Faculty Bibliography

D-amino acid oxidase activator (DAOA) gene, which plays a crucial role in the process of glutamatergic transmission and mitochondrial function, is frequently linked with the liability for schizophrenia. We aimed to investigate whether the variation of DAOA rs2391191 is associated with alterations in white matter integrity of first-episode schizophrenia (FES) patients; and whether it influences the association between white matter integrity, cognitive function and clinical symptoms of schizophrenia. Forty-six patients with FES and forty-nine healthy controls underwent DTI and were genotyped for DAOA rs2391191. Psychopathological assessments were performed by Brief Psychiatric Rating Scale (BPRS) and Scale for Assessment of Negative Symptoms (SANS). Cognitive function was assessed by MATRICS Consensus Cognitive Battery (MCCB). Schizophrenia patients presented lower fractional anisotropy (FA) and higher radial diffusivity (RD), mainly spreading over the corpus callosum and corona radiata compared with healthy controls. Compared with patients carrying G allele, patients with AA showed lower FA in the body of corpus callosum, and higher RD in the genu of corpus callosum, right superior and anterior corona radiata, and left posterior corona radiata. In patients carrying G allele, FA in body of corpus callosum was positively correlated with working memory, RD in genu of corpus callosum was negatively associated with the speed of processing, working memory, and the composite score of MCCB, while no significant correlations were found in AA homozygotes. In our study, patients with FES presented abnormal white matter integrity in corpus callosum and corona radiata. Furthermore, this abnormality was associated with the genetic variation of DAOA rs2391191, with AA homozygotes showing less white matter integrity in the corpus callosum. Our findings possibly provide further support to the evidence that DAOA regulates the process of glutamatergic neurotransmission and mitochondrial function in the pathophysiological mechanism of schizophrenia.

Reports an error in "Association of aripiprazole with reduced hippocampal atrophy during maintenance treatment of first-episode schizophrenia" by John Wang, Kamber L. Hart, Wei Qi, Babak A. Ardekani, Chenxiang Li, Julia Marx, Oliver Freudenreich, Corinne Cather, Daphne Holt, Iruma Bello, Erica D. Diminich, Yingying Tang, Michelle Worthington, Botao Zeng, Renrong Wu, Xiaoduo Fan, Jingping Zhao, Jijun Wang and Donald C. Goff (Journal of Clinical Psychopharmacology, 2021[May-Jun], Vol 41[3], 244-249). In the originally published article, there were errors in the affiliations for two authors. The correct affiliations are provided in the erratum and appear in this record. In addition, in the footnotes to Table 3, the words "Bonferroni correction" should have been deleted after the P value of 0.05. (The following abstract of the original article appeared in record 2021-44706-004). Purpose/Background: Hippocampal volume loss in early schizophrenia has been linked with markers of inflammation and oxidative stress, and with less response of negative symptoms. Aripiprazole has been reported to preserve hippocampal volume and to reduce inflammation. Methods/Procedures: Study 1 was a 12-month multicenter randomized placebo-controlled trial of citalopram added to clinician-determined second-generation antipsychotic medication in 95 patients with first-episode schizophrenia (FES), 19 of whom received aripiprazole. We compared participants taking aripiprazole with those on other antipsychotics to determine whether those on aripiprazole had less hippocampal volume loss. We also examined peripheral biomarker data from medication-naive patients with schizophrenia receiving 8 weeks of antipsychotic treatment (n = 24) to see whether markers of inflammation and oxidative stress that previously predicted hippocampal volume differed between aripiprazole (n = 9) and other antipsychotics (study 2). Findings/Results: Aripiprazole was associated with a mean increase in hippocampal volume of 0.35% (SD, 0.80%) compared with a 0.53% decrease (SD, 1.2%) with other antipsychotics during the first year of maintenance treatment in patients with FES. This difference was significant after adjusting for age, sex, citalopram treatment, and baseline Brief Psychiatric Rating Scale score (B = 0.0079, P = 0.03). Aripiprazole was also associated with reduced concentrations of the inflammatory cytokines interleukin-8 and tumor necrosis factor (P < 0.01) during the first 8 weeks of treatment in medication-naive patients with FES. Implications/Conclusions: These results suggest that aripiprazole may protect against hippocampal atrophy via an anti-inflammatory mechanism, but these results require replication in larger, randomized trials, and the clinical relevance of hippocampal volume loss is not established. (PsycInfo Database Record (c) 2022 APA, all rights reserved)

PURPOSE/BACKGROUND/OBJECTIVE:Hippocampal volume loss in early schizophrenia has been linked with markers of inflammation and oxidative stress, and with less response of negative symptoms. Aripiprazole has been reported to preserve hippocampal volume and to reduce inflammation. METHODS/PROCEDURES/UNASSIGNED:Study 1 was a 12-month multicenter randomized placebo-controlled trial of citalopram added to clinician-determined second-generation antipsychotic medication in 95 patients with first-episode schizophrenia (FES), 19 of whom received aripiprazole. We compared participants taking aripiprazole with those on other antipsychotics to determine whether those on aripiprazole had less hippocampal volume loss. We also examined peripheral biomarker data from medication-naive patients with schizophrenia receiving 8 weeks of antipsychotic treatment (n = 24) to see whether markers of inflammation and oxidative stress that previously predicted hippocampal volume differed between aripiprazole (n = 9) and other antipsychotics (study 2). FINDINGS/RESULTS/UNASSIGNED:Aripiprazole was associated with a mean increase in hippocampal volume of 0.35% (SD, 0.80%) compared with a 0.53% decrease (SD, 1.2%) with other antipsychotics during the first year of maintenance treatment in patients with FES. This difference was significant after adjusting for age, sex, citalopram treatment, and baseline Brief Psychiatric Rating Scale score (B = 0.0079, P = 0.03). Aripiprazole was also associated with reduced concentrations of the inflammatory cytokines interleukin-8 and tumor necrosis factor (P < 0.01) during the first 8 weeks of treatment in medication-naive patients with FES. IMPLICATIONS/CONCLUSIONS/UNASSIGNED:These results suggest that aripiprazole may protect against hippocampal atrophy via an anti-inflammatory mechanism, but these results require replication in larger, randomized trials, and the clinical relevance of hippocampal volume loss is not established.

Hippocampal volume loss is prominent in first episode schizophrenia (FES) and has been associated with poor clinical outcomes and with BDNF genotype; antidepressants are believed to reverse hippocampal volume loss via release of BDNF. In a 12-month, placebo-controlled add-on trial of the antidepressant, citalopram, during the maintenance phase of FES, negative symptoms were improved with citalopram. We now report results of structural brain imaging at baseline and 6 months in 63 FES patients (34 in citalopram group) from the trial to assess whether protection against hippocampal volume loss contributed to improved negative symptoms with citalopram. Hippocampal volumetric integrity (HVI) did not change significantly in the citalopram or placebo group and did not differ between treatment groups, whereas citalopram was associated with greater volume loss of the right CA1 subfield. Change in cortical thickness was associated with SANS change in 4 regions (left rostral anterior cingulate, right frontal pole, right cuneus, and right transverse temporal) but none differed between treatment groups. Our findings suggest that minimal hippocampal volume loss occurs after stabilization on antipsychotic treatment and that citalopram's potential benefit for negative symptoms is unlikely to result from protection against hippocampal volume loss or cortical thinning.

Importance/UNASSIGNED:To date, the association of psychiatric diagnoses with mortality in patients infected with coronavirus disease 2019 (COVID-19) has not been evaluated. Objective/UNASSIGNED:To assess whether a diagnosis of a schizophrenia spectrum disorder, mood disorder, or anxiety disorder is associated with mortality in patients with COVID-19. Design, Setting, and Participants/UNASSIGNED:This retrospective cohort study assessed 7348 consecutive adult patients for 45 days following laboratory-confirmed COVID-19 between March 3 and May 31, 2020, in a large academic medical system in New York. The final date of follow-up was July 15, 2020. Patients without available medical records before testing were excluded. Exposures/UNASSIGNED:Patients were categorized based on the following International Statistical Classification of Diseases, Tenth Revision, Clinical Modification diagnoses before their testing date: (1) schizophrenia spectrum disorders, (2) mood disorders, and (3) anxiety disorders. Patients with these diagnoses were compared with a reference group without psychiatric disorders. Main Outcomes and Measures/UNASSIGNED:Mortality, defined as death or discharge to hospice within 45 days following a positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) test result. Results/UNASSIGNED:Of the 26 540 patients tested, 7348 tested positive for SARS-CoV-2 (mean [SD] age, 54 [18.6] years; 3891 [53.0%] women). Of eligible patients with positive test results, 75 patients (1.0%) had a history of a schizophrenia spectrum illness, 564 (7.7%) had a history of a mood disorder, and 360 (4.9%) had a history of an anxiety disorder. After adjusting for demographic and medical risk factors, a premorbid diagnosis of a schizophrenia spectrum disorder was significantly associated with mortality (odds ratio [OR], 2.67; 95% CI, 1.48-4.80). Diagnoses of mood disorders (OR, 1.14; 95% CI, 0.87-1.49) and anxiety disorders (OR, 0.96; 95% CI, 0.65-1.41) were not associated with mortality after adjustment. In comparison with other risk factors, a diagnosis of schizophrenia ranked behind only age in strength of an association with mortality. Conclusions and Relevance/UNASSIGNED:In this cohort study of adults with SARS-CoV-2-positive test results in a large New York medical system, adults with a schizophrenia spectrum disorder diagnosis were associated with an increased risk for mortality, but those with mood and anxiety disorders were not associated with a risk of mortality. These results suggest that schizophrenia spectrum disorders may be a risk factor for mortality in patients with COVID-19.

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.

Myelin abnormalities have been reported in schizophrenia spectrum disorders (SSD) in white matter. However, in vivo examinations of cortical myeloarchitecture in SSD, especially those using quantitative measures, are limited. Here, we employed macromolecular proton fraction (MPF) obtained from quantitative magnetization transfer imaging to characterize intracortical myelin organization in 30 SSD patients versus 34 healthy control (HC) participants. We constructed cortical myelin profiles by extracting MPF values at various cortical depths and quantified their shape using a nonlinearity index (NLI). To delineate the association of illness duration with myelin changes, SSD patients were further divided into 3 duration groups. Between-group comparisons revealed reduced NLI in the SSD group with the longest illness duration (>5.5 years) compared with HC predominantly in bilateral prefrontal areas. Within the SSD group, cortical NLI decreased with disease duration and was positively associated with a measure of spatial working memory capacity as well as with cortical thickness (CT). Layer-specific analyses suggested that NLI decreases in the long-duration SSD group may arise in part from significantly increased MPF values in the midcortical layers. The current study reveals cortical myelin profile changes in SSD with illness progression, which may reflect an abnormal compensatory mechanism of the disorder.