Risk of Incident Psychosis and Mania With Prescription Amphetamines.

OBJECTIVE: Amphetamine prescribing has increased in the United States in recent years. Previous research identified an increased risk of incident psychosis with prescription amphetamines. The purpose of this study was to examine the impact of dose levels of prescription amphetamines on the risk of this rare but serious adverse outcome. METHODS: A case-control study using electronic health records was conducted to compare the odds of incident psychosis or mania with past-month exposure to prescription amphetamines. Case subjects were patients ages 16-35 hospitalized at McLean Hospital for incident psychosis or mania between 2005 and 2019. Control subjects were patients with an initial psychiatric hospitalization for other reasons, most commonly depression and/or anxiety. Amphetamine doses were converted to dextroamphetamine equivalents and divided into terciles. Secondary analyses evaluated the odds of psychosis or mania with methylphenidate use. RESULTS: Among 1,374 case subjects and 2,748 control subjects, the odds of psychosis and mania were increased for individuals with past-month prescription amphetamine use compared with no use (adjusted odds ratio=2.68, 95% CI=1.90-3.77). A dose-response relationship was observed; high doses of amphetamines (>30 mg dextroamphetamine equivalents) were associated with 5.28-fold increased odds of psychosis or mania. Past-month methylphenidate use was not associated with increased odds of psychosis or mania compared with no use (adjusted odds ratio=0.91, 95% CI=0.54-1.55). CONCLUSIONS: Although use of hospitalized control subjects excludes individuals with less severe disease, leading to selection bias, the study results suggest that caution should be exercised when prescribing high doses of amphetamines, with regular screening for symptoms of psychosis or mania.

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.

Differential deficits in social versus monetary reinforcement learning in schizophrenia: Associations with facial emotion recognition.

Despite evidence that individuals with schizophrenia (SZ) have an intact desire for social relationships, they have small social networks and report high levels of loneliness. Difficulty with reinforcement learning (RL), the ability to update behavior based on feedback, may inhibit the formation and maintenance of social relationships in SZ. However, impaired RL in SZ has largely been demonstrated via monetary tasks. Thus, it remains unclear whether SZ are similarly impaired in social and monetary RL, or whether social-specific factors may further inhibit their ability to learn from social feedback. Thirty-one individuals with SZ and 31 healthy controls (HCs) participated in a RL paradigm to test hypotheses about social versus monetary RL. SZ exhibited impaired RL compared to HCs in both social and monetary tasks. Further, a Group × Task interaction demonstrated that SZ was more impaired when learning from social than monetary reinforcement, F(1, 59) = 5.99, p = .017. This differential deficit to social RL was not accounted for by reported pleasure from social feedback, which did not differ between groups. Instead, SZ had poorer emotion recognition than HCs, t(1, 60) = 4.80, p < .001, particularly for negative emotions, and controlling for this eliminated the differential social RL impairment. These results suggest the possibility that difficulty recognizing social cues, especially those indicating negative feedback, may relate to a reduced ability to learn from others' feedback. Thus, future research could elucidate whether targeting these emotion recognition difficulties in treatment could serve as a potential mechanism for improving social functioning in SZ. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Associations with youth psychotic-like experiences over time: Evidence for trans-symptom and specific cognitive and neural risk factors.

The current study examined whether impairments in cognitive and neural factors at baseline (ages 9-10) predict initial levels or changes in psychotic-like experiences (PLEs) and whether such impairments generalize to other psychopathology symptoms (i.e., internalizing and externalizing symptoms). Using unique longitudinal Adolescent Brain Cognitive Development Study data, the study examined three time points from ages 9 to 13. Univariate latent growth models examined associations between baseline cognitive and neural metrics with symptom measures using discovery (n = 5,926) and replication (n = 5,952) data sets. For symptom measures (i.e., PLEs, internalizing, externalizing), we examined mean initial levels (i.e., intercepts) and changes over time (i.e., slopes). Predictors included neuropsychological test performance, global structural MRI, and several a priori within-network resting-state functional connectivity metrics. Results showed a pattern whereby baseline cognitive and brain metric impairments showed the strongest associations with PLEs over time. Lower cognitive, volume, surface area, and cingulo-opercular within-network connectivity metrics showed associations with increased PLEs and higher initial levels of externalizing and internalizing symptoms. Several metrics were uniquely associated with PLEs, including lower cortical thickness with higher initial PLEs and lower default mode network connectivity with increased PLEs slopes. Neural and cognitive impairments in middle childhood were broadly associated with increased PLEs over time, and showed stronger associations with PLEs compared with other psychopathology symptoms. The current study also identified markers potentially uniquely associated with PLEs (e.g., cortical thickness). Impairments in broad cognitive metrics, brain volume and surface area, and a network associated with information integration may represent risk factors for general psychopathology. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Correlates of real-world goal-directed behavior in schizophrenia.

BACKGROUND: Deficits in goal-directed behavior (i.e. behavior conducted to achieve a specific goal or outcome) are core to schizophrenia, difficult to treat, and associated with poor functional outcomes. Factors such as negative symptoms, effort-cost decision-making, cognition, and functional skills have all been associated with goal-directed behavior in schizophrenia as indexed by clinical interviews or laboratory-based tasks. However, little work has examined whether these factors relate to the real-world pursuit of goal-directed activities in this population. METHODS: This study aimed to fill this gap by using Ecological Momentary Assessment (four survey prompts per day for 1 week) to test hypotheses about symptom, effort allocation, cognitive, and functional measures associated with planned and completed goal-directed behavior in the daily lives of 63 individuals with schizophrenia. RESULTS: Individuals with schizophrenia completed more goal-directed activities than they planned [t(62) = -4.01, p < 0.001]. Motivation and pleasure (i.e. experiential) negative symptoms, controlling for depressive symptoms, negatively related to planned goal-directed behavior [odds ratio (OR) 0.92, p = 0.005]. Increased effort expenditure for high probability rewards (planned: OR 1.01, p = 0.034, completed: OR 1.01, p = 0.034) along with performance on a daily functional skills task (planned: OR 1.04, p = 0.002, completed: OR 1.03, p = 0.047) negatively related to both planned and completed goal-directed activity. CONCLUSIONS: Our results present correlates of real-world goal-directed behavior that largely align with impaired ability to make future estimations in schizophrenia. This insight could help identify targeted treatments for the elusive motivated behavior deficits in this population.

Cognitive Dysfunction as a Risk Factor for Psychosis.

The current chapter summarizes recent evidence for cognition as a risk factor for the development of psychosis, including the range of cognitive impairments that exist across the spectrum of psychosis risk symptoms. The chapter examines several possible theories linking cognitive deficits with the development of psychotic symptoms, including evidence that cognitive deficits may be an intermediate risk factor linking genetic and/or neural metrics to psychosis spectrum symptoms. Although there is not strong evidence for unique cognitive markers associated specifically with psychosis compared to other forms of psychopathology, psychotic disorders are generally associated with the greatest severity of cognitive deficits. Cognitive deficits precede the development of psychotic symptoms and may be detectable as early as childhood. Across the psychosis spectrum, both the presence and severity of psychotic symptoms are associated with mild to moderate impairments across cognitive domains, perhaps most consistently for language, cognitive control, and working memory domains. Research generally indicates the size of these cognitive impairments worsens as psychosis symptom severity increases. The chapter points out areas of unclarity and unanswered questions in each of these areas, including regarding the mechanisms contributing to the association between cognition and psychosis, the timing of deficits, and whether any cognitive systems can be identified that function as specific predictors of psychosis risk symptoms.

Negative and depressive symptoms differentially relate to real-world anticipatory and consummatory pleasure in schizophrenia.

It has been suggested that schizophrenia is associated with deficits in anticipatory but not consummatory pleasure, though there is mixed support for this hypothesis. As individuals with schizophrenia can experience both negative and depressive symptoms, symptom heterogeneity in this population could contribute to these mixed hedonic findings. Specifically, while some research suggests that negative symptoms of schizophrenia are related to reduced anticipatory but not consummatory pleasure, research on major depressive disorder suggests that depressive symptoms are associated with both decreased anticipatory and consummatory pleasure. Still, it is unclear whether depressive symptoms are associated with experiences of pleasure in schizophrenia as they are in major depressive disorder. Thus, the present study used Ecological Momentary Assessment (four prompts per day over one week) to investigate the unique relationships of negative and depressive symptoms with daily reports of real-world anticipatory and consummatory pleasure in 63 individuals with schizophrenia. Higher negative symptoms related to reduced anticipatory but not consummatory pleasure. On the other hand, higher depressive symptoms related to reductions in both anticipatory and consummatory pleasure. Overall, these results indicate that negative and depressive symptoms are differentially associated with hedonic experience in schizophrenia, and suggest the need to account for the severity of both these symptom types when examining pleasure in this population. Elucidating the nature of these symptom contributions to hedonic impairments could increase causal understanding of these deficits and contribute to the development of more targeted treatments to enhance motivation and pleasure in schizophrenia.

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.

The effects of cognitive remediation in patients with affective psychosis: A systematic review: Special Section on "Translational and Neuroscience Studies in Affective Disorders". Section Editor, Maria Nobile MD, PhD. This Section of JAD focuses on the relevance of translational and neuroscience studies in providing a better understanding of the neural basis of affective disorders. The main aim is to briefly summaries relevant research findings in clinical neuroscience with particular regards to specific innovative topics in mood and anxiety disorders.

BACKGROUND: Schizophrenia, schizoaffective disorder, and related illnesses are associated with significant impairment in cognitive functioning which is among the strongest predictors of disability and poor quality of life. Cognitive remediation (CR) was developed as a set of behavioral interventions directly targeting cognitive symptoms. Studies have shown that CR produces cognitive improvements in patients with schizophrenia and bipolar disorder that may be associated with improvements in functioning. However, the relative efficacy of CR across diagnoses has not been established. Indirect evidence suggests that CR is effective in patients with affective illness as well as patients with schizophrenia (SZ); however, the one study to evaluate the effects of diagnosis on outcomes directly in patients with SZ versus schizoaffective disorder (SZA) found no differences by diagnosis. METHODS: In this systematic review, we evaluated cognitive and functional outcomes after CR in studies including patients with SZA, and examined specificity of training content to outcomes. RESULTS: Sixteen studies met inclusion criteria: 10 studies that compared CR to a control condition (n = 779) and 6 comparative effectiveness studies. None of the studies explicitly compared patients by diagnosis. Studies included a mixture of patients with SZA or SZ. Of the CR versus control studies, effect sizes for cognitive outcomes were moderate-large (d = .36-.94). Studies comparing CR paradigms targeting different cognitive domains showed specificity of training focus to outcomes. Five of studies reported significant functional improvement after CR as secondary outcomes. CONCLUSIONS: In this review, we found support for the use of CR paradigms in patients with affective psychosis, with evidence that reported treatment effects in mixed affective and non-affective samples are at or above the levels previously reported in SZ. However, lack of availability of data directly comparing patients by diagnosis or examining moderator or mediator effects of diagnosis or diagnosis-related patient characteristics limits our understanding of the relative efficacy of CR across patient group.