Using Computational Phenotyping to Identify Divergent Strategies for Effort Allocation Across the Psychosis Spectrum.

BACKGROUND AND HYPOTHESIS: Disturbances in effort-cost decision-making have been highlighted as a potential transdiagnostic process underpinning negative symptoms in individuals with schizophrenia. However, recent studies using computational phenotyping show that individuals employ a range of strategies to allocate effort, and use of different strategies is associated with unique clinical and cognitive characteristics. Building on prior work in schizophrenia, this study evaluated whether effort allocation strategies differed in individuals with distinct psychotic disorders. STUDY DESIGN: We applied computational modeling to effort-cost decision-making data obtained from individuals with psychotic disorders (n = 190) who performed the Effort Expenditure for Rewards Task. The sample included 91 individuals with schizophrenia/schizoaffective disorder, 90 individuals with psychotic bipolar disorder, and 52 controls. STUDY RESULTS: Different effort allocation strategies were observed both across and within different disorders. Relative to individuals with psychotic bipolar disorder, a greater proportion of individuals with schizophrenia/schizoaffective disorder did not use reward value or probability information to guide effort allocation. Furthermore, across disorders, different effort allocation strategies were associated with specific clinical and cognitive features. Those who did not use reward value or probability information to guide effort allocation had more severe positive and negative symptoms, and poorer cognitive and community functioning. In contrast, those who only used reward value information showed a trend toward more severe positive symptoms. CONCLUSIONS: These findings indicate that similar deficits in effort-cost decision-making may arise from different computational mechanisms across the psychosis spectrum.

Isolation of Distinct Networks Driving Action and Cognition in Psychomotor Processes.

BACKGROUND: Psychomotor disturbances are observed across psychiatric disorders and often manifest as psychomotor slowing, agitation, disorganized behavior, or catatonia. Psychomotor function includes both cognitive and motor components, but the neural circuits driving these subprocesses and how they relate to symptoms have remained elusive for centuries. METHODS: We analyzed data from the HCP-EP (Human Connectome Project for Early Psychosis), a multisite study of 125 participants with early psychosis and 58 healthy participants with resting-state functional magnetic resonance imaging and clinical characterization. Psychomotor function was assessed using the 9-hole pegboard task, a timed motor task that engages mechanical and psychomotor components of action, and tasks assessing processing speed and task switching. We used multivariate pattern analysis of whole-connectome data to identify brain correlates of psychomotor function. RESULTS: We identified discrete brain circuits driving the cognitive and motor components of psychomotor function. In our combined sample of participants with psychosis (n = 89) and healthy control participants (n = 52), the strongest correlates of psychomotor function (pegboard performance) (p < .005) were between a midline cerebellar region and left frontal region and presupplementary motor area. Psychomotor function was correlated with both cerebellar-frontal connectivity (r = 0.33) and cerebellar-presupplementary motor area connectivity (r = 0.27). However, the cognitive component of psychomotor performance (task switching) was correlated only with cerebellar-frontal connectivity (r = 0.19), whereas the motor component (processing speed) was correlated only with cerebellar-presupplementary motor area connectivity (r = 0.15), suggesting distinct circuits driving unique subprocesses of psychomotor function. CONCLUSIONS: We identified cerebellar-cortical circuits that drive distinct subprocesses of psychomotor function. Future studies should probe relationships between cerebellar connectivity and psychomotor performance using neuromodulation.

Data-driven, connectome-wide analysis identifies psychosis-specific brain correlates of fear and anxiety.

Decades of psychosis research highlight the prevalence and the clinical significance of negative emotions, such as fear and anxiety. Translational evidence demonstrates the pivotal role of the amygdala in fear and anxiety. However, most of these approaches have used hypothesis-driven analyses with predefined regions of interest. A data-driven analysis may provide a complimentary, unbiased approach to identifying brain correlates of fear and anxiety. The aim of the current study was to identify the brain basis of fear and anxiety in early psychosis and controls using a data-driven approach. We analyzed data from the Human Connectome Project for Early Psychosis, a multi-site study of 125 people with psychosis and 58 controls with resting-state fMRI and clinical characterization. Multivariate pattern analysis of whole-connectome data was used to identify shared and psychosis-specific brain correlates of fear and anxiety using the NIH Toolbox Fear-Affect and Fear-Somatic Arousal scales. We then examined clinical correlations of Fear-Affect scores and connectivity patterns. Individuals with psychosis had higher levels of Fear-Affect scores than controls (p < 0.05). The data-driven analysis identified a cluster encompassing the amygdala and hippocampus where connectivity was correlated with Fear-Affect score (p < 0.005) in the entire sample. The strongest correlate of Fear-Affect was between this cluster and the anterior insula and stronger connectivity was associated with higher Fear-Affect scores (r = 0.31, p = 0.0003). The multivariate pattern analysis also identified a psychosis-specific correlate of Fear-Affect score between the amygdala/hippocampus cluster and a cluster in the ventromedial prefrontal cortex (VMPFC). Higher Fear-Affect scores were correlated with stronger amygdala/hippocampal-VMPFC connectivity in the early psychosis group (r = 0.33, p = 0.002), but not in controls (r = -0.15, p = 0.28). The current study provides evidence for the transdiagnostic role of the amygdala, hippocampus, and anterior insula in the neural basis of fear and anxiety and suggests a psychosis-specific relationship between fear and anxiety symptoms and amygdala/hippocampal-VMPFC connectivity. Our novel data-driven approach identifies novel, psychosis-specific treatment targets for fear and anxiety symptoms and provides complimentary evidence to decades of hypothesis-driven approaches examining the brain basis of threat processing.

Efficacy and safety of established and off-label ADHD drug therapies for cognitive impairment or attention-deficit hyperactivity disorder symptoms in bipolar disorder: A systematic review by the ISBD Targeting Cognition Task Force.

BACKGROUND: Abnormalities in dopamine and norepinephrine signaling are implicated in cognitive impairments in bipolar disorder (BD) and attention-deficit hyperactivity disorder (ADHD). This systematic review by the ISBD Targeting Cognition Task Force therefore aimed to investigate the possible benefits on cognition and/or ADHD symptoms and safety of established and off-label ADHD therapies in BD. METHODS: We included studies of ADHD medications in BD patients, which involved cognitive and/or safety measures. We followed the procedures of the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) 2020 statement. Searches were conducted on PubMed, Embase and PsycINFO from inception until June 2023. Two authors reviewed the studies independently using the Revised Cochrane Collaboration's Risk of Bias tool for Randomized trials. RESULTS: Seventeen studies were identified (N = 2136), investigating armodafinil (k = 4, N = 1581), methylphenidate (k = 4, N = 84), bupropion (k = 4, n = 249), clonidine (k = 1, n = 70), lisdexamphetamine (k = 1, n = 25), mixed amphetamine salts (k = 1, n = 30), or modafinil (k = 2, n = 97). Three studies investigated cognition, four ADHD symptoms, and 10 the safety. Three studies found treatment-related ADHD symptom reduction: two involved methylphenidate and one amphetamine salts. One study found a trend towards pro-cognitive effects of modafinil on some cognitive domains. No increased risk of (hypo)mania was observed. Five studies had low risk of bias, eleven a moderate risk, and one a serious risk of bias. CONCLUSIONS: Methylphenidate or mixed amphetamine salts may improve ADHD symptoms in BD. However, there is limited evidence regarding the effectiveness on cognition. The medications produced no increased mania risk when used alongside mood stabilizers. Further robust studies are needed to assess cognition in BD patients receiving psychostimulant treatment alongside mood stabilizers.

Accelerating Medicines Partnership® Schizophrenia (AMP® SCZ): Rationale and Study Design of the Largest Global Prospective Cohort Study of Clinical High Risk for Psychosis.

This article describes the rationale, aims, and methodology of the Accelerating Medicines Partnership® Schizophrenia (AMP® SCZ). This is the largest international collaboration to date that will develop algorithms to predict trajectories and outcomes of individuals at clinical high risk (CHR) for psychosis and to advance the development and use of novel pharmacological interventions for CHR individuals. We present a description of the participating research networks and the data processing analysis and coordination center, their processes for data harmonization across 43 sites from 13 participating countries (recruitment across North America, Australia, Europe, Asia, and South America), data flow and quality assessment processes, data analyses, and the transfer of data to the National Institute of Mental Health (NIMH) Data Archive (NDA) for use by the research community. In an expected sample of approximately 2000 CHR individuals and 640 matched healthy controls, AMP SCZ will collect clinical, environmental, and cognitive data along with multimodal biomarkers, including neuroimaging, electrophysiology, fluid biospecimens, speech and facial expression samples, novel measures derived from digital health technologies including smartphone-based daily surveys, and passive sensing as well as actigraphy. The study will investigate a range of clinical outcomes over a 2-year period, including transition to psychosis, remission or persistence of CHR status, attenuated positive symptoms, persistent negative symptoms, mood and anxiety symptoms, and psychosocial functioning. The global reach of AMP SCZ and its harmonized innovative methods promise to catalyze the development of new treatments to address critical unmet clinical and public health needs in CHR individuals.

20-year neurocognitive development following a schizophrenia spectrum disorder and associations with symptom severity and functional outcomes.

BACKGROUND: Cognitive deficits are a core feature of schizophrenia and are closely associated with poor functional outcomes. It remains unclear if cognitive deficits progress over time or remain stable. Determining patients at increased risk of progressive worsening might help targeted neurocognitive remediation approaches. METHODS: This 20-year follow-up study examined neurocognitive outcomes of 156 participants from the OPUS I trial. Neurocognition was assessed using the brief assessment of cognition in schizophrenia at the 10- and 20-year follow-up, allowing us to examine changes in neurocognition over ten years. RESULTS: We found that 30.5% of patients had a declining course of neurocognition, 49.2% had a stable course of neurocognition and 20.3% experienced improvements in neurocognition. Good cognitive functioning at the 20-year follow-up was significantly associated with higher levels of social functioning (B 6.86, CI 4.71-9.02, p < 0.001) while increasing experiential negative symptoms were significantly correlated to cognitive worsening (PC-0.231, p = 0.029). Younger age at inclusion (B: 0.23 per 10-years, CI 0.00-0.045, p = 0.047) and low level of education (below ten years) (mean difference: -0.346, CI -0.616 to -0.076, p = 0.012) predicted declining neurocognition. CONCLUSION: Our findings support the notion of different schizophrenia subtypes with varying trajectories. Neurocognitive impairment at the 20-year follow-up was associated with other poor outcomes, highlighting the importance of treatments aimed at improving neurocognition in patients with schizophrenia spectrum disorders.

A preliminary choroid plexus volumetric study in individuals with psychosis.

The choroid plexus (ChP) is part of the blood-cerebrospinal fluid barrier, regulating brain homeostasis and the brain's response to peripheral events. Its upregulation and enlargement are considered essential in psychosis. However, the timing of the ChP enlargement has not been established. This study introduces a novel magnetic resonance imaging-based segmentation method to examine ChP volumes in two cohorts of individuals with psychosis. The first sample consists of 41 individuals with early course psychosis (mean duration of illness = 1.78 years) and 30 healthy individuals. The second sample consists of 30 individuals with chronic psychosis (mean duration of illness = 7.96 years) and 34 healthy individuals. We utilized manual segmentation to measure ChP volumes. We applied ANCOVAs to compare normalized ChP volumes between groups and partial correlations to investigate the relationship between ChP, LV volumes, and clinical characteristics. Our segmentation demonstrated good reliability (.87). We further showed a significant ChP volume increase in early psychosis (left: p < .00010, right: p < .00010) and a significant positive correlation between higher ChP and higher LV volumes in chronic psychosis (left: r = .54, p = .0030, right: r = .68; p < .0010). Our study suggests that ChP enlargement may be a marker of acute response around disease onset. It might also play a modulatory role in the chronic enlargement of lateral ventricles, often reported in psychosis. Future longitudinal studies should investigate the dynamics of ChP enlargement as a promising marker for novel therapeutic strategies.

Can magnetic resonance imaging enhance the assessment of potential new treatments for cognitive impairment in mood disorders? A systematic review and position paper by the International Society for Bipolar Disorders Targeting Cognition Task Force.

BACKGROUND: Developing treatments for cognitive impairment is key to improving the functioning of people with mood disorders. Neuroimaging may assist in identifying brain-based efficacy markers. This systematic review and position paper by the International Society for Bipolar Disorders Targeting Cognition Task Force examines the evidence from neuroimaging studies of pro-cognitive interventions. METHODS: We included magnetic resonance imaging (MRI) studies of candidate interventions in people with mood disorders or healthy individuals, following the procedures of the Preferred Reporting Items for Systematic reviews and Meta-Analysis 2020 statement. Searches were conducted on PubMed/MEDLINE, PsycInfo, EMBASE, Cochrane Library, and Clinicaltrials.gov from inception to 30th April 2021. Two independent authors reviewed the studies using the National Heart, Lung, Blood Institutes of Health Quality Assessment Tool for Controlled Intervention Studies and the quality of neuroimaging methodology assessment checklist. RESULTS: We identified 26 studies (N = 702). Six investigated cognitive remediation or pharmacological treatments in mood disorders (N = 190). In healthy individuals, 14 studies investigated pharmacological interventions (N = 319), 2 cognitive training (N = 73) and 4 neuromodulatory treatments (N = 120). Methodologies were mostly rated as 'fair'. 77% of studies investigated effects with task-based fMRI. Findings varied but most consistently involved treatment-associated cognitive control network (CCN) activity increases with cognitive improvements, or CCN activity decreases with no cognitive change, and increased functional connectivity. In mood disorders, treatment-related default mode network suppression occurred. CONCLUSIONS: Modulation of CCN and DMN activity is a putative efficacy biomarker. Methodological recommendations are to pre-declare intended analyses and use task-based fMRI, paradigms probing the CCN, longitudinal assessments, mock scanning, and out-of-scanner tests.

Cell type-specific manifestations of cortical thickness heterogeneity in schizophrenia.

Brain morphology differs markedly between individuals with schizophrenia, but the cellular and genetic basis of this heterogeneity is poorly understood. Here, we sought to determine whether cortical thickness (CTh) heterogeneity in schizophrenia relates to interregional variation in distinct neural cell types, as inferred from established gene expression data and person-specific genomic variation. This study comprised 1849 participants in total, including a discovery (140 cases and 1267 controls) and a validation cohort (335 cases and 185 controls). To characterize CTh heterogeneity, normative ranges were established for 34 cortical regions and the extent of deviation from these ranges was measured for each individual with schizophrenia. CTh deviations were explained by interregional gene expression levels of five out of seven neural cell types examined: (1) astrocytes; (2) endothelial cells; (3) oligodendrocyte progenitor cells (OPCs); (4) excitatory neurons; and (5) inhibitory neurons. Regional alignment between CTh alterations with cell type transcriptional maps distinguished broad patient subtypes, which were validated against genomic data drawn from the same individuals. In a predominantly neuronal/endothelial subtype (22% of patients), CTh deviations covaried with polygenic risk for schizophrenia (sczPRS) calculated specifically from genes marking neuronal and endothelial cells (r = -0.40, p = 0.010). Whereas, in a predominantly glia/OPC subtype (43% of patients), CTh deviations covaried with sczPRS calculated from glia and OPC-linked genes (r = -0.30, p = 0.028). This multi-scale analysis of genomic, transcriptomic, and brain phenotypic data may indicate that CTh heterogeneity in schizophrenia relates to inter-individual variation in cell-type specific functions. Decomposing heterogeneity in relation to cortical cell types enables prioritization of schizophrenia subsets for future disease modeling efforts.

Randomised controlled cognition trials in remitted patients with mood disorders published between 2015 and 2021: A systematic review by the International Society for Bipolar Disorders Targeting Cognition Task Force.

BACKGROUND: Cognitive impairments are an emerging treatment target in mood disorders, but currently there are no evidence-based pro-cognitive treatments indicated for patients in remission. With this systematic review of randomised controlled trials (RCTs), the International Society for Bipolar Disorders (ISBD) Targeting Cognition Task force provides an update of the most promising treatments and methodological recommendations. METHODS: The review included RCTs of candidate pro-cognitive interventions in fully or partially remitted patients with major depressive disorder or bipolar disorder. We followed the procedures of the Preferred Reporting Items for Systematic reviews and Meta-Analysis (PRISMA) 2020 statement. Searches were conducted on PubMed/MEDLINE, PsycInfo, EMBASE and Cochrane Library from January 2015, when two prior systematic reviews were conducted, until February 2021. Two independent authors reviewed the studies with the Revised Cochrane Collaboration's Risk of Bias tool for Randomised trials. RESULTS: We identified 16 RCTs (N = 859) investigating cognitive remediation (CR; k = 6; N = 311), direct current or repetitive magnetic stimulation (k = 3; N = 127), or pharmacological interventions (k = 7; N = 421). CR showed most consistent cognitive benefits, with two trials showing improvements on primary outcomes. Neuromodulatory interventions revealed no clear efficacy. Among pharmacological interventions, modafinil and lurasidone showed early positive results. Sources of bias included small samples, lack of pre-screening for objective cognitive impairment, no primary outcome and no information on allocation sequence masking. CONCLUSIONS: Evidence for pro-cognitive treatments in mood disorders is emerging. Recommendations are to increase sample sizes, pre-screen for impairment in targeted domain(s), select one primary outcome, aid transfer to real-world functioning, investigate multimodal interventions and include neuroimaging.

Dynamic and progressive changes in thalamic functional connectivity over the first five years of psychosis.

The early stage of psychosis (ESP) is a critical period where effective intervention has the most favorable impact on outcomes. Thalamic connectivity abnormalities have been consistently found in psychosis, and are associated with clinical symptoms and cognitive deficits. However, most studies consider ESP patients as a homogeneous population and fail to take the duration of illness into account. In this study, we aimed to capture the progression of thalamic connectivity changes over the first five years of psychosis. Resting-state functional MRI scans were collected from 156 ESP patients (44 with longitudinal data) and 82 healthy controls (24 with longitudinal data). We first performed a case-control analysis comparing thalamic connectivity with 13 networks in the cortex and cerebellum. Next, we modelled the shape (flat, linear, curvilinear) of thalamic connectivity trajectories by comparing flexible non-linear versus linear models. We then tested the significance of the duration of illness and diagnosis in trajectories that changed over time. Connectivity changed over the ESP period between the thalamus and default mode network (DMN) and fronto-parietal network (FPN) nodes in both the cortex and cerebellum. Three models followed a curvilinear trajectory (early increase followed by a subsequent decrease), while thalamo-cerebellar FPN connectivity followed a linear trajectory of steady reductions over time, indicating different rates of change. Finally, diagnosis significantly predicted thalamic connectivity. Thalamo-cortical and thalamo-cerebellar connectivity change in a dynamic fashion during the ESP period. A better understanding of these changes may provide insights into the compensatory and progressive changes in functional connectivity in the early stages of illness.

Smoking as a Common Modulator of Sensory Gating and Reward Learning in Individuals with Psychotic Disorders.

Motivational and perceptual disturbances co-occur in psychosis and have been linked to aberrations in reward learning and sensory gating, respectively. Although traditionally studied independently, when viewed through a predictive coding framework, these processes can both be linked to dysfunction in striatal dopaminergic prediction error signaling. This study examined whether reward learning and sensory gating are correlated in individuals with psychotic disorders, and whether nicotine-a psychostimulant that amplifies phasic striatal dopamine firing-is a common modulator of these two processes. We recruited 183 patients with psychotic disorders (79 schizophrenia, 104 psychotic bipolar disorder) and 129 controls and assessed reward learning (behavioral probabilistic reward task), sensory gating (P50 event-related potential), and smoking history. Reward learning and sensory gating were correlated across the sample. Smoking influenced reward learning and sensory gating in both patient groups; however, the effects were in opposite directions. Specifically, smoking was associated with improved performance in individuals with schizophrenia but impaired performance in individuals with psychotic bipolar disorder. These findings suggest that reward learning and sensory gating are linked and modulated by smoking. However, disorder-specific associations with smoking suggest that nicotine may expose pathophysiological differences in the architecture and function of prediction error circuitry in these overlapping yet distinct psychotic disorders.

Diagnostic Stability of Primary Psychotic Disorders in a Research Sample.

Psychiatric diagnosis is often treated as a stable construct both clinically and in research; however, some evidence suggests that diagnostic change may be common, which may impact research validity and clinical care. In the present study we examined diagnostic stability in individuals with psychosis over time. Participants with a diagnosis of any psychotic disorder (n = 142) were assessed at two timepoints using the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders. We found a 25.4% diagnostic change rate across the total sample. People with an initial diagnosis of psychosis not otherwise specified and schizophreniform disorder had the highest rates of change, followed by those with schizophrenia and schizoaffective disorder; people with bipolar disorder had the lowest change rate. Most participants with an unstable initial diagnosis of schizophrenia, schizophreniform disorder, bipolar disorder, or psychosis not otherwise specified converted to a final diagnosis of schizoaffective disorder. Participants with an unstable initial diagnosis of schizoaffective disorder most frequently converted to a diagnosis of schizophrenia. Our findings suggest that diagnostic change is relatively common, occurring in approximately a quarter of patients. People with an initial diagnosis of schizophrenia-spectrum disorder were more likely to have a diagnostic change, suggesting a natural stability of some diagnoses more so than others.

Feasibility and tolerability of a cognitive remediation clinical service in first episode coordinated specialty care.

AIM: Cognitive remediation is an evidence-based intervention targeting the common and disabling cognitive deficits in people with psychosis. Findings from efficacy studies and meta-analyses show that cognitive remediation produces medium to large effects on cognition in both chronic and first episode patients. However, clinical availability of this treatment remains scarce, reflecting a major gap between science and practice. Here we describe the development of a cognitive remediation programme in an outpatient first episode psychosis clinical service, and preliminary feasibility and acceptability outcomes. METHODS: Based on evidence from efficacy trials and assessment within the clinic of perceived benefits and barriers, we developed a CR programme that involved both internet-based computer training exercises and a weekly in-person therapy group. Outcomes were assessed based on data from three consecutive 12-week group series. Feasibility outcomes included adoption, fill, cost, and utilization; tolerability outcomes were based on user survey and focus group feedback. RESULTS: We found evidence of feasibility including good adoption, fill, utilization, and cost. We also found good tolerability and satisfaction based on feedback from a user survey and focus groups, with more than 80% of respondents reporting high overall satisfaction with the programme and subjective cognitive and functional improvements. CONCLUSIONS: The present report provides preliminary evidence that cognitive remediation can be translated into real world clinical practice for first episode psychosis. Systematic evaluation of implementation and dissemination of cognitive remediation is needed, and has the potential to improve access to cognitive health interventions for people with psychosis.

Cerebellar-Cortical Connectivity Is Linked to Social Cognition Trans-Diagnostically.

Background: Psychotic disorders are characterized by impairment in social cognitive processing, which is associated with poorer community functioning. However, the neural mechanisms of social impairment in psychosis remain unclear. Social impairment is a hallmark of other psychiatric illnesses as well, including autism spectrum disorders (ASD), and the nature and degree of social cognitive impairments across psychotic disorders and ASD are similar, suggesting that mechanisms that are known to underpin social impairments in ASD may also play a role in the impairments seen in psychosis. Specifically, in both humans and animal models of ASD, a cerebellar-parietal network has been identified that is directly related to social cognition and social functioning. In this study we examined social cognition and resting-state brain connectivity in people with psychosis and in neurotypical adults. We hypothesized that social cognition would be most strongly associated with cerebellar-parietal connectivity, even when using a whole-brain data driven approach. Methods: We examined associations between brain connectivity and social cognition in a trans-diagnostic sample of people with psychosis (n = 81) and neurotypical controls (n = 45). Social cognition was assessed using the social cognition domain score of the MATRICS Consensus Cognitive Battery. We used a multivariate pattern analysis to correlate social cognition with resting-state functional connectivity at the individual voxel level. Results: This approach identified a circuit between right cerebellar Crus I, II and left parietal cortex as the strongest correlate of social cognitive performance. This connectivity-cognition result was observed in both people with psychotic disorders and in neurotypical adults. Conclusions: Using a data-driven whole brain approach we identified a cerebellar-parietal circuit that was robustly associated with social cognitive ability, consistent with findings from people with ASD and animal models. These findings suggest that this circuit may be marker of social cognitive impairment trans-diagnostically and support cerebellar-parietal connectivity as a potential therapeutic target for enhancing social cognition.

Dissociable mechanisms underpinning effort-cost decision-making across the psychosis spectrum.

Recent theoretical models propose that abnormal effort-cost decision-making (ECDM) likely has divergent underpinnings across mood and psychotic disorders. However, whether this same model applies to individuals across the psychosis spectrum, including individuals with affective psychosis, remains unclear. This study aimed to empirically test whether two component processes - working memory and reward learning - contribute to ECDM impairment across the psychosis spectrum. ECDM was assessed using the Effort Expenditure for Rewards Task in individuals with psychotic disorders (n = 190) and healthy controls (n = 52). Working memory was assessed using a Digit Sequencing Task and reward learning was assessed using a Probabilistic Reward Task. Relative to the control group, the psychosis group showed reduced willingness to expend effort for higher probability, higher value rewards. This effect was most pronounced in individuals with schizophrenia and schizoaffective disorder relative to individuals with psychotic bipolar disorder. Across the whole sample, better working memory but not reward learning predicted greater willingness to expend effort for higher probability rewards. However, the link between working memory and ECDM differed as a function of patient symptom profile. Specifically, working memory was only predictive of ECDM for individuals with less severe negative symptoms and minimal depressive symptoms. For individuals with more severe negative symptoms, poorer ECDM was instead predicted by deficits in reward learning. Although these findings reiterate the important link between working memory and ECDM in individuals with psychotic disorders, they also show that this link varies in accordance with the presence of prominent negative and depressive symptoms.