresponding differences in symptoms, premorbid function or the performance-based test. It is therefore not appropriate only to present functional outcome as an expression of how successful treatment has been.

Unmet needs in patients with first-episode schizophrenia: a longitudinal perspective.

BACKGROUND: This study aimed to identify the course of unmet needs by patients with a first episode of schizophrenia and to determine associated variables. METHOD: We investigated baseline assessments in the European First Episode Schizophrenia Trial (EUFEST) and also follow-up interviews at 6 and 12 months. Latent class growth analysis was used to identify patient groups based on individual differences in the development of unmet needs. Multinomial logistic regression determined the predictors of group membership. RESULTS: Four classes were identified. Three differed in their baseline levels of unmet needs whereas the fourth had a marked decrease in such needs. Main predictors of class membership were prognosis and depression at baseline, and the quality of life and psychosocial intervention at follow-up. Depression at follow-up did not vary among classes. CONCLUSIONS: We identified subtypes of patients with different courses of unmet needs. Prognosis of clinical improvement was a better predictor for the decline in unmet needs than was psychopathology. Needs concerning social relationships were particularly persistent in patients who remained high in their unmet needs and who lacked additional psychosocial treatment.

Neurocognitive functioning in bulimia nervosa: the role of neuroendocrine, personality and clinical aspects.

BACKGROUND: Studies investigating neurocognitive impairment in subjects with eating disorders (EDs) have reported heterogeneous patterns of impairment and, in some instances, no dysfunction. The present study aimed to define the pattern of neurocognitive impairment in a large sample of bulimia nervosa (BN) patients and to demonstrate that neuroendocrine, personality and clinical characteristics influence neurocognitive performance in BN. METHOD: Attention/immediate memory, set shifting, perseveration, conditional and implicit learning were evaluated in 83 untreated female patients with BN and 77 healthy controls (HC). Cortisol and 17ß-estradiol plasma levels were assessed. Cloninger's Temperament and Character Inventory - Revised (TCI-R), the Bulimic Investigation Test Edinburgh (BITE) and the Montgomery-Asberg Depression Rating Scale (MADRS) were administered. RESULTS: No impairment of cognitive performance was found in subjects with BN compared with HC. Cortisol and 'Self-directedness' were associated with better performance on conditional learning whereas 17ß-estradiol had a negative influence on this domain; 'Reward dependence' was associated with worse performance on implicit learning; and depressive symptomatology influenced performance on the Wisconsin Card Sorting Test (WCST) negatively. CONCLUSIONS: No cognitive impairment was found in untreated patients with BN. Neuroendocrine, personality and clinical variables do influence neurocognitive functioning and might explain discrepancies in literature findings.