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    Too Much of a Good Thing? Detrimental Health Effects Linked to Environmental Lithium Exposure through Drinking Water
    (The American Psychiatric Association, 2024) Patterson, Andrea; Bartlett, Zane; Fisher, Sarah; Stumpff, Julia C.; Schwab, Rebecca; Unfried, Gregory
    For centuries, people have made pilgrimages to lithium springs in search of better health. In modern times, relatively high levels of lithium in drinking water are linked to lower suicide and homicide rates as well as possible neuroprotective benefits. However, with increased mining of lithium, metallic contaminants in the environment are a growing concern. The goal of this systematic review is to determine whether there is a risk to humans from higher levels of environmental lithium in the water supply. Methods: Systematic Review. Between searches in October 2021 and May 2023, a total of 10,234 citations were retrieved from three databases, one citation index, and one clinical trial registry. 6106 duplicates were removed. 4127 records were screened. 3873 were excluded. 254 reports were retrieved and assessed for eligibility based on population, study design, and outcomes. 26 studies were included in the final review. Results: Of the 26 studies selected for extraction, 12 showed negative effects related to lithium exposure through drinking water. The studies reviewed included data from five continents. Study subjects ranged from newborn to adult, including pregnant women. The data reflected the possibility for detrimental effects to the nervous system, the cardiovascular system, the endocrine system, the lymphatic system, the urinary system, and the integumentary system. Of note, the suggested effects included increased risk of autism spectrum disorder and up to 1.88-fold increase in the risk of schizophrenia spectrum disorder. It also indicated possible teratogenicity. Conclusion: The findings of this review indicate that lithium, even at the non-therapeutic levels found in drinking water, is linked to negative impacts on human health. This suggests the need for further studies and the development of clear guidelines regarding monitoring and maximum permissible concentrations of lithium in municipal and bottled water supplies [Note: Due to APA’s conference restrictions on the number of authors, Schwab, R was left off as an author on the poster. However, she contributed to the study by doing initial work on parameters.]
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    Heart rate variability measures indicating sex differences in autonomic regulation during anxiety-like behavior in rats
    (Frontiers Media, 2023-10-31) Frasier, Raizel M.; De Oliveira Sergio, Thatiane; Starski, Phillip A.; Grippo, Angela J.; Hopf, F. Woodward; Psychiatry, School of Medicine
    Introduction: Mental health conditions remain a substantial and costly challenge to society, especially in women since they have nearly twice the prevalence of anxiety disorders. However, critical mechanisms underlying sex differences remain incompletely understood. Measures of cardiac function, including heart rate (HR) and HR variability (HRV), reflect balance between sympathetic (SNS) and parasympathetic (PNS) systems and are potential biomarkers for pathological states. Methods: To better understand sex differences in anxiety-related autonomic mechanisms, we examined HR/HRV telemetry in food-restricted adult rats during novelty suppression of feeding (NSF), with conflict between food under bright light in the arena center. To assess HRV, we calculated the SDNN (reflective of both SNS and PNS contribution) and rMSSD (reflective of PNS contribution) and compared these metrics to behaviors within the anxiety task. Results: Females had greater HR and lower SNS indicators at baseline, as in humans. Further, females (but not males) with higher basal HR carried this state into NSF, delaying first approach to center. In contrast, males with lower SNS measures approached and spent more time in the brightly-lit center. Further, females with lower SNS indicators consumed significantly more food. In males, a high-SNS subpopulation consumed no food. Among consumers, males with greater SNS ate more food. Discussion: Together, these are congruent with human findings suggesting women engage PNS more, and men SNS more. Our previous behavior-only work also observed female differences from males during initial movement and food intake. Thus, high basal SNS in females reduced behavior early in NSF, while subsequent reduced SNS allowed greater food intake. In males, lower SNS increased engagement with arena center, but greater SNS predicted higher consumption. Our findings show novel and likely clinically relevant sex differences in HRV-behavior relationships.
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    Promoting Meaning and Recovery for Psychosis: Comparison of Metacognitively-Oriented Psychotherapists and Clinicians in Psychiatric Rehabilitation
    (Dove Press, 2023-10-18) Faith, Laura; Wiesepape, Courtney; Kukla, Marina; Lysaker, Paul; Psychiatry, School of Medicine
    Introduction: Recovery from psychosis is an expected and desired outcome in psychiatric rehabilitation that may involve subjective outcomes related to personal recovery. While a considerable amount of qualitative research has examined patients' experience of recovery oriented approaches, there are less studies examining clinicians' perspectives. Examining the clinician point of view is important for both supporting clinicians within recovery-oriented practice, as well as for understanding underlying therapeutic processes. The aims of this study were to explore clinician experience of offering different psychiatric rehabilitation treatments for individuals with psychosis, and to understand similarities and differences of clinicians whose work differed in its recovery emphasis. Methods: Open-ended interviews were conducted with 10 psychotherapists providing Metacognitive Reflection and Insight Therapy (MERIT), a recovery oriented form of integrative psychotherapy focused on subjective aspects of recovery, and 10 clinicians providing standard psychiatric rehabilitation services. Results: Thematic analysis revealed important similarities and differences between these two groups of providers. There were seven themes found for MERIT therapists: Comfort with uncertainty, Emphasis on collaboration, Being part of therapeutic change, Connecting with clients, Emphasis on patient autonomy, Experiencing growth, and Therapist use of self-awareness. There were four themes found for psychiatric rehabilitation clinicians: Value of a structured approach, Focus on a strengths-based approach, Witnessing behavioral change, and Building rapport to support the work. Discussion: As expected, both similarities and differences arose between clinician groups. Results indicated that both groups focused on the therapeutic relationship and monitoring progress and outcomes. Unexpectedly, MERIT therapists reported growth as well as comfort with uncertainty. These findings suggest that MERIT is a a psychotherapy that offers unique opportunities for creative and flexible exploration of meaning and agency that is both challenging and rewarding for clinicians. Implications for supporting healthy clinician practice and the development of services are discussed.
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    Atypical Cortical Activation during Risky Decision-making in Disruptive Behavior Disordered Youth with Histories of Suicidal Ideation
    (Elsevier, 2020) Dir, Allyson L.; Allebach, Christian L.; Hummer, Tom A.; Adams, Zachary; Aalsma, Matthew C.; Finn, Peter R.; Nurnberger, John I.; Hulvershorn, Leslie A.; Psychiatry, School of Medicine
    Background: Suicidality is a leading cause of death among adolescents. In addition to other psychiatric conditions, youths with attention-deficit/hyperactivity disorder (ADHD) and disruptive behavior disorders (DBDs) are at heightened risk for suicide. Decision-making deficits are a hallmark symptom of ADHD and DBDs and are also implicated in suicidal behavior. We examined behavioral and neural differences in decision making among youths with ADHD and DBDs with (SI+) and without (SI-) histories of suicidal ideation. Methods: The Balloon Analog Risk Task, a risky decision-making task, was completed by 57 youths with ADHD and DBDs (38% SI+) during functional magnetic resonance imaging. Mean stop wager (mean wager at which youths bank money) was the primary measure of risk taking. We conducted whole-brain and region-of-interest analyses in the anterior cingulate cortex and orbitofrontal cortex (OFC) during choice (win vs. inflate) and outcome (inflate vs. explode) contrasts using parametric modulators accounting for probability of balloon explosion. Results: There were no differences between SI+ and SI- youths in Balloon Analog Risk Task performance. SI+ youths showed decreasing activation in the right medial frontal gyrus when choosing inflate as explosion probability increased compared with SI- youths. During explosions, SI- youths showed increasing activation in the left OFC as explosions became more likely. SI+ showed increasing left medial OFC activity in response to inflations as explosion probability increased. Conclusions: SI+ youths may show heightened sensitivity to immediate reward and decreased sensitivity to potential loss as evidenced by medial frontal gyrus activity. OFC findings suggest that SI+ youths may be drawn to reward even when there is high probability of loss.
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    Nursing Home Transfers for Behavioral Concerns: Findings from the OPTIMISTIC Demonstration Project
    (Wiley, 2021) Hathaway, Elizabeth E.; Carnahan, Jennifer L.; Unroe, Kathleen T.; Stump, Timothy E.; O’Kelly Phillips, Erin; Hickman, Susan E.; Fowler, Nicole R.; Sachs, Greg A.; Bateman, Daniel R.; Psychiatry, School of Medicine
    Objectives: To characterize pretransfer on-site nursing home (NH) management, transfer disposition, and hospital discharge diagnoses of long-stay residents transferred for behavioral concerns. Design: This was a secondary data analysis of the Optimizing Patient Transfers, Impacting Medical Quality, Improving Symptoms: Transforming Institutional Care project, in which clinical staff employed in the NH setting conducted medical, transitional, and palliative care quality improvement initiatives and gathered data related to resident transfers to the emergency department/hospital setting. R software and Microsoft Excel were used to characterize a subset of transfers prompted by behavioral concerns. Setting: NHs in central Indiana were utilized (N = 19). Participants: This study included long-stay NH residents with behavioral concerns prompting transfer for acute emergency department/hospital evaluation (N = 355 transfers). Measurements: The measures used in this study were symptoms prompting transfer, resident demographics and baseline characteristics (Minimum Data Set 3.0 variables including scores for the Cognitive Function Scale, ADL Functional Status, behavioral symptoms directed toward others, and preexisting psychiatric diagnoses), on-site management (e.g., medical evaluation in person or by phone, testing, and interventions), avoidability rating, transfer disposition (inpatient vs emergency department only), and hospital discharge diagnoses. Results: Over half of the transfers, 56%, had a medical evaluation before transfer, and diagnostic testing was conducted before 31% of transfers. After transfer, 80% were admitted. The most common hospital discharge diagnoses were dementia-related behaviors (27%) and altered mental status (27%), followed by a number of medical diagnoses. Conclusion: Most transfers for behavioral concerns merited hospital admission, and medical discharge diagnoses were common. There remain significant opportunities to improve pretransfer management of NH transfers for behavioral concerns.
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    Circadian rhythms in bipolar disorder patient-derived neurons predict lithium response: Preliminary studies
    (Springer Nature, 2021) Mishra, Himanshu K.; Ying, Noelle M.; Luis, Angelica; Wei, Heather; Nguyen, Metta; Nakhla, Timothy; Vandenburgh, Sara; Alda, Martin; Berrettini, Wade H.; Brennand, Kristen J.; Calabrese, Joseph R.; Coryell, William H.; Frye, Mark A.; Gage, Fred H.; Gershon, Elliot S.; McInnis, Melvin G.; Nievergelt, Caroline M.; Nurnberger, John I.; Shilling, Paul D.; Oedegaard, Ketil J.; Zandi, Peter P.; The Pharmacogenomics of Bipolar Disorder Study; Kelsoe, John R.; Welsh, David K.; McCarthy, Michael J.; Psychiatry, School of Medicine
    Bipolar disorder (BD) is a neuropsychiatric illness defined by recurrent episodes of mania/hypomania, depression and circadian rhythm abnormalities. Lithium is an effective drug for BD, but 30–40% of patients fail to respond adequately to treatment. Previous work has demonstrated that lithium affects the expression of “clock genes” and that lithium responders (Li-R) can be distinguished from non-responders (Li-NR) by differences in circadian rhythms. However, circadian rhythms have not been evaluated in BD patient neurons from Li-R and Li-NR. We used induced pluripotent stem cells (iPSCs) to culture neuronal precursor cells (NPC) and glutamatergic neurons from BD patients characterized for lithium responsiveness and matched controls. We identified strong circadian rhythms in Per2-luc expression in NPCs and neurons from controls and Li-R, but NPC rhythms in Li-R had a shorter circadian period. Li-NR rhythms were low-amplitude and profoundly weakened. In NPCs and neurons, expression of PER2 was higher in both BD groups compared to controls. In neurons, PER2 protein levels were higher in BD than controls, especially in Li-NR samples. In single cells, NPC and neuron rhythms in both BD groups were desynchronized compared to controls. Lithium lengthened period in Li-R and control neurons but failed to alter rhythms in Li-NR. In contrast, temperature entrainment increased amplitude across all groups, and partly restored rhythms in Li-NR neurons. We conclude that neuronal circadian rhythm abnormalities are present in BD and most pronounced in Li-NR. Rhythm deficits in BD may be partly reversible through stimulation of entrainment pathways.
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    Plasma phosphorylated tau181 as a biomarker of mild traumatic brain injury: findings from THINC and NCAA-DoD CARE Consortium prospective cohorts
    (Frontiers Media, 2023-08-17) Devoto, Christina; Vorn, Rany; Mithani, Sara; Meier, Timothy B.; Lai, Chen; Broglio, Steven P.; McAllister, Thomas; Giza, Christopher C.; Huber, Daniel; Harezlak, Jaroslaw; Cameron, Kenneth L.; McGinty, Gerald; Jackson, Jonathan; Guskiewicz, Kevin; Mihalik, Jason P.; Brooks, Alison; Duma, Stefan; Rowson, Steven; Nelson, Lindsay D.; Pasquina, Paul; Turtzo, Christine; Latour, Lawrence; McCrea, Michael A.; Gill, Jessica M.; Psychiatry, School of Medicine
    Objective: The aim of this study was to investigate phosphorylated tau (p-tau181) protein in plasma in a cohort of mild traumatic brain injury (mTBI) patients and a cohort of concussed athletes. Methods: This pilot study comprised two independent cohorts. The first cohort-part of a Traumatic Head Injury Neuroimaging Classification (THINC) study-with a mean age of 46 years was composed of uninjured controls (UIC, n = 30) and mTBI patients (n = 288) recruited from the emergency department with clinical computed tomography (CT) and research magnetic resonance imaging (MRI) findings. The second cohort-with a mean age of 19 years-comprised 133 collegiate athletes with (n = 112) and without (n = 21) concussions. The participants enrolled in the second cohort were a part of a multicenter, prospective, case-control study conducted by the NCAA-DoD Concussion Assessment, Research and Education (CARE) Consortium at six CARE Advanced Research Core (ARC) sites between 2015 and 2019. Blood was collected within 48 h of injury for both cohorts. Plasma concentration (pg/ml) of p-tau181 was measured using the Single Molecule Array ultrasensitive assay. Results: Concentrations of plasma p-tau181 in both cohorts were significantly elevated compared to controls within 48 h of injury, with the highest concentrations of p-tau181 within 18 h of injury, with an area under the curve (AUC) of 0.690-0.748, respectively, in distinguishing mTBI patients and concussed athletes from controls. Among the mTBI patients, the levels of plasma p-tau181 were significantly higher in patients with positive neuroimaging (either CT+/MRI+, n = 74 or CT-/MRI+, n = 89) compared to mTBI patients with negative neuroimaging (CT-/MRI-, n = 111) findings and UIC (P-values < 0.05). Conclusion: These findings indicate that plasma p-tau181 concentrations likely relate to brain injury, with the highest levels in patients with neuroimaging evidence of injury. Future research is needed to replicate and validate this protein assay's performance as a possible early diagnostic biomarker for mTBI/concussions.
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    Autism Rating Scale: A New Tool for Characterizing the Schizophrenia Phenotype
    (Frontiers Media, 2021-01-26) Palumbo, Davide; Stanghellini, Giovanni; Mucci, Armida; Ballerini, Massimo; Giordano, Giulia Maria; Lysaker, Paul H.; Galderisi, Silvana; Psychiatry, School of Medicine
    Social dysfunctions (SD) are frequently observed in subjects with schizophrenia. Some of these dysfunctions are also observed in other neuropsychiatric disorders such as autism spectrum disorders (ASD), major depression, bipolar disorder, or Alzheimer disease. Recently, a characterization of a specific type of SD in schizophrenia has been proposed, with the concept of dis-sociality, which form the core aspect of “Schizophrenic Autism” (SA). The present study aimed to explore the presence in people with schizophrenia of SA, independent of other autistic traits, which can be often found in schizophrenia and other neurodevelopmental disorders. We used a structured interview—the Autism Rating Scale (ARS), an instrument devised to detect and measure SA. Fifty-one outpatients affected by schizophrenia (26 remitted, SCZ-r) and 28 affected by bipolar disorder type 1, with psychotic features, in the euthymic phase (BD-e) were recruited. Before assessing the specificity for schizophrenia of SA, we tested the internal consistency, the convergent and divergent validity of the ARS in the schizophrenia sample. Specificity was assessed by examining potential differences in ARS scores between SCZ-r and BD-e subjects. ARS showed good internal consistency, as well as convergent and divergent validity. ARS items were more frequently of moderate severity in SCZ-r than in BD-e subjects. This scale can contribute to establish more precise phenomenal boundaries between schizophrenia and bipolar disorder, and opens up the possibility of identifying a different type of SD in schizophrenia, independent of autistic traits and negative symptoms, which might benefit from different treatments.
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    Exposure to Epstein Barr Virus and Cognitive Functioning in Individuals with Schizophrenia
    (Elsevier, 2021) Dickerson, Faith; Katsafanas, Emily; Origoni, Andrea; Squire, Amalia; Khushalani, Sunil; Newman, Theresa; Rowe, Kelly; Stallings, Cassie; Savage, Christina L. G.; Sweeney, Kevin; Nguyen, Tanya T.; Breier, Alan; Goff, Donald; Ford, Glen; Jones-Brando, Lorraine; Yolken, Robert; Psychiatry, School of Medicine
    Cognitive deficits are a central feature of schizophrenia whose etiology is not fully understood. Epstein Barr Virus (EBV) is a potentially neurotropic infectious agent that can generate persistent infections with immunomodulatory effects. Previous studies have found an association between EBV antibodies and cognitive functioning in different populations, but there has been limited investigation in schizophrenia. In this study, 84 individuals with schizophrenia were administered a comprehensive neuropsychological battery, the MATRICS Consensus Cognitive Battery (MCCB). Participants also provided a blood sample, from which antibodies to the EBV whole virion and specific proteins were measured. Multivariate models were constructed to determine the association between these antibodies and cognitive performance on the MCCB overall and domain scores. Using these models, we found a significant association between the MCCB overall percent composite score and level of antibodies to the EBV Nuclear Antigen-1 (EBNA-1) protein, the Viral Capsid Antigen (VCA) protein, and the EBV whole virion. A significant association was also found for the MCCB social cognition domain with the level of antibodies to the EBV Nuclear Antigen-1 (EBNA-1) protein, the Viral Capsid Antigen (VCA) protein, and the EBV whole virion. In all cases, a higher level of antibodies was associated with a lower level cognitive performance. These findings suggest that exposure to EBV may contribute to cognitive deficits in schizophrenia, a finding which may have implications for new methods of prevention and treatment.
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    Lipoprotein(a) and risk of cognitive impairment in Black and White Americans: the Reasons for Geographic and Racial Differences in Stroke cohort
    (Elsevier, 2023-08-08) Rentería, Miguel Arce; McClure, Leslie A.; Callas, Peter W.; LaBode-Richman, Vanessa M.; Kroll, Danielle S.; Manly, Jennifer J.; Kroll, Danielle S.; Manly, Jennifer J.; Zakai, Neil A.; Unverzagt, Frederick; Cushman, Mary; Psychiatry, School of Medicine
    Background: Cognitive impairment has a substantial vascular etiology. Higher lipoprotein(a) [Lp(a)] is associated with cardiovascular disease risk, but its association with cognitive function is uncertain. We hypothesized that Lp(a) is a risk factor for cognitive impairment, a relationship that would be modified by race and sex. Objectives: To study the association of Lp(a) with cognitive impairment in a biracial cohort. Methods: The Reasons for Geographic and Racial Differences in Stroke (REGARDS) study recruited 30,239 Black and White Americans aged >45 years from 2003 to 2007. After 3.4 years, among participants with normal baseline cognition, baseline Lp(a) was measured in 434 cases of incident cognitive impairment and 557 controls. Cognitive impairment was defined as scores below the sixth percentile based on age, sex, race, and education norms on 2 or 3 components of a 3-test battery administered every 2 years. Results: Median Lp(a) was higher in Black than in White individuals. Among Black participants, the adjusted odds ratio (OR) of cognitive impairment per SD higher increment Lp(a) was 1.39 (95% CI: 1.05, 1.84). The OR in White participants was 1.03 (95% CI: 0.87, 1.21; P for race difference = .03). The relationship of Lp(a) with cognitive trajectory differed by sex and race. Elevated Lp(a) was associated with worse baseline memory in Black men and a steeper trajectory of verbal fluency decline in Black men than in White men and women. Conclusion: Higher Lp(a) was associated with increased risk of cognitive impairment in Black but not White individuals. Future studies should evaluate the biological and social mechanisms through which race and Lp(a) interact to increase risk of cognitive impairment.