Schizophrenia Interactome-Derived Repurposable Drugs and Randomized Controlled Trials of Two Candidates.

There is a substantial unmet need for effective and patient-acceptable drugs to treat severe mental illnesses such as schizophrenia (SZ). Computational analysis of genomic, transcriptomic, and pharmacologic data generated in the past 2 decades enables repurposing of drugs or compounds with acceptable safety profiles, namely those that are U.S. Food and Drug Administration approved or have reached late stages in clinical trials. We developed a rational approach to achieve this computationally for SZ by studying drugs that target the proteins in its protein interaction network (interactome). This involved contrasting the transcriptomic modulations observed in the disorder and the drug; our analyses resulted in 12 candidate drugs, 9 of which had additional supportive evidence whereby their target networks were enriched for pathways relevant to SZ etiology or for genes that had an association with diseases pathogenically similar to SZ. To translate these computational results to the clinic, these shortlisted drugs must be tested empirically through randomized controlled trials, in which their previous safety approvals obviate the need for time-consuming phase 1 and 2 studies. We selected 2 among the shortlisted candidates based on likely adherence and side-effect profiles. We are testing them through adjunctive randomized controlled trials for patients with SZ or schizoaffective disorder who experienced incomplete resolution of psychotic features with conventional treatment. The integrated computational analysis for identifying and ranking drugs for clinical trials can be iterated as additional data are obtained. Our approach could be expanded to enable disease subtype-specific drug discovery in the future and should also be exploited for other psychiatric disorders.

RNA-Seq time-course analysis of neural precursor cell transcriptome in response to herpes simplex Virus-1 infection.

The neurogenic niches within the central nervous system serve as essential reservoirs for neural precursor cells (NPCs), playing a crucial role in neurogenesis. However, these NPCs are particularly vulnerable to infection by the herpes simplex virus 1 (HSV-1). In the present study, we investigated the changes in the transcriptome of NPCs in response to HSV-1 infection using bulk RNA-Seq, compared to those of uninfected samples, at different time points post infection and in the presence or absence of antivirals. The results showed that NPCs upon HSV-1 infection undergo a significant dysregulation of genes playing a crucial role in aspects of neurogenesis, including genes affecting NPC proliferation, migration, and differentiation. Our analysis revealed that the CREB signaling, which plays a crucial role in the regulation of neurogenesis and memory consolidation, was the most consistantly downregulated pathway, even in the presence of antivirals. Additionally, cholesterol biosynthesis was significantly downregulated in HSV-1-infected NPCs. The findings from this study, for the first time, offer insights into the intricate molecular mechanisms that underlie the neurogenesis impairment associated with HSV-1 infection.

Truncated ring-A amaryllidaceae alkaloid modulates the host cell integrated stress response, exhibiting antiviral activity to HSV-1 and SARSCoV-2.

The total synthesis of four novel mono-methoxy and hydroxyl substituted ring-A dihydronarciclasine derivatives enabled identification of the 7-hydroxyl derivative as a potent and selective antiviral agent targeting SARSCoV-2 and HSV-1. The concentration of this small molecule that inhibited HSV-1 infection by 50% (IC50), determined by using induced pluripotent stem cells (iPCS)-derived brain organ organoids generated from two iPCS lines, was estimated to be 0.504 µM and 0.209 µM. No significant reduction in organoid viability was observed at concentrations up to 50 mM. Genomic expression analyses revealed a significant effect on host-cell innate immunity, revealing activation of the integrated stress response via PERK kinase upregulation, phosphorylation of eukaryotic initiation factor 2α (eIF2α) and type I IFN, as factors potentiating multiple host-defense mechanisms against viral infection. Following infection of mouse eyes with HSV-1, treatment with the compound dramatically reduced HSV-1 shedding in vivo.

The Impaired Neurodevelopment of Human Neural Rosettes in HSV-1-Infected Early Brain Organoids.

Intrauterine infections during pregnancy by herpes simplex virus (HSV) can cause significant neurodevelopmental deficits in the unborn/newborn, but clinical studies of pathogenesis are challenging, and while animal models can model some aspects of disease, in vitro studies of human neural cells provide a critical platform for more mechanistic studies. We utilized a reductionist approach to model neurodevelopmental outcomes of HSV-1 infection of neural rosettes, which represent the in vitro equivalent of differentiating neural tubes. Specifically, we employed early-stage brain organoids (ES-organoids) composed of human induced pluripotent stem cells (hiPSCs)-derived neural rosettes to investigate aspects of the potential neuropathological effects induced by the HSV-1 infections on neurodevelopment. To allow for the long-term differentiation of ES-organoids, viral infections were performed in the presence of the antiviral drug acyclovir (ACV). Despite the antiviral treatment, HSV-1 infection caused organizational changes in neural rosettes, loss of structural integrity of infected ES-organoids, and neuronal alterations. The inability of ACV to prevent neurodegeneration was associated with the generation of ACV-resistant mutants during the interaction of HSV-1 with differentiating neural precursor cells (NPCs). This study models the effects of HSV-1 infection on the neuronal differentiation of NPCs and suggests that this environment may allow for accelerated development of ACV-resistance.

Insights into bioinformatic approaches for repurposing compounds as anti-viral drugs.

BACKGROUND: Drug repurposing is a cost-effective strategy to identify drugs with novel effects. We searched for drugs exhibiting inhibitory activity to Herpes Simplex virus 1 (HSV-1). Our strategy utilized gene expression data generated from HSV-1-infected cell cultures which was paired with drug effects on gene expression. Gene expression data from HSV-1 infected and uninfected neurons were analyzed using BaseSpace Correlation Engine (Illumina®). Based on the general Signature Reversing Principle (SRP), we hypothesized that the effects of candidate antiviral drugs on gene expression would be diametrically opposite (negatively correlated) to those effects induced by HSV-1 infection. RESULTS: We initially identified compounds capable of inducing changes in gene expression opposite to those which were consequent to HSV-1 infection. The most promising negatively correlated drugs (Valproic acid, Vorinostat) did not significantly inhibit HSV-1 infection further in African green monkey kidney epithelial cells (Vero cells). Next, we tested Sulforaphane and Menadione which showed effects similar to those caused by viral infections (positively correlated). Intriguingly, Sulforaphane caused a modest but significant inhibition of HSV-1 infection in Vero cells (IC50 = 180.4 µM, p = 0.008), but exhibited toxicity when further explored in human neuronal progenitor cells (NPCs) derived from induced pluripotent stem cells. CONCLUSIONS: These results reveal the limits of the commonly used SRP strategy when applied to the identification of novel antiviral drugs and highlight the necessity to refine the SRP strategy to increase its utility.

Adjunctive yoga training for persons with schizophrenia: who benefits?

OBJECTIVE: The aim of this study was to identify factors associated with acceptability and efficacy of yoga training (YT) for improving cognitive dysfunction in individuals with schizophrenia (SZ). METHODS: We analysed data from two published clinical trials of YT for cognitive dysfunction among Indians with SZ: (1) a 21-day randomised controlled trial (RCT, N = 286), 3 and 6 months follow-up and (2) a 21-day open trial (n = 62). Multivariate analyses were conducted to examine the association of baseline characteristics (age, sex, socio-economic status, educational status, duration, and severity of illness) with improvement in cognition (i.e. attention and face memory) following YT. Factors associated with acceptability were identified by comparing baseline demographic variables between screened and enrolled participants as well as completers versus non-completers. RESULTS: Enrolled participants were younger than screened persons who declined participation (t = 2.952, p = 0.003). No other characteristics were associated with study enrollment or completion. Regarding efficacy, schooling duration was nominally associated with greater and sustained cognitive improvement on a measure of facial memory. No other baseline characteristics were associated with efficacy of YT in the open trial, the RCT, or the combined samples (n = 148). CONCLUSIONS: YT is acceptable even among younger individuals with SZ. It also enhances specific cognitive functions, regardless of individual differences in selected psychosocial characteristics. Thus, yoga could be incorporated as adjunctive therapy for patients with SZ. Importantly, our results suggest cognitive dysfunction is remediable in persons with SZ across the age spectrum.

Outcomes from Indo-United States-Egypt tri-national psychiatric research training programmes.

BACKGROUND: The prevalence of mental health disorders is increasing globally. Countries in South Asia, Southeast Asia and the Middle East regions carry high burdens of mental health need; however, there are relatively few mental health research publications from this region, suggesting inadequate research funds and a paucity of qualified research personnel. To increase and strengthen the pool of mental health researchers in India and Egypt, we conducted three psychiatric research programmes in these countries: the Training Program for Psychiatric Genetics in India (2002-2011), the Tri-National Training Program for Psychiatric Genetics (2009-2014) and the Cross-Fertilized Research Training for New Investigators in Egypt and India (2014-2019). A total of 66 trainees, including psychiatrists, psychiatric social workers, clinical psychologists and research psychologists, were supported in research development, which included didactic training, proposal development, hands-on research and manuscript preparation. METHODS: The aim of this study is to evaluate these three training programmes using the four-level Kirkpatrick Model of Training Evaluation that assesses reaction, learning, behaviour and outcomes. A descriptive analysis was used to explore the data collected throughout the duration of the three training programmes. Online surveys were crafted and sent to the mentors and trainees of the three programmes to supplement objective training data. RESULTS: In addition to positive changes in the areas of reaction, learning and behaviour, significant outcomes were demonstrated. As of the writing of this manuscript, the trainees published a total of 130 papers, 59 as first author. In addition, 26 trainees have co-authored papers with one or more trainees or mentors, which demonstrates successful research networking and collaboration. CONCLUSION: Our findings suggest that our training approach is a successful model for building independent mental health researchers. This is a critical step in the development of effective mental health interventions in low- and middle-income countries.

Herpes Simplex Virus Type-1 Infection: Associations with Inflammation and Cognitive Aging in Relation to Schizophrenia.

Most persons experience cognitive decline as they grow older. The term "cognitive aging," coined to describe milder varieties of cognitive decline, is likely to be due to multiple causes. Persistent or repeated infections of the central nervous system (whether subclinical or diagnosable) can cause damage to neurons directly or indirectly through inflammation resulting in incremental neuronal damage, thus eroding cognitive reserve. This possibility has not been considered widely. We evaluated the data linking persistent infection with herpes simplex virus type 1 (HSV-1) and cognitive aging by applying the Bradford Hill criteria. Despite inherent problems in establishing causal relations for chronic disorders, our analyses suggest plausible links. These studies are pertinent for patients with schizophrenia, who are particularly vulnerable due to disorder-related cognitive impairment. Further investigations are warranted to test a causal hypothesis, particularly prospective studies and intervention studies.

Mirtazapine in comorbid major depression and an alcohol use disorder: A double-blind placebo-controlled pilot trial.

This was a first double-blind, placebo-controlled pilot study to evaluate the efficacy of the novel antidepressant medication mirtazapine for treating both the depressive symptoms and the level of alcohol consumption of subjects with comorbid major depressive disorder and an alcohol use disorder (MDD/AUD). The results of two previous studies of mirtazapine in MDD/AUD subjects had suggested efficacy for mirtazapine for decreasing their level of depressive symptoms, but level of alcohol consumption had not been assessed in those studies. All subjects in this 12-week pilot study were randomized to either mirtazapine or placebo, and also received motivational enhancement therapy. Between-group analyses involving the outcome measures of depressive symptoms, level of alcohol consumption, and level of alcohol craving indicated no significant differences between groups, possibly because of limited sample size. However, within-group t tests in the mirtazapine group showed a significant decrease in depressive symptoms by week 2, also noted at all subsequent assessments (weeks 3, 4, 6, 8, 10, and 12) during the 12-week study. In contrast, no significant decrease in depressive symptoms was noted in the placebo group until week 8. No evidence of efficacy was found for mirtazapine for decreasing level of alcohol consumption in MDD /AUD subjects.

Mirtazapine in Comorbid Major Depression and Alcohol Use Disorder: A Long-Term Follow-Up Study.

BACKGROUND/OBJECTIVE: To date, pharmacotherapy trials of depressed alcoholics (MDD/AUD) have focused on SSRI medications, with disappointing results, so effective treatments for that comorbid population are lacking. Mirtazapine is an FDA-approved medication for treating MDD with a unique pharmacological profile whose efficacy may exceed that of SSRIs. Results from our recent open label study suggest robust acute phase efficacy for mirtazapine for decreasing both the depression and the drinking of that population. However, to date, no studies have evaluated the longer-term efficacy of mirtazapine in that population. We now report findings from a first long-term (two-year) naturalistic follow-up evaluation involving subjects from the acute phase trial. We hypothesized that the improvements would persist at follow-up. METHODS: An eight-week open label study of mirtazapine and motivation therapy was conducted involving persons 18 to 55 years of age with DSM-IV diagnoses of comorbid MDD/AD. Two years after entry into the acute phase study, a long-term evaluation was conducted using the same instruments that had been used at baseline to assess whether the improvements seen during the acute phase trial had persisted. RESULTS: Ten of the twelve patients who entered the acute phase study participated in the follow-up study. The large magnitude improvements (p<.01) in depressive symptoms (BDI), drinking (TLFB), and sleep disturbance (HDRS) persisted at the follow-up evaluation. Two of the subjects demonstrated MDD on structured interview at follow-up, while all ten had demonstrated MDD at baseline. Six of the ten used antidepressants during the follow-up period. At baseline, three were employed, while at follow-up seven were employed. CONCLUSIONS: These findings suggest long-term efficacy for mirtazapine for decreasing the drinking and depression of depressed alcoholics. Double-blind, placebo-controlled studies are warranted to clarify the efficacy of mirtazapine in depressed alcoholics.