Major depressive disorder (MDD) is the leading cause of disability worldwide and is associated with high rates of suicide and medical comorbidities. Current antidepressant medications are suboptimal, as most MDD patients fail to achieve complete remission from symptoms. At present, clinicians are unable to predict which antidepressant is most effective for a particular patient, exposing patients to multiple medication trials and side effects. Since MDD’s etiology includes interactions between genes and environment, the epigenome is of interest for predictive utility and treatment monitoring. Epigenetic mechanisms of antidepressant medications are incompletely understood. Differences in epigenetic profiles may impact treatment response. A systematic literature search yielded 24 studies reporting the interaction between antidepressants and eight genes (BDNF, MAOA, SLC6A2, SLC6A4, HTR1A, HTR1B, IL6, IL11) and whole genome methylation. Methylation of certain sites within BDNF, SLC6A4, HTR1A, HTR1B, IL11, and the whole genome was predictive of antidepressant response. Comparing DNA methylation in patients during depressive episodes, during treatment, in remission, and after antidepressant cessation would help clarify the influence of antidepressant medications on DNA methylation. Individuals’ unique methylation profiles may be used clinically for personalization of antidepressant choice in the future.
Key points Rates of anxiety and depression have increased during the COVID‐19 pandemic in older adults. Younger generations have reported higher rates of anxiety and depression during the pandemic compared to older adults. Factors influencing the risk of mental illness in older adults during the pandemic include sex, age group, location, living situation, socioeconomic status, and medical and psychiatric comorbidities. Strategies for older adults, caregivers, and health‐care providers may mitigate the effects of social isolation on the older adult population.
Glutamate is implicated in the neuropathology of both major depressive disorder and bipolar disorder. Excitatory amino acid transporter 2 (EAAT2) is the major glutamate transporter in the mammalian brain, removing glutamate from the synaptic cleft and transporting it into glia for recycling. It is thereby the principal regulator of extracellular glutamate levels and prevents neuronal excitotoxicity. EAAT2 is a promising target for elucidating the mechanisms by which the glutamate-glutamine cycle interacts with neuronal systems in mood disorders. Forty EAAT2 studies (published January 1992–January 2018) were identified via a systematic literature search. The studies demonstrated that chronic stress/steroids were most commonly associated with decreased EAAT2. In rodents, EAAT2 inhibition worsened depressive behaviors. Human EAAT2 expression usually decreased in depression, with some regional brain differences. Fewer data have been collected regarding the roles and regulation of EAAT2 in bipolar disorder. Future directions for research include correlating EAAT2 and glutamate levels<i></i>in vivo, elucidating genetic variability and epigenetic regulation, clarifying intracellular protein and pharmacologic interactions, and examining EAAT2 in different bipolar mood states. As part of a macromolecular complex within glia, EAAT2 may contribute significantly to intracellular signaling, energy regulation, and cellular homeostasis. An enhanced understanding of this system is needed.
The diagnosis of sarcoid optic neuropathy is time-sensitive, as delayed treatment risks irreversible vision loss. We sought to analyze its characteristics and outcomes. Methods: We performed a multi-center retrospective study of sarcoid optic neuropathy among 5 USA medical centers. Inclusion criteria were: 1) clinical optic neuropathy; 2) optic nerve/sheath enhancement on neuroimaging; 3) pathological confirmation of systemic or nervous system sarcoidosis.Results: Fifty-one patients were included. The median onset age of sarcoid optic neuropathy was 50 years (range, 17-70 years) and 71% were female. The median visual acuity at nadir in the most affected eye was 20/80 (range, 20/20 to no-light-perception). Thirty-four of 50 (68%) patients had radiologic evidence of other nervous system involvement and 20 (39%) patients had symptoms/signs of other cranial nerve dysfunction. Cerebrospinal fluid analysis revealed an elevated white blood cell count in 22 of 31 (71%) patients (median: 14/μL; range: 1-643/ μL). Pathologic confirmation of sarcoidosis was by biopsy of systemic/pulmonary site, 34 (67%); optic nerve/ sheath, 9 (18%); or other nervous system region, 8 (16%). Forty patients improved with treatment (78%), 98% receiving corticosteroids and 65% receiving steroid-sparing immunosuppressants, yet 11/46 patients (24%) had a visual acuity of 20/200 or worse at last follow-up. Conclusions: Sarcoid optic neuropathy frequently occurs with other clinical and radiologic abnormalities caused by neurosarcoidosis and diagnostic confirmation occasionally requires optic nerve/sheath biopsy. Improvement with treatment is common but most patients have some residual visual disability. Improved recognition and a more expeditious diagnosis and treatment may spare patients from permanent vision loss.
Introduction In vivo and in vitro studies suggest that inflammation and oxidative damage may contribute to the pathogenesis of major depressive disorder (MDD) and bipolar disorder (BD). Imbalance between DNA damage and repair is an emerging research area examining pathophysiological mechanisms of these major mood disorders. Objectives This systematic review sought to examine current evidence on the association between mood disorders and deficits in base excision repair (BER), the primary repair mechanism for repair of oxidation-induced DNA lesions. Methods We conducted a comprehensive literature search of Ovid MEDLINE® Epub Ahead of Print, Ovid MEDLINE® In-Process & Other Non-Indexed Citations, Ovid MEDLINE® Daily, EMBASE (1947), and PsycINFO for studies investigating the alterations in base excision repair in patients with MDD or BD. Results A total of 1,364 records were identified. 1,352 records remained after duplicates were removed. 24 records were selected for full-text screening and a remaining 12 articles were included in the qualitative synthesis. SNPs (Single Nucleotide Polymorphisms) of several BER genes have been shown to be associated with MDD and BD. However, it was difficult to draw conclusions from BER gene expression studies due to conflicting findings and the small number of studies. Conclusions Future studies comparing DNA repair during the manic or depressive episode to remission will give us a better insight regarding the role of DNA repair in mood disorders. These alterations might be utilized as diagnostic and prognostic biomarkers as well as measuring treatment response. Disclosure No significant relationships.
Rapid cycling (RC) burdens bipolar disorder (BD) patients further by causing more severe disability and increased suicidality. Because diagnosing RC can be challenging, RC patients are at risk of rapid decline due to delayed suitable treatment. Here, we aimed to identify the differences in the circulating cell-free DNA (cfDNA) methylome between BD patients with and without RC. The cfDNA methylome could potentially be developed as a diagnostic test for BD RC. We extracted cfDNA from plasma samples of BD1 patients (46 RC and 47 non-RC). cfDNA methylation levels were measured by 850K Infinium MethylationEPIC array. Principal component analysis (PCA) was conducted to assess global differences in methylome. cfDNA methylation levels were compared between RC groups using a linear model adjusted for age and sex. PCA suggested differences in methylation profiles between RC groups (p = 0.039) although no significant differentially methylated probes (DMPs; q > 0.15) were found. The top four CpG sites which differed between groups at p < 1E-05 were located in CGGPB1, PEX10, NR0B2, and TP53I11. Gene set enrichment analysis (GSEA) on top DMPs (p < 0.05) showed significant enrichment of gene sets related to nervous system tissues, such as neurons, synapse, and glutamate neurotransmission. Other top notable gene sets were related to parathyroid regulation and calcium signaling. To conclude, our study demonstrated the feasibility of utilizing a microarray method to identify circulating cfDNA methylation sites associated with BD RC and found the top differentially methylated CpG sites were mostly related to the nervous system and the parathyroid.
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