Digital Medicine System in Veterans With Severe Mental Illness: Feasibility and Acceptability Study.

BACKGROUND: Suboptimal medication adherence is a significant problem for patients with serious mental illness. Measuring medication adherence through subjective and objective measures can be challenging, time-consuming, and inaccurate. OBJECTIVE: The primary purpose of this feasibility and acceptability study was to evaluate the impact of a digital medicine system (DMS) among Veterans (patients) with serious mental illness as compared with treatment as usual (TAU) on medication adherence. METHODS: This open-label, 2-site, provider-randomized trial assessed aripiprazole refill adherence in Veterans with schizophrenia, schizoaffective disorder, bipolar disorder, or major depressive disorder. We randomized 26 providers such that their patients either received TAU or DMS for a period of 90 days. Semistructured interviews with patients and providers were used to examine the feasibility and acceptability of using the DMS. RESULTS: We enrolled 46 patients across 2 Veterans Health Administration sites: 21 (46%) in DMS and 25 (54%) in TAU. There was no difference in the proportion of days covered by medication refill over 3 and 6 months (0.82, SD 0.24 and 0.75, SD 0.26 in DMS vs 0.86, SD 0.19 and 0.82, SD 0.21 in TAU, respectively). The DMS arm had 0.85 (SD 0.20) proportion of days covered during the period they were engaged with the DMS (mean 144, SD 100 days). Interviews with patients (n=14) and providers (n=5) elicited themes salient to using the DMS. Patient findings described the positive impact of the DMS on medication adherence, challenges with the DMS patch connectivity and skin irritation, and challenges with the DMS app that affected overall use. Providers described an overall interest in using a DMS as an objective measure to support medication adherence in their patients. However, providers described challenges with the DMS dashboard and integrating DMS data into their workflow, which decreased the usability of the DMS for providers. CONCLUSIONS: There was no observed difference in refill rates. Among those who engaged in the DMS arm, the proportion of days covered by refills were relatively high (mean 0.85, SD 0.20). The qualitative analyses highlighted areas for further refinement of the DMS. TRIAL REGISTRATION: ClinicalTrials.gov NCT03881449; https://clinicaltrials.gov/ct2/show/NCT03881449.

Challenges and Considerations in Treating Negative and Cognitive Symptoms of Schizophrenia Spectrum Disorders.

Background: The prototypical patient with schizophrenia spectrum disorders (SSDs) is often thought to possess positive symptoms. However, patients with SSDs can present with predominantly negative and cognitive symptoms, which can create diagnostic and treatment challenges. Case Presentation: A 33-year-old female veteran presented to the emergency department with diminished speech output, markedly blunted affect, tangential speech, was not oriented to situation, and appeared to be responding to internal stimuli. Following inpatient admission, the veteran was diagnosed with schizoaffective disorder, which was misdiagnosed as major depressive disorder and borderline personality disorder during her military service. She was initially treated with olanzapine injections and psychotherapy but continued to experience worsening symptoms, resulting in multiple hospitalizations. After starting clozapine, she demonstrated marked improvement and continued with outpatient mental health care. Conclusions: Predominant negative and cognitive symptom presentations of SSDs require unique considerations to accurately identify and provide optimal treatment for the patient. Clozapine is a promising treatment for addressing these symptoms. This case demonstrates how careful multidisciplinary evaluations, review of health records, collateral information from family members, and other diagnostic and treatment considerations in patients with predominant negative and cognitive symptoms of SSDs can refine and enhance the clinical care offered to such patients.

History of Suicide Attempt and Clozapine Treatment in Veterans With Schizophrenia or Schizoaffective Disorder.

Objective: To evaluate whether a history of suicide attempt increases the odds of receiving clozapine treatment in veterans with schizophrenia or schizoaffective disorder.Methods: Electronic health record data were obtained for veterans with schizophrenia or schizoaffective disorder treated at any US Veterans Affairs Medical Center between January 1, 2000, and January 31, 2021 (N = 134,692). Logistic regression (adjusted and unadjusted) was applied to estimate odds ratios (ORs) for clozapine treatment in suicide attempters relative to nonattempters.Results: 3,407 patients had a documented history of suicide attempt, while 6,867 patients had received clozapine treatment. Also, 9.4% (n = 321) of suicide attempters versus 5.0% (n = 6546) of nonattempters had received clozapine treatment. The odds of being treated with clozapine was approximately 2-fold in patients with a history of suicide attempt in unadjusted (OR = 1.98, 95% CI, 1.76-2.22) and adjusted (OR = 1.91, 95% CI, 1.67-2.15) analyses.Conclusions: Despite the higher odds of clozapine treatment in suicide attempters with schizophrenia or schizoaffective disorder, clozapine was underutilized in the current sample of veterans. Concerted efforts should be made to expand the use of clozapine in patients with schizophrenia or schizoaffective disorder, especially those with a history of suicide attempt.

Plasma Soluble P-selectin, Interleukin-6 and S100B Protein in Patients with Schizophrenia: a Pilot Study.

Microglial activation has long been posited to be involved in the neurobiology of schizophrenia. However, recent studies indicate that schizophrenia is associated with astrocytic activation, rather than microglia activation. Moreover, elevated levels of peripheral inflammatory cytokines associated with schizophrenia could induce or reflect brain inflammation. Therefore, based on: 1) findings of a periphery-to-brain communication pathway involving the cell adhesion molecule, P-selectin, in animal models; 2) dysregulated interleukin-6 (IL-6) and elevated levels of the astrocytic marker, S100B protein, in patients with schizophrenia, we sought to determine correlations between plasma soluble P-selectin (sP-selectin), S100B and IL-6 respectively. We recruited 106 patients with schizophrenia (mean age 33 years, 71.60% male) from the inpatient. sP-selectin, S100B and IL-6 were measured in fasting plasma. We calculated Pearson's and partial correlations between sP-selectin, S100B and IL-6. After controlling for potential confounders, sP-selectin positively correlated with S100B (r=0.31, p=0.004) and IL-6 (r=0.28, P=0.046). The correlation between IL-6 and S100B (r=0.28, p=0.066) did not reach statistical significance. We propose that in some patients with schizophrenia, immune activation in the periphery is associated with P-selectin-mediated trafficking of inflammation into the brain (most likely via leukocytes), which might be associated with astrocytic activation. Future studies should include healthy controls and first episode/early-onset psychosis patients. Importantly, in vivo imaging of neuroinflammation should be correlated with sP-selectin, IL-6 and S100B in the periphery and the CSF. Finally, the utility of combining sP-selectin, IL-6 and S100B as biomarkers for subtyping patients with schizophrenia, treatment selection and prognosis, should be evaluated in longitudinal studies.

Biological and Psychological Factors Determining Neuropsychiatric Outcomes in COVID-19.

PURPOSE OF REVIEW: We present biological and psychological factors implicated in psychiatric manifestations of SARS-CoV-2, as well as its neuroinvasive capability and immune pathophysiology. RECENT FINDINGS: Preexisting mental illness leads to worse clinical outcomes in COVID-19. The presence of the virus was reported in the cerebrospinal fluid (CSF) and brain tissue post-mortem. Most common psychiatric manifestations include delirium, mood disorders, anxiety disorders, and posttraumatic stress disorder. "Long-COVID" non-syndromal presentations include "brain-fogginess," autonomic instability, fatigue, and insomnia. SARS-CoV-2 infection can trigger prior vulnerabilities based on the priming of microglia and other cells, induced or perpetuated by aging and mental and physical illnesses. COVID-19 could further induce priming of neuroimmunological substrates leading to exacerbated immune response and autoimmunity targeting structures in the central nervous system (CNS), in response to minor immune activating environmental exposures, including stress, minor infections, allergens, pollutants, and traumatic brain injury.

Repetitive Transcranial Magnetic Stimulation: A Potential Treatment for Obesity in Patients with Schizophrenia.

Obesity is highly prevalent in patients with schizophrenia and, in association with metabolic syndrome, contributes to premature deaths of patients due to cardiovascular disease complications. Moreover, pharmacologic, and behavioral interventions have not stemmed the tide of obesity in schizophrenia. Therefore, novel effective interventions are urgently needed. Repetitive transcranial magnetic stimulation (rTMS) has shown efficacy for inducing weight loss in obese non-psychiatric samples but this promising intervention has not been evaluated as a weight loss intervention in patients with schizophrenia. In this narrative review, we describe three brain mechanisms (hypothalamic inflammation, dysregulated mesocorticolimbic reward system, and impaired prefrontal cortex function) implicated in the pathogenesis and pathophysiology of obesity and emphasize how the three mechanisms have also been implicated in the neurobiology of schizophrenia. We then argue that, based on the three overlapping brain mechanisms in obesity and schizophrenia, rTMS would be effective as a weight loss intervention in patients with schizophrenia and comorbid obesity. We end this review by describing how deep TMS, relative to conventional TMS, could potentially result in larger effect size for weight loss. While this review is mainly conceptual and based on an extrapolation of findings from non-schizophrenia samples, our aim is to stimulate research in the use of rTMS for weight loss in patients with schizophrenia.

Toxoplasma gondii, Suicidal Behavior, and Intermediate Phenotypes for Suicidal Behavior.

Within the general literature on infections and suicidal behavior, studies on Toxoplasma gondii (T. gondii) occupy a central position. This is related to the parasite's neurotropism, high prevalence of chronic infection, as well as specific and non-specific behavioral alterations in rodents that lead to increased risk taking, which are recapitulated in humans by T. gondii's associations with suicidal behavior, as well as trait impulsivity and aggression, mental illness and traffic accidents. This paper is a detailed review of the associations between T. gondii serology and suicidal behavior, a field of study that started 15 years ago with our publication of associations between T. gondii IgG serology and suicidal behavior in persons with mood disorders. This "legacy" article presents, chronologically, our primary studies in individuals with mood disorders and schizophrenia in Germany, recent attempters in Sweden, and in a large cohort of mothers in Denmark. Then, it reviews findings from all three meta-analyses published to date, confirming our reported associations and overall consistent in effect size [ranging between 39 and 57% elevation of odds of suicide attempt in T. gondii immunoglobulin (IgG) positives]. Finally, the article introduces certain links between T. gondii and biomarkers previously associated with suicidal behavior (kynurenines, phenylalanine/tyrosine), intermediate phenotypes of suicidal behavior (impulsivity, aggression) and state-dependent suicide risk factors (hopelessness/dysphoria, sleep impairment). In sum, an abundance of evidence supports a positive link between suicide attempts (but not suicidal ideation) and T. gondii IgG (but not IgM) seropositivity and serointensity. Trait impulsivity and aggression, endophenotypes of suicidal behavior have also been positively associated with T. gondii seropositivity in both the psychiatrically healthy as well as in patients with Intermittent Explosive Disorder. Yet, causality has not been demonstrated. Thus, randomized interventional studies are necessary to advance causal inferences and, if causality is confirmed, to provide hope that an etiological treatment for a distinct subgroup of individuals at an increased risk for suicide could emerge.

History of Suicide Attempts and COVID-19 Infection in Veterans with Schizophrenia or Schizoaffective Disorder: Moderating Effects of Age and Body Mass Index.

INTRODUCTION: Relative to the general population, patients with schizophrenia or schizoaffective disorder have higher rates of suicide attempts and mortality from COVID-19 infection. Therefore, determining whether a history of suicide attempt is associated with COVID-19 in patients with schizophrenia or schizoaffective disorder has implications for COVID-19 vulnerability stratification in this patient population. METHODS: We carried out cross-sectional analyses of electronic health records of veterans with a diagnosis of schizophrenia or schizoaffective disorder that received treatment at any United States Veterans Affairs Medical Center between January 1, 2020, and January 31, 2021. We used logistic regression to estimate unadjusted and adjusted (including age, sex, race, marital status, body mass index (BMI), and a medical comorbidity score) odds ratios (ORs) for COVID-19 positivity in suicide attempters relative to nonattempters. RESULTS: A total of 101,032 veterans (mean age 56.67 ± 13.13 years; males 91,715 [90.8%]) were included in the analyses. There were 2,703 (2.7%) suicide attempters and 719 (0.7%) patients were positive for COVID-19. The association between history of suicide attempt and COVID-19 positivity was modified by age and BMI, such that the relationship was only significant in patients younger than 59 years, and in obese (BMI ≥30) patients (adjusted OR 3.42, 95% CI 2.02-5.79 and OR 2.85, 95% CI 1.65-4.94, respectively). CONCLUSIONS: Higher rates of COVID-19 in young or obese suicide attempters with a diagnosis of schizophrenia or schizoaffective disorder might be due to the elevated risk for the infection in this subgroup of patients.

Plasma soluble P-selectin correlates with triglycerides and nitrite in overweight/obese patients with schizophrenia.

BACKGROUND: Soluble P-selectin (sP-selectin) is associated with risk factors for cardiovascular disease (CVD) but this association has not been evaluated in patients with schizophrenia. This study primarily evaluated the association of sP-selectin with plasma lipids and nitrite (NO2-) respectively in overweight/obese adults with schizophrenia. METHODS: One-hundred and six patients with schizophrenia (mean age 32.9 years; 71.60% male) were recruited from a psychiatric hospital. Participants completed a structured interview and provided a fasting blood sample. Body mass index (BMI) was used to divide the sample into normal weight and overweight/obese groups. Pearson's and partial correlation coefficients (controlling for age, sex, race, education, and inflammation) were calculated to examine the association of sP-selectin with plasma lipids, and NO2- in the overweight/obese patients (primary analysis), as well as in the normal weight patients and the total sample (exploratory analyses). RESULTS: After controlling for potential confounders, sP-selectin positively correlated with triglycerides (r = 0.38, p = 0.01) and NO2- (r = 0.40, p < 0.01) in the overweight/obese group only. CONCLUSIONS: Future longitudinal studies should evaluate the utility of sP-selectin as a biomarker of CVD in overweight/obese adults with schizophrenia (for example, by relating sP-selectin to incidence of cardiovascular events).

Hospital Stay in Synthetic Cannabinoid Users With Bipolar Disorder, Schizophrenia, or Other Psychotic Disorders Compared With Cannabis Users.

OBJECTIVE: The use of synthetic cannabinoid (SC) products has become popular in recent years, but data regarding their impact on hospital stays are limited. The impact of SC and cannabis use on hospital length of stay and doses of antipsychotics at discharge was assessed in this study. METHOD: The sample consisted of inpatients with discharge diagnoses of bipolar disorder, schizophrenia, or other psychotic disorders. Medical records of patients with self-reported SC use and negative urine drug screens (SC group, n = 77), with cannabis use confirmed by urine drug screen (cannabis group, n = 248), and with no drug use confirmed by urine drug screen (no-drug group, n = 1,336) were examined retrospectively. RESULTS: Length of stay (mean [SD] days) significantly differed (p < .001) among the SC (8.29 [4.29]), cannabis (8.02 [5.21]), and no-drug groups (10.19 [9.08]). Antipsychotic doses (chlorpromazine milligram equivalent doses) also significantly differed (p = .002) among the SC (254.64 [253.63]), cannabis (219.16 [216.71]), and no-drug groups (294.79 [287.85]). Unadjusted and adjusted pairwise comparisons showed that the cannabis group had a shorter length of stay (p < .001) and received lower doses of antipsychotics (p = .003) than the no-drug group. SC users did not differ significantly from the other two groups in either length of stay or doses of antipsychotics. CONCLUSIONS: Our findings suggest that acute SC exposure is not predictive of a more prolonged time for response to antipsychotic medications or of a need for larger doses of these medications compared with cannabis users.

Traumatic Brain Injury and Suicidal Behavior: A Review.

Given the increasing rate of death by suicide in the United States, it is imperative to examine specific risk factors and to identify possible etiologies of suicidal behavior in at-risk clinical subpopulations. There is accumulating evidence to support an elevated risk of death by suicide in individuals with a history of traumatic brain injury (TBI). In this review article, after defining terms used in suicidology, we discuss the associations of TBI with death by suicide, suicide attempt, and suicidal ideation. A model for repetitive TBIs, leading to chronic traumatic encephalopathy, is also discussed as a neuroinflammatory process, with discussion about its possible link with suicide. The review concludes with an overview of interventions to prevent suicidal behavior.

Correlations between Body Mass Index, Plasma High-Sensitivity C-Reactive Protein and Lipids in Patients with Schizophrenia.

High prevalence of obesity in individuals with schizophrenia, associated with metabolic syndrome, leads to high rate of premature deaths from cardiovascular disease (CVD) in this population. Body mass index (BMI) and C-reactive protein (CRP) are correlated in the general population but this relationship has not been fully elucidated in patients with schizophrenia. We aimed to evaluate the correlation between BMI and CRP while relating both variables to plasma lipids in patients with schizophrenia. BMI, fasting high sensitivity CRP (hs-CRP), cotinine, and lipids were measured in 106 patients with schizophrenia (diagnosis confirmed with MINI). Pearson's and partial correlations (adjusting for age, sex, race, education and cotinine) between BMI, hs-CRP and lipids were calculated. Based on BMI, the patients were divided into normal-weight vs. overweight/obese and t-tests and linear regression were done to compare hs-CRP and lipids in the 2 groups. BMI positively correlated with hs-CRP (r = 0.29, p = 0.004). BMI and hs-CRP negatively correlated with HDL in the total sample (r = -0.29, p = 0.004; r = -0.37, p < 0.001 respectively). Furthermore, hs-CRP negatively correlated with HDL in overweight/obese patients (r = -0.41, p = 0.003), but not in normal-weight patients. hs-CRP and triglycerides were higher (1.62 ± 0.09 mg/L vs. 0.56 ± 0.08 mg/L, p < 0.001; 121.77 ± 8.96 mg/dL vs. 91.23 ± 6.52 mg/dL, p = 0.008 respectively) and HDL lower (39.55 ± 1.48 mg/dL vs. 50.68 ± 2.24 mg/dL, p < 0.001) in overweight/obese patients. Being overweight/obese is associated with increased inflammation and dyslipidemia in patients with schizophrenia. Effective interventions to prevent weight gain in schizophrenia are urgently needed.

Ethnic differences in the diagnosis of schizophrenia and mood disorders during admission to an academic safety-net psychiatric hospital.

U.S. Hispanics, now the single largest minority group in the country, face unique mental health disparities. The current study utilizes Andersen's Behavioral Model of Health Service Use to examine ethnic disparities in receiving a schizophrenia or mood disorder diagnosis at psychiatric hospital admission. Our retrospective cohort study examined electronic health record data at an academic safety-net psychiatric hospital for adult patients (n = 5571) admitted between 2010 and 2013. Logistic regression with block-wise entry of predisposing, enabling and need variables was used to examine ethnic disparities in receiving a schizophrenia diagnosis at admission. The block of need factors was the strongest predictor of receiving a schizophrenia diagnosis compared to predisposing and enabling factors. Compared to non-Hispanic whites, Hispanics and African Americans had a greater likelihood of receiving a schizophrenia diagnosis at admission. Additionally, patients diagnosed with schizophrenia had elevated positive and negative symptoms and were more likely to be male, single/unmarried, homeless, high inpatient service utilizers, involuntarily hospitalized, and to exhibit functional impairment at psychiatric hospital admission. To address elevated positive and negative symptoms of schizophrenia, functional impairment, social withdrawal, and high inpatient service utilization, promising psychosocial interventions should be adapted for racial and ethnic minority populations and utilized as an adjuvant to antipsychotic medication.

Impact of synthetic cannabinoid use on hospital stay in patients with bipolar disorder versus schizophrenia, or other psychotic disorders.

Synthetic cannabinoid products have become popular and have led to an increased number of patients presenting to emergency departments and psychiatric hospitals. The purpose of this study was to evaluate the impact of synthetic cannabinoid use at admission on length of stay and doses of antipsychotics at discharge in individuals with bipolar disorder, schizophrenia and other psychotic disorders. We retrospectively examined medical records of 324 inpatients admitted from January 2014 to July 2015. We found that synthetic cannabinoid use predicted length of stay and antipsychotic dose using structural equation modeling. Further, the association of synthetic cannabinoid use with length of stay was partly mediated by antipsychotic dose. These associations were independent of specific diagnosis. In conclusion, patients with bipolar disorder, schizophrenia, or other psychotic disorders who reported synthetic cannabinoid use at admission had shorter length of stay and received lower doses of antipsychotics, irrespective of clinical diagnoses.

Elevated Plasma S100B, Psychotic Symptoms, and Cognition in Schizophrenia.

S100B is a calcium binding protein mainly produced by glial cells. Previous studies have shown elevated levels of S100B in patients with schizophrenia. We measured S100B levels in fasting plasma of 39 patients with schizophrenia and 19 adult healthy controls. We used linear regression to compare S100B between patients and controls. In patients only, we also investigated the relationship between S100B levels and psychotic symptoms (assessed by the Positive and Negative Syndrome Scale), and cognitive function (assessed by the NIH Toolbox Cognition Battery), respectively by calculating Pearson's correlation coefficients. Mean plasma S100B was significantly higher in the patient group than in the control group. There were no significant correlations between plasma S100B and psychotic symptoms or cognition.

Toxoplasma gondii infection and chronic schizophrenia: is there any association?

ABSTRACT Background: Toxoplasma gondii (T. gondii) infection has been identified as a risk factor for schizophrenia. Objectives: Herein, we sought to evaluate the association between T. gondii infection and clinical symptoms and quality of life in patients with schizophrenia. Methods: We conducted a cross-sectional study with 48 patients with chronic schizophrenia and 40 controls. Peripheral blood was drawn, and IgM and IgG anti-T. gondii antibodies were evaluated by Enzyme-Linked Immunosorbent Assay (ELISA). Depressive, positive and negative symptoms were assessed, respectively, by the Calgary Depression Scale (CDS) and the Positive and Negative Syndrome Scale (PANSS). Cognitive performance was assessed in patients by the Brazilian version of the Schizophrenia Cognition Rating Scale (SCoRS-BR). Quality of life was assessed by the Brazilian version of the Quality of Life in Schizophrenia scale (QLS-BR). Results: The prevalence and titers of T. gondii IgM and IgG antibodies did not differ between patients and controls. The positive serology for T. gondii IgG antibodies was not associated with illness symptoms, cognitive performance, depressive symptoms or quality of life. Discussion: Our findings suggest that toxoplasmosis infection is not associated with severity of symptoms, quality of life, cognitive or depressive symptoms in schizophrenia patients.