The impact of inflammation on neurocognition and risk for psychosis: a critical review.

Neurocognitive difficulties are highly prevalent among people with schizophrenia and have been linked to increased inflammation, as well as dysfunction and disability. Poor neurocognitive functioning has also been documented in individuals at clinical high risk for psychosis (CHR) and a burgeoning literature point to alterations in inflammation markers in this population. However, there is limited information regarding the putative link between inflammation and neurocognition in CHR individuals, and the potential role of inflammation in the development of cognitive difficulties and psychosis. As previous reports indicate that early treatment in schizophrenia is associated with better outcomes, there is an urgent need to identify neurobiological mechanisms underlying cognitive deterioration and psychosis in CHR individuals to provide them with care prior to significant cognitive and functional declines. To address this gap in the literature, we review and summarize the relevant literatures on inflammation and neurocognitive dysfunction in schizophrenia and CHR individuals, point to remaining gaps, and suggest directions for future research.

Inflammation in individuals with schizophrenia - Implications for neurocognition and daily function.

Individuals with schizophrenia display substantial deficits in neurocognition, resulting in poor daily functioning and disability. Recent reports have suggested that neurocognitive dysfunction in this population is linked to increased inflammation. However, there is paucity of evidence supporting this link, as well as lack of information about the putative link of inflammation to daily functioning. We examined neurocognition (MCCB) and daily functioning (SLOF), as well as inflammatory markers (TNF-α, IL-6, IL-1ß, and IL-12p70) in 41 individuals with schizophrenia. Poor neurocognition was significantly associated with increased peripheral TNF-α and IL-12p70 (r = -0.44 and r = -0.38, respectively, controlling for BMI, depression and antipsychotic medication). Notably, difficulties with daily functioning were significantly associated with increased peripheral TNF-α (r = -0.51) and a trend with increased IL-12p70. Our findings support previous hypotheses linking neurocognitive impairment to increased inflammation in individuals with schizophrenia. Our results extend these associations in this population, linking inflammation to poor daily functioning in this population.

Organizational Learning Strategies and Verbal Memory Deficits in Bipolar Disorder.

BACKGROUND: Verbal memory (VM) impairment is prominent in bipolar disorder (BD) and is linked to functional outcomes. However, the intricacies of VM impairment have not yet been studied in a large sample of BD patients. Moreover, some have proposed VM deficits that may be mediated by organizational strategies, such as semantic or serial clustering. Thus, the exact nature of VM break-down in BD patients is not well understood, limiting remediation efforts. We investigated the intricacies of VM deficits in BD patients versus healthy controls (HCs) and examined whether verbal learning differences were mediated by use of clustering strategies. METHODS: The California Verbal Learning Test (CVLT) was administered to 113 affectively stable BD patients and 106 HCs. We compared diagnostic groups on all CVLT indices and investigated whether group differences in verbal learning were mediated by clustering strategies. RESULTS: Although BD patients showed significantly poorer attention, learning, and memory, these indices were only mildly impaired. However, BD patients evidenced poorer use of effective learning strategies and lower recall consistency, with these indices falling in the moderately impaired range. Moreover, relative reliance on semantic clustering fully mediated the relationship between diagnostic category and verbal learning, while reliance on serial clustering partially mediated this relationship. CONCLUSIONS: VM deficits in affectively stable bipolar patients were widespread but were generally mildly impaired. However, patients displayed inadequate use of organizational strategies with clear separation from HCs on semantic and serial clustering. Remediation efforts may benefit from education about mnemonic devices or "chunking" techniques to attenuate VM deficits in BD. (JINS, 2017, 23, 358-366).

The effects of cigarette smoking behavior and psychosis history on general and social cognition in bipolar disorder.

OBJECTIVES: Several studies have documented the prevalence and effects of cigarette smoking on cognition in psychotic disorders; fewer have focused on bipolar disorder (BD). Cognitive and social dysfunction are common in BD, and the severity of these deficits may be related both to illness features (e.g., current symptoms, psychosis history) and health-related behaviors (e.g., smoking, alcohol use). The current study assessed the influence of cigarette smoking on general and social cognition in a BD cohort, accounting for illness features with a focus on psychosis history. METHODS: We assessed smoking status in 105 euthymic patients with BD, who completed a comprehensive battery including social (facial affect recognition, emotional problem-solving, and theory of mind) and general (the MATRICS Consensus Cognitive Battery and executive functioning) cognitive measures. We compared smokers vs nonsmokers on cognitive performance and tested for the effects of psychosis history, premorbid intellectual functioning, substance use, and current affective symptoms. RESULTS: Within the nonpsychotic subgroup with BD (n=45), smokers generally outperformed nonsmokers; by contrast, for subjects with BD with a history of psychosis (n=41), nonsmokers outperformed smokers. This pattern was noted more globally using a general composite cognitive score and on social/affective measures assessing patients' ability to identify emotions of facial stimuli and solve emotional problems. CONCLUSIONS: Cigarette smoking differentially affects performance on both general and social cognition in patients with BD as a function of psychosis history. These results suggest that there may be at least partially divergent underlying neurobiological causes for cognitive dysfunction in patients with BD with and without psychosis.

Psychiatric and affective predictors of negative racial attitudes.

Negative Racial Attitudes (NRA) have been identified as major contributors to discrimination and inequalities. Previous studies of predictors of NRA have focused largely on socioeconomic, socialization, social attitudes, and personality characteristics. Yet, the potential links of psychiatric and affective indicators to NRA have received little scientific inquiry. Three-hundred-and-two participants completed measures of explicit, covert, and implicit NRA, along with indices of psychotic-like experiences (PLEs), mood symptoms, affective processing, social attitudes, and personality characteristics. Explicit and covert NRA were significantly correlated with difficulty identifying and describing feelings, use of suppression to regulate emotion, and the PLEs domains of perceptual abnormalities, bizarre experiences, and persecutory ideation, along with social attitudes and personality characteristics. Implicit NRA was not associated with any indicators. Next, employing hierarchical multiple linear regression analyses, the affective and psychiatric indicators accounted 5.2% and 10.4% of the explicit and covert NRA variance, respectively, controlling for previously identified predictors including demographics, social attitudes, and personality characteristics. Our results point to newly identified predictors of NRA including difficulties identifying and describing emotions, use of suppression to regulate emotions, as well as PLEs, specifically perceptual abnormalities. We discuss the implications of the findings to the development and adaptation of anti-racism interventions.

Inflammation and emotion regulation: Findings from the MIDUS II study.

Emotion regulation (ER) strategies are thought to contribute to mental as well as physical health outcomes. Two common ER strategies include expressive suppression, or inhibition of emotional expression, and cognitive reappraisal, which involves changing how to think about an emotion-eliciting event in order to change its emotional impact. Recent reports have hypothesized that one potential way in which ER may be linked to health outcomes is via the immune system. However, information on this putative link is scarce. The present study aims to explore whether peripheral inflammatory biomarkers are associated with individual differences in ER-strategy use. Participants (n = 117) from the Midlife in the United States II (MIDUS II) study completed the Emotion Regulation Questionnaire (ERQ), and provided a blood sample for immune biomarker extraction including interleukin (IL)-6, IL-8, IL-10, tumor necrosis factor-α (TNF-α), C-reactive protein (CRP), E-selectin, Intercellular Adhesion Molecule-1 (ICAM-1), and fibrinogen. Results showed higher levels of expressive suppression were associated with decreased IL-10, TNF-α, and ICAM-1 levels (controlling for age, sex, BMI, total prescribed medications, and depressive symptoms). Consistent with these findings, hierarchical regression results identified TNF-α as a significant predictor of expressive suppression use. In contrast, no inflammatory markers were associated with predicted use of cognitive reappraisal. Our findings suggest a link between inflammation and specific ER-strategy use. Future research should consider the effects of pro-vs. anti-inflammatory cytokines on adaptive ER and subsequent mental and physical health.

Psychosis risk individuals show poor fitness and discrepancies with objective and subjective measures.

Exercise is a promising intervention for individuals at clinical high-risk for psychosis (CHR). However, these youth may not be reliable reporters on fitness. There have been no investigations that utilized objective fitness assessment in this population. The present study objectively characterizes the level of fitness in CHR youth, compares the accuracy of self-report measures to objective fitness indices, and explores clinical factors that may influence the accuracy of self-reported measures of fitness. Forty CHR individuals completed an exercise survey and objective indices of fitness (i.e., VO2max and BMI). Forty healthy volunteers completed objective indices of fitness and a structured clinical interview ruling out the presence of psychiatric illness. CHR youth showed greater BMI and lowered VO2max compared to healthy volunteers. In the CHR group, self-report items (perceived fitness) did not reflect objective indices of fitness, whereas specific exercise behaviors (intensity of exercise) showed stronger correlations with objective fitness measurements. Exploratory analyses suggested that symptoms (grandiosity and avolition) related to errors in self-perception. Results indicate that CHR individuals are less fit than controls as indexed by objective measures of fitness and that it is important to consider unique population clinical characteristics when employing self-report data.

Suicide Reduction in Schizophrenia via Exercise (SUnRISE): study protocol for a multi-site, single-blind, randomized clinical trial of aerobic exercise for suicide risk reduction in individuals with schizophrenia.

BACKGROUND: Suicide risk among individuals with schizophrenia (SZ) is intractably high, with over 40% of individuals attempting to take their own lives during their lifetime and an estimated 5-10% completing suicide. At present, available pharmacological and psychotherapeutic treatments offer limited risk reduction benefits, and thus, there remains an urgent need to explore novel interventions that will ameliorate this risk. Aerobic exercise (AE) has been shown to improve a number of predictors of suicide risk (e.g., depressed mood, sleeping difficulties). As individuals with SZ display a highly sedentary lifestyle, AE may reduce suicide risk. METHODS: Employing a multi-site, single-blind, randomized clinical trial design, we will examine the impact of AE on risk for suicide and related variables in individuals with SZ. Participants will be randomized to one of two 12-week exercise interventions: AE or a stretching and toning (ST) control intervention. Primary outcome measures will include suicide risk (Columbia Suicide Severity Rating Scale, C-SSRS) and aerobic fitness (VO2max), along with additional measures of suicide risk, mood, emotion regulation, sleep, cognition, and physical activity, with assessments completed at baseline and after 6 and 12 weeks of interventions. DISCUSSION: It is hypothesized that AE will reduce suicide risk among individuals with SZ. This study may offer support for a more efficacious treatment method for this population in addition to the pre-existing pharmacological and psychotherapeutic treatment regimens. TRIAL REGISTRATION: Clinicaltrials.gov, NCT03270098 . Registered on September 1, 2017.

The impact of emotion awareness and regulation on psychotic symptoms during daily functioning.

Emotion regulation (ER) difficulties are ubiquitous among individuals with schizophrenia and have been hypothesized to contribute to stress sensitivity and exacerbation of psychotic symptoms in this population. However, the evidence supporting this link is equivocal, potentially due to previous studies' reliance on retrospective assessments of ER and psychosis, as well as lack of consideration of putative moderators such as emotion awareness. To address these limitations, we employed experience sampling method using mobile electronic devices to investigate the links between momentary in vivo use of ER strategies (mER), emotion awareness, and psychotic symptoms during daily functioning. Fifty-four individuals with schizophrenia completed assessment of mER and psychotic symptoms, along with traditional retrospective measures of ER and symptoms. Use of mER suppression predicted significant increases in momentary experiences of thought insertion, mind reading, auditory and visual hallucinations. Use of mER reappraisal predicted significant increases in momentary experiences of suspiciousness, thought insertion, and mind reading. Emotion awareness, driven primarily by difficulties identifying feelings, moderated the impact of ER on psychotic symptoms. There were no associations between retrospective measures of ER and symptoms. Our results indicate that, among individuals with schizophrenia, emotion awareness significantly impacts the relationship between use of ER and exacerbations in psychotic symptoms during the course of daily functioning. Our results highlight the need to incorporate emotion awareness and regulation difficulties into the development of treatment models and interventions for psychosis. In addition, our results underscore the need to employ in vivo, high time-resolution assessment methods to study dynamic clinical phenomena such as ER and psychotic symptoms.

Premorbid adjustment trajectories in schizophrenia and bipolar disorder: A transdiagnostic cluster analysis.

Despite the overlap between schizophrenia and bipolar disorder, neurodevelopmental abnormalities are thought to be associated primarily with schizophrenia. Transdiagnostic and empirical identification of subgroups based on premorbid adjustment (PMA) may enhance understanding of illness trajectories. 160 patients with bipolar I or II disorder (BD; n = 104) or schizophrenia or schizoaffective disorder (SZ; n = 56) were assessed on PMA course from childhood to late adolescence and current symptoms and functioning. A hierarchical cluster analysis was performed using social and academic PMA scores, resulting in three optimal clusters. Cluster 1 (n = 28 SZ, 65 BD) had normal social and academic PMA, the most education, and mildest current symptoms. Cluster 2 (n = 15 SZ, 24 BD) had normal social PMA but an impaired-declining academic course and had a greater proportion of males than Cluster 1. Cluster 3 (n = 13 SZ, 15 BD) had an impaired-stable social PMA and an impaired-declining academic course and the most severe current negative symptoms and childhood trauma. The proportions of SZ and BD diagnoses, current neurocognition, and functioning did not differ between clusters. These findings suggest shared neurodevelopmental abnormalities between SZ and BD, with subgroups exhibiting distinct PMA trajectories that cut across disorders.

Improving Cognition via Exercise (ICE): Study Protocol for a Multi-Site, Parallel-Group, Single-Blind, Randomized Clinical Trial Examining the Efficacy of Aerobic Exercise to Improve Neurocognition, Daily Functioning, and Biomarkers of Cognitive Change in Individuals with Schizophrenia.

Individuals with schizophrenia (SZ) display cognitive deficits that have been identified as major determinants of poor functioning and disability, representing a serious public health concern and an important target for interventions. At present, available treatments offer only minimal to moderate benefits to ameliorate cognitive deficits. Thus, there remains an urgent need to identify novel interventions to improve cognition in people with SZ. Emerging evidence from animal and basic human research suggests aerobic exercise training (AE) has beneficial effects on cognition. Preliminary findings suggest that AE is efficacious in improving cognitive functioning in SZ, however the extant studies have been limited by small samples, a dearth of information on biologically-relevant covariates, and limited information on impact on daily functioning. Additionally, while AE-related cognitive benefits have been linked to Brain-Derived Neurotrophic Factor (BDNF) upregulation, this putative mechanism needs confirmation. The present report describes a study protocol designed to address these limitations-we review and summarize the current literature on treatment of cognitive deficits in SZ, state the rationale for employing AE to target these deficits, and describe the current protocol-a multi-site, single-blind, randomized clinical trial aiming to recruit 200 community-dwelling individuals with SZ. Participants are randomized to one of two 12-week interventions: AE using active-play video games (i.e., Xbox Kinect) and traditional cardiovascular exercise equipment or a stretching-and-toning (ST) control intervention. Participants undergo assessments of aerobic fitness, cognition, and daily functioning, as well as BDNF and other biomarkers of cognitive change, at baseline and after 6-and 12-weeks.

Effects of childhood trauma on adult moral decision-making: Clinical correlates and insights from bipolar disorder.

BACKGROUND: Childhood adversity has been shown to exert profound effects on basic psychological processes well into adulthood. Some of these processes, such as those related to reward and emotion, play critical roles in moral decision-making. As a population with high rates of childhood trauma as well as heterogenous clinical presentation, individuals with bipolar disorder (BD) constitute an enriched group in which to examine the correlates of trauma and other clinical variables with moral cognition. METHODS: 62 euthymic BD patients and 27 controls responded to moral dilemma scenarios and completed the Childhood Trauma Questionnaire. RESULTS: Results revealed a main effect of diagnosis on moral decision-making only when both personal force and an intention were required, indicating a more utilitarian style in BD patients relative to controls. Several interesting patterns also emerged regardless of diagnostic status. Higher ratings of physical neglect were significantly associated with higher ratings of acceptability (a utilitarian tendency) across dilemma types, and a similar pattern was observed at the trend level for experiences of emotional neglect. Significant main effects on moral decision-making were also observed for sex, illness duration, and history of psychotic features in the BD sample. LIMITATIONS: The present study is limited by the self-reported nature of the CTQ and by the small number of trials of moral dilemmas. In addition, practical and clinical implications of the moral dilemmas paradigm are limited due to its abstract nature. CONCLUSIONS: Our results indicate that certain clinical features as well as childhood maltreatment (in particular neglect) may significantly impact moral decision making in adult life. Surprisingly, childhood trauma was associated with a more utilitarian style, which is in the opposite direction from previous effects shown in PTSD. Although speculative, our results suggest that there may be a protective quality associated with utilitarian moral decision-making tendencies.