Mismatch negativity and clinical trajectories in psychotic disorders: Five-year stability and predictive utility.

BACKGROUND: Mismatch negativity (MMN) amplitude is reduced in psychotic disorders and associated with symptoms and functioning. Due to these robust associations, it is often considered a biomarker for psychotic illness. The relationship between MMN and clinical outcomes has been examined well in early onset psychotic illness; however, its stability and predictive utility in chronic samples are not clear. METHOD: We examined the five-year stability of MMN amplitude over two timepoints in individuals with established psychotic disorders (cases; N = 132) and never-psychotic participants (NP; N = 170), as well as longitudinal associations with clinical symptoms and functioning. RESULTS: MMN amplitude exhibited good temporal stability (cases, r = 0.53; never-psychotic, r = 0.52). In cases, structural equation models revealed MMN amplitude to be a significant predictor of worsening auditory hallucinations (ß = 0.19), everyday functioning (ß = -0.13), and illness severity (ß = -0.12) at follow-up. Meanwhile, initial IQ (ß = -0.24), negative symptoms (ß = 0.23), and illness severity (ß = -0.16) were significant predictors of worsening MMN amplitude five years later. CONCLUSIONS: These results imply that MMN measures a neural deficit that is reasonably stable up to five years. Results support disordered cognition and negative symptoms as preceding reduced MMN, which then may operate as a mechanism driving reductions in everyday functioning and the worsening of auditory hallucinations in chronic psychotic disorders. This pattern may inform models of illness course, clarifying the relationships amongst biological mechanisms of predictive processing and clinical deficits in chronic psychosis and allowing us to better understand the mechanisms driving such impairments over time.

Dynamic interplay between life events and course of psychotic disorders: 10-year longitudinal study following first admission.

BACKGROUND: Life events (LEs) are a risk factor for first onset and relapse of psychotic disorders. However, the impact of LEs on specific symptoms - namely reality distortion, disorganization, negative symptoms, depression, and mania - remains unclear. Moreover, the differential effects of negative v. positive LEs are poorly understood. METHODS: The present study utilizes an epidemiologic cohort of patients (N = 428) ascertained at first-admission for psychosis and followed for a decade thereafter. Symptoms were assessed at 6-, 24-, 48-, and 120-month follow-ups. RESULTS: We examined symptom change within-person and found that negative events in the previous 6 months predicted an increase in reality distortion (ß = 0.07), disorganized (ß = 0.07), manic (ß = 0.08), and depressive symptoms (ß = 0.06), and a decrease in negative symptoms (ß = -0.08). Conversely, positive LEs predicted fewer reality distortion (ß = -0.04), disorganized (ß = -0.04), and negative (ß = -0.13) symptoms, and were unrelated to mood symptoms. A between-person approach to the same hypotheses confirmed that negative LEs predicted change in all symptoms, while positive LEs predicted change only in negative symptoms. In contrast, symptoms rarely predicted future LEs. CONCLUSIONS: These findings confirm that LEs have an effect on symptoms, and thus contribute to the burden of psychotic disorders. That LEs increase positive symptoms and decrease negative symptoms suggest at least two different mechanisms underlying the relationship between LEs and symptoms. Our findings underscore the need for increased symptom monitoring following negative LEs, as symptoms may worsen during that time.

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).

Understanding anxiety through uncertainty quantification.

Uncertainty has been a central concept in psychological theories of anxiety. However, this concept has been plagued by divergent connotations and operationalizations. The lack of consensus hinders the current search for cognitive and biological mechanisms of anxiety, jeopardizes theory creation and comparison, and restrains translation of basic research into improved diagnoses and interventions. Drawing upon uncertainty decomposition in Bayesian Decision Theory, we propose a well-defined conceptual structure of uncertainty in cognitive and clinical sciences, with a focus on anxiety. We discuss how this conceptual structure provides clarity and can be naturally applied to existing frameworks of psychopathology research. Furthermore, it allows formal quantification of various types of uncertainty that can benefit both research and clinical practice in the era of computational psychiatry.

Hallucination-Proneness is Associated With a Decrease in Robust Averaging of Perceptual Evidence.

BACKGROUND AND HYPOTHESIS: Hallucinations are characterized by disturbances in perceptual decision-making about environmental stimuli. When integrating across multiple stimuli to form a perceptual decision, typical observers engage in "robust averaging" by down-weighting extreme perceptual evidence, akin to a statistician excluding outlying data. Furthermore, observers adapt to contexts with more unreliable evidence by increasing this down-weighting strategy. Here, we test the hypothesis that hallucination-prone individuals (n = 38 high vs n = 91 low) would show a decrease in this robust averaging and diminished sensitivity to changes in evidence variance. STUDY DESIGN: We used a multielement perceptual averaging task to elicit dichotomous judgments about the "average color" (red/blue) of an array of stimuli in trials with varied strength (mean) and reliability (variance) of decision-relevant perceptual evidence. We fitted computational models to task behavior, with a focus on a log-posterior-ratio (LPR) model which integrates evidence as a function of the log odds of each perceptual option and produces a robust averaging effect. STUDY RESULTS: Hallucination-prone individuals demonstrated less robust averaging, seeming to weigh inlying and outlying extreme or untrustworthy evidence more equally. Furthermore, the model that integrated evidence as a function of the LPR of the two perceptual options and produced robust averaging showed poorer fit for the group prone to hallucinations. Finally, the weighting strategy in hallucination-prone individuals remained insensitive to evidence variance. CONCLUSIONS: Our findings provide empirical support for theoretical proposals regarding evidence integration aberrations in psychosis and alterations in the perceptual systems that track statistical regularities in environmental stimuli.

Modafinil's effects on cognition and sleep quality in affectively-stable patients with bipolar disorder: a pilot study.

Introduction: Despite advances in the treatment of bipolar disorder (BD), most patients do not achieve complete inter-episode recovery and functional disability is common. During periods of relative remission, many patients continue to experience neurocognitive dysfunction, reduced daytime activity levels, and sleep disturbances. This 8-week, randomized, placebo-controlled pilot study evaluated the feasibility, safety and preliminary efficacy of the wake-promoting drug, modafinil (Provigil®), on neurocognitive functioning, daytime sleepiness, and sleep quality in affectively-stable BD patients. Methods: Twelve individuals with affectively-stable BD were recruited and randomized to a flexible dose of modafinil (100 to 200 mg/day) or placebo, adjunctive to a therapeutic dose of a mood stabilizer. Weekly in-person visits tracked sleep quality and daytime sleepiness as well as side effects and mood symptoms. Neurocognitive functioning was assessed at baseline, week 4, and week 8. Results: No serious adverse events were reported. Newly emergent side effects in the modafinil group included heart palpitations, itching, fatigue, and decreased energy. Two patients discontinued modafinil owing to side effects and one of these patients withdrew from the study. One patient discontinued placebo and was withdrawn from the study. Preliminary evaluations of clinical efficacy showed a marginally significant interaction between treatment group and time in two cognitive domains (speed of processing and verbal learning), indicating greater improvement in the modafinil group versus placebo. Additionally, there was a marginally significant effect of treatment group on daytime sleepiness, suggesting lower daytime sleepiness in the modafinil group versus placebo. Counterintuitively, we found a significant treatment group by time interaction effect on sleep quality, suggesting greater improvement in sleep quality in the placebo group versus the modafinil group. Discussion: Results suggest that modafinil is a relatively safe medication for affectively-stable BD patients when given with adjunctive mood stabilizers. Results are suggestive of cognitive benefit and improved daytime sleepiness, but worse sleep quality in those patients prescribed modafinil. A fully powered clinical trial is warranted with specific attention to the characteristics of patients who are most likely to benefit from treatment with modafinil and other methodological lessons learned from this pilot. Clinical trial registration: ClinicalTrials.gov, identifier NCT01965925.

The association between mental health stigma and face emotion recognition in individuals at risk for psychosis.

Self-stigma has been associated with reduced accuracy of face emotion recognition in individuals at clinical high risk for psychosis (CHR). Stigma may also relate to slowing of performance during cognitive tasks for which a negative stereotype is relevant. This study aimed to investigate the association of mental illness stigma with face emotion recognition among CHR individuals. Participants were 143 CHR individuals identified using the Structured Interview for Psychosis-Risk Syndromes (SIPS). Face emotion recognition was assessed using the Penn Emotion Recognition Task (ER-40). Stigma was assessed using discrimination, stereotype awareness, and stereotype agreement subscales of the Mental Health Attitudes Interview for CHR. We tested associations of ER-40 accuracy and response times with these stigma variables, including the role of clinical and demographic factors. Racial/ethnic minoritized participants had higher attenuated positive symptoms than non-minoritized participants. Longer ER-40 response times were correlated with greater stereotype agreement (r=.17, p=.045) and discrimination (r=.22, p=.012). A regression model predicting ER-40 response times revealed an interaction of stereotype agreement with minoritized status (p=.008), with slower response times for minoritized participants as stereotype agreement increased. Greater disorganized symptoms and male gender also predicted longer response times. ER-40 accuracy was not associated with stigma. Overall, minoritized CHR individuals with greater internalized stigma took longer to identify face emotions. Future research is needed to assess whether slower response times are specific to social cues, and if internalized stigma interferes with performance in real-world social situations. Reducing stigma may be an important target for interventions that aim to improve social skills.

Pleasant and unpleasant odor identification ability is associated with distinct dimensions of negative symptoms transdiagnostically in psychotic disorders.

Negative symptoms are among the greatest sources of functional impairment for individuals with schizophrenia, yet their mechanisms remain poorly understood. Olfactory impairment is associated with negative symptoms. The processing of pleasant olfactory stimuli is subserved by reward-related neural circuitry while unpleasant olfactory processing is subserved by emotion-related neural circuitry, suggesting that these two odor dimensions may offer a window into differential mechanisms of negative symptoms. We examined whether pleasant and unpleasant odor identification bears differential relationships with avolition and inexpressivity dimensions of negative symptoms, whether these relationships are transdiagnostic, and whether pleasant and unpleasant odor processing also relate differently to other domains of functioning in a sample of individuals diagnosed with schizophrenia (N = 54), other psychotic disorders (N = 65), and never-psychotic adults (N = 160). Hierarchical regressions showed that pleasant odor identification was uniquely associated with avolition, while unpleasant odor identification was uniquely associated with inexpressivity. These relationships were largely transdiagnostic across groups. Additionally, pleasant and unpleasant odor identification displayed signs of specificity with other functional and cognitive measures. These results align with past work suggesting dissociable pathomechanisms of negative symptoms and provide a potential avenue for future work using valence-specific olfactory dysfunction as a semi-objective and low-cost marker for understanding and predicting the severity of specific negative symptom profiles.

Conspiratorial Thinking During COVID-19: The Roles of Paranoia, Delusion-Proneness, and Intolerance of Uncertainty.

The COVID-19 global pandemic has left many feeling a sense of profound uncertainty about their world, safety, and livelihood. Sources espousing misinformation and conspiracy theories frequently offer information that can help make sense of this uncertainty. Individuals high in intolerance of uncertainty (IU) may be particularly impacted by the impoverished epistemic environment and may thus be more drawn to conspiratorial thinking (CT). In the present work, we show across 2 studies (N = 519) that COVID-19-specific CT is associated with higher levels of IU as well as delusion-proneness, and paranoia. Furthermore, delusion-proneness and paranoia explained the relationship between IU and CT and emerged as independent partial correlates of CT even when controlling for other facets of schizotypy. In contrast, anxiety did not explain the relationship between IU and CT. Overall, our findings highlight the importance of individual differences in IU, delusion-proneness and paranoia in the development of CT in the context of the acute uncertainty of a global crisis, in which conspiracy theories are more prevalent and salient. Informational intervention designs may benefit from leveraging the body of work demonstrating the efficacy of targeting IU to incite meaningful changes in thinking.

Moral Cognition About Harm in Anxiety Disorders: The Importance of Experienced Emotion.

Recent work has shown that emotional arousal influences decision-making in sacrificial moral dilemmas, with heightened levels of arousal associated with increased aversion to committing moral transgressions to maximize utilitarian outcomes. Patients with anxiety disorders experience pathologically heightened states of arousal and thus may be expected to exhibit reduced utilitarian responding on such dilemmas. Extant evidence has been mixed, however, regarding whether anxious patients differ in their moral decisions from controls, and no study has conducted a careful examination of emotions experienced during decision-making. We administered sacrificial moral dilemmas to a cohort of 95 patients from across the spectrum of anxiety disorders to test whether they differed from matched controls on a) utilitarian decision-making, and b) ratings of experienced emotion during the moral deliberative process. Results showed no group differences between patients and controls on endorsement of utilitarian sacrificial action or on reported experience of emotionality during the experiment. Additionally, exploratory analysis revealed that specific emotions were correlated with utilitarian judgments. These results are in line with the Dual Process Theory model's prediction that decreased utilitarian responding will be concomitant with an increased emotional arousal. Our findings support past work indicating that moral cognition is intact in anxiety disorders despite the emotional dysregulation characteristic of anxious psychopathology. Future work would benefit from the use of process-dissociation techniques to further clarify whether emotional or cognitive processes may differ in anxiety disorders during moral cognition.

Mismatch negativity amplitude in first-degree relatives of individuals with psychotic disorders: Links with cognition and schizotypy.

Mismatch negativity (MMN) amplitude is reliably reduced in psychotic disorders. While several studies have examined this effect in first-degree relatives of individuals with schizophrenia, few have sought to quantify deficits in relatives of individuals with other psychotic disorders. While some conclude that, compared to healthy subjects, first-degree relatives of schizophrenia show reduced MMN, others contradict this finding. Furthermore, though MMN is often shown to be associated with cognitive impairments and clinical symptoms in psychotic disorders, to our knowledge no studies have sought to fully examine these relationships in studies of first-degree relatives. The present study sought to clarify the extent of MMN amplitude reductions in a large sample of siblings of individuals with diverse psychotic disorders (n = 67), compared to probands with psychosis (n = 221) and never psychotic comparison subjects (n = 251). We further examined associations of MMN amplitude with cognition and schizotypal symptoms across these groups. We found that MMN amplitude was intact in siblings compared to probands. MMN amplitude was associated with cognition and schizotypal symptoms dimensionally across levels of familial risk. The present results imply that MMN reductions do not reflect genetic risk for psychotic disorders per se, and instead emerge as a result of, or in conjunction with, clinical features associated with psychosis. Such findings carry important implications for the utility of MMN amplitude as an indicator of inherited risk, and suggest that this component may be best conceptualized as an endophenotype for clinical symptoms and cognitive impairments, rather than risk for psychosis per se.

Online Survey of the Impact of COVID-19 Risk and Cost Estimates on Worry and Health Behavior Compliance in Young Adults.

The novel coronavirus COVID-19 pandemic is associated with elevated rates of anxiety and relatively lower compliance with public health guidelines in younger adults. To develop strategies for reducing anxiety and increasing adherence with health guidelines, it is important to understand the factors that contribute to anxiety and health compliance in the context of COVID-19. Earlier research has shown that greater perceived risk of negative events and their costs are associated with increased anxiety and compliance with health behaviors, but it is unclear what role they play in a novel pandemic surrounded by uncertainty. In the present study we measured (1) perceived risk as the self-reported probability of being infected and experiencing serious symptoms due to COVID-19 and (2) perceived cost as financial, real-world, physical, social, and emotional consequences of being infected with COVID-19. Worry was assessed using the Penn State Worry Questionnaire (PWSQ) and health compliance was measured as endorsement of the World Health Organization (WHO) health directives for COVID-19. Our results showed that greater perceived risk and costs of contracting the COVID-19 virus were associated with greater worry and while only costs were associated with greater compliance with health behaviors. Neither self-reported worry nor its interaction with cost estimates was associated with increased engagement in health behaviors. Our results provide important insight into decision making mechanisms involved in both increased anxiety and health compliance in COVID-19 and have implications for developing psychoeducational and psychotherapeutic strategies to target both domains.

A molecular approach to treating cognition in schizophrenia by calcium channel blockade: An open-label pilot study of the calcium-channel antagonist isradipine.

Cognitive impairment is a prominent and difficult to treat symptom in schizophrenia (SZ), which is directly related to functional disability. A variant in the gene coding for the alpha 1C subunit of L-type voltage gated calcium channel (CACNA1C) has been shown to negatively affect several neurocognitive domains. We conducted a 4-week, open label, pilot study of isradipine, a calcium channel blocker, to determine its feasibility, safety, and efficacy in improving cognition in SZ patients. Ten adults with stable SZ were started on a flexible dose of isradipine 5 mg/day (up to 10 mg/day) for 4 weeks. Weekly in-person visits tracked side effects and symptoms while neurocognition and functional capacity were assessed at baseline and week 4. There were no serious adverse events reported. Newly emergent side effects were dizziness (1 new incidence at week 4); difficulty sleeping (2 new incidences at week 4); and decreased energy (3 new incidences at week 4). 1 patient discontinued medication and was withdrawn. Treatment did not exacerbate clinical symptoms. Although power is limited, results indicate no clear benefit on neurocognition but a positive effect (baseline mean = 6.8 ± 1.3 to week 4 mean = 7.9 ± 1.1; t = 2.91, p = 0.017) on functional capacity was noted. This open label, pilot study provides preliminary evidence that isradipine is a relatively safe medication when used adjunctively in SZ patients. This study suggests that isradipine offers no clear cognitive and only minimal functional benefit; however, additional studies may be warranted in symptomatic patients, or those with specific CACNA1C genotypes.

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.

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.