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Introduction: Predictors of functioning are well-studied in schizophrenia, but much less so in treatment-resistant schizophrenia (TRS). In this study, we aim to investigate contributions of schizophrenia symptom domains and neurocognition to predict functioning in a TRS population (n = 146). Methods: Participants were assessed on the Positive and Negative Syndrome Scale (PANSS), to calculate scores for five symptomfactors (Positive, Negative, Cognitive, Depressive and Hostility) and two negative symptom constructs (Diminished Expressivity (DE), and Social Anhedonia (SA) as part of the Motivation and Pleasure-related dimension), based on a previously validated model, modified in accordance with EPA guidelines on negative symptoms assessment. Neurocognition was assessed with symbol coding and digit sequencing tasks from the Brief Assessment of Cognition in Schizophrenia (BACS). Functioning was assessed with the Social and Occupational Functioning Assessment Scale (SOFAS), employment status andWorld Health Organization Disability Assessment Schedule 2.0 (WHODAS 2.0). Multiple regression analyses were performed on psychopathology scores and BACS scores against all three measures of functioning, controlling for age and sex. For WHODAS, regression with PANSS scores of significant symptom factors were also performed. Results: A lower severity of negative symptoms in the SA dimension was the strongest predictor of higher functioning across all three functioning measures. Neurocognition, in particular processing speed and attention assessed on the symbol coding task, predicted employment. A lower severity of somatic concerns and depressive symptoms was associated with lesser self-reported disability on WHODAS. Discussion: This study represents a first attempt at elucidating significant predictors of functioning in TRS. We highlight negative symptoms and neurocognition as important treatment targets to improve functioning in TRS, consistent with previous studies in general schizophrenia. [ABSTRACT FROM AUTHOR]

Background: The development of neuroimaging biomarkers in patients with schizophrenia (SCZ) requires a refined clinical characterization. A limitation of the neuroimaging literature is the partial uptake of progress in characterizing disease-related features, particularly negative symptoms (NS) and cognitive impairment (CI). In the present study, we assessed NS and CI using up-to-date instruments and investigated the associations of abnormalities in brain restingstate (rs)-activity with disease-related features. Methods: Sixty-two community-dwelling SCZ subjects participated in the study. Multiple regression analyses were performed with the rs-activity of nine regions of interest as dependent variables and disease-related features as explanatory variables. Results: Attention/vigilance deficits were negatively associated with dorsal anterior cingulate rs-activity and, together with depression, were positively associated with right dorsolateral prefrontal cortex rs-activity. These deficits and impairment of Reasoning/problem-solving, together with conceptual disorganization, were associated with right inferior parietal lobule and temporal parietal junction rs-activity. Independent of other features, the NS Expressive Deficit domain was associated with the left ventral caudate, while the Motivational Deficit was associated with the dorsal caudate rs-activity. Conclusion: Neurocognitive deficits and the two negative symptom domains are associated with different neural markers. Replications of these findings could foster the identification of clinically actionable biomarkers of poor functional outcomes. [ABSTRACT FROM AUTHOR]

Background: Negative symptoms and cognitive impairments are highly frequent in schizophrenia spectrum disorders (SSD), associated with adverse functional outcomes and quality of life. Repetitive transcranial magnetic stimulation (rTMS) has been considered a promising therapeutic option in SSD. However, placebo effects of rTMS on these symptoms remained unclear. Objective: To investigate placebo effects of rTMS on alleviating negative symptoms and cognitive impairment in patients with SSD and to explore potential moderators. Methods: We systematically searched five electronic databases up to 15 July 2023. Randomized, double-blind, sham-controlled trials investigating effects of rTMS on negative symptoms or cognition in patients with SSD were included. The pooled placebo effect sizes, represented by Hedges' g, were estimated using the random-effects model. Potential moderators were explored through subgroup analysis and meta-regression. Results: Forty-four randomized controlled trials with 961 patients (mean age 37.53 years; 28.1% female) in the sham group were included. Significant low-tomoderate pooled placebo effect sizes were observed for negative symptoms (g=0.44, p<0.001), memory (g=0.31, p=0.010), executive function (g=0.35, p<0.001), working memory (g=0.26, p=0.004), and processing speed (g=0.36, p=0.004). Subgroup analysis indicated that placebo effects were affected by sham stimulation methods, rTMS targeting approaches, and stimulation frequency. Conclusions: Placebo effects of rTMS on negative symptoms and cognition in patients with SSD are significant in a small-to-moderate magnitude, which might be mediated by rTMS parameters. Our findings will provide new insights for practitioners to further optimize and establish standardized rTMS protocols for future RCTs tackling cardinal symptoms in SSD. [ABSTRACT FROM AUTHOR]

Early initiation of antipsychotic treatment plays a crucial role in the management of first-episode schizophrenia (FES) patients, significantly improving their prognosis. However, limited attention has been given to the long-term effects of antipsychotic drug therapy on FES patients. In this research, we examined the changes in abnormal brain regions among FES patients undergoing long-term treatment using a dynamic perspective. A total of 98 participants were included in the data analysis, comprising 48 FES patients, 50 healthy controls, 22 patients completed a follow-up period of more than 6 months with qualified data. We processed resting-state fMRI data to calculate coefficient of variation of fractional amplitude of low-frequency fluctuations (CVfALFF), which reflects the brain regional activity stability. Data analysis was performed at baseline and after long-term treatment. We observed that compared with HCs, patients at baseline showed an elevated CVfALFF in the supramarginal gyrus (SMG), parahippocampal gyrus (PHG), caudate, orbital part of inferior frontal gyrus (IOG), insula, and inferior frontal gyrus (IFG). After long-term treatment, the instability in SMG, PHG, caudate, IOG, insula and inferior IFG have ameliorated. Additionally, there was a positive correlation between the decrease in dfALFF in the SMG and the reduction in the SANS total score following long-term treatment. In conclusion, FES patients exhibit unstable regional activity in widespread brain regions at baseline, which can be ameliorated with long-term treatment. Moreover, the extent of amelioration in SMG instability is associated with the amelioration of negative symptoms. [ABSTRACT FROM AUTHOR]

Management of negative symptoms is one of the most challenging and important unmet needs of schizophrenia treatment. Negative symptoms together with positive symptoms result in significant psychosocial impairment and poor quality of life. Existing studies on atypical antipsychotics reported limited treatment adherence due to higher prevalence of treatment-emergent adverse events, such as diabetes, weight gain, hyperlipidemia, hyperprolactinemia and hypertension. A compound with greater affinity for dopamine D2/D3 receptors may improve negative symptoms, mood, and cognitive impairment associated with schizophrenia. In 2015, the US FDA has approved cariprazine, a partial D2/D3 agonist for treatment of schizophrenia, mania or mixed episodes. Midlands and Lancashire Commissioning Support Unit, UK (2019) has particularly suggested cariprazine for the treatment of predominant negative symptoms of schizophrenia. India's Central Drugs Standard Control Organization (CDSCO) has approved cariprazine in 2021 for the treatment of schizophrenia, manic or mixed episodes associated with bipolar I disorder. A ten-fold greater affinity for D3 receptors and partial agonism to serotonin receptors, along with longer half-lifemake cariprazine distinct when compared with other atypical antipsychotics. Cariprazine is also reported to have fewer incidents of metabolic and hormonal adverse events, and has been shown to provide better relapse prevention. Recent evidence indicates promising effect of cariprazine in ameliorating negative symptoms as well as psychotic symptoms in patients with schizophrenia. In addition, improved adherence to treatment (adjunctive/monotherapy) with cariprazine in patients having inadequate response to an ongoing antipsychotic treatment has also been clinically established. This review presents the evidence-based safety and efficacy of cariprazine for treatment of predominant negative symptoms of schizophrenia. [ABSTRACT FROM AUTHOR]

This document is an editorial titled "Psychosis in low- and middle-income countries (LMIC)" published in Frontiers in Psychiatry. The authors discuss the challenges and implications of psychosis in LMICs, emphasizing the importance of addressing the treatment gap and improving access to care. They also explore the role of negative symptoms and the potential benefits of clozapine in treating psychosis. The editorial presents five original research studies that cover topics such as heterogeneity in schizophrenia, prescribing patterns of clozapine, negative symptoms in China, and traditional healing practices in Asia and Africa. The findings highlight the need for person-centered approaches and the integration of traditional and clinical healthcare systems to improve the well-being of individuals with psychosis in LMICs. The authors call for further research and alignment with international clinical guidelines. [Extracted from the article]

BackgroundThe development of neuroimaging biomarkers in patients with schizophrenia (SCZ) requires a refined clinical characterization. A limitation of the neuroimaging literature is the partial uptake of progress in characterizing disease-related features, particularly negative symptoms (NS) and cognitive impairment (CI). In the present study, we assessed NS and CI using up-to-date instruments and investigated the associations of abnormalities in brain resting-state (rs)-activity with disease-related features.MethodsSixty-two community-dwelling SCZ subjects participated in the study. Multiple regression analyses were performed with the rs-activity of nine regions of interest as dependent variables and disease-related features as explanatory variables.ResultsAttention/vigilance deficits were negatively associated with dorsal anterior cingulate rs-activity and, together with depression, were positively associated with right dorsolateral prefrontal cortex rs-activity. These deficits and impairment of Reasoning/problem-solving, together with conceptual disorganization, were associated with right inferior parietal lobule and temporal parietal junction rs-activity. Independent of other features, the NS Expressive Deficit domain was associated with the left ventral caudate, while the Motivational Deficit was associated with the dorsal caudate rs-activity.ConclusionNeurocognitive deficits and the two negative symptom domains are associated with different neural markers. Replications of these findings could foster the identification of clinically actionable biomarkers of poor functional outcomes.

Introduction: In this study we assessed the contribution of psychopathology, including the two domains of negative symptoms (motivational deficit and expressive deficit), processing speed as an index of neurocognition, and emotion recognition, as an index of social cognition, to poor functional outcomes in people with schizophrenia. Methods: The Positive and Negative Syndrome Scale was used to evaluate positive symptoms and disorganization and the Brief Negative Symptom Scale to assess negative symptoms. The Symbol Coding and the Trail Making Test A and B were used to rate processing speed and the Facial Emotion Identification Test to assess emotion recognition. Functional outcome was assessed with the Personal and Social Performance Scale (PSP). Regression analyses were performed to identify predictors of functional outcome. Mediation analyses was used to investigate whether social cognition and negative symptom domains fully or partially mediated the impact of processing speed on functional outcome. Results: One hundred and fifty subjects from 8 different European centers were recruited. Our data showed that the expressive deficit predicted global functioning and together with motivational deficit fully mediated the effects of neurocognition on it. Motivational deficit was a predictor of personal and social functioning and fully mediated neurocognitive impairment effects on the same outcome. Both motivational deficit and neurocognitive impairment predicted socially useful activities, and the emotion recognition domain of social cognition partially mediated the impact of neurocognitive deficits on this outcome. Conclusions: Our results indicate that pathways to functional outcomes are specific for different domains of real-life functioning and that negative symptoms and social cognition mediate the impact of neurocognitive deficits on different domains of functioning. Our results suggest that both negative symptoms and social cognition should be targeted by psychosocial interventions to enhance the functional impact of neurocognitive remediation. [ABSTRACT FROM AUTHOR]

Background: In randomized clinical trials (RCTs) investigating the application of transcranial alternating current stimulation (tACS) in schizophrenia, inconsistent results have been reported. The purpose of this exploratory systematic review of RCTs was to evaluate tACS as an adjunct treatment for patients with schizophrenia based on its therapeutic effects, tolerability, and safety. Methods: Our analysis included RCTs that evaluated adjunctive tACS' effectiveness, tolerability, and safety in schizophrenia patients. Three independent authors extracted data and synthesized it using RevMan 5.3 software. Results: Three RCTs involving 76 patients with schizophrenia were encompassed in the analysis, with 40 participants receiving active tACS and 36 receiving sham tACS. Our study revealed a significant superiority of active tACS over sham tACS in improving total psychopathology (standardized mean difference [SMD] = -0.61, 95% confidence interval [CI]: -1.12, -0.10; I² = 16%, p = 0.02) and negative psychopathology (SMD = -0.65, 95% CI: -1.11, -0.18; I² = 0%, p = 0.007) in schizophrenia. The two groups, however, showed no significant differences in positive psychopathology, general psychopathology, or auditory hallucinations (all p > 0.05). Two RCTs examined the neurocognitive effects of tACS, yielding varied findings. Both groups demonstrated similar rates of discontinuation due to any reason and adverse events (all p > 0.05). Conclusion: Adjunctive tACS is promising as a viable approach for mitigating total and negative psychopathology in individuals diagnosed with schizophrenia. However, to gain a more comprehensive understanding of tACS's therapeutic effects in schizophrenia, it is imperative to conduct extensive, meticulously planned, and well-documented RCTs. [ABSTRACT FROM AUTHOR]

We present a male patient carrying a pathogenic MECP2 p. Arg179Trp variant with predominant negative psychiatric features and multilevel evidence of mitochondrial dysfunction who responded to the cariprazine treatment. He had delayed speech development and later experienced severe social anxiety, learning disabilities, cognitive slowing, and predominant negative psychiatric symptoms associated with rigidity. Clinical examinations showed multisystemic involvement. Together with elevated ergometric lactate levels, the clinical picture suggested mitochondrial disease, which was also supported by muscle histopathology. Exploratory transcriptome analysis also revealed the involvement of metabolic and oxidative phosphorylation pathways. Whole-exome sequencing identified a pathogenic MECP2 variant, which can explain both the dopamine imbalance and mitochondrial dysfunction in this patient. Mitochondrial dysfunction was previously suggested in classical Rett syndrome, and we detected related phenotype evidence on multiple consistent levels for the first time in a MECP2 variant carriermale. This study further supports the importance of theMECP2 gene in the mitochondrial pathways, which can open the gate for more personalized therapeutic interventions. Good cariprazine response highlights the role of dopamine dysfunction in the complex psychiatric symptoms of Rett syndrome. This can help identify the optimal treatment strategy from a transdiagnostic perspective instead of a classical diagnostic category. [ABSTRACT FROM AUTHOR]

The aim of our study was to evaluate the efficacy of cariprazine augmentation of clozapine in treatment-resistant schizophrenia in a retrospective chart review. Among 916 medical records of schizophrenia patients, we identified 12 individuals treated with a combination of those drugs for a duration of 3–60 weeks [median 32 (10–40)]. Clinical Global Impression–Improvement (CGI-I) scores were used to measure the treatment response between the introduction of cariprazine augmentation of clozapine and the last point of observation. The majority of the patients presented treatment response (9/12 patients, 75%) after 4–16 weeks of therapy [median 6 (4–12)]. Treatment was associated with the decrease in positive, negative, affective, and anxiety symptom severity, as well as improvement of patient global functioning. One patient discontinued the treatment due to side effects (akathisia), and two patients halted the therapy due to the exacerbation of psychotic symptoms. Our study presents a thorough clinical description of the largest number of treatment-resistant schizophrenia patients medicated using cariprazine augmentation of clozapine in a “real-world” setting. Our results suggest that the use of this combination may lead to the improvement in a broad range of symptoms of patients with this condition. [ABSTRACT FROM AUTHOR]

Management of negative symptoms is one of the most challenging and important unmet needs of schizophrenia treatment. Negative symptoms together with positive symptoms result in significant psychosocial impairment and poor quality of life. Existing studies on atypical antipsychotics reported limited treatment adherence due to higher prevalence of treatment-emergent adverse events, such as diabetes, weight gain, hyperlipidemia, hyperprolactinemia and hypertension. A compound with greater affinity for dopamine D2/D3 receptors may improve negative symptoms, mood, and cognitive impairment associated with schizophrenia. In 2015, the US FDA has approved cariprazine, a partial D2/D3 agonist for treatment of schizophrenia, mania or mixed episodes. Midlands and Lancashire Commissioning Support Unit, UK (2019) has particularly suggested cariprazine for the treatment of predominant negative symptoms of schizophrenia. India’s Central Drugs Standard Control Organization (CDSCO) has approved cariprazine in 2021 for the treatment of schizophrenia, manic or mixed episodes associated with bipolar I disorder. A ten-fold greater affinity for D3 receptors and partial agonism to serotonin receptors, along with longer half-life make cariprazine distinct when compared with other atypical antipsychotics. Cariprazine is also reported to have fewer incidents of metabolic and hormonal adverse events, and has been shown to provide better relapse prevention. Recent evidence indicates promising effect of cariprazine in ameliorating negative symptoms as well as psychotic symptoms in patients with schizophrenia. In addition, improved adherence to treatment (adjunctive/monotherapy) with cariprazine in patients having inadequate response to an ongoing antipsychotic treatment has also been clinically established. This review presents the evidence-based safety and efficacy of cariprazine for treatment of predominant negative symptoms of schizophrenia.

IntroductionIn this study we assessed the contribution of psychopathology, including the two domains of negative symptoms (motivational deficit and expressive deficit), processing speed as an index of neurocognition, and emotion recognition, as an index of social cognition, to poor functional outcomes in people with schizophrenia.MethodsThe Positive and Negative Syndrome Scale was used to evaluate positive symptoms and disorganization and the Brief Negative Symptom Scale to assess negative symptoms. The Symbol Coding and the Trail Making Test A and B were used to rate processing speed and the Facial Emotion Identification Test to assess emotion recognition. Functional outcome was assessed with the Personal and Social Performance Scale (PSP). Regression analyses were performed to identify predictors of functional outcome. Mediation analyses was used to investigate whether social cognition and negative symptom domains fully or partially mediated the impact of processing speed on functional outcome.ResultsOne hundred and fifty subjects from 8 different European centers were recruited. Our data showed that the expressive deficit predicted global functioning and together with motivational deficit fully mediated the effects of neurocognition on it. Motivational deficit was a predictor of personal and social functioning and fully mediated neurocognitive impairment effects on the same outcome. Both motivational deficit and neurocognitive impairment predicted socially useful activities, and the emotion recognition domain of social cognition partially mediated the impact of neurocognitive deficits on this outcome.ConclusionsOur results indicate that pathways to functional outcomes are specific for different domains of real-life functioning and that negative symptoms and social cognition mediate the impact of neurocognitive deficits on different domains of functioning. Our results suggest that both negative symptoms and social cognition should be targeted by psychosocial interventions to enhance the functional impact of neurocognitive remediation.

We present a male patient carrying a pathogenic MECP2 p. Arg179Trp variant with predominant negative psychiatric features and multilevel evidence of mitochondrial dysfunction who responded to the cariprazine treatment. He had delayed speech development and later experienced severe social anxiety, learning disabilities, cognitive slowing, and predominant negative psychiatric symptoms associated with rigidity. Clinical examinations showed multisystemic involvement. Together with elevated ergometric lactate levels, the clinical picture suggested mitochondrial disease, which was also supported by muscle histopathology. Exploratory transcriptome analysis also revealed the involvement of metabolic and oxidative phosphorylation pathways. Whole-exome sequencing identified a pathogenic MECP2 variant, which can explain both the dopamine imbalance and mitochondrial dysfunction in this patient. Mitochondrial dysfunction was previously suggested in classical Rett syndrome, and we detected related phenotype evidence on multiple consistent levels for the first time in a MECP2 variant carrier male. This study further supports the importance of the MECP2 gene in the mitochondrial pathways, which can open the gate for more personalized therapeutic interventions. Good cariprazine response highlights the role of dopamine dysfunction in the complex psychiatric symptoms of Rett syndrome. This can help identify the optimal treatment strategy from a transdiagnostic perspective instead of a classical diagnostic category.

The aim of our study was to evaluate the efficacy of cariprazine augmentation of clozapine in treatment-resistant schizophrenia in a retrospective chart review. Among 916 medical records of schizophrenia patients, we identified 12 individuals treated with a combination of those drugs for a duration of 3–60 weeks [median 32 (10–40)]. Clinical Global Impression–Improvement (CGI-I) scores were used to measure the treatment response between the introduction of cariprazine augmentation of clozapine and the last point of observation. The majority of the patients presented treatment response (9/12 patients, 75%) after 4–16 weeks of therapy [median 6 (4–12)]. Treatment was associated with the decrease in positive, negative, affective, and anxiety symptom severity, as well as improvement of patient global functioning. One patient discontinued the treatment due to side effects (akathisia), and two patients halted the therapy due to the exacerbation of psychotic symptoms. Our study presents a thorough clinical description of the largest number of treatment-resistant schizophrenia patients medicated using cariprazine augmentation of clozapine in a “real-world” setting. Our results suggest that the use of this combination may lead to the improvement in a broad range of symptoms of patients with this condition.

Background: There is sufficient evidence of the high prevalence of obesity in schizophrenia (SZ) compared to the general population. Previous studies have reported that weight gain correlated with the response to antipsychotics in patients with SZ. Nonetheless, the relationship between body mass index (BMI) and therapeutic benefits remains unclear. This study was designed to investigate the association between baseline BMI and improvements in clinical symptoms after treatment with antipsychotics in first-episode and medication-naïve SZ (FEMNS). Methods: A total of 241 FEMNS patients were enrolled and received risperidone over 12 weeks. The severity of symptoms was assessed by the Positive and Negative Syndrome Scale (PANSS) and BMI was measured at baseline and 12-week follow-up. Results: We found that risperidone treatment raised the body weight of FEMNS patients and baseline BMI was negatively correlated with the improvement in negative symptoms (r = -0.14, p = 0.03) after 12-week treatment. Linear regression analysis indicated that baseline BMI was an independent predictor of response to risperidone in the early stage of SZ. Conclusion: The current study suggests a close relationship between baseline BMI and improvement in negative symptoms in SZ. [ABSTRACT FROM AUTHOR]

Evidence regarding the association of Negative Symptoms (NS) dimensions with Health-related Quality of Life (HRQoL) is limited and no prior study has looked into contributions of NS domains on HRQoL. This study bridges the gap by examining the associations of NS, its two dimensions (Motivation and Pleasure, and Emotional Expressivity) and five domains (Anhedonia, Avolition, Asociality, Blunted affect and Alogia) with HRQoL in schizophrenia. 274 individuals with schizophrenia were assessed on the Positive and Negative Syndrome Scale (PANSS) and Brief Negative Symptom Scale (BNSS). PANSS scores were mapped to EuroQol five-dimensional (EQ-5D-5L) utility scores using an algorithm previously validated in Singapore, and the resulting EQ-5D-5L scores were used as a measure of HRQoL. Multiple linear regression analyses of the two NS dimensions and five NS domains against EQ-5D-5L showed that a lower severity of NS, specifically that of the Motivation and Pleasure (MAP) dimension and asociality domain was associated with higher HRQoL. Our findings highlight the importance of targeting NS, particularly MAP and asociality, in improving HRQoL in schizophrenia. [ABSTRACT FROM AUTHOR]

The current study aims to identify meaningful psychotic patients' profiles by examining certain combinations of patient's demographic and socio-economic variables (sex, age, marital status, number of children, cohabitant and level of education). Moreover, we aim to assess whether there is any significant effect of class membership (profile) on negative symptoms, health state, and quality of life among psychotic patients. A convenience sample of 103 patients (age: M = 22, SD = 1.75), was drawn from the clinical populations of Kosovo. Demographic and socio-economic data was obtained through individual interviews, meanwhile a battery of questionnaires was used to assess negative symptoms, mental health, and quality of life of patients. The 4-class solution was selected as the best fitting model and used in subsequent analyses. Results indicated a significant effect of class membership on health state, quality of life and negative symptoms. Practical implications are discussed. [ABSTRACT FROM AUTHOR]

Background: It is common practice to associate schizophrenia (SCZ) patients with substance use. The most commonly used substances in China are tobacco and alcohol. However, few studies have focused on alcohol consumption itself in patients with SCZ. Thus the purpose of this study was to detect the prevalence of alcohol use and associated clinical factors in Chinese patients with SCZ. Methods: A total of 616 male inpatients who met the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) criteria for SCZ participated in this study. A detailed questionnaire, including data on alcohol consumption was used to collect demographic and clinical information on all patients. The five-factor model of the positive and negative syndrome scale (PANSS) was adopted to assess psychiatric symptoms. Results: In this study, 31.49% of SCZ inpatients had a history of alcohol use, and 82.9% of these patients abstained from alcohol use after the onset of SCZ. Compared to nondrinkers, patients who drank were more likely to smoke (p = 0.004), more likely to have suicide attempts (p = 0.002) and suicidal ideation (p = 0.001), more severe positive (p < 0.001) and depressive symptoms (p = 0.034), but less severe negative symptoms (p = 0.04). Conclusion: These findings suggest that alcohol use is common during the lifetime of SCZ patients and that alcohol use may be associated with clinical symptoms in SCZ patients. [ABSTRACT FROM AUTHOR]

Background: Cariprazine, a novel antipsychotic drug that is a partial agonist with preferential binding to the D3 receptor, has demonstrated efficacy in clinical trials across all symptom domains, including negative symptoms, which can occur early in the course of psychotic illness. However, evidence, to date regarding its effects in early psychosis patients with primary negative symptoms has been limited. Objectives: To evaluate the efficacy of cariprazine for negative symptoms in early psychosis patients. Methods: Demographic and clinical information of the study population were collected from the electronic records and PANSS scale administered at baseline, 3 and 6 months. Tolerability and discontinuation reasons, where applicable, were also recorded. Results: Ten patients with early psychosis (four men and six women, mean age - 25.5 years) with prominent or predominant negative symptoms were treated with cariprazine (range 1.5 - 3 mg). Three patients discontinued cariprazine within the first 3 months due to patient choice, lack of response and non-compliance, respectively. In the remaining patients, there was a significant reduction in the mean negative PANSS score from baseline to 6 months (from 26.3 to 10.6), mean total PANSS score (from 81.4 to 43.3) and in the mean positive PANSS score (from 14.4 to 9.9) which correspond to a 53.1, 41.5, and 28.5% mean score reduction. Conclusion: This pilot study suggests that cariprazine is a safe and effective treatment in early psychosis, particularly for the alleviation of negative symptoms which remains an area of unmet treatment need. [ABSTRACT FROM AUTHOR]

Background: Negative symptoms are increasingly recognized as transdiagnostic phenomena, linked to reduced quality of life and functioning, and often caused or worsened by amendable external factors such as depression, social deprivation, side-effects of antipsychotics or substance use. The structure of negative symptoms fits into two dimensions: diminished expression and apathy. These may differ in association with external factors that influence their severity and may thus require different treatment approaches. The dimensions are comprehensively established in non-affective psychotic disorders but are understudied in bipolar disorders. Methods: We conducted exploratory and confirmatory factor analyses in a sample of 584 individuals with bipolar disorder to assess the latent factor structure of negative symptoms as measured by the Positive and Negative Syndrome Scale (PANSS), and performed correlational analyses and multiple hierarchical regression analyses to investigate links between the two dimensions of negative symptoms and clinical and sociodemographic correlates. Results: The latent factor structure of negative symptoms fits into two dimensions, i.e., diminished expression and apathy. A diagnosis of bipolar type I or a history of psychotic episodes predicted more severe levels of diminished expression. Depressive symptoms were associated with more severe negative symptoms across dimensions, yet 26.3% of euthymic individuals still displayed at least one mild or more severe negative symptom (PANSS score = 3). Discussion: The two-dimensional structure of negative symptoms seen in nonaffective psychotic disorders reproduces in bipolar disorders indicating similarities in their phenomenology. Diminished expression was associated with a history of psychotic episodes and a diagnosis of BD-I, which may infer closer connections to psychosis liability. We found significantly less severe negative symptoms in euthymic than depressed participants. Nevertheless, more than a quarter of the euthymic individuals had at least one mild negative symptom, demonstrating some degree of persistence beyond depressed states. [ABSTRACT FROM AUTHOR]

Objectives: Examine whether change in clinical outcomes for patients with schizophrenia and negative symptoms randomized to either Music Therapy (MT) or Music Listening (ML) is associated to moderators and mediators, with focus on alliance, attendance and dropout. Method: An exploratory post-hoc analysis of data from an original randomized controlled trial (RCT) investigating the effect of MT vs. ML for people with schizophrenia and negative symptoms. Inclusion to the study was implemented through screening of referred patients for symptoms of schizophrenia and negative symptoms. A total of 57 patients were randomly assigned, 28 to MT and 29 to ML. Session logs and notes were included in this study. Statistical analysis investigated moderator and mediator relation to outcome variables: Negative symptoms, functioning, quality of life, and retention to treatment. Results: On average, participants in MT attended 18.86 sessions (SD = 7.17), whereas those in ML attended 12.26 (SD = 9.52), a statistically significant difference (p = 0.0078). Dropout at 25 weeks was predicted by intervention, with dropout being 2.65 (SE = 1.01) times more likely in ML than in music therapy (p = 0.009). Helping alliance score at weeks was explained by intervention, with mean score being 0.68 (SE = 0.32) points lower in ML than in MT (p = 0.042). The number of sessions attended was also explained by intervention, with participants in ML attending on average 6.17 (SE = 2.24) fewer sessions than those randomized to MT (p = 0.008). Though both groups improved significantly, improvements in negative symptoms, depression, and functioning tended to be higher in ML, whereas improvements in alliance and quality of life tended to be higher in MT. Conclusion: The analysis could not detect a direct link between helping alliance score and outcome variables. However, the analysis documented a stronger alliance developed in the MT group, a lower dropout rate, as well as higher attendance in treatment. [ABSTRACT FROM AUTHOR]

Background: Treatment-resistant schizophrenia (TRS) is a major clinical challenge. Current antipsychotic medications do not adequately address negative and depressive symptoms in patients with TRS, and novel treatments are thus needed. This study examines the efficacy of low-dose combined olanzapine (OLA) and sertraline on depressive and negative symptoms in patients with TRS. Methods: A total of 34 TRS outpatients with acutely exacerbated schizophrenia were randomly assigned to OLA monotherapy (12.5–20 mg/day) (control group) or low-dose combined OLA (7.5–10 mg/day) and sertraline (50–100 mg/day) (OS group). Clinical symptoms were assessed using the Positive and Negative Syndrome Scale (PANSS) at baseline and at the end of treatment in weeks 4, 8, 12, and 24. Depressive symptoms and social functioning were also assessed. Results: Compared to the control group, the OS group showed significant improvements in depressive and negative symptoms over time. In addition, the low-dose combination of OLA and sertraline significantly improved social functioning compared with OLA monotherapy. There were no significant between-group differences in psychotic symptom improvement. However, the reduction in Hamilton Depression Rating Scale total score and PANSS negative subscore were not associated with improvements in social functioning, suggesting that these effects of combined treatment are independent. Conclusion: Low-dose combined OLA and sertraline may be effective in the treatment of negative and depressive symptoms compared with standard OLA monotherapy in patients with TRS who are experiencing an acute exacerbation of schizophrenia. [ABSTRACT FROM AUTHOR]

Objective: Schizophrenia is a debilitating mental disorder with a high disability rate that is characterized by negative symptoms such as apathy, hyperactivity, and anhedonia that can make daily life challenging and impair social functioning. In this study, we aim to investigate the effectiveness of homestyle rehabilitation in mitigating these negative symptoms and associated factors. Methods: A randomized controlled trial was conducted to compare the efficacy of hospital rehabilitation and homestyle rehabilitation for negative symptoms in 100 individuals diagnosed with schizophrenia. The participants were divided randomly into two groups, each persisting for 3 months. The primary outcome measures were the Scale for Assessment of Negative Symptoms (SANS) and Global Assessment of Functioning (GAF). The secondary outcome measures included the Positive Symptom Assessment Scale (SAPS), Calgary Schizophrenia Depression Scale (CDSS), Simpson-Angus Scale (SAS), and Abnormal Involuntary Movement Scale (AIMS). The trial aimed to compare the effectiveness of the two rehabilitation methods. Results: Homestyle rehabilitation for negative symptoms was found to be more effective than hospital rehabilitation, according to the changes in SANS (T = 2.07, p = 0.04). Further analysis using multiple regression indicated that improvements in depressive symptoms (T = 6.88, p < 0.001) and involuntary motor symptoms (T = 2.75, p = 0.007) were associated with a reduction in negative symptoms. Conclusion: Homestyle rehabilitation may have greater potential than hospital rehabilitation in improving negative symptoms, making it an effective rehabilitation model. Further research is necessary to investigate factors such as depressive symptoms and involuntary motor symptoms, which may be associated with the improvement of negative symptoms. Additionally, more attention should be given to addressing secondary negative symptoms in rehabilitation interventions. [ABSTRACT FROM AUTHOR]

Introduction: Negative symptoms are part of the clinical manifestations of schizophrenia and their presence is associated with a poorer prognosis, significantly limited vocational opportunities, impaired quality of life and social functioning. In the clinical practice, treatment of negative symptoms in patients with schizophrenia, is a challenge. Cariprazine is a novel partial agonist of D3 and D2 receptors, and shows a high affinity for D3, with good tolerability, good response to schizophrenic symptoms and limited side effects. We present two cases of young patients with predominantly negative symptoms during treatment with an atypical antipsychotic, administered in a stable dose and therapeutic range, and for at least 4 weeks prior to the Cariprazine switch. Methods: Two patients (men aged 21 and 22) with schizophrenia, exhibiting predominantly negative symptoms, are presented. Their diagnosis was based on, DSM-5 criteria (295.10). Patients were treated with Cariprazine at a daily dose of 4.5 mg. They were followed for a period of 18 months and assessed with Positive and Negative Syndrome Scale (PANSS), Global Assessment of Functioning (GAF) and Clinical Global Impression-Severity (CGI-S), at the fourth week of initiation of treatment with Cariprazine, at 6 months, at 12 months and at 18 months. Their mean initial value was 75.5 on PANSS, 4.0 on CGI-S, and 52.5 on GAF. Both patients were treated with stable doses of atypical antipsychotic-Risperidone at a daily dose of 4,5 mg. Cross-titration to Cariprazine was initiated, from 1.5 mg daily dose up to 4,5 mg daily dose, during a period of 2 weeks. Results: After 18 months of treatment with Cariprazine at a daily dose of 4.5 mg, the following results were reported: mean value was 57.5 on PANSS, 3.0 on CGI-S, and 74.5 on GAF. The overall PANSS mean score decreased by 23.8%, the CGI-S mean score improved by 25% and the mean GAF score increased by 29.5%. The positive PANSS subscale score decreased minimally, from 20 to 16, while for the negative subscale the improvement was 29.8%. Cariprazine was well tolerated by patients and no side effects were observed from it during therapy. Discussion: After 18 months Cariprazine succeeded in improving negative symptoms, global functioning, and global clinical impression. In young schizophrenic patients with a predominance of negative symptoms, the cariprazine may be a successful alternative. [ABSTRACT FROM AUTHOR]

The current study aims to identify meaningful psychotic patients’ profiles by examining certain combinations of patient’s demographic and socio-economic variables (sex, age, marital status, number of children, cohabitant and level of education). Moreover, we aim to assess whether there is any significant effect of class membership (profile) on negative symptoms, health state, and quality of life among psychotic patients. A convenience sample of 103 patients (age: M = 22, SD = 1.75), was drawn from the clinical populations of Kosovo. Demographic and socio-economic data was obtained through individual interviews, meanwhile a battery of questionnaires was used to assess negative symptoms, mental health, and quality of life of patients. The 4-class solution was selected as the best fitting model and used in subsequent analyses. Results indicated a significant effect of class membership on health state, quality of life and negative symptoms. Practical implications are discussed.

BackgroundCariprazine, a novel antipsychotic drug that is a partial agonist with preferential binding to the D3 receptor, has demonstrated efficacy in clinical trials across all symptom domains, including negative symptoms, which can occur early in the course of psychotic illness. However, evidence, to date regarding its effects in early psychosis patients with primary negative symptoms has been limited.ObjectivesTo evaluate the efficacy of cariprazine for negative symptoms in early psychosis patients.MethodsDemographic and clinical information of the study population were collected from the electronic records and PANSS scale administered at baseline, 3 and 6 months. Tolerability and discontinuation reasons, where applicable, were also recorded.ResultsTen patients with early psychosis (four men and six women, mean age – 25.5 years) with prominent or predominant negative symptoms were treated with cariprazine (range 1.5 – 3 mg). Three patients discontinued cariprazine within the first 3 months due to patient choice, lack of response and non-compliance, respectively. In the remaining patients, there was a significant reduction in the mean negative PANSS score from baseline to 6 months (from 26.3 to 10.6), mean total PANSS score (from 81.4 to 43.3) and in the mean positive PANSS score (from 14.4 to 9.9) which correspond to a 53.1, 41.5, and 28.5% mean score reduction.ConclusionThis pilot study suggests that cariprazine is a safe and effective treatment in early psychosis, particularly for the alleviation of negative symptoms which remains an area of unmet treatment need.

BackgroundNegative symptoms are increasingly recognized as transdiagnostic phenomena, linked to reduced quality of life and functioning, and often caused or worsened by amendable external factors such as depression, social deprivation, side-effects of antipsychotics or substance use. The structure of negative symptoms fits into two dimensions: diminished expression and apathy. These may differ in association with external factors that influence their severity and may thus require different treatment approaches. The dimensions are comprehensively established in non-affective psychotic disorders but are understudied in bipolar disorders.MethodsWe conducted exploratory and confirmatory factor analyses in a sample of 584 individuals with bipolar disorder to assess the latent factor structure of negative symptoms as measured by the Positive and Negative Syndrome Scale (PANSS), and performed correlational analyses and multiple hierarchical regression analyses to investigate links between the two dimensions of negative symptoms and clinical and sociodemographic correlates.ResultsThe latent factor structure of negative symptoms fits into two dimensions, i.e., diminished expression and apathy. A diagnosis of bipolar type I or a history of psychotic episodes predicted more severe levels of diminished expression. Depressive symptoms were associated with more severe negative symptoms across dimensions, yet 26.3% of euthymic individuals still displayed at least one mild or more severe negative symptom (PANSS score ≥ 3).DiscussionThe two-dimensional structure of negative symptoms seen in non-affective psychotic disorders reproduces in bipolar disorders indicating similarities in their phenomenology. Diminished expression was associated with a history of psychotic episodes and a diagnosis of BD-I, which may infer closer connections to psychosis liability. We found significantly less severe negative symptoms in euthymic than depressed participants. Nevertheless, more than a quarter of the euthymic individuals had at least one mild negative symptom, demonstrating some degree of persistence beyond depressed states.

ObjectivesExamine whether change in clinical outcomes for patients with schizophrenia and negative symptoms randomized to either Music Therapy (MT) or Music Listening (ML) is associated to moderators and mediators, with focus on alliance, attendance and dropout.MethodAn exploratory post-hoc analysis of data from an original randomized controlled trial (RCT) investigating the effect of MT vs. ML for people with schizophrenia and negative symptoms. Inclusion to the study was implemented through screening of referred patients for symptoms of schizophrenia and negative symptoms. A total of 57 patients were randomly assigned, 28 to MT and 29 to ML. Session logs and notes were included in this study. Statistical analysis investigated moderator and mediator relation to outcome variables: Negative symptoms, functioning, quality of life, and retention to treatment.ResultsOn average, participants in MT attended 18.86 sessions (SD = 7.17), whereas those in ML attended 12.26 (SD = 9.52), a statistically significant difference (p = 0.0078). Dropout at 25 weeks was predicted by intervention, with dropout being 2.65 (SE = 1.01) times more likely in ML than in music therapy (p = 0.009). Helping alliance score at weeks was explained by intervention, with mean score being 0.68 (SE = 0.32) points lower in ML than in MT (p = 0.042). The number of sessions attended was also explained by intervention, with participants in ML attending on average 6.17 (SE = 2.24) fewer sessions than those randomized to MT (p = 0.008). Though both groups improved significantly, improvements in negative symptoms, depression, and functioning tended to be higher in ML, whereas improvements in alliance and quality of life tended to be higher in MT.ConclusionThe analysis could not detect a direct link between helping alliance score and outcome variables. However, the analysis documented a stronger alliance developed in the MT group, a lower dropout rate, as well as higher attendance in treatment.Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT02942459.

IntroductionNegative symptoms are part of the clinical manifestations of schizophrenia and their presence is associated with a poorer prognosis, significantly limited vocational opportunities, impaired quality of life and social functioning. In the clinical practice, treatment of negative symptoms in patients with schizophrenia, is a challenge. Cariprazine is a novel partial agonist of D3 and D2 receptors, and shows a high affinity for D3, with good tolerability, good response to schizophrenic symptoms and limited side effects. We present two cases of young patients with predominantly negative symptoms during treatment with an atypical antipsychotic, administered in a stable dose and therapeutic range, and for at least 4 weeks prior to the Cariprazine switch.MethodsTwo patients (men aged 21 and 22) with schizophrenia, exhibiting predominantly negative symptoms, are presented. Their diagnosis was based on, DSM-5 criteria (295.10).Patients were treated with Cariprazine at a daily dose of 4.5 mg. They were followed for a period of 18 months and assessed with Positive and Negative Syndrome Scale (PANSS), Global Assessment of Functioning (GAF) and Clinical Global Impression-Severity (CGI-S), at the fourth week of initiation of treatment with Cariprazine, at 6 months, at 12 months and at 18 months. Their mean initial value was 75.5 on PANSS, 4.0 on CGI-S, and 52.5 on GAF. Both patients were treated with stable doses of atypical antipsychotic–Risperidone at a daily dose of 4,5 mg. Cross-titration to Cariprazine was initiated, from 1.5 mg daily dose up to 4,5 mg daily dose, during a period of 2 weeks.ResultsAfter 18 months of treatment with Cariprazine at a daily dose of 4.5 mg, the following results were reported: mean value was 57.5 on PANSS, 3.0 on CGI-S, and 74.5 on GAF. The overall PANSS mean score decreased by 23.8%, the CGI-S mean score improved by 25% and the mean GAF score increased by 29.5%. The positive PANSS subscale score decreased minimally, from 20 to 16, while for the negative subscale the improvement was 29.8%.Cariprazine was well tolerated by patients and no side effects were observed from it during therapy.DiscussionAfter 18 months Cariprazine succeeded in improving negative symptoms, global functioning, and global clinical impression. In young schizophrenic patients with a predominance of negative symptoms, the cariprazine may be a successful alternative.

A 22-year-old male was admitted to an in-patient psychiatric unit for treatment, after a period of 2 years of increasing psychotic symptoms corresponding to a very severe case of schizophrenia across the entire scale of symptomdisorder domains along with some drug abuse comorbidity. Previous treatments with olanzapine (OLA) and risperidone (RIS) had been at best partly successful toward his positive symptoms with no, or even worsening effects on the negative symptomatology. Given the gravity of the latter symptoms and functional impairment of our patient, he might thus have been a candidate for clozapine (CLZ) treatment. It was however decided to switch his antipsychotic treatment to cariprazine (CAR), an agent with a novel pharmacological and clinical profile, because of its favorable pharmacodynamic, pharmacokinetic, and tolerability/safety properties. In a follow-up on the patient 6 months after discharge he is not fully recovered, but the recovery attained reflects a marked functional improvement compared to before the RIS-to-CAR switch. The remarkable response to CAR observed may, speculatively, be in line with the suggestion that CAR could offer an alternative, safer, andmore tolerablemonotherapy approach (vs. CLZ) for patients with severe negative symptoms and functional deficiency resistant to standard antipsychotic treatment. He appears to occasionally still be taking drugs, but no worsening of positive symptoms has been noted. Whether or not he could reach full recovery if he would abstain entirely from drugs of abuse remains an open question. [ABSTRACT FROM AUTHOR]

Background: Negative symptoms have long been conceptualized as a core aspect of schizophrenia. Despite widespread recognition of the status of these symptoms as independent dimensions of schizophrenia, they are sometimes difficult to distinguish from depression or cognitive impairment. Therefore, objective assessment of schizophrenia symptoms is critical by obtaining a valid and reliable Indonesian version of the SANS instrument. This study aimed to determine the content validity, concurrent, internal consistency reliability, inter-rater, cut-off value, sensitivity, and specificity of the SANS instrument. Methods: This is a diagnostic study using the cross-sectional method to determine the relationship between the SANS and PANSS instruments on the negative symptom subscale. It was located at the Prof. Dr. M. Ildrem Mental Hospital of North Sumatera Province. Results: Of the 400 subjects, 67.5% were males, and the median age of the subjects was 37 years (18-45). The results of the content validity test were good (mean l-CVI=1.00), and the concurrent validity test comparing the SANS and PANSS instruments on the negative symptom subscale obtained significant results (p < 0.001) with a strong correlation (r = 0.763). Additionally, the consistency reliability test had a very high internal score (Cronbach alpha = 0.969), the overall inter-rater reliability test was "very good" (ICC = 0.985), and the cut-off value was 10.5 with sensitivity and specificity values of 72.9 and 77.9%, respectively. Conclusion: The Indonesian version of the SANS instrument is valid and reliable for measuring negative symptoms in people with schizophrenia in Indonesia. [ABSTRACT FROM AUTHOR]

BackgroundNegative symptoms have long been conceptualized as a core aspect of schizophrenia. Despite widespread recognition of the status of these symptoms as independent dimensions of schizophrenia, they are sometimes difficult to distinguish from depression or cognitive impairment. Therefore, objective assessment of schizophrenia symptoms is critical by obtaining a valid and reliable Indonesian version of the SANS instrument. This study aimed to determine the content validity, concurrent, internal consistency reliability, inter-rater, cut-off value, sensitivity, and specificity of the SANS instrument.MethodsThis is a diagnostic study using the cross-sectional method to determine the relationship between the SANS and PANSS instruments on the negative symptom subscale. It was located at the Prof. Dr. M. Ildrem Mental Hospital of North Sumatera Province.ResultsOf the 400 subjects, 67.5% were males, and the median age of the subjects was 37 years (18–45). The results of the content validity test were good (mean I-CVI=1.00), and the concurrent validity test comparing the SANS and PANSS instruments on the negative symptom subscale obtained significant results (p < 0.001) with a strong correlation (r = 0.763). Additionally, the consistency reliability test had a very high internal score (Cronbach alpha = 0.969), the overall inter-rater reliability test was “very good” (ICC = 0.985), and the cut-off value was 10.5 with sensitivity and specificity values of 72.9 and 77.9%, respectively.ConclusionThe Indonesian version of the SANS instrument is valid and reliable for measuring negative symptoms in people with schizophrenia in Indonesia.

Background: Cerebellar structural and functional abnormalities underlie widespread deficits in clinical, cognitive, and motor functioning that are observed in schizophrenia. Consequently, the cerebellum is a promising target for novel schizophrenia treatments. Here we conducted an updated systematic review examining the literature on cerebellar stimulation efficacy and tolerability for mitigating symptoms of schizophrenia. We discuss the purported mechanisms of cerebellar stimulation, current methods for implementing stimulation, and future directions of cerebellar stimulation for intervention development with this population. Methods: Two independent authors identified 20 published studies (7 randomized controlled trials, 7 open-label studies, 1 pilot study, 4 case reports, 1 preclinical study) that describe the effects of cerebellar circuitry modulation in patients with schizophrenia or animal models of psychosis. Published studies up to October 11, 2022 were identified from a search within PubMed, Scopus, and PsycInfo. Results: Most studies stimulating the cerebellum used transcranial magnetic stimulation or transcranial direct-current stimulation, specifically targeting the cerebellar vermis/midline. Accounting for levels of methodological rigor across studies, these studies detected post-cerebellar modulation in schizophrenia as indicated by the alleviation of certain clinical symptoms (mainly negative and depressive symptoms), as well as increased frontalcerebellar connectivity and augmentation of canonical neuro-oscillations known to be abnormal in schizophrenia. In contrast to a prior review, we did not find consistent evidence for cognitive improvements following cerebellar modulation stimulation. Modern cerebellar stimulation methods appear tolerable for individuals with schizophrenia, with only mild and temporary side effects. Conclusion: Cerebellar stimulation is a promising intervention for individuals with schizophrenia that may be more relevant to some symptom domainsthan others. Initial results highlight the need for continued research using more methodologically rigorous designs, such as additional longitudinal and randomized controlled trials. [ABSTRACT FROM AUTHOR]

Objective: Negative symptoms can seriously affect social functioning in patients with schizophrenia. However, the role of various components of negative symptoms in social functioning remains unclear. This study aimed to explore the associations among three different dimensions of negative symptoms (i.e., communication, emotion, and motivation) and social functioning to identify potential therapeutic targets. Methods: This cross-sectional study enrolled 202 Chinese participants with schizophrenia. Negative symptoms were evaluated using the Negative Symptom Assessment (NSA). Social functioning was represented by the Personal and Social Performance Scale (PSP) total score and employment status. Correlation analysis was conducted to clarify the relationship between negative symptoms and the PSP total score. Regression analysis was performed to explore the determinants of the PSP total score and employment status, considering negative symptoms and possible confounders, such as demographic features, positive symptoms, cognitive symptoms, depressive symptoms, and extrapyramidal side effects. Results: The PSP total score was correlated with all three dimensions of negative symptoms (i.e., emotion, motivation, and communication; rs = –0.509, –0.662, and –0.657, respectively). Motivation, instead of emotion or communication, predicted both low PSP total scores and unemployment. Conclusion: Social functioning in patients with schizophrenia was significantly related to motivation. Further studies should focus on motivation and consider it as a therapeutic target to improve patients’ social functioning. [ABSTRACT FROM AUTHOR]

BackgroundCerebellar structural and functional abnormalities underlie widespread deficits in clinical, cognitive, and motor functioning that are observed in schizophrenia. Consequently, the cerebellum is a promising target for novel schizophrenia treatments. Here we conducted an updated systematic review examining the literature on cerebellar stimulation efficacy and tolerability for mitigating symptoms of schizophrenia. We discuss the purported mechanisms of cerebellar stimulation, current methods for implementing stimulation, and future directions of cerebellar stimulation for intervention development with this population.MethodsTwo independent authors identified 20 published studies (7 randomized controlled trials, 7 open-label studies, 1 pilot study, 4 case reports, 1 preclinical study) that describe the effects of cerebellar circuitry modulation in patients with schizophrenia or animal models of psychosis. Published studies up to October 11, 2022 were identified from a search within PubMed, Scopus, and PsycInfo.ResultsMost studies stimulating the cerebellum used transcranial magnetic stimulation or transcranial direct-current stimulation, specifically targeting the cerebellar vermis/midline. Accounting for levels of methodological rigor across studies, these studies detected post-cerebellar modulation in schizophrenia as indicated by the alleviation of certain clinical symptoms (mainly negative and depressive symptoms), as well as increased frontal-cerebellar connectivity and augmentation of canonical neuro-oscillations known to be abnormal in schizophrenia. In contrast to a prior review, we did not find consistent evidence for cognitive improvements following cerebellar modulation stimulation. Modern cerebellar stimulation methods appear tolerable for individuals with schizophrenia, with only mild and temporary side effects.ConclusionCerebellar stimulation is a promising intervention for individuals with schizophrenia that may be more relevant to some symptom domains than others. Initial results highlight the need for continued research using more methodologically rigorous designs, such as additional longitudinal and randomized controlled trials.Systematic review registration[https://www.crd.york.ac.uk/prospero/], identifier [CRD42022346667].

Background and aimsAlcohol Use Disorder (AUD) is characterized by a reduction in goal-directed behavior, with alcohol use taking precedence over other areas of life. These features in AUD resemble negative symptoms in schizophrenia, especially the reduction in motivation and pleasure (MAP). Given the clinical similarities of negative symptoms across diagnostic categories, it comes as a surprise that there are few investigations on negative symptoms in alcohol and other substance use disorders. To our knowledge, our study is the first to assess negative symptoms in AUD based on a two-factorial approach, and to investigate the interrelation of these dimensions with the severity of AUD, and alcohol craving.Materials and methodsWe examined a sample of 42 patients with AUD at the Psychiatric University Hospital in Zurich. Participants provided self-report and interview-based measures of the severity of AUD, negative symptoms, and alcohol craving. Finally, we used data from the electronic health records of the patients.ResultsPatients with AUD show negative symptoms to a similar extent as patients with schizophrenia or bipolar disorder. We found a positive correlation between the extent of impairment within the MAP factor and overall severity of AUD. Furthermore, MAP negative symptoms were correlated with alcohol craving. In a linear regression, negative symptoms predicted alcohol craving whereas depression did not.SummaryNegative symptoms as conceptualized for schizophrenia are prevalent in patients with AUD and associated with the severity of AUD. More specifically, severity of AUD correlates with diminished motivation and pleasure, highlighting the importance of disturbances in motivational functions in AUD. This is further supported by the correlation between negative symptoms and craving, a hallmark of AUD. Taken together, our findings suggest that negative symptoms might be a highly relevant but hitherto often neglected therapeutic target in AUD.

BackgroundDeficits in psychosocial functioning are present in the early stages of psychosis. Several factors, such as premorbid adjustment, neurocognitive performance, and cognitive reserve (CR), potentially influence functionality. Sex differences are observed in individuals with psychosis in multiple domains. Nonetheless, few studies have explored the predictive factors of poor functioning according to sex in first-episode psychosis (FEP). This study aimed to explore sex differences, examine changes, and identify predictors of functioning according to sex after onset.Materials and methodsThe initial sample comprised 588 individuals. However, only adults with non-affective FEP (n = 247, 161 males and 86 females) and healthy controls (n = 224, 142 males and 82 females) were included. A comprehensive assessment including functional, neuropsychological, and clinical scales was performed at baseline and at 2-year follow-up. A linear regression model was used to determine the predictors of functioning at 2-year follow-up.ResultsFEP improved their functionality at follow-up (67.4% of both males and females). In males, longer duration of untreated psychosis (β = 0.328, p = 0.003) and worse premorbid adjustment (β = 0.256, p = 0.023) were associated with impaired functioning at 2-year follow-up, while in females processing speed (β = 0.403, p = 0.003), executive function (β = 0.299, p = 0.020) and CR (β = −0.307, p = 0.012) were significantly associated with functioning.ConclusionOur data indicate that predictors of functioning at 2-year follow-up in the FEP group differ according to sex. Therefore, treatment and preventative efforts may be adjusted taking sex into account. Males may benefit from functional remediation at early stages. Conversely, in females, early interventions centered on CR enhancement and cognitive rehabilitation may be recommended.

The integration of pharmacotherapy with psychosocial interventions has an important role to play in the improvement of functional outcome of subjects with schizophrenia (SCZ), in all stages of the disorder. It is essential for the adequate management of unmet therapeutic needs, such as negative symptoms and cognitive dysfunctions which account for most of the functional impairment of subjects with SCZ and do not respond to available antipsychotics. Enhancing the knowledge on factors involved in the effectiveness of integrated treatment plans is an important step forward for SCZ care. This review aims to identify factors that might influence the impact of integrated treatments on functional outcome. Most studies on the impact of psychosocial treatments on functional outcome of subjects with SCZ did not control for the effect of prescribed antipsychotics or concomitant medications. However, several factors relevant to ongoing pharmacological treatment might influence the outcome of integrated therapy, with an impact on the adherence to treatment (e.g., therapeutic alliance and polypharmacotherapy) or on illness-related factors addressed by the psychosocial interventions (e.g., cognitive dysfunctions or motivational deficits). Indirect evidence suggests that treatment integration should consider the possible detrimental effects of different antipsychotics or concomitant medications on cognitive functions, as well as on secondary negative symptoms. Cognitive dysfunctions can interfere with participation to an integrated treatment plan and can be worsened by extrapyramidal ormetabolic side effects of antipsychotics, or concomitant treatment with anticholinergics or benzodiazepines. Secondary negative symptoms, due to positive symptoms, sedation, extrapyramidal side effects or untreated depression, might cause early drop-out and poor adherence to treatment. Researchers and clinicians should examine all the above-mentioned factors and implement appropriate and personalized integrated treatments to improve the outcome of SCZ. [ABSTRACT FROM AUTHOR]

Brain structural abnormalities have been demonstrated in schizophrenia (SZ); these resemble those seen in typical aging, but are seen at younger ages. Furthermore, SZ is associated with accelerated global brain aging, as measured by brain structure-based brain predicted age difference (Brain-PAD). High heterogeneity exists in the degree of brain abnormalities in SZ, and individual differences may be related to levels of peripheral inflammation and may relate to cognitive deficits and negative symptoms. The goal of our study was to investigate the relationship between brain aging, peripheral inflammation, and symptoms of SZ. We hypothesized older brain-PAD in SZ vs. healthy comparison (HC) participants, as well as positive relationships of brain-PAD with peripheral inflammation markers and symptoms in SZ. We analyzed data from two cross-sectional studies in SZ (n = 26; M/F: 21/5) and HC (n = 28; 20/8) (22–64 years). Brain-PAD was calculated using a previously validated Gaussian process regression model applied to raw T1-weighted MRI data. Plasma levels of inflammatory biomarkers (CRP, Eotaxin, Fractalkine, IP10, IL6, IL10, ICAM1, IFNγ, MCP1, MIP1β, SAA, TNFα, VEGF, VCAM1) and cognitive and negative symptoms were assessed. We observed a higher brain-PAD in SZ vs. HC, and advanced brain age relative to chronological age was related to higher peripheral levels of TNFα in the overall group and in the SZ group; other inflammatory markers were not related to brain-PAD. Within the SZ group, we observed no association between cognitive or negative symptoms and brain-PAD. These results support our hypothesis of advanced brain aging in SZ. Furthermore, our findings on the relationship of the pro-inflammatory cytokine TNFα with higher brain-PAD of SZ are relevant to explain heterogeneity of brain ages in SZ, but we did not find strong evidence for cognitive or negative symptom relationships with brain-PAD. [ABSTRACT FROM AUTHOR]

In the last decades, third wave approaches in cognitive-behavioral therapies (CBT) have shown eectiveness in treating several mental disorders, including schizophrenia spectrum disorders (SSD). Three crucial processes associated with clinical changes in patients include mindfulness, psychological flexibility (PF) and self-compassion (SC). PF is generally assessed by cognitive fusion (CF), a negative formulated key process of PF. The current study encompasses a cross-sectional design to examine the interplay of mindfulness, CF, SC and symptom severity in SSD. It was hypothesized that mindfulness is negatively correlated with symptom severity, CF mediates the negative relation between mindfulness and symptom severity, and SC moderates the link between mindfulness and CF. In total, 79 persons with SSD were recruited at the Department of Psychiatry and Neurosciences at the Charité - Universitätsmedizin Berlin. Correlations, as well as moderated mediation analyses, were performed using the analysis modeling tool PROCESS with total symptom severity and negative symptom severity as outcome variables, measured by the Positive and Negative Syndrome Scale (PANSS) and the Self-Evaluation of Negative Symptoms Scale (SNS). Results show that the moderated mediation hypothesis was confirmed for negative symptom severity assessed by SNS, however, not for total symptom severity assessed by PANSS. In general, the association between mindfulness and CF was stronger for participants with higher SC scores in our data. Future studies should investigate the relationship between mindfulness, SC, and PF regarding symptom severity in SSD in longitudinal designs while considering the impact on dierent outcomes and dirences regarding assessment tools. [ABSTRACT FROM AUTHOR]

The integration of pharmacotherapy with psychosocial interventions has an important role to play in the improvement of functional outcome of subjects with schizophrenia (SCZ), in all stages of the disorder. It is essential for the adequate management of unmet therapeutic needs, such as negative symptoms and cognitive dysfunctions which account for most of the functional impairment of subjects with SCZ and do not respond to available antipsychotics. Enhancing the knowledge on factors involved in the effectiveness of integrated treatment plans is an important step forward for SCZ care. This review aims to identify factors that might influence the impact of integrated treatments on functional outcome. Most studies on the impact of psychosocial treatments on functional outcome of subjects with SCZ did not control for the effect of prescribed antipsychotics or concomitant medications. However, several factors relevant to ongoing pharmacological treatment might influence the outcome of integrated therapy, with an impact on the adherence to treatment (e.g., therapeutic alliance and polypharmacotherapy) or on illness-related factors addressed by the psychosocial interventions (e.g., cognitive dysfunctions or motivational deficits). Indirect evidence suggests that treatment integration should consider the possible detrimental effects of different antipsychotics or concomitant medications on cognitive functions, as well as on secondary negative symptoms. Cognitive dysfunctions can interfere with participation to an integrated treatment plan and can be worsened by extrapyramidal or metabolic side effects of antipsychotics, or concomitant treatment with anticholinergics or benzodiazepines. Secondary negative symptoms, due to positive symptoms, sedation, extrapyramidal side effects or untreated depression, might cause early drop-out and poor adherence to treatment. Researchers and clinicians should examine all the above-mentioned factors and implement appropriate and personalized integrated treatments to improve the outcome of SCZ.

Deficit syndrome schizophrenia is a characteristic subtype defined by persistent negative symptoms and poor functional outcomes; however, the biological mechanisms underlying this specific subtype have not yet been elucidated in detail. The present magnetic resonance imaging study examined the prevalence of duplicated Heschl's gyrus (HG), a potential neurodevelopmental marker, in schizophrenia patients with (N = 38) and without (N = 37) the deficit syndrome. The prevalence of the HG duplication pattern bilaterally was higher in the whole schizophrenia group than in 59 matched healthy controls. Furthermore, the prevalence of right HG duplication was significantly higher in the deficit schizophrenia group than in the non-deficit schizophrenia group. The HG pattern in schizophrenia was not associated with clinical variables, including illness duration, medication, and symptom severity, while right HG duplication correlated with higher scores for Proxy for the Deficit Syndrome. The present results suggest that the prominent neurodevelopmental pathology associated with gyral formation of HG may contribute to enduring negative symptomatology in schizophrenia. [ABSTRACT FROM AUTHOR]

Current pharmacological therapy has limited effects on the cognitive impairments and negative symptoms associated with schizophrenia. Therefore, understanding the molecular underpinnings of this disorder is essential for the development of effective treatments. It appears that a reduction in calcium/calmodulin-dependent protein kinase II (α-CaMKII) activity is a common mechanism underlying the abnormal social behavior and cognitive deficits associated with schizophrenia. In addition, in a previous study social interaction with a partner of the same sex and weight increased the activity of α-CaMKII in rats. Here, we propose that boosting of CaMKII signaling, in a manner that counteracts this neuropsychiatric disease without disrupting the normal brain function, might ameliorate the abnormalities in social cognition and the negative symptoms of schizophrenia. [ABSTRACT FROM AUTHOR]

Current research suggests that emotion recognition is impaired in individuals affected by schizophrenia spectrum disorders (SSD). However, the specific impact of negative symptoms on the ability to recognize single basic emotions has not yet been explored sufficiently and is the aim of the present study. A sample of N = 66 individuals diagnosed with SSD was recruited at the Charité – Universitätsmedizin Berlin. In a first step, correlation analyses were conducted between seven different negative symptom subdomains of the Positive and Negative Syndrome Scale (PANSS) and the accuracy and latency in recognizing the six basic emotions (anger, disgust, fear, happiness, sadness, surprise) using the Emotion Recognition Task (ERT) of the Cambridge Neuropsychological Test Automated Battery (CANTAB). The significant correlations were subjected to linear regression models that controlled for the significant covariates diagnoses, age, sex, and education. Results revealed that in individuals with SSD the negative symptom domain of blunted affect significantly predicted the accuracy of emotion recognition performance (p < 0.05), particularly, when recognizing happiness (p < 0.05). Additionally, we found that stereotyped thinking also predicted the performance of emotion recognition, especially the response latency (p < 0.05) and difficulty in abstract thinking predicted the recognition of fear (p < 0.05). However, the nominal significances did not withstand correction for multiple tests and therefore need to be followed up in further studies with a larger sample. [ABSTRACT FROM AUTHOR]

Negative symptoms have attracted growing attention as a psychological treatment target and the past 10 years has seen an expansion of mechanistic studies and clinical trials aimed at improving treatment options for this frequently neglected sub-group of people diagnosed with schizophrenia. The recent publication of several randomized controlled trials of psychological treatments that pre-specified negative symptoms as a primary outcome warrants a carefully targeted review and analysis, not least because these treatments have generally returned disappointing therapeutic benefits. This mini-review dissects these trials and offers an account of why we continue to have significant gaps in our understanding of how to support recovery in people troubled by persistent negative symptoms. Possible explanations for mixed trial results include a failure to separate the negative symptom phenotype into the clinically relevant sub-types that will respond to mechanistically targeted treatments. For example, the distinction between experiential and expressive deficits as separate components of the wider negative symptom construct points to potentially different treatment needs and techniques. The 10 negative symptom-focused RCTs chosen for analysis in this mini-review present over 16 different categories of treatment techniques spanning a range of cognitive, emotional, behavioral, interpersonal, and metacognitive domains of functioning. The argument is made that treatment development will advance more rapidly with the use of more precisely targeted psychological treatments that match interventions to a focused range of negative symptom maintenance processes. [ABSTRACT FROM AUTHOR]

Introduction: Minimum clinically important difference (MCID) is a measure that defines the minimum amount of change in an objective score of a clinical test that must be reached for that change to be clinically noticeable. We aimed to find the MCID for patients with predominantly negative symptoms of schizophrenia at its earliest occurrence. Methods: Data of a 26-week long, double-blind study with 454 patients [Positive and Negative Symptom Scale Negative Factor Score (PANSS-FSNS) ≥24, Positive and Negative Symptom Scale Positive Factor Score (PANSS-FSPS) ≤ 19] treated with cariprazine 4.5 mg/d or risperidone 4 mg/d were analyzed. The Clinical Global Impression—Improvement scale was used to quantify minimum improvement (CGI-I = 3) and no clinical change (CGI-I = 4) on the PANSS-FSNS, and the MCID was estimated with the following methods: as the mean PANSS-FSNS changes corresponding to the first instance of minimal improvement across all visits (MCID1); as the difference between the PANSS-FSNS change associated with the first instance and the PANSS-FSNS changes associated with the last recorded clinically unchanged status across all visits (MCID2); with the effect size approach (MCID3); as the Youden Index based cut-off value between no clinical change and minimal improvement (MCID4); as the relative likelihood of minimal improvement (MCID5). Results: The MCID1 and MCID2 resulted in, respectively, a 3.8-point (18.5%) and a 1.5-point (7.3%) decrease from baseline severity on the PANSS-FSNS. Greater values were required for the MCID at later evaluation times. The cut-off between minimum improvement and no clinical change defined by the Youden Index was a−3-point (15%) change in the PANSS-FSNS. The effect size approach indicated the 1.5-point difference between minimally improved and unchanged patients to be a medium effect (ES = 0.6). Conclusion: Applying different methods led to different results, ranging between 7.3 and 18.5% improvement from the baseline for the MCID at its earliest occurrence in patients with predominantly negative symptoms of schizophrenia. [ABSTRACT FROM AUTHOR]