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Despite a large body of schizophrenia research, we still have no reliable predictors to guide treatment from illness onset. The present study aimed to identify baseline clinical or neurobiological factors — including peripheral brain-derived neurotrophic factor (BDNF) levels and amygdala or hippocampal relative volumes — that could predict negative symptomatology and persistent negative symptoms in first-episode psychosis after 1 year of follow-up. We recruited 50 drug-naive patients with first-episode psychosis and 50 age- and sex-matched healthy controls to study brain volumes. We performed univariate and multiple and logistic regression analyses to determine the association between baseline clinical and neurobiological variables, score on the PANSS negative subscale and persistent negative symptoms after 1 year of follow-up. Low baseline serum BDNF levels (p = 0.011), decreased left amygdala relative volume (p = 0.001) and more severe negative symptomatology (p = 0.021) predicted the severity of negative symptoms at 1 year, as measured by the PANSS negative subscale. Low baseline serum BDNF levels (p = 0.012) and decreased left amygdala relative volume (p = 0.010) predicted persistent negative symptoms at 1 year. We were unable to assess negative symptoms and their dimensions with next-generation scales, which were not available when the study was initiated. This study shows that a set of variables at baseline, including low BDNF levels, smaller left amygdala relative volume and score on the PANSS negative subscale are significant predictors of outcomes in first-episode psychosis. These findings might offer an initial step for tailoring treatments in first-episode psychosis.

The ability to assign safety to stimuli in the environment is integral to everyday functioning. A key brain region for this evaluation is the ventromedial prefrontal cortex (vmPFC). To investigate the importance of vmPFC safety signaling, we used neuroimaging of Pavlovian fear reversal, a paradigm that involves flexible updating when the contingencies for a threatening (CS+) and safe (CS−) stimulus reverse, in a prototypical disorder of inflexible behavior influenced by anxiety, Obsessive Compulsive Disorder (OCD). Skin conductance responses in OCD patients (n = 43) failed to differentiate during reversal compared with healthy controls (n = 35), although significant differentiation did occur during early conditioning and amygdala BOLD signaling was unaffected in these patients. Increased vmPFC activation (for CS+ > CS−) during early conditioning predicted the degree of generalization in OCD patients during reversal, whereas vmPFC safety signals were absent throughout learning in these patients. Regions of the salience network (dorsal anterior cingulate, insula, and thalamus) showed early learning task-related hyperconnectivity with the vmPFC in OCD, consistent with biased processing of the CS+. Our findings reveal an absence of vmPFC safety signaling in OCD, undermining flexible threat updating and explicit contingency knowledge. Although differential threat learning can occur to some extent in the absence of vmPFC safety signals, effective CS− signaling becomes crucial during conflicting threat and safety cues. These results promote further investigation of vmPFC safety signaling in other anxiety disorders, with potential implications for the development of exposure-based therapies, in which safety signaling is likely to play a key role.

The negative symptoms of schizophrenia are strong prognostic factors but remain poorly understood and treated. Five negative symptom domains are frequently clustered into the motivation and pleasure (MAP) and emotional expression (EE) ‘dimensions’, but whether this structure remains stable and behaves as a single entity or not remains unclear. We examined a cohort of 153 patients taking clozapine for treatment-resistant schizophrenia in a regional mental health clinic. Patients were assessed longitudinally over a mean period of 45 months using validated scales for positive, negative and mood symptoms. Network analyses were performed to identify symptom ‘communities’ and their stability over time. The influence of common causes of secondary negative symptoms as well as centrality measures were also examined. Across patients at baseline, two distinct communities matching the clinical domains of MAP and EE were found. These communities remained highly stable and independent over time. The communities remained stabled when considering psychosis, depression, and sedation severity, and these causes of secondary negative symptoms were clustered into the MAP community. Centrality measures also remained stable over time, with similar centrality measures across symptoms. Our results suggest that MAP and EE are independent dimensions that remain highly stable over time in chronic schizophrenia patients treated with clozapine. Common causes of secondary negative symptoms mapped onto the MAP dimension. Our results emphasise the need for clinical trials to address either MAP or EE, and that treating causes of secondary negative symptoms may improve MAP. •Negative symptoms cluster into two independent dimensions: emotional expressivity and motivation-pleasure.•These dimensions remain independent and stable over time.•Psychosis, depression, and sedation severity do not change this structure.•No consistently central symptoms within negative symptoms emerge.

Negative symptoms are a debilitating feature of schizophrenia which are often resistant to pharmacological intervention. The mechanisms underlying them remain poorly understood, and diagnostic methods rely on phenotyping through validated questionnaires. Deeper endo-phenotyping is likely to be necessary in order to improve current understanding. In the last decade, valuable behavioural insights have been gained through the use of effort-based decision making (EBDM) tasks. These have highlighted impairments in reward-related processing in schizophrenia, particularly associated with negative symptom severity. Neuroimaging investigations have related these changes to dysfunction within specific brain networks including the ventral striatum (VS) and frontal brain regions. Here, we review the behavioural and neural evidence associated with negative symptoms, shedding light on potential underlying mechanisms and future therapeutic possibilities. Findings in the literature suggest that schizophrenia is characterised by impaired reward based learning and action selection, despite preserved hedonic responses. Associations between amotivation and reward-processing deficits have not always been clear, and may be mediated by factors including cognitive dysfunction or dysfunctional or self-defeatist beliefs. Successful endo-phenotyping of negative symptoms as a function of objective behavioural and neural measurements is crucial in advancing our understanding of this complex syndrome. Additionally, transdiagnostic research–leveraging findings from other brain disorders, including neurological ones–can shed valuable light on the possible common origins of motivation disorders across diseases and has important implications for future treatment development.

Hypothetically, psychotic disorders could be caused or conditioned by immunological mechanisms. If so, one might expect there to be peripheral immune system phenotypes that are measurable in blood cells as biomarkers of psychotic states. We used multi-parameter flow cytometry of venous blood to quantify and determine the activation state of 73 immune cell subsets for 18 patients with chronic schizophrenia (17 treated with clozapine), and 18 healthy volunteers matched for age, sex, BMI and smoking. We used multivariate methods (partial least squares) to reduce dimensionality and define populations of differentially co-expressed cell counts in the cases compared to controls. Schizophrenia cases had increased relative numbers of NK cells, naïve B cells, CXCR5+ memory T cells and classical monocytes; and decreased numbers of dendritic cells (DC), HLA-DR+ regulatory T-cells (Tregs), and CD4+ memory T cells. Likewise, within the patient group, more severe negative and cognitive symptoms were associated with decreased relative numbers of dendritic cells, HLA-DR+ Tregs, and CD4+ memory T cells. Motivated by the importance of central nervous system dopamine signalling for psychosis, we measured dopamine receptor gene expression in separated CD4+ cells. Expression of the dopamine D3 (DRD3) receptor was significantly increased in clozapine-treated schizophrenia and covaried significantly with differentiated T cell classes in the CD4+ lineage. Peripheral immune cell populations and dopaminergic signalling are disrupted in clozapine-treated schizophrenia. Immuno-phenotypes may provide peripherally accessible and mechanistically specific biomarkers of residual cognitive and negative symptoms in this treatment-resistant subgroup of patients.

Anhedonia, a symptom prevalent in schizophrenia patients, is thought to arise either within negative symptomatology or from secondary sources, such as depression. The common co-occurrence of these diseases complicates the assessment of anhedonia in schizophrenia. In a sample of 40 outpatients with chronic schizophrenia, we explored both the validity of the Snaith-Hamilton Pleasure Scale (SHAPS) self-report for anhedonia assessment and those factors influenced its scoring. We assessed negative symptoms using the Brief Negative Symptom Scale (BNSS), depression symptoms using the Calgary Depression Scale for Schizophrenia (CDSS) and cognitive impairment using the Brief Assessment of Cognition in Schizophrenia (BACS), before exploring associations between these scales. The SHAPS was validated for use in schizophrenia. SHAPS scores were not associated with negative symptoms or cognitive impairment, but were linked to a single Depression symptom: Hopelessness (r = 0.52, p < 0.001). SHAPS scores, therefore, appear to only reflect anticipatory anhedonia arising from the affective domain. We advocate the development of multi-faceted self-report measures to more holistically assess anhedonia in schizophrenia. •The Snaith-Hamilton Pleasure Scale validly assesses anhedonia in schizophrenia.•The SHAPS showed no association with measures of negative symptomatology.•The SHAPS was strongly associated with a single symptom of depression, Hopelessness.•SHAPS assessment appears to measure specifically affective anticipatory anhedonia.

BackgroundPeople with severe mental illness (SMI) have a higher prevalence of several chronic physical health conditions, and the prevalence of physical multimorbidity is expected to rise. The aim of this study was to assess the strength of the association between SMI and physical multimorbidity.Study selection and analysisWe systematically searched PubMed/Medline, Scopus, Embase, Web of Science, PsycINFO and the behavioural sciences collection databases, from inception to 31 January 2023, for studies that investigated the association between SMI and physical multimorbidity. Humans of any age either clinically diagnosed and/or currently receiving treatment for SMI, specified as schizophrenia (and related psychotic disorders), bipolar disorder and psychotic depression, were eligible. Data from studies selected for inclusion were converted into ORs, with a subsequent meta-analysis conducted.FindingsWe included 19 studies with a total of 194 123 patients with SMI with different diagnoses and drawn from the general population. The pooled OR for physical multimorbidity in people with versus without SMI was 1.84 (95% CI 1.33 to 2.54), with the analysis indicating a high level of heterogeneity (98.38%). The other 15 studies included in the systematic review for which it was not possible to conduct a meta-analysis showed strong associations between SMI and physical multimorbidity.ConclusionsThe current evidence highlights the link between SMI and physical multimorbidity. A multidisciplinary approach is now urgent to develop the best models of services tailored to patients with SMI with physical multimorbidities to improve physical, mental and social outcomes. PROSPERO registration number CRD42023395165.

Background:Optimal behavioral performance results from a balance between goal-directed and habitual systems of behavioral control, which are modulated by ascending monoaminergic projections. While the role of the dopaminergic system in behavioral control has been recently addressed, the extent to which changes in global serotonin neurotransmission could influence these 2 systems is still poorly understood.Methods:We employed the dietary acute tryptophan depletion procedure to reduce serotonin neurotransmission in 18 healthy volunteers and 18 matched controls. We used a 3-stage instrumental learning paradigm that includes an initial instrumental learning stage, a subsequent outcome-devaluation test, and a slip-of-action stage, which directly tests the balance between hypothetical goal-directed and habitual systems. We also employed a separate response inhibition control test to assess the behavioral specificity of the results.Results:Acute tryptophan depletion produced a shift of behavioral performance towards habitual responding as indexed by performance on the slip-of-action test. Moreover, greater habitual responding in the acute tryptophan depletion group was predicted by a steeper decline in plasma tryptophan levels. In contrast, acute tryptophan depletion left intact the ability to use discriminative stimuli to guide instrumental choice as indexed by the instrumental learning stage and did not impair inhibitory response control.Conclusions:The major implication of this study is that serotonin modulates the balance between goal-directed and stimulus-response habitual systems of behavioral control. Our findings thus imply that diminished serotonin neurotransmission shifts behavioral control towards habitual responding.

Purpose People with eating disorders may be at increased risk for physical health problems, but there are no data on the relationship between eating disorders and physical multimorbidity (i.e., ≥ 2 physical conditions) and its potential mediators. Thus, we investigated this association in a representative sample of adults from the UK, and quantified the extent to which this can be explained by various psychological and physical conditions, and lifestyle factors. Methods Cross-sectional data of the 2007 Adult Psychiatric Morbidity Survey were analyzed. Questions from the five-item SCOFF screening instrument were used to identify possible eating disorder. Respondents were asked about 20 physical health conditions. Multivariable logistic regression and mediation analysis were conducted. Results Data on 7403 individuals aged ≥ 16 years were analyzed [mean (SD) age 46.3 (18.6) years; 48.6% males]. After adjustment, possible eating disorder was associated with 2.11 (95%CI = 1.67–2.67) times higher odds for physical multimorbidity. Anxiety disorder explained the largest proportion this association (mediated percentage 26.3%), followed by insomnia (21.8%), perceived stress (13.4%), depression (13.1%), obesity (13.0%), and alcohol dependence (4.3%). Conclusion Future longitudinal studies are warranted to understand potential causality and the underlying mechanisms in the association between eating disorder and multimorbidity, and whether addressing the identified potential mediators in people with eating disorders can reduce multimorbidity.

Impairments in mismatch negativity (MMN) generation have been consistently reported in patients with schizophrenia. However, underlying oscillatory activity of MMN deficits in schizophrenia and the relationship with cognitive impairments have not been investigated in detail. Time-frequency power and phase analyses can provide more detailed measures of brain dynamics of MMN deficits in schizophrenia. 21 patients with schizophrenia and 21 healthy controls were tested with a roving frequency paradigm to generate MMN. Time-frequency domain power and phase-locking (PL) analysis was performed on all trials using short-time Fourier transforms with Hanning window tapering. A comprehensive battery (CANTAB) was used to assess neurocognitive functioning. Mean MMN amplitude was significantly lower in patients with schizophrenia (95% CI 0.18 - 0.77). Patients showed significantly lower EEG power (95% CI -1.02 - -0.014) in the ~4-7 Hz frequency range (theta band) between 170 and 210 ms. Patients with schizophrenia showed cognitive impairment in multiple domains of CANTAB. However, MMN impairments in amplitude and power were not correlated with clinical measures, medication dose, social functioning or neurocognitive performance. The findings from this study suggested that while MMN may be a useful marker to probe NMDA receptor mediated mechanisms and associated impairments in gain control and perceptual changes, it may not be a useful marker in association with clinical or cognitive changes. Trial-by-trial EEG power analysis can be used as a measure of brain dynamics underlying MMN deficits which also can have implications for the use of MMN as a biomarker for drug discovery.