Faculty Bibliography

OBJECTIVE:Exposure to antidepressants, particularly agents that work through serotonin-reuptake inhibition, may increase potential for bleeding, especially among patients with other bleeding risk factors. There is limited guidance for clinicians in the use of serotonin reuptake inhibitors (SRIs) and other antidepressants in the setting of increased bleeding risk. METHODS:A PubMed literature search was conducted for English-language articles (1992-2024) examining the bleeding risk associated with antidepressants. Physicians from the Association of Medicine and Psychiatry then convened to develop consensus recommendations. RESULTS:Consensus recommendations were established for managing antidepressant use in patients with medical and psychiatric comorbidities. Additionally, a clinical decision algorithm was created to assist clinicians in assessing the appropriateness of antidepressant prescribing in patients at risk for bleeding. CONCLUSIONS:The proposed algorithm can aid clinicians in determining whether antidepressant (including SRI) initiation, discontinuation, or dose adjustment should be considered for patients susceptible to bleeding. These guidelines preserve a role for clinical judgment in selection of treatments that balance the risks and benefits, which may be particularly relevant for patients with complex medical and psychiatric comorbidities. Additional studies are needed to better guide clinical decision making.

The COVID-19 pandemic profoundly impacted global health, with disproportionate consequences for healthcare workers (HCWs). Religious beliefs and practices may improve psychological resilience by fostering community, providing purpose and giving meaning to hardships. Yet, how religiosity impacts HCWs during a time of crisis is unclear. We therefore performed a cross-sectional study to investigate how religiosity contributes to resilience among HCWs who were routinely exposed to high levels of stress during the pandemic, through a physiological measure (the Auditory Sustained Attention Test; ASAT) and psychological self-reports. Forty-two HCWs were recruited from COVID-19 units and 44 HCWs from general internal medicine units during June and July 2022. COVID-19 HCWs showed significantly elevated emotional and attentional dysregulation with the ASAT, as measured by acoustic startle and prepulse inhibition, that was undetectable with self-reports. Furthermore, after dividing the HCWs into a 'high' and 'low' religiosity group, those in the 'low' group showed higher emotional and attentional dysregulation with the ASAT. Findings suggest that the ASAT has greater sensitivity at detecting emotional and attentional dysregulations than self-reports. Moderate or high religiosity may lead to better performance on the ASAT which could suggest greater resilience to mental health problems in the face of a crisis.

Tardive dyskinesia (TD) is a syndrome that causes chronic, involuntary, and disruptive movements of the body and/or face that is a severe, potentially irreversible adverse effect of long-term antipsychotic use. It has wide-reaching effects on patients' well-being, quality of life,¹ and treatment adherence.² Thus, TD is debilitating, leading to social withdrawal,³ and workplace absenteeism.¹ Current data on tardive dyskinesia treatment are limited, and prevention, primarily through the modification of antipsychotic regimens, remains the most effective strategy.⁴ Recent systematic review has shown valbenazine and vitamin E are the only treatments significantly more effective compared to placebo in treatment of TD, although valbenazine is associated with significant side effects.⁵ We present a case of a 76-year-old female with a diagnosis of Bipolar II Disorder (BD) who developed TD after treatment with lurasidone for 10 years. After struggling with both her BD and TD symptoms for 3 years, she sought care at our clinic where we prescribed 300 mg daily of lithium. At her follow-up visit 5 weeks later, her TD symptoms were greatly improved, with sustained benefits observed at following visits. This article reviews the literature discussing the interplay between lithium and TD and presents a case report of TD improvement after lithium augmentation for treatment-resistant depression. While this case suggests a potential role in TD treatment, the role of lithium in TD treatment remains controversial.

Major depressive disorder is one of the most burdensome mental health disorders. Probiotics have been shown to ameliorate depressive symptoms, though the mechanism remains unclear. This study was conducted to investigate whether extracellular vesicles (EVs) extracted from the probiotic beverage water kefir could influence gene and protein expression in human-derived neuroblastoma cells in vitro. EVs were extracted from lab-cultured water kefir and a control solution without water kefir grains by ultracentrifugation. Water kefir vesicles were imaged via electron microscopy. Neuroblastoma, microglia, and neuroblastoma-microglia co-cultures were exposed to water kefir EVs or negative control medium. Uptake of water kefir EVs was identified by microscopy. All conditions were quantified for brain derived neurotrophic factor, fractalkine, and synaptophysin RNA and protein. Data were analyzed using factorial ANOVAs with significance set at 0.05. Water kefir vesicles were taken up by neuroblastoma cells, and incubation in neuroblastoma-microglia co-culture resulted in significantly higher levels of fractalkine protein compared to media-only control (p = 0.029). To our knowledge, this is the first study to identify potential interactions between EVs derived from the probiotic beverage water kefir and human neuronal cells. Further research is needed to fully elucidate the role played by probiotic-derived EVs in human health.

Alzheimer's disease (AD) is an incurable and progressive neurodegenerative disease with increasing prevalence worldwide. Previous trials of anti-amyloid and anti-tau immunotherapy indicate that additional research needs to be conducted on other mechanisms to find curative or disease-modifying therapy. This review focuses on apolipoprotein E (ApoE), a critical protein in brain lipid metabolism that acts specifically in the clearance and transport of lipids and cholesterol. The ApoE4 allele confers substantial gene dose-dependent risk of developing AD and lowers the age of onset of AD, although the mechanisms of influence remain incompletely understood. The other isoforms bring different levels of AD risk. ApoE2 is protective while ApoE3 is the most common isoform and is considered neutral. An overview is presented of the latest information on the role of ApoE in AD pathogenesis with an emphasis on pathways that are involved in AD development and interactions with crucial processes in different cell types in the brain. Elucidating the key interactions of ApoE with multiple aspects of brain function can be useful for designing novel ApoE-targeted therapeutic approaches.

Nilotinib, a tyrosine kinase inhibitor that targets the Abelson tyrosine kinase (c-Abl) signaling pathway, is FDA-approved to treat chronic myeloid leukemia. Nilotinib has properties indicative of a possible utility in neuroprotection that have prompted exploration of repurposing the drug for the treatment of Alzheimer's disease (AD) and Parkinson's disease (PD). AD is a progressive age-related neurodegenerative disorder characterized by the deposition of extracellular amyloid-β plaques and intracellular neurofibrillary tangles. It is incurable and affects approximately 50 million patients worldwide. Nilotinib reduces c-Abl phosphorylation, amyloid-β levels, and dopaminergic neuron degeneration in preclinical AD models. This study explores the effects of nilotinib on amyloid processing and mitochondrial functioning in the SH-SY5Y human neuroblastoma cell line. SH-SY5Y cells were exposed to nilotinib (1, 5, and 10 µM). Real-time PCR and immunoblot analysis were performed to quantify the expression of genes pertaining to amyloid-β processing and neuronal health. Nilotinib did not significantly change APP, BACE1, or ADAM10 mRNA levels. However, BACE1 protein was significantly increased at 1 µM, and ADAM10 was increased at 10 µM nilotinib without affecting APP protein expression. Further, nilotinib treatment did not affect the expression of genes associated with neuronal health and mitochondrial functioning. Taken together, our findings do not support the efficacy of nilotinib treatment for neuroprotection.

Alzheimer's disease (AD) is the most common form of dementia in older persons [...].

Alzheimer's disease (AD) is a progressive and incurable neurodegenerative disorder that primarily affects persons aged 65 years and above. It causes dementia with memory loss and deterioration in thinking and language skills. AD is characterized by specific pathology resulting from the accumulation in the brain of extracellular plaques of amyloid-β and intracellular tangles of phosphorylated tau. The importance of mitochondrial dysfunction in AD pathogenesis, while previously underrecognized, is now more and more appreciated. Mitochondria are an essential organelle involved in cellular bioenergetics and signaling pathways. Mitochondrial processes crucial for synaptic activity such as mitophagy, mitochondrial trafficking, mitochondrial fission, and mitochondrial fusion are dysregulated in the AD brain. Excess fission and fragmentation yield mitochondria with low energy production. Reduced glucose metabolism is also observed in the AD brain with a hypometabolic state, particularly in the temporo-parietal brain regions. This review addresses the multiple ways in which abnormal mitochondrial structure and function contribute to AD. Disruption of the electron transport chain and ATP production are particularly neurotoxic because brain cells have disproportionately high energy demands. In addition, oxidative stress, which is extremely damaging to nerve cells, rises dramatically with mitochondrial dyshomeostasis. Restoring mitochondrial health may be a viable approach to AD treatment.

Dysregulated cholesterol metabolism represents an increasingly recognized feature of autism spectrum disorder (ASD). Children with fetal valproate syndrome caused by prenatal exposure to valproic acid (VPA), an anti-epileptic and mood-stabilizing drug, have a higher incidence of developing ASD. However, the role of VPA in cholesterol homeostasis in neurons and microglial cells remains unclear. Therefore, we examined the effect of VPA exposure on regulation of cholesterol homeostasis in the human microglial clone 3 (HMC3) cell line and the human neuroblastoma cell line SH-SY5Y. HMC3 and SH-SY5Y cells were each incubated in increasing concentrations of VPA, followed by quantification of mRNA and protein expression of cholesterol transporters and cholesterol metabolizing enzymes. Cholesterol efflux was evaluated using colorimetric assays. We found that VPA treatment in HMC3 cells significantly reduced ABCA1 mRNA, but increased ABCG1 and CD36 mRNA levels in a dose-dependent manner. However, ABCA1 and ABCG1 protein levels were reduced by VPA in HMC3. Furthermore, similar experiments in SH-SY5Y cells showed increased mRNA levels for ABCA1, ABCG1, CD36, and 27-hydroxylase with VPA treatment. VPA exposure significantly reduced protein levels of ABCA1 in a dose-dependent manner, but increased the ABCG1 protein level at the highest dose in SH-SY5Y cells. In addition, VPA treatment significantly increased cholesterol efflux in SH-SY5Y, but had no impact on efflux in HMC3. VPA differentially controls the expression of ABCA1 and ABCG1, but regulation at the transcriptional and translational levels are not consistent and changes in the expression of these genes do not correlate with cholesterol efflux in vitro.