Publications by authors named "Elizabeth A Martin"

87 Publications

Calculating qualified non-mutagenic impurity levels: Harmonization of approaches.

Regul Toxicol Pharmacol 2021 Aug 4;126:105023. Epub 2021 Aug 4.

Gilead Sciences, Inc., Nonclinical Safety and Pathobiology, Foster City, CA, USA.

The presence of impurities in drugs is unavoidable. As impurities offer no direct benefit to the patient, it is critical that impurities do not compromise patient safety. Current guidelines on the derivation of acceptable impurity levels leave aspects of calculations open for interpretation, resulting in inconsistencies across industry and regulators. To understand current impurity qualification practices from a safety standpoint, regulatory expectations and the safety risk that impurities pose, the IQ DruSafe Impurities Working Group (WG) conducted a pharmaceutical industry-wide survey. Survey results highlighted areas that could benefit from harmonization, including nonclinical species/sex selection and the application of adjustment factors (i.e., body surface area). Recommendations for alignment on these topics is included in this publication. Additionally, the WG collated repeat-dose toxicity information for 181 starting materials and intermediates, reflective of pharmaceutical impurities, to understand the toxicological risks they generally pose in relation to the drug substance (DS) and the assumptions surrounding the calculation of qualified impurity levels. An evaluation of this dataset and the survey were used to harmonize how to calculate a safe limit for an impurity based on toxicology testing of the impurity when present within the DS.
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http://dx.doi.org/10.1016/j.yrtph.2021.105023DOI Listing
August 2021

Relations Among Anhedonia, Reinforcement Learning, and Global Functioning in Help-seeking Youth.

Schizophr Bull 2021 Jul 8. Epub 2021 Jul 8.

Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore, MD, USA.

Dysfunction in the neural circuits underlying salience signaling is implicated in symptoms of psychosis and may predict conversion to a psychotic disorder in youth at clinical high risk (CHR) for psychosis. Additionally, negative symptom severity, including consummatory and anticipatory aspects of anhedonia, may predict functional outcome in individuals with schizophrenia-spectrum disorders. However, it is unclear whether anhedonia is related to the ability to attribute incentive salience to stimuli (through reinforcement learning [RL]) and whether measures of anhedonia and RL predict functional outcome in a younger, help-seeking population. We administered the Salience Attribution Test (SAT) to 33 participants who met criteria for either CHR or a recent-onset psychotic disorder and 29 help-seeking youth with nonpsychotic disorders. In the SAT, participants must identify relevant and irrelevant stimulus dimensions and be sensitive to different reinforcement probabilities for the 2 levels of the relevant dimension ("adaptive salience"). Adaptive salience attribution was positively related to both consummatory pleasure and functioning in the full sample. Analyses also revealed an indirect effect of adaptive salience on the relation between consummatory pleasure and both role (αβ = .22, 95% CI = 0.02, 0.48) and social functioning (αβ = .14, 95% CI = 0.02, 0.30). These findings suggest a distinct pathway to poor global functioning in help-seeking youth, via impaired reward sensitivity and RL.
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http://dx.doi.org/10.1093/schbul/sbab075DOI Listing
July 2021

Development of the Thought Disorder Measure for the Hierarchical Taxonomy of Psychopathology.

Assessment 2021 May 28:10731911211015355. Epub 2021 May 28.

Stony Brook University, Stony Brook, NY, USA.

The Hierarchical Taxonomy of Psychopathology consortium aims to develop a comprehensive self-report measure to assess psychopathology dimensionally. The current research describes the initial conceptualization, development, and item selection for the thought disorder spectrum and related constructs from other spectra. The thought disorder spectrum is defined primarily by the positive and disorganized traits and symptoms of schizophrenia-spectrum disorders. The Thought Disorder Sub-Workgroup identified and defined 16 relevant constructs and wrote 10 to 15 items per each construct. These items were administered, along with detachment and mania items, to undergraduates and people with serious mental illness. Three hundred and sixty-five items across 25 scales were administered. An exploratory factor analysis of the scale scores suggested a two-factor structure corresponding to positive and negative symptoms for two samples. The mania scales loaded with the positive factor, while the detachment scales loaded with the negative factor. Item-level analyses resulted in 19 preliminary scales, including 215 items that cover the range of thought disorder pathology, and will be carried forward for the next phase of data collection/analysis.
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http://dx.doi.org/10.1177/10731911211015355DOI Listing
May 2021

Predicting Long-Term Outcomes in First-Admission Psychosis: Does the Hierarchical Taxonomy of Psychopathology Aid DSM in Prognostication?

Schizophr Bull 2021 Aug;47(5):1331-1341

Department of Psychiatry, Stony Brook University, Stony Brook, NY.

The Hierarchical Taxonomy of Psychopathology (HiTOP) is an empirical, dimensional model of psychological symptoms and functioning. Its goals are to augment the use and address the limitations of traditional diagnoses, such as arbitrary thresholds of severity, within-disorder heterogeneity, and low reliability. HiTOP has made inroads to addressing these problems, but its prognostic validity is uncertain. The present study sought to test the prediction of long-term outcomes in psychotic disorders was improved when the HiTOP dimensional approach was considered along with traditional (ie, DSM) diagnoses. We analyzed data from the Suffolk County Mental Health Project (N = 316), an epidemiologic study of a first-admission psychosis cohort followed for 20 years. We compared 5 diagnostic groups (schizophrenia/schizoaffective, bipolar disorder with psychosis, major depressive disorder with psychosis, substance-induced psychosis, and other psychoses) and 5 dimensions derived from the HiTOP thought disorder spectrum (reality distortion, disorganization, inexpressivity, avolition, and functional impairment). Both nosologies predicted a significant amount of variance in most outcomes. However, except for cognitive functioning, HiTOP showed consistently greater predictive power across outcomes-it explained 1.7-fold more variance than diagnoses in psychiatric and physical health outcomes, 2.1-fold more variance in community functioning, and 3.4-fold more variance in neural responses. Even when controlling for diagnosis, HiTOP dimensions incrementally predicted almost all outcomes. These findings support a shift away from the exclusive use of categorical diagnoses and toward the incorporation of HiTOP dimensions for better prognostication and linkage with neurobiology.
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http://dx.doi.org/10.1093/schbul/sbab043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8379532PMC
August 2021

The Canonical Wnt Signaling Pathway Inhibits the Glucocorticoid Receptor Signaling Pathway in the Trabecular Meshwork.

Am J Pathol 2021 06 8;191(6):1020-1035. Epub 2021 Mar 8.

Department of Ophthalmology, Eugene and Marilyn Glick Eye Institute, Indiana University School of Medicine, Indianapolis, Indiana; Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana. Electronic address:

Glucocorticoid-induced glaucoma is a secondary open-angle glaucoma. About 40% of the general population may develop elevated intraocular pressure on prolonged glucocorticoid treatment secondary to damages in the trabecular meshwork (TM), a tissue that regulates intraocular pressure. Therefore, identifying the key molecules responsible for glucocorticoid-induced ocular hypertension is crucial. In this study, Dickkopf-related protein 1 (Dkk1), a canonical Wnt signaling inhibitor, was found to be elevated in the aqueous humor and TM of glaucoma patients. At the signaling level, Dkk1 enhanced glucocorticoid receptor (GR) signaling, whereas Dkk1 knockdown or Wnt signaling activators decreased GR signaling in human TM cells as indicated by luciferase assays. Similarly, activation of the GR signaling inhibited Wnt signaling. At the protein level, glucocorticoid-induced extracellular matrix was inhibited by Wnt activation using Wnt activators or Dkk1 knockdown in primary human TM cells. In contrast, inhibition of canonical Wnt signaling by β-catenin knockdown increased glucocorticoid-induced extracellular matrix proteins. At the physiological level, adenovirus-mediated Wnt3a expression decreased glucocorticoid-induced ocular hypertension in mouse eyes. In summary, Wnt and GR signaling inhibit each other in the TM, and canonical Wnt signaling activators may prevent the adverse effect of glucocorticoids in the eye.
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http://dx.doi.org/10.1016/j.ajpath.2021.02.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8176142PMC
June 2021

Emotional context effects on memory accuracy for neutral information.

Cogn Emot 2021 06 20;35(4):774-789. Epub 2021 Jan 20.

Center for Healthy Minds, University of Wisconsin-Madison, Madison, WI, USA.

Despite decades of study, it remains unclear how emotional contexts influence memory for non-emotional information. In two studies, we previously found memory accuracy for neutral information encoded in an emotional context differed by valence. Specifically, neutral images encoded in a negative context were remembered with similar accuracy as those encoded in a non-emotional context, and neutral images encoded in a positive context were remembered with less accuracy than a non-emotional context. This Registered Report contains a third study to replicate our original results and allow for direct comparison between the negative and positive encoding conditions. People in the positive condition showed decreased memory accuracy, but this effect was very small in size and only significant when compared to the neutral condition. Given the lack of difference between negative and neutral conditions, effects of emotion on memory are not only a function of emotional arousal. At the same time, given the nonsignificant, small difference between positive and negative conditions, effects of emotion on memory are also not solely attributable to valence. This series of studies represents a step towards re-examining the tenet that emotion enhances memory unless the experience elicits sufficiently high arousal levels such that memory is impaired.
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http://dx.doi.org/10.1080/02699931.2021.1874880DOI Listing
June 2021

Comparability of social anhedonia across epidemiological dimensions: A multinational study of measurement invariance of the Revised Social Anhedonia Scale.

Psychol Assess 2021 Feb 22;33(2):171-179. Epub 2020 Oct 22.

Department of Psychological Science, University of California, Irvine.

Social anhedonia, or the loss of motivation in and pleasure from social engagement, is an important feature in understanding the etiology and outcome of various psychopathologies. While the Revised Social Anhedonia Scale (RSAS) represents one of the most commonly used self-report measures of social anhedonia, little is known regarding the construct comparability across populations. We examined measurement invariance of the full and brief RSAS in a diverse, international sample of 14,064 participants across nine epidemiological dimensions, including gender, age, ethnicity, education, community income, continent, migrant status, ethnic density, and urbanicity. Both the full and brief RSAS, as represented by a three-factor structure, achieved metric invariance for all dimensions. The full version showed considerable scalar noninvariance for ethnicity and continent, which was significantly reduced in the brief version. These findings suggest that while the scales measure the same construct across diverse groups, mean comparisons are only appropriate for the brief, and not the full, version. Future research may consider using the brief RSAS to ensure cross-national comparability. (PsycInfo Database Record (c) 2021 APA, all rights reserved).
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http://dx.doi.org/10.1037/pas0000972DOI Listing
February 2021

Changes in weight and BMI with first-line doravirine-based therapy.

AIDS 2021 01;35(1):91-99

Clinical Research, Merck & Co., Inc., Kenilworth, New Jersey, USA.

Objective: To evaluate changes in weight and BMI in adults with HIV-1 at 1 and 2 years after starting an antiretroviral regimen that included doravirine, ritonavir-boosted darunavir, or efavirenz.

Design: Post-hoc analysis of pooled data from three randomized controlled trials.

Methods: We evaluated weight change from baseline, weight gain at least 10%, and increase in BMI after 48 and 96 weeks of treatment with doravirine, ritonavir-boosted darunavir, or efavirenz-based regimens. Risk factors for weight gain and metabolic outcomes associated with weight gain were also examined.

Results: Mean (and median) weight changes were similar for doravirine [1.7 (1.0) kg] and ritonavir-boosted darunavir [1.4 (0.6) kg] and were lower for efavirenz [0.6 (0.0) kg] at week 48 but were similar across all treatment groups at week 96 [2.4 (1.5), 1.8 (0.7), and 1.6 (1.0) kg, respectively]. No significant differences between treatment groups were found in the proportion of participants with at least 10% weight gain or the proportion with BMI class increase at either time point. Low CD4 T-cell count and high HIV-1 RNA at baseline were associated with at least 10% weight gain and BMI class increase at both timepoints, but treatment group, age, sex, and race were not.

Conclusion: Weight gains over 96 weeks were low in all treatment groups and were similar to the average yearly change in adults without HIV-1. Significant weight gain and BMI class increase were similar across the treatment groups and were predicted by low baseline CD4 T-cell count and high baseline HIV-1 RNA.
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http://dx.doi.org/10.1097/QAD.0000000000002725DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7752237PMC
January 2021

Considerations when deriving compound-specific limits for extractables and leachables from pharmaceutical products: Four case studies.

Regul Toxicol Pharmacol 2020 Dec 7;118:104802. Epub 2020 Oct 7.

Faegre Drinker Biddle & Reath LLP, Washington, DC, USA.

Leachables from pharmaceutical container closure systems are a subset of impurities that present in drug products and may pose a risk to patients or compromise product quality. Extractable studies can identify potential leachables, and extractables and leachables (E&Ls) should be evaluated during development of the impurity control strategy. Currently, there is a lack of specific regulatory guidance on how to risk assess E&Ls; this may lead to inconsistency across the industry. This manuscript is a cross-industry Extractables and Leachables Safety Information Exchange (ELSIE) consortium collaboration and follow-up to Broschard et al. (2016), which aims to provide further clarity and detail on the conduct of E&L risk assessments. Where sufficient data are available, a health-based exposure limit termed Permitted Daily Exposure (PDE) may be calculated and to exemplify this, case studies of four common E&Ls are described herein, namely bisphenol-A, butylated hydroxytoluene, Irgafos® 168, and Irganox® 1010. Relevant discussion points are further explored, including the value of extractable data, how to perform route-to-route extrapolations and considerations around degradation products. By presenting PDEs for common E&L substances, the aim is to encourage consistency and harmony in approaches for deriving compound-specific limits.
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http://dx.doi.org/10.1016/j.yrtph.2020.104802DOI Listing
December 2020

Pathologic Hip Fracture by Virtue of a Rare Osseous Manifestation of Gout: A Case Report.

JBJS Case Connect 2020 Jul-Sep;10(3):e2000231

1Department of Orthopaedic Surgery, University of Pennsylvania, Philadelphia, Pennsylvania 2Department of Orthopaedic Surgery, Lahey Hospital & Medical Center, Burlington, Massachusetts 3Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 4Department of Anatomic Pathology, Lahey Hospital & Medical Center, Burlington, Massachusetts 5Department of Orthopaedic Surgery, Brigham & Women's Hospital, Boston, Massachusetts.

Case: A 76-year-old woman without a personal or family history of gout presented with complaints of left hip pain after a mechanical fall from her wheelchair. Advanced imaging revealed a nonspecific lesion and nondisplaced fracture of the femoral neck. Intraoperative biopsy from the lesion/fracture demonstrated tophaceous gout.

Conclusion: Fractures resulting from osseous manifestations of the gout are rare with this report describing a hip fracture secondary to tophaceous gout. We emphasize the importance of including this potential etiology in the differential diagnosis of elderly patients presenting with hip pain, with or without a known history of gout.
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http://dx.doi.org/10.2106/JBJS.CC.20.00231DOI Listing
April 2021

Effects of a monocarboxylate transport 1 inhibitor, AZD3965, on retinal and visual function in the rat.

Br J Pharmacol 2020 10 13;177(20):4734-4749. Epub 2020 Sep 13.

Regulatory Safety Centre of Excellence, Clinical Pharmacology & Safety Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK.

Background And Purpose: Inhibition of monocarboxylate transport 1 (MCT1) is of interest in targeting highly glycolytic tumours. However, MCT1 is expressed in retina, and so inhibition of MCT1 could affect retinal function.

Experimental Approach: AZD3965, an MCT1 inhibitor selected for clinical development, and two additional MCT1 inhibitors were evaluated for effects on visual acuity in albino (Han Wistar) rats. The effects of AZD3965 on visual acuity and electroretinography (ERG) were further investigated in pigmented (Long-Evans) rats, with dosing for up to 7 days.

Key Results: All three MCT1 inhibitors reduced visual acuity within 2 h of dosing, suggesting a class effect. The deficit caused by AZD3965 (1,000 mg·kg p.o. per day for 4 days) in Long Evans rats recovered to pre-dose levels 7 days after cessation of dosing. AZD3965 (50 to 1,000 mg·kg p.o.) reduced the amplitude of scotopic a- and b-waves, and photopic b-wave of the ERG in a dose-related fashion, within 2 h of dosing. The effects on the scotopic ERG had diminished by Day 7 of dosing, demonstrating partial restoration of function despite continued treatment. Seven days after cessation of dosing at the highest dose tested (1,000 mg·kg ), there was recovery of both scotopic a- and b- waves and, to a lesser extent, photopic b-wave. ERG was affected at lower plasma exposures than was visual function.

Conclusions And Implications: This study clarifies the role of the MCT1 transporter in retinal function. The monitorability of the functional effects on the retina enabled safe clinical use of AZD3965.
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http://dx.doi.org/10.1111/bph.15239DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7520442PMC
October 2020

Neurobiology and the Hierarchical Taxonomy of Psychopathology: progress toward ontogenetically informed and clinically useful nosology
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Dialogues Clin Neurosci 2020 03;22(1):51-63

Department of Psychology, Vanderbilt University, Nashville, Tennessee, US .

The Hierarchical Taxonomy of Psychopathology (HiTOP) is an empirical structural model of psychological symptoms formulated to improve the reliability and validity of clinical assessment. Neurobiology can inform assessments of early risk and intervention strategies, and the HiTOP model has greater potential to interface with neurobiological measures than traditional categorical diagnoses given its enhanced reliability. However, one complication is that observed biological correlates of clinical symptoms can reflect various factors, ranging from dispositional risk to consequences of psychopathology. In this paper, we argue that the HiTOP model provides an optimized framework for conducting research on the biological correlates of psychopathology from an ontogenetic perspective that distinguishes among indicators of liability, current symptoms, and consequences of illness. Through this approach, neurobiological research can contribute more effectively to identifying individuals at high dispositional risk, indexing treatment-related gains, and monitoring the consequences of mental illness, consistent with the aims of the HiTOP framework.
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http://dx.doi.org/10.31887/DCNS.2020.22.1/eperkinsDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7365294PMC
March 2020

What you want may not be what you like: A test of the aberrant salience hypothesis in schizophrenia risk.

Cogn Affect Behav Neurosci 2020 08;20(4):873-887

Department of Psychological Science, 4201 Social and Behavioral Sciences Gateway, University of California, Irvine, CA, 92697-7085, USA.

Motivational abnormalities represent a key area of dysfunction in individuals with, or at risk for, schizophrenia and severely limit broad domains of functioning in these populations. The aberrant salience hypothesis posits that motivational abnormalities are the result of an over-attribution of salience to nonpleasurable stimuli but an under-attribution of salience to pleasurable ones. Consequently, people "want" what they do not "like" but do not "want" what they "like." However, it is unclear how this hypothesis manifests in schizophrenia risk beyond monetary rewards. The current research provided a multimodal investigation of the aberrant salience hypothesis in people with elevated psychotic-like experiences (PLEs) who are at risk for developing psychosis. Study 1 examined the link between liking and incentive salience using a neurobiological indicator of incentive salience (contingent negative variation/CNV) in 23 PLEs and 21 Control participants. The PLEs group showed diminished CNV reactivity to pleasant (vs. neutral) social images, which was driven by an augmented response to neutral stimuli. Study 2 examined liking, incentive salience, and conscious wanting experience using a psychological indicator of incentive salience (positive spontaneous thoughts/PSTs) in 38 PLEs and 246 Control participants. The PLEs group showed diminished correspondence between liking, PSTs, and conscious wanting across diverse reward contexts. Collectively, individuals with PLEs over-attribute salience to neutral stimuli and, to a lesser degree, under-attribute salience to rewards. Findings of the current research support abnormal salience attribution as a trait-like feature implicated in the pathophysiology and development of schizophrenia and provide valuable insights on research and treatment of this illness.
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http://dx.doi.org/10.3758/s13415-020-00807-3DOI Listing
August 2020

Schizotypy dimensions are associated with altered resting state alpha connectivity.

Int J Psychophysiol 2020 09 26;155:175-183. Epub 2020 Jun 26.

Department of Psychological Science, University of California, Irvine, Irvine, CA, USA. Electronic address:

The disconnection hypothesis of schizophrenia says that symptoms are explained by dysfunctional connections across a wide range of brain networks. Despite some support for this hypothesis, there have been mixed findings. One reason for these may be the multidimensional nature of schizophrenia symptoms. In order to clarify the relationship between symptoms and brain networks, the current study included individuals at risk for schizophrenia-spectrum disorders who either report extreme levels of positive schizotypy traits (perceptual aberrations and magical ideation, or "PerMag"; n = 23), or an extreme negative schizotypy trait (social anhedonia, or "SocAnh"; n = 19), as well as a control group (n = 18). Resting-state alpha electroencephalography was collected, and functional networks for each subject were measured using the phase-lag index to calculate the connectivity between channel pairs based on the symmetry of instantaneous phase differences over time. Furthermore, graph theory measures were introduced to identify network features exclusive to schizotypy groups. We found that the PerMag group exhibited a smaller difference in node strength and clustering coefficient in frontal/occipital and central/occipital regional comparisons compared to controls, suggesting a more widespread network. The SocAnh group exhibited a larger difference in degree in the central/occipital regional comparison relative to controls, suggesting a localized occipital focus in the connectivity network. Regional differences in functional connectivity suggest that different schizotypy dimensions are manifested at the network level by different forms of disconnections. Taken together, these findings lend further support to the disconnection hypothesis and suggest that altered connectivity networks may serve as a potential biomarker for schizophrenia risk.
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http://dx.doi.org/10.1016/j.ijpsycho.2020.06.012DOI Listing
September 2020

Electrophysiological responses to images ranging in motivational salience: Attentional abnormalities associated with schizophrenia-spectrum disorder risk.

Sci Rep 2020 03 12;10(1):4578. Epub 2020 Mar 12.

Department of Psychological Science, University of California, Irvine, Irvine, California, USA.

Individuals at risk for schizophrenia-spectrum disorders display abnormalities related to motivational salience, or the ability of stimuli to elicit attention due to associations with rewards or punishments. However, the nature of these abnormalities is unclear because most focus on responses to stimuli from broad "pleasant" and "unpleasant" categories and ignore the variation of motivational salience within these categories. In two groups at risk for schizophrenia-spectrum disorders-a Social Anhedonia group and a Psychotic-like Experiences group-and a control group, the current study examined event-related potential components sensitive to motivational salience-the Early Posterior Negativity (EPN), reflecting earlier selective attention, and the Late Positive Potential (LPP), reflecting sustained attention. Compared to controls, the Social Anhedonia group showed smaller increases in the EPN in response to erotica and smaller increases in the LPP as the motivational salience of pleasant images increased (exciting
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http://dx.doi.org/10.1038/s41598-020-61504-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7067785PMC
March 2020

Differential item functioning of the Multidimensional Schizotypy Scale and Multidimensional Scale-Brief across ethnicity.

Psychol Assess 2020 Apr 16;32(4):383-393. Epub 2020 Jan 16.

Department of Psychology.

Schizotypy refers to traits or symptoms similar to schizophrenia, but in a diminished form, and schizotypy is thought to reflect a liability for the future development of schizophrenia. The Multidimensional Schizotypy Scale (MSS) is a new measure of schizotypy that improves on existing measures. The MSS contains full and brief subscales for positive, negative, and disorganized schizotypy. Although MSS scores have been validated in a variety of populations, the scales have not been thoroughly examined for differential item functioning in East Asian, Southeast Asian, Hispanic, Multiracial, and White participants. The current study included 567 East Asian, 351 Southeast Asian, 360 Hispanic, 230 Multiracial, and 345 White undergraduate participants from the United States. Overall, few of the items in the full or brief versions of the scales displayed differential item functioning across groups. The full and brief versions of the scales also displayed similar and not-significantly different validity coefficients with the Detachment and Psychoticism scales of the Personality Inventory for . These findings suggest that the MSS measures the same constructs across ethnic groups, and the scale scores represent the same latent level of schizotypy among groups. Future research may use the MSS in these diverse groups without concern that the psychometric properties differ significantly among groups. (PsycInfo Database Record (c) 2020 APA, all rights reserved).
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http://dx.doi.org/10.1037/pas0000798DOI Listing
April 2020

Affective forecasting in individuals with social anhedonia: The role of social components in anticipated emotion, prospection and neural activation.

Schizophr Res 2020 01 11;215:322-329. Epub 2019 Oct 11.

Neuropsychology and Applied Cognitive Neuroscience Laboratory, CAS Key Laboratory of Mental Health, Institute of Psychology, Chinese Academy of Sciences, 16 Lincui Road, Beijing, 100101, China; Department of Psychology, University of Chinese Academy of Sciences, No.19(A) Yuquan Road, Shijingshan District, Beijing, 100049, China; Sino-Danish College, University of Chinese Academy of Sciences, 380 Huaibeizhuang, Huairou District, Beijing, 101407, China. Electronic address:

Background: Affective forecasting, or the ability to forecast emotional responses to future events, is essential to everyday life adaption. Previous research suggests that individuals with social anhedonia exhibit deficits in affective forecasting, but the pattern of these deficits and their neural correlates are not known.

Methods: Individuals with social anhedonia (n = 40) and healthy controls (n = 46) completed a social affective forecasting task and underwent resting-state fMRI scanning.

Results: Compared with healthy controls, social anhedonia individuals anticipated reduced pleasure especially in social conditions and their prospection contained less visualization, voice, taste, self-referential thoughts, other-referential thoughts and language communication. Moreover, anticipated pleasure (valence and arousal for positive events) was positively associated with effort level, especially in social conditions. The social anhedonia group also exhibited stronger functional connectivity between the retrosplenial cortex and the insula and reduced functional connectivity between the hippocampal formation and the parahippocampus. These altered functional connectivities were correlated with anticipated valence in social, but not non-social, conditions.

Conclusions: These findings suggest that individuals with social anhedonia anticipate less pleasure predominately in social conditions and impaired prospection may contribute to the reduced anticipated pleasure. Reduced anticipated pleasure may be a target to improve social motivation in social anhedonia individuals.
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http://dx.doi.org/10.1016/j.schres.2019.10.006DOI Listing
January 2020

Late electrophysiological potentials and emotion in schizophrenia: A meta-analytic review.

Schizophr Res 2019 09 17;211:21-31. Epub 2019 Jul 17.

University of California, Irvine, United States of America. Electronic address:

Introduction: There is mixed evidence about emotional processing abnormalities in schizophrenia and schizoaffective disorder, with self-reports and clinician ratings indicating significant differences between patients and controls, but studies of in-the-moment, self-reported emotional experience finding only small differences between these groups. The current meta-analysis synthesizes statistics from studies measuring the P3 and LPP, two event-related potential (ERP) components sensitive to attentional allocation, to examine whether patients exhibit ERP response abnormalities to neutral and valenced visual stimuli.

Methods: Standardized mean amplitudes and standard errors of P3 and/or LPP waveforms (300-2000 ms) in response to neutral and valenced images were calculated for 13 studies (total n = 339 individuals with schizophrenia, 331 healthy controls).

Results: In response to neutral images, there were very small, non-significant differences in ERP amplitudes between patient and control groups (k = 9; Hedges' g = -0.06, 95% CI: -055, 0.43, p = 0.81). In contrast, patients showed a small, significant reduction in ERP amplitudes compared to controls in response to negative images (k = 13; Hedges' g = -0.32, 95% CI: -0.59, -0.05, p = 0.02) and a small, but nonsignificant, reduction in amplitudes in response to positive images (k = 7; Hedges' g = -0.27, 95% CI: -0.71, 0.18, p = 0.24).

Conclusions And Implications: The current review indicates that compared to controls, patients have slightly diminished P3 and LPP amplitudes in response to positive and negative stimuli. This small reduction may reflect decreased attention allocation, possibly indicating an abnormality during a distinct stage of early processing related to evaluating the motivational salience of a stimulus.
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http://dx.doi.org/10.1016/j.schres.2019.07.013DOI Listing
September 2019

Explicit and Implicit Affect and Judgment in Schizotypy.

Front Psychol 2019 1;10:1491. Epub 2019 Jul 1.

Department of Psychological Sciences, University of Missouri, Columbia, MO, United States.

Although emotion deficits in schizotypy have been reported, the exact nature of these deficits is now well understood. Specifically, for social anhedonia (SocAnh), there are questions about whether any decrease in positive affect only reflects an explicit bias not observed in other measures (e.g., implicit affect measure). At the same time, for individuals with elevated levels of perceptual aberrations or magical ideation (PerMag), there is some evidence of an increased influence of affect on judgment. It is also possible that the influence of implicit affect on judgment might be especially pronounced in PerMag; however, this has not been previously examined. The current study involved people with elevated levels of SocAnh ( = 95), elevated levels of PerMag ( = 62), and people with average or lower levels of both ( = 246). We found that SocAnh was associated with decreases in both explicit and implicit positive affect. We also found that PerMag was related to stronger relationships between implicit affect, both positive and negative, and a judgment task. These results suggest that decreased positive affect is a core feature of SocAnh and that a heightened influence of affect could be related to the development of peculiar beliefs/experiences associated with PerMag.
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http://dx.doi.org/10.3389/fpsyg.2019.01491DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6613436PMC
July 2019

Affective forecasting and accuracy in social anhedonia: Predicted and experienced emotion for a social interaction.

J Clin Psychol 2019 09 6;75(9):1684-1700. Epub 2019 May 6.

Department of Psychological Science, University of California, Irvine, California.

Objective: Previous research suggests people with social anhedonia (SocAnh) exhibit deficits in anticipated pleasure for social stimuli relative to controls. However, previous research has relied on hypothetical social stimuli and has focused on anticipated pleasure without examining negative affect.

Method: Participants were informed that they would complete an "enjoyable" sharing task with a peer and were asked to forecast positive and negative affect during the interaction. After the interaction, participants reported their experienced emotions.

Results: We found SocAnh and controls anticipated and experienced similar levels of positive affect and that both groups underpredicted positive affect. The SocAnh group anticipated and experienced more negative affect than controls and was more accurate in forecasting negative affect.

Conclusion: This is the first study to show that SocAnh is associated with the heightened anticipation of negative affect and that experiencing heightened negative affect during social interactions could drive reduced motivation and desire to engage in future social interaction.
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http://dx.doi.org/10.1002/jclp.22796DOI Listing
September 2019

Reply to Lanzafame et al.

Clin Infect Dis 2019 10;69(10):1832-1833

Ambrose King Centre, Royal London Hospital, Barts Health National Health Service Trust, UK.

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http://dx.doi.org/10.1093/cid/ciz229DOI Listing
October 2019

Emotional response in schizophrenia to the "36 questions that lead to love": Predicted and experienced emotions regarding a live social interaction.

PLoS One 2019 27;14(2):e0212069. Epub 2019 Feb 27.

Department of Psychological Science, University of California, Irvine, Irvine, CA, United States of America.

Evidence suggests that individuals with schizophrenia (SZ) report anticipatory pleasure deficits compared to controls and that these deficits are linked to decreased motivation to engage socially. However, these deficits have been identified via self-report measures of hypothetical pleasant stimuli, leaving it unclear whether they exist in reference to actual social situations. To address this issue, we created a live social interaction that minimized the reliance of higher-order cognitive processes. SZ and control participants were told that they would be playing an "enjoyable sharing game" with another study participant (who was actually a confederate) that involved asking and answering questions (36 interpersonal closeness generation questions; Aron et al., 1997). Participants then reported their current mood and the emotions they anticipated experiencing during the pleasant social interaction. Immediately following the interaction, they reported their experienced emotions. We found that the SZ group anticipated more negative emotion (d = 1.0), but were less accurate in forecasting negative emotion (d = .81), than controls, and these effects were large. There were small, non-significant group differences in anticipation, experience, and accuracy in forecasting of positive emotion (all ds < .29). Also, social anhedonia was positively correlated with anticipated negative affect and negatively associated with experienced positive emotion. At the same time, controls reported finding the interaction to be a more positive emotional experience overall, d = 0.75. This is the first study to show that "anticipatory pleasure deficits" in SZ might actually be heightened anticipated negative emotion and that inaccurate forecasting could be linked to decreased social motivation.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0212069PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6392255PMC
November 2019

The subjective-objective deficit paradox in schizotypy extends to emotion regulation and awareness.

J Psychiatr Res 2019 04 31;111:160-168. Epub 2019 Jan 31.

Department of Psychological Science, University of California, Irvine, Irvine, CA, USA. Electronic address:

There is an emerging subjective-objective deficit paradox in schizotypy. Individuals with schizotypy report severe subjective complaints in several key functional domains commensurate with that of individuals with schizophrenia. However, objective assessments of the same domains show relatively intact performance. We examined whether this subjective-objective deficit paradox extends to two closely linked affective processes: emotion regulation and awareness. Individuals with elevated social anhedonia (SocAnh; n = 61) and elevated perceptual aberration/magical ideation (PerMag; n = 73) were compared to control participants (n = 81) on subjective and objective measures of emotion regulation and awareness. Subjective measures included self-report questionnaires assessing regulatory ability, attention to emotion, and emotional clarity. Implicit emotion regulation was assessed by the Emotion Regulation-Implicit Association Test (ER-IAT) while objective emotional awareness was assessed by the Levels of Emotional Awareness Scale (LEAS), a performance-based test. Results showed that both SocAnh and PerMag groups reported notable deficits in almost all subjective measures relative to controls (composite ds > 0.55). In contrast, performance on ER-IAT and LEAS was very similar to controls (composite ds < 0.11). The current study suggests that the subjective-objective deficit paradox extends to emotion regulation and awareness, highlighting the importance of higher-order cognitive bias in understanding emotional abnormalities in schizotypy.
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http://dx.doi.org/10.1016/j.jpsychires.2019.01.026DOI Listing
April 2019

Differential emotional abnormalities among schizotypy clusters.

Schizophr Res 2019 06 4;208:285-292. Epub 2019 Feb 4.

Department of Psychological Science, University of California, Irvine, Irvine, CA, USA. Electronic address:

Schizotypy, a multidimensional personality organization that reflects liability to develop schizophrenia-spectrum disorders, has been associated with a number of emotional abnormalities. Yet, the exact nature of any emotional abnormalities in schizotypy is relatively unclear. Using an ethnically diverse nonclinical sample (N = 2637), the present study identified homogenous clusters of individuals based on positive and negative schizotypy dimensions and explored three interrelated domains of emotion traits closely tied to functional outcomes and quality of life: affective experience, emotional awareness, and meta-level emotions. Consistent with prior research, four schizotypy clusters were obtained: low ("nonschizotypic"), high positive, high negative, and mixed (high positive and high negative). Regarding emotion correlates of schizotypy clusters, the mixed cluster was found to be the most deviant on almost all emotion traits (e.g., heightened trait negative affect, diminished emotional clarity), suggesting that the effects of positive and negative schizotypy are additive. In addition, positive and negative schizotypy clusters were associated with differential abnormalities, with the negative cluster presenting a wider range of, and more severe, impairments compared to the low cluster (e.g., reduced trait positive affect and reduced attention to positive emotion). The current study highlights the heterogeneity in emotional traits among schizotypy dimensions and the importance of studying the mixed schizotypy in terms of emotional dysfunction.
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http://dx.doi.org/10.1016/j.schres.2019.01.042DOI Listing
June 2019

Doravirine/Lamivudine/Tenofovir Disoproxil Fumarate is Non-inferior to Efavirenz/Emtricitabine/Tenofovir Disoproxil Fumarate in Treatment-naive Adults With Human Immunodeficiency Virus-1 Infection: Week 48 Results of the DRIVE-AHEAD Trial.

Clin Infect Dis 2019 02;68(4):535-544

Merck Sharp & Dohme, a subsidiary of Merck & Co., Inc., Kenilworth, New Jersey.

Background: Doravirine (DOR), a novel non-nucleoside reverse-transcriptase inhibitor (NNRTI), is active against wild-type Human Immunodeficiency Virus (HIV)-1 and the most common NNRTI-resistant variants, and has a favorable and unique in vitro resistance profile.

Methods: DRIVE-AHEAD is a phase 3, double-blind, non-inferiority trial. Antiretroviral treatment-naive adults with ≥1000 HIV-1 RNA copies/mL were randomized (1:1) to once-daily, fixed-dose DOR at 100 mg, lamivudine at 300 mg, and tenofovir disoproxil fumarate (TDF) at 300 mg (DOR/3TC/TDF) or to efavirenz at 600 mg, emtricitabine at 200 mg, and TDF at 300 mg (EFV/FTC/TDF) for 96 weeks. The primary efficacy endpoint was the proportion of participants with <50 HIV-1 RNA copies/mL at week 48 (Food and Drug Administration snapshot approach; non-inferiority margin 10%).

Results: Of the 734 participants randomized, 728 were treated (364 per group) and included in the analyses. At week 48, 84.3% (307/364) of DOR/3TC/TDF recipients and 80.8% (294/364) of EFV/FTC/TDF recipients achieved <50 HIV-1 RNA copies/mL (difference 3.5%, 95% CI, -2.0, 9.0). DOR/3TC/TDF recipients had significantly lower rates of dizziness (8.8% vs 37.1%), sleep disorders/disturbances (12.1% vs 25.2%), and altered sensorium (4.4% vs 8.2%) than EFV/FTC/TDF recipients. Mean changes in fasting low-density lipoprotein cholesterol (LDL-C) and non-high-density lipoprotein cholesterol (non-HDL-C) were significantly different between DOR/3TC/TDF and EFV/FTC/TDF (-1.6 vs +8.7 mg/dL and -3.8 vs +13.3 mg/dL, respectively).

Conclusions: In HIV-1 treatment-naive adults, DOR/3TC/TDF demonstrated non-inferior efficacy to EFV/FTC/TDF at week 48 and was well tolerated, with significantly fewer neuropsychiatric events and minimal changes in LDL-C and non-HDL-C compared with EFV/FTC/TDF.

Clinical Trials Registration: NCT02403674.
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http://dx.doi.org/10.1093/cid/ciy540DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6355823PMC
February 2019

Timing matters in elaborative processing of positive stimuli: Gamma band reactivity in schizophrenia compared to depression and healthy adults.

Schizophr Res 2019 02 16;204:111-119. Epub 2018 Aug 16.

Biometrics Research Program, Pittsburgh, PA 15213, United States of America.

Some individuals with schizophrenia report similar feelings of positive affect "in the moment" compared to control participants but report decreased trait positive affect overall. One possible explanation for this disconnection between state and trait positive affect is the extent to which individuals with schizophrenia engage in elaborative processing of positive stimuli. To assess this, we examined evoked gamma band activity in response to positive words over several seconds in a group with schizophrenia, a group with major depressive disorder, and a healthy control group. From a pre-stimulus baseline to 2000 ms after onset of the stimulus (henceforth, "early period"), the schizophrenia group showed a reliable increase in gamma activity compared to both the control and depressed groups, who did not differ from each other. In contrast, the depressed group showed a reliable increase in gamma activity from 2001 to 8000 ms (henceforth, "late period") compared to the other groups, who did not differ from each other. At the same time, the schizophrenia group showed a reliable decrease from the early to late period while the depressed group showed the opposite pattern. In addition, self-reported depression and social anhedonia in the schizophrenia group were related to decreased gamma band activity over the entire processing window. Overall, these results suggest that schizophrenia is associated with increased initial reactivity but decreased sustained elaborative processing over time, which could be related to decreased trait positive affect. The results also highlight the importance of considering depressive symptomology and anhedonia when examining emotional abnormalities in schizophrenia.
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http://dx.doi.org/10.1016/j.schres.2018.08.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6377351PMC
February 2019

ERP indices of performance monitoring and feedback processing in psychosis: A meta-analysis.

Int J Psychophysiol 2018 10 10;132(Pt B):365-378. Epub 2018 Aug 10.

VA Greater Los Angeles Healthcare System, United States of America; Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, United States of America.

Background: Although individuals with, or at risk for, psychotic disorders often show difficulties with performance monitoring and feedback processing, findings from studies using event-related potentials (ERPs) to index these processes are not consistent. This meta-analytic review focused on studies of two different indexes of performance monitoring, the early error-related negativity (ERN; n = 25) and the later error positivity (Pe; n = 17), and one index of feedback processing, the feedback negativity (FN; n = 6).

Methods: We evaluated whether individuals (1) with psychotic disorders, or (2) at heightened risk for these disorders differ from healthy controls in available studies of the ERN, Pe, and FN.

Results: There was a significant, large ERN reduction in those with psychosis (g = -0.96) compared to controls, and a significant, moderate ERN reduction in those at-risk (g = -0.48). In contrast, there were uniformly non-significant, small between-group differences for Pe and FN (gs ≤ |0.16|).

Conclusions: The results reveal a differential pattern of impairment in psychosis. Early performance monitoring (ERN) impairments are substantial among those with psychotic disorders in general and may be a useful vulnerability indicator for these disorders. However, later performance monitoring (Pe) and basic feedback processing (FN) appear to be relatively spared in psychosis.
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http://dx.doi.org/10.1016/j.ijpsycho.2018.08.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6157731PMC
October 2018

Mental stress peripheral vascular reactivity is elevated in women with coronary vascular dysfunction: Results from the NHLBI-sponsored Cardiac Autonomic Nervous System (CANS) study.

Int J Cardiol 2018 Jan 22;251:8-13. Epub 2017 Oct 22.

Barbra Streisand Women's Heart Center, Cedars-Sinai Heart Institute, Los Angeles, CA, United States.

Background: Women with chest pain, ischemia, and no obstructive coronary artery disease often have coronary vascular dysfunction (CVaD). Peripheral vascular reactivity to mental stress may contribute mechanistic understanding of stress-induced ischemia in women with CVaD.

Methods: 62 women (41 CVaD and 21 controls) underwent mental stress testing (MST) with anger recall, mental arithmetic, and forehead cold pressor (COP) challenge. Emotional arousal was measured (Likert scale). Reactive hyperemia index (RHI) was calculated before and after MST by peripheral arterial tonometry (PAT). Stress PAT ratio (SPR) of pulse amplitude during stress to rest was obtained to measure vasoconstriction. Wilcoxson rank sum test was used for analysis.

Results: Mean age of CVaD and control groups was 58±9 and 55±10years (p=0.73). Baseline RHI correlated with coronary endothelial function (r=0.36, p=0.03) and inversely with RHI change post-MST (r=-0.51, p<0.001). During MST, 10% of controls reported chest pain vs. 41% of CVaD subjects (p=0.01). RHI did not change significantly after MST in either group. CVaD subjects had lower SPR vs. controls during mental arithmetic (0.54 [0.15, 1.46] vs. 0.67 [0.36, 1.8], p=0.039), not evident in the other tasks. Vasoconstriction inversely correlated with anxiety (r=-3.4, p=0.03), frustration (r=-0.37, p=0.02), and feeling challenged (r=-0.37, p=0.02) in CVaD but not controls.

Conclusions: Mental stress peripheral vascular reactivity is elevated in women with CVaD compared to controls. Elevated vascular reactivity may be one contributor to stress-induced chest pain in CVaD. Interventions that modulate vasoconstrictive responses may be of benefit and should be tested in clinical trials in women with CVaD.
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http://dx.doi.org/10.1016/j.ijcard.2017.10.061DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5870901PMC
January 2018

Differential Item Functioning of the Full and Brief Wisconsin Schizotypy Scales in Asian, White, Hispanic, and Multiethnic Samples and Between Sexes.

Assessment 2019 09 14;26(6):1001-1013. Epub 2017 Jul 14.

1 University of Hawai'i at Manoa, Honolulu, HI, USA.

The Wisconsin Schizotypy Scales, including their brief versions, are among the most commonly used self-report measures of schizotypy. Although they have been used extensively in many ethnic groups, few studies have examined their differential item functioning (DIF) across groups. The current study included 1,056 Asian, 408 White, 476 Multiethnic, and 372 Hispanic undergraduates. Unidimensional models of the brief Magical Ideation Scale and Perceptual Aberration Scales fit the data well. For both scales, global tests of measurement invariance provided mixed evidence, but few of the items displayed DIF across ethnicities or between sexes within a multiple indicator multiple causes model. For the full versions of the scales and the brief Revised Social Anhedonia Scale, multiple indicator multiple causes models within an exploratory structural equation modeling framework found that few of the items had DIF. These findings suggest that some of the items may have different psychometric properties across groups, but most items do not.
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http://dx.doi.org/10.1177/1073191117719509DOI Listing
September 2019

Emotional word usage in groups at risk for schizophrenia-spectrum disorders: An objective investigation of attention to emotion.

Psychiatry Res 2017 06 22;252:29-37. Epub 2017 Feb 22.

Department of Psychology and Social Behavior, University of California, Irvine, Irvine, CA, USA. Electronic address:

Both extreme levels of social anhedonia (SocAnh) and extreme levels of perceptual aberration/magical ideation (PerMag) indicate increased risk for schizophrenia-spectrum disorders and are associated with emotional deficits. For SocAnh, there is evidence of self-reported decreased trait positive affect and abnormalities in emotional attention. For PerMag, there is evidence of increased trait negative affect and increased attention to negative emotion. Yet, the nature of more objective emotional abnormalities in these groups is unclear. The goal of this study was to assess attention to emotions more objectively in a SocAnh, PerMag, and control group by using a positive (vs. neutral) mood induction procedure followed by a free writing period. Linguistic analyses revealed that the SocAnh group used fewer positive emotion words than the control group, with the PerMag group falling in between the others. In addition, both at-risk groups used more negative emotion words than the control group. Also, for the control group only, those in the positive mood induction used more positive emotion words, suggesting their emotions influenced their linguistic expression. Overall, SocAnh is associated with decreased positive emotional expression and at-risk groups are associated with increased negative emotional expression and a decreased influence of emotions on linguistic expression.
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http://dx.doi.org/10.1016/j.psychres.2017.01.098DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5438895PMC
June 2017
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