{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T21:38:43Z","timestamp":1792013923809,"version":"4.4.0"},"reference-count":121,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2021,7,10]],"date-time":"2021-07-10T00:00:00Z","timestamp":1625875200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Late-life depression (LLD), compared to depression at a young age, is more likely to have poor prognosis and high risk of progression to dementia. A recent systemic review and meta-analysis of the present antidepressants for LLD showed that the treatment response rate was 48% and the remission rate was only 33.7%, thus implying the need to improve the treatment with other approaches in the future. Recently, agents modulating the glutamatergic system have been tested for mental disorders such as schizophrenia, dementia, and depressive disorder. Ketamine, a noncompetitive NMDA receptor (NMDAR) antagonist, requires more evidence from randomized clinical trials (RCTs) to prove its efficacy and safety in treating LLD. The metabotropic receptors (mGluRs) of the glutamatergic system are family G-protein-coupled receptors, and inhibition of the Group II mGluRs subtypes (mGlu2 and mGlu3) was found to be as effective as ketamine in exerting rapid antidepressant activity in some animal studies. Inflammation has been thought to contribute to depression for a long time. The cytokine levels not only increase with age but also decrease serotonin. Regarding LLD, interleukin 6 (IL-6) and tumor necrosis factor \u03b1 (TNF-\u03b1) released in vivo are likely to contribute to the reduced serotonin level. Brain-derived neurotrophic factor (BDNF), a growth factor and a modulator in the tropomyosin receptor kinase (Trk) family of tyrosine kinase receptors, probably declines quantitatively with age. Recent studies suggest that BDNF\/TrkB decrement may contribute to learning deficits and memory impairment. In the process of aging, physiological changes in combination with geriatric diseases such as vascular diseases result in poorer prognosis of LLD in comparison with that of young-age depression. Treatments with present antidepressants have been generally unsatisfactory. Novel treatments such as anti-inflammatory agents or NMDAR agonists\/antagonists require more studies in LLD. Last but not least, LLD and dementia, which share common pathways and interrelate reciprocally, are a great concern. If it is possible to enhance the treatment of LDD, dementia can be prevented or delated.<\/jats:p>","DOI":"10.3390\/ijms22147421","type":"journal-article","created":{"date-parts":[[2021,7,12]],"date-time":"2021-07-12T00:23:36Z","timestamp":1626049416000},"page":"7421","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":57,"title":["Molecular Basis of Late-Life Depression"],"prefix":"10.3390","volume":"22","author":[{"given":"Chien-Yi","family":"Kuo","sequence":"first","affiliation":[{"name":"Department of Psychiatry, China Medical University Hospital, Taichung 40402, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chieh-Hsin","family":"Lin","sequence":"additional","affiliation":[{"name":"Graduate Institute of Biomedical Sciences, China Medical University, Taichung 40402, Taiwan"},{"name":"Department of Psychiatry, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan"},{"name":"School of Medicine, Chang Gung University, Taoyuan 33302, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2162-8174","authenticated-orcid":false,"given":"Hsien-Yuan","family":"Lane","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, China Medical University Hospital, Taichung 40402, Taiwan"},{"name":"Graduate Institute of Biomedical Sciences, China Medical University, Taichung 40402, Taiwan"},{"name":"Department of Psychology, College of Medical and Health Sciences, Asia University, Taichung 41354, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,7,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"M22","DOI":"10.1093\/geronj\/44.1.M22","article-title":"Depression Among Institutionalized Aged: Assessment and Prevalence Estimation","volume":"44","author":"Parmelee","year":"1989","journal-title":"J. Gerontol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/j.jad.2012.02.036","article-title":"Efficacy of treatment in older depressed patients: A systematic review and meta-analysis of double-blind randomized controlled trials with antidepressants","volume":"141","author":"Kok","year":"2012","journal-title":"J. Affect. Disord."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1961","DOI":"10.1016\/S0140-6736(05)66665-2","article-title":"Depression in the elderly","volume":"365","author":"Alexopoulos","year":"2005","journal-title":"Lancet"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1503\/cmaj.080697","article-title":"Neurobiological mechanisms in major depressive disorder","volume":"180","author":"Rot","year":"2009","journal-title":"Can. Med. Assoc. J."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"5291","DOI":"10.2741\/3598","article-title":"Neurobiology of depression, fibromyalgia and neuropathic pain","volume":"14","author":"Maletic","year":"2009","journal-title":"Front. Biosci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"540","DOI":"10.1177\/0706743716659417","article-title":"Canadian Network for Mood and Anxiety Treatments (CANMAT) 2016 Clinical Guidelines for the Management of Adults with Major Depressive Disorder: Section 3. Pharmacological Treatments","volume":"61","author":"Kennedy","year":"2016","journal-title":"Can. J. Psychiatry"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"588","DOI":"10.1177\/0706743716659276","article-title":"Canadian Network for Mood and Anxiety Treatments (CANMAT) 2016 Clinical Guidelines for the Management of Adults with Major Depressive Disorder: Section 6. Special Populations: Youth, Women, and the Elderly","volume":"61","author":"MacQueen","year":"2016","journal-title":"Can. J. Psychiatry"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2836","DOI":"10.1001\/jama.288.22.2836","article-title":"Collaborative Care Management of Late-Life Depression in the Primary Care Setting","volume":"288","author":"Katon","year":"2002","journal-title":"JAMA"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"785","DOI":"10.1097\/00005650-200108000-00005","article-title":"Improving Primary Care for Depression in Late Life: The Design of a Multicenter Randomized Trial","volume":"39","author":"Katon","year":"2001","journal-title":"Med. Care"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"718","DOI":"10.1176\/appi.ajp.162.4.718","article-title":"Remission in Depressed Geriatric Primary Care Patients: A Report from the PROSPECT Study","volume":"162","author":"Alexopoulos","year":"2005","journal-title":"Am. J. Psychiatry"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1002\/gps.465","article-title":"Pharmacological treatment of depression in older primary care patients: The PROSPECT algorithm","volume":"16","author":"Mulsant","year":"2001","journal-title":"Int. J. Geriatr. Psychiatry"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1016\/S0193-953X(05)70396-8","article-title":"Depression in the elderly: Myths and Misconceptions","volume":"20","author":"Blazer","year":"1997","journal-title":"Psychiatr. Clin. N. Am."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1192\/bjp.bp.111.095950","article-title":"Phenomenology of depression in older compared with younger adults: Meta-analysis","volume":"200","author":"Hegeman","year":"2012","journal-title":"Br. J. Psychiatry"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1016\/j.jad.2012.12.012","article-title":"Age-dependent symptomatology of depression in hospitalized patients and its implications for DSM-5","volume":"150","author":"Szelenberger","year":"2013","journal-title":"J. Affect. Disord."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"543","DOI":"10.1017\/S0033291716002579","article-title":"Age-related variability in the presentation of symptoms of major depressive disorder","volume":"47","author":"Schaakxs","year":"2016","journal-title":"Psychol. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"558","DOI":"10.1097\/01.JGP.0000308883.64832.ed","article-title":"Efficacy of Second Generation Antidepressants in Late-Life Depression: A Meta-Analysis of the Evidence","volume":"16","author":"Nelson","year":"2008","journal-title":"Am. J. Geriatr. Psychiatry"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1660","DOI":"10.4088\/JCP.10r06531","article-title":"Efficacy of Antidepressants for Late-Life Depression: A meta-analysis and meta-regression of placebo-controlled randomized trials","volume":"72","author":"Tedeschini","year":"2011","journal-title":"J. Clin. Psychiatry"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1905","DOI":"10.1176\/ajp.2006.163.11.1905","article-title":"Acute and Longer-Term Outcomes in Depressed Outpatients Requiring One or Several Treatment Steps: A STAR*D Report","volume":"163","author":"Rush","year":"2006","journal-title":"Am. J. Psychiatry"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2404","DOI":"10.1016\/S0140-6736(15)00308-6","article-title":"Efficacy, safety, and tolerability of augmentation pharmacotherapy with aripiprazole for treatment-resistant depression in late life: A randomised, double-blind, placebo-controlled trial","volume":"386","author":"Lenze","year":"2015","journal-title":"Lancet"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"681","DOI":"10.1176\/appi.ajp.2011.10081165","article-title":"A Systematic Review of Treatments for Refractory Depression in Older People","volume":"168","author":"Cooper","year":"2011","journal-title":"Am. J. Psychiatry"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"973","DOI":"10.1016\/j.jagp.2013.01.030","article-title":"Going Beyond Antidepressant Monotherapy for Incomplete Response in Nonpsychotic Late-Life Depression: A Critical Review","volume":"21","author":"Maust","year":"2013","journal-title":"Am. J. Geriatr. Psychiatry"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1016\/j.jagp.2019.10.008","article-title":"Efficacy and Safety of Esketamine Nasal Spray Plus an Oral Antidepressant in Elderly Patients With Treatment-Resistant Depression\u2014TRANSFORM-3","volume":"28","author":"Daly","year":"2020","journal-title":"Am. J. Geriatr. Psychiatry"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"815","DOI":"10.1192\/bjp.150.6.815","article-title":"Range of Mental Illness Among the Elderly in the Community","volume":"150","author":"Copeland","year":"1987","journal-title":"Br. J. Psychiatry"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1001\/archpsyc.57.6.601","article-title":"Prevalence of Depression and Its Treatment in an Elderly Population: The Cache County Study","volume":"57","author":"Steffens","year":"2000","journal-title":"Arch. Gen. Psychiatry"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1885","DOI":"10.2105\/AJPH.90.12.1885","article-title":"Suicide acts in 8 states: Incidence and case fatality rates by demographics and method","volume":"90","author":"Spicer","year":"2000","journal-title":"Am. J. Public Health"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"958","DOI":"10.1093\/eurpub\/ckaa114","article-title":"Sociodemographic and gender determinants of late-life suicide in users and non-users of antidepressants","volume":"30","author":"Hedna","year":"2020","journal-title":"Eur. J. Public Health"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1080\/07317115.2019.1666442","article-title":"Determinants of Suicide-related Ideation in Late Life Depression: Associations with Perceived Stress","volume":"43","author":"Bickford","year":"2020","journal-title":"Clin. Gerontol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1016\/j.jad.2011.02.008","article-title":"Suicide in later life: A comparison between cases with early-onset and late-onset depression","volume":"132","author":"Voshaar","year":"2011","journal-title":"J. Affect. Disord."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1212\/WNL.0b013e3181e62138","article-title":"Depressive symptoms and risk of dementia: The Framingham Heart Study","volume":"75","author":"Saczynski","year":"2010","journal-title":"Neurology"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1055\/s-0032-1321908","article-title":"Changes of Serum Concentrations of Brain-Derived Neurotrophic Factor (BDNF) during Treatment with Venlafaxine and Mirtazapine: Role of Medication and Response to Treatment","volume":"46","author":"Deuschle","year":"2012","journal-title":"Pharmacopsychiatry"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"3354","DOI":"10.1111\/j.1460-9568.2006.05232.x","article-title":"Chronic treatment with high doses of corticosterone decreases cytoskeletal proteins in the rat hippocampus","volume":"24","author":"Cereseto","year":"2006","journal-title":"Eur. J. Neurosci."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"715","DOI":"10.1016\/S0006-3223(00)01021-0","article-title":"Regulation of hippocampal neurogenesis in adulthood","volume":"48","author":"Gould","year":"2000","journal-title":"Biol. Psychiatry"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1007\/s00406-008-0838-3","article-title":"Inverse association of cortisol serum levels with T-tau, P-tau 181 and P-tau 231 peptide levels and T-tau\/A\u03b2 1\u201342 ratios in CSF in patients with mild Alzheimer\u2019s disease dementia","volume":"259","author":"Laske","year":"2008","journal-title":"Eur. Arch. Psychiatry Clin. Neurosci."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41398-019-0514-6","article-title":"Mechanisms and treatment of latelife depression","volume":"9","author":"Alexopoulos","year":"2019","journal-title":"Transl. Psychiatry"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1046\/j.1471-4159.2002.00955.x","article-title":"Effects of systemic and central nervous system localized inflammation on the contributions of metabolic precursors to the l-kynurenine and quinolinic acid pools in brain","volume":"82","author":"Kita","year":"2002","journal-title":"J. Neurochem."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1001\/jamapsychiatry.2014.2427","article-title":"Role of Translocator Protein Density, a Marker of Neuroinflammation, in the Brain During Major Depressive Episodes","volume":"72","author":"Setiawan","year":"2015","journal-title":"JAMA Psychiatry"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1017\/S0033291708003723","article-title":"Associations of C-reactive protein and interleukin-6 with cognitive symptoms of depression: 12-year follow-up of the Whitehall II study","volume":"39","author":"Gimeno","year":"2008","journal-title":"Psychol. Med."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1169","DOI":"10.1017\/S1461145708009309","article-title":"A systematic review and meta-analysis of clinical studies on major depression and BDNF levels: Implications for the role of neuroplasticity in depression","volume":"11","author":"Brunoni","year":"2008","journal-title":"Int. J. Neuropsychopharmacol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1263","DOI":"10.3233\/JAD-2010-100510","article-title":"Amyloid-\u03b2 Peptides in Plasma and Cognitive Decline After 1 Year Follow-Up in Alzheimer\u2019s Disease Patients","volume":"21","author":"Laske","year":"2010","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1017\/S1461145710001008","article-title":"Higher BDNF serum levels predict slower cognitive decline in Alzheimer\u2019s disease patients","volume":"14","author":"Laske","year":"2010","journal-title":"Int. J. Neuropsychopharmacol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3310\/hta17070","article-title":"Study of the use of antidepressants for depression in dementia: The HTA-SADD trial\u2014A multicentre, randomised, double-blind, placebo-controlled trial of the clinical effectiveness and cost-effectiveness of sertraline and mirtazapine","volume":"17","author":"Banerjee","year":"2013","journal-title":"Health Technol. Assess."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"881","DOI":"10.1097\/JGP.0b013e3181b4bf4a","article-title":"Change in Cognitive Functioning Following Acute Antidepressant Treatment in Late-Life Depression","volume":"17","author":"Culang","year":"2009","journal-title":"Am. J. Geriatr. Psychiatry"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1007\/s40266-016-0434-6","article-title":"Management of Depression in Patients with Dementia: Is Pharmacological Treatment Justified?","volume":"34","author":"Ford","year":"2017","journal-title":"Drugs Aging"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1097\/JGP.0b013e3181c796eb","article-title":"Sertraline for the Treatment of Depression in Alzheimer Disease","volume":"18","author":"Rosenberg","year":"2010","journal-title":"Am. J. Geriatr. Psychiatry"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"950","DOI":"10.1176\/appi.ajp.2015.15040465","article-title":"The APA Council of Research Task Force on Novel Biomarkers and Treatments Ketamine and Other NMDA Antagonists: Early Clinical Trials and Possible Mechanisms in Depression","volume":"172","author":"Newport","year":"2015","journal-title":"Am. J. Psychiatry"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1111\/j.1749-6632.1989.tb12485.x","article-title":"Introduction and Overview","volume":"568","author":"Khachaturian","year":"1989","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1007\/s11357-008-9067-y","article-title":"Blueberry-enriched diet ameliorates age-related declines in NMDA receptor-dependent LTP","volume":"30","author":"Coultrap","year":"2008","journal-title":"AGE"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1016\/S0169-328X(01)00344-8","article-title":"Age-related changes in the protein expression of subunits of the NMDA receptor","volume":"99","author":"Magnusson","year":"2002","journal-title":"Mol. Brain Res."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1815","DOI":"10.1111\/j.1460-9568.2007.05431.x","article-title":"Maintenance of superior learning and memory function in NR2B transgenic mice during ageing","volume":"25","author":"Cao","year":"2007","journal-title":"Eur. J. Neurosci."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/j.neuropharm.2011.08.044","article-title":"Signaling pathways underlying the rapid antidepressant actions of ketamine","volume":"62","author":"Duman","year":"2012","journal-title":"Neuropharmacology"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1017\/S1461145711001702","article-title":"mTOR activation is required for the antidepressant effects of mGluR2\/3 blockade","volume":"15","author":"Dwyer","year":"2011","journal-title":"Int. J. Neuropsychopharmacol."},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Wei, Y., Chang, L., and Hashimoto, K. (2021). Molecular mechanisms underlying the antidepressant actions of arketamine: Beyond the NMDA receptor. Mol. Psychiatry, 1\u201315.","DOI":"10.1038\/s41380-021-01121-1"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1119","DOI":"10.1016\/j.jad.2018.12.016","article-title":"Altered mRNA expressions for N-methyl-D-aspartate receptor-related genes in WBC of patients with major depressive disorder","volume":"245","author":"Lin","year":"2019","journal-title":"J. Affect. Disord."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1016\/j.jpsychires.2014.12.007","article-title":"Behavioral and cognitive effects of the N-methyl-D-aspartate receptor co-agonist D-serine in healthy humans: Initial findings","volume":"61","author":"Levin","year":"2015","journal-title":"J. Psychiatr. Res."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"10792","DOI":"10.1021\/acs.jafc.7b04217","article-title":"Acute Amino Acidd-Serine Administration, Similar to Ketamine, Produces Antidepressant-like Effects through Identical Mechanisms","volume":"65","author":"Wei","year":"2017","journal-title":"J. Agric. Food Chem."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"5160","DOI":"10.2174\/1381612819666140110121139","article-title":"The Co-agonist Site of NMDA-glutamate Receptors: A Novel Therapeutic Target for Age-related Cognitive Decline","volume":"20","author":"Scoriels","year":"2014","journal-title":"Curr. Pharm. Des."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1267","DOI":"10.1001\/jamapsychiatry.2013.2159","article-title":"Add-on treatment of benzoate for schizophrenia: A randomized, double-blind, placebo-controlled trial of D-amino acid oxidase inhibitor","volume":"70","author":"Lane","year":"2013","journal-title":"JAMA Psychiatry"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"678","DOI":"10.1016\/j.biopsych.2013.08.010","article-title":"Benzoate, a D-Amino Acid Oxidase Inhibitor, for the Treatment of Early-Phase Alzheimer Disease: A Randomized, Double-Blind, Placebo-Controlled Trial","volume":"75","author":"Lin","year":"2014","journal-title":"Biol. Psychiatry"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"e216156","DOI":"10.1001\/jamanetworkopen.2021.6156","article-title":"Effect of Sodium Benzoate on Cognitive Function Among Patients With Behavioral and Psychological Symptoms of Dementia","volume":"4","author":"Lin","year":"2021","journal-title":"JAMA Netw. Open"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"392","DOI":"10.1093\/ijnp\/pyab001","article-title":"Brain Activity of Benzoate, a D-Amino Acid Oxidase Inhibitor, in Patients With Mild Cognitive Impairment in a Randomized, Double-Blind, Placebo Controlled Clinical Trial","volume":"24","author":"Lane","year":"2021","journal-title":"Int. J. Neuropsychopharmacol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1016\/j.molmed.2015.05.002","article-title":"Molecular aspects of age-related cognitive decline: The role of GABA signaling","volume":"21","author":"McQuail","year":"2015","journal-title":"Trends Mol. Med."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"634","DOI":"10.1111\/acel.12605","article-title":"The space where aging acts: Focus on the GABAergic synapse","volume":"16","year":"2017","journal-title":"Aging Cell"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"705","DOI":"10.1001\/archpsyc.61.7.705","article-title":"Subtype-Specific Alterations of \u03b3-Aminobutyric Acid and Glutamatein Patients with Major Depression","volume":"61","author":"Sanacora","year":"2004","journal-title":"Arch. Gen. Psychiatry"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1002\/(SICI)1097-0029(19981001)43:1<68::AID-JEMT10>3.0.CO;2-W","article-title":"Changes in NMDA receptor\/nitric oxide signaling pathway in the brain with aging","volume":"43","author":"Yamada","year":"1998","journal-title":"Microsc. Res. Tech."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1618","DOI":"10.1126\/science.7907431","article-title":"Requirement for BDNF in activity-dependent survival of cortical neurons","volume":"263","author":"Ghosh","year":"1994","journal-title":"Science"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1016\/j.brainresbull.2009.11.013","article-title":"Neurochemical and behavioural effects of acute and chronic memantine administration in rats: Further support for NMDA as a new pharmacological target for the treatment of depression?","volume":"81","author":"Stringari","year":"2010","journal-title":"Brain Res. Bull."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"648","DOI":"10.1002\/gps.4375","article-title":"Combined treatment with memantine\/es-citalopram for older depressed patients with cognitive impairment: A pilot study","volume":"31","author":"Pelton","year":"2016","journal-title":"Int. J. Geriatr. Psychiatry"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1016\/j.neuron.2010.01.016","article-title":"Group 1 mGluR-Dependent Synaptic Long-Term Depression: Mechanisms and Implications for Circuitry and Disease","volume":"65","author":"Huber","year":"2010","journal-title":"Neuron"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1146\/annurev.pharmtox.37.1.205","article-title":"Pharmacology and functions of metabotropic glutamate receptors","volume":"37","author":"Conn","year":"1997","journal-title":"Annu. Rev. Pharmacol. Toxicol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"597","DOI":"10.1126\/science.1329206","article-title":"Molecular diversity of glutamate receptors and implications for brain function","volume":"258","author":"Nakanishi","year":"1992","journal-title":"Science"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1124\/pr.109.001735","article-title":"Metabotropic Glutamate Receptor-Mediated Long-Term Depression: Molecular Mechanisms","volume":"61","author":"Gladding","year":"2009","journal-title":"Pharmacol. Rev."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"697","DOI":"10.1016\/S0306-4522(02)00652-8","article-title":"Effects of ketamine and n-methyl-d-aspartate on glutamate and dopamine release in the rat prefrontal cortex: Modulation by a group II selective metabotropic glutamate receptor agonist LY379268","volume":"117","author":"Lorrain","year":"2003","journal-title":"Neuroscience"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1723","DOI":"10.1523\/JNEUROSCI.0878-15.2016","article-title":"Metabotropic Glutamate Receptors Induce a Form of LTP Controlled by Translation and Arc Signaling in the Hippocampus","volume":"36","author":"Wang","year":"2016","journal-title":"J. Neurosci."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1007\/7854_2010_36","article-title":"Metabotropic Glutamate Receptors: Their Therapeutic Potential in Anxiety","volume":"2","author":"Spooren","year":"2010","journal-title":"Curr. Top. Behav. Neurosci."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"508","DOI":"10.3389\/fncel.2018.00508","article-title":"Group II Metabotropic Glutamate Receptors Mediate Presynaptic Inhibition of Excitatory Transmission in Pyramidal Neurons of the Human Cerebral Cortex","volume":"12","author":"Bocchio","year":"2019","journal-title":"Front. Cell. Neurosci."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"388","DOI":"10.1016\/j.neuropharm.2015.04.003","article-title":"Group II mGluRs modulate baseline and arthritis pain-related synaptic transmission in the rat medial prefrontal cortex","volume":"95","author":"Kiritoshi","year":"2015","journal-title":"Neuropharmacology"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1016\/S0306-4522(01)00199-3","article-title":"A major role for thalamocortical afferents in serotonergic hallucinogen receptor function in the rat neocortex","volume":"105","author":"Marek","year":"2001","journal-title":"Neuroscience"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"916","DOI":"10.1038\/s41380-017-0015-z","article-title":"Metabotropic glutamate receptor subtype 3 gates acute stress-induced dysregulation of amygdalo-cortical function","volume":"24","author":"Joffe","year":"2019","journal-title":"Mol. Psychiatry"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.neuropharm.2018.10.013","article-title":"Mechanisms underlying prelimbic prefrontal cortex mGlu3\/mGlu5-dependent plasticity and reversal learning deficits following acute stress","volume":"144","author":"Joffe","year":"2019","journal-title":"Neuropharmacology"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1124\/jpet.116.238121","article-title":"Comparative Effects of LY3020371, a Potent and Selective Metabotropic Glutamate (mGlu) 2\/3 Receptor Antagonist, and Ketamine, a Noncompetitive N-Methyl-d-Aspartate Receptor Antagonist in Rodents: Evidence Supporting the Use of mGlu2\/3 Antagonists, for the Treatment of Depression","volume":"361","author":"Witkin","year":"2017","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1046\/j.1471-4159.1995.65010268.x","article-title":"Effect of Acute Stress on Hippocampal Glutamate Levels and Spectrin Proteolysis in Young and Aged Rats","volume":"65","author":"Lowy","year":"2002","journal-title":"J. Neurochem."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1016\/0306-4522(95)00259-L","article-title":"Stress-induced atrophy of apical dendrites of hippocampal CA3c neurons: Involvement of glucocorticoid secretion and excitatory amino acid receptors","volume":"69","author":"Magarinos","year":"1995","journal-title":"Neuroscience"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"763","DOI":"10.3109\/15622971003611319","article-title":"Serum and plasma BDNF levels in major depression: A replication study and meta-analyses","volume":"11","author":"Bagnardi","year":"2010","journal-title":"World J. Biol. Psychiatry"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"1116","DOI":"10.1016\/j.biopsych.2006.02.013","article-title":"A Neurotrophic Model for Stress-Related Mood Disorders","volume":"59","author":"Duman","year":"2006","journal-title":"Biol. Psychiatry"},{"key":"ref_85","first-page":"894","article-title":"The molecular neurobiology of depression","volume":"455","author":"Krishnan","year":"2008","journal-title":"Nat. Cell Biol."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"176","DOI":"10.2174\/1570159X15666170828163048","article-title":"Therapeutic Strategies for Treatment of Inflammation-related Depression","volume":"16","author":"Adzic","year":"2018","journal-title":"Curr. Neuropharmacol."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.bbi.2006.08.009","article-title":"Cytokine-effects on glucocorticoid receptor function: Relevance to glucocorticoid resistance and the pathophysiology and treatment of major depression","volume":"21","author":"Pace","year":"2007","journal-title":"Brain Behav. Immun."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1016\/j.pnpbp.2018.02.004","article-title":"Longitudinal associations between glucocorticoid receptor methylation and late-life depression","volume":"84","author":"Kang","year":"2018","journal-title":"Prog. Neuro-Psychopharmacol. Biol. Psychiatry"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"1017","DOI":"10.1038\/nature04223","article-title":"BDNF from microglia causes the shift in neuronal anion gradient underlying neuropathic pain","volume":"438","author":"Coull","year":"2005","journal-title":"Nature"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"1596","DOI":"10.1016\/j.cell.2013.11.030","article-title":"Microglia promote learning-dependent synapse formation through brain-derived neurotrophic factor","volume":"155","author":"Parkhurst","year":"2013","journal-title":"Cell"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"3518","DOI":"10.1523\/JNEUROSCI.5714-08.2009","article-title":"P2X4-Receptor-Mediated Synthesis and Release of Brain-Derived Neurotrophic Factor in Microglia Is Dependent on Calcium and p38-Mitogen-Activated Protein Kinase Activation","volume":"29","author":"Trang","year":"2009","journal-title":"J. Neurosci."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"689","DOI":"10.1126\/science.7901908","article-title":"Oxidative stress, glutamate, and neurodegenerative disorders","volume":"262","author":"Coyle","year":"1993","journal-title":"Science"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1007\/BF00964611","article-title":"l-Kynurenine Its synthesis and possible regulatory function in brain","volume":"5","author":"Sherman","year":"1980","journal-title":"Neurochem. Res."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1093\/oxfordjournals.jbchem.a131115","article-title":"Properties and Function of Indoleamine 2, 3-Dioxygenase1","volume":"79","author":"Hayaishi","year":"1976","journal-title":"J. Biochem."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1016\/0014-2999(81)90587-2","article-title":"Quinolinic acid: A potent endogenous excitant at amino acid receptors in CNS","volume":"72","author":"Stone","year":"1981","journal-title":"Eur. J. Pharmacol."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"743","DOI":"10.1038\/npp.2012.248","article-title":"Connecting inflammation with glutamate agonism in suicidality","volume":"38","author":"Erhardt","year":"2012","journal-title":"Neuropsychopharmacology"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"446","DOI":"10.1016\/j.biopsych.2009.09.033","article-title":"A Meta-Analysis of Cytokines in Major Depression","volume":"67","author":"Dowlati","year":"2010","journal-title":"Biol. Psychiatry"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"853","DOI":"10.1006\/cyto.1997.0238","article-title":"Increased serum Il-6 and Il-1 receptor antagonist concentrations in major depression and treatment resistant depression","volume":"9","author":"Maes","year":"1997","journal-title":"Cytokine"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1155\/2007\/76396","article-title":"Pro- and Anti-Inflammatory Cytokine Balance in Major Depression: Effect of Sertraline Therapy","volume":"2007","author":"Sutcigil","year":"2007","journal-title":"Clin. Dev. Immunol."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/j.pnpbp.2014.01.013","article-title":"Inflamed moods: A review of the interactions between inflammation and mood disorders","volume":"53","author":"Rosenblat","year":"2014","journal-title":"Prog. Neuro-Psychopharmacol. Biol. Psychiatry"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1016\/j.jad.2007.07.002","article-title":"Inflammatory markers in late-life depression: Results from a population-based study","volume":"106","author":"Bremmer","year":"2008","journal-title":"J. Affect. Disord."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1016\/j.psyneuen.2018.02.006","article-title":"Changes in pro-inflammatory cytokine levels and late-life depression: A two year population based longitudinal study","volume":"90","author":"Kim","year":"2018","journal-title":"Psychoneuroendocrinology"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1002\/gps.4686","article-title":"Associations between pro-inflammatory cytokines, learning, and memory in late-life depression and healthy aging","volume":"33","author":"Charlton","year":"2017","journal-title":"Int. J. Geriatr. Psychiatry"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"1179","DOI":"10.1046\/j.1460-9568.1999.00551.x","article-title":"Expression of TrkB and TrkC but not BDNF mRNA in neurochemically identified interneurons in rat visual cortexin vivoand in organotypic cultures","volume":"11","author":"Gorba","year":"1999","journal-title":"Eur. J. Neurosci."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1016\/0306-4522(96)00093-0","article-title":"Comparative study of brain-derived neurotrophic factor messenger rna and protein at the cellular level suggests multiple roles in hippocampus, striatum and cortex","volume":"74","author":"Wetmore","year":"1996","journal-title":"Neuroscience"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"1525","DOI":"10.1016\/0896-6273(89)90040-8","article-title":"Trophic factors and neuronal survival","volume":"2","author":"Barde","year":"1989","journal-title":"Neuron"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/j.brainresrev.2009.11.008","article-title":"Gliotransmission: Exocytotic release from astrocytes","volume":"63","author":"Parpura","year":"2010","journal-title":"Brain Res. Rev."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1038\/nature19766","article-title":"Autocrine BDNF-TrkB signalling within a single dendritic spine","volume":"538","author":"Harward","year":"2016","journal-title":"Nature"},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"E4475","DOI":"10.1073\/pnas.1511830112","article-title":"Activity-dependent BDNF release via endocytic pathways is regulated by synaptotagmin-6 and complexin","volume":"112","author":"Wong","year":"2015","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"9872","DOI":"10.1074\/jbc.M116.720029","article-title":"Brain-derived Neurotrophic Factor in Megakaryocytes","volume":"291","author":"Fernandez","year":"2016","journal-title":"J. Biol. Chem."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1124\/pr.111.005108","article-title":"Brain-Derived Neurotrophic Factor and Neuropsychiatric Disorders","volume":"64","author":"Autry","year":"2012","journal-title":"Pharmacol. Rev."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"10037","DOI":"10.1073\/pnas.88.22.10037","article-title":"Interplay between glutamate and gamma-aminobutyric acid transmitter systems in the physiological regulation of brain-derived neurotrophic factor and nerve growth factor synthesis in hippocampal neurons","volume":"88","author":"Zafra","year":"1991","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"1199","DOI":"10.1016\/j.jagp.2017.06.007","article-title":"Pilot Randomized Controlled Trial of Titrated Subcutaneous Ketamine in Older Patients with Treatment-Resistant Depression","volume":"25","author":"George","year":"2017","journal-title":"Am. J. Geriatr. Psychiatry"},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"1370","DOI":"10.1038\/mp.2017.144","article-title":"BDNF at the synapse: Why location matters","volume":"22","author":"Song","year":"2017","journal-title":"Mol. Psychiatry"},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1016\/j.jad.2014.07.022","article-title":"Brain-derived neurotrophic factor (BDNF)\u2014Epigenetic regulation in unipolar and bipolar affective disorder","volume":"168","author":"Carlberg","year":"2014","journal-title":"J. Affect. Disord."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1016\/j.jad.2014.05.020","article-title":"Epigenetic modulation of BDNF gene: Differences in DNA methylation between unipolar and bipolar patients","volume":"166","author":"Palazzo","year":"2014","journal-title":"J. Affect. Disord."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"244","DOI":"10.1016\/j.biopsych.2005.06.036","article-title":"Regulation of Hippocampal Gene Expression Is Conserved in Two Species Subjected to Different Stressors and Antidepressant Treatments","volume":"59","author":"Alfonso","year":"2006","journal-title":"Biol. Psychiatry"},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1146\/annurev.pharmtox.011008.145533","article-title":"Metabotropic Glutamate Receptors: Physiology, Pharmacology, and Disease","volume":"50","author":"Niswender","year":"2010","journal-title":"Annu. Rev. Pharmacol. Toxicol."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1016\/j.psc.2013.08.001","article-title":"What Are the Causes of Late-Life Depression?","volume":"36","author":"Aziz","year":"2013","journal-title":"Psychiatr. Clin. N. Am."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1016\/j.pnpbp.2007.07.027","article-title":"Acute administration of ketamine induces antidepressant-like effects in the forced swimming test and increases BDNF levels in the rat hippocampus","volume":"32","author":"Garcia","year":"2008","journal-title":"Prog. Neuro-Psychopharmacol. Biol. Psychiatry"},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1016\/j.jpsychires.2013.11.004","article-title":"Brain-derived neurotrophic factor levels in late-life depression and comorbid mild cognitive impairment: A longitudinal study","volume":"49","author":"Diniz","year":"2014","journal-title":"J. Psychiatr. Res."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/14\/7421\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:28:50Z","timestamp":1760164130000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/14\/7421"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,7,10]]},"references-count":121,"journal-issue":{"issue":"14","published-online":{"date-parts":[[2021,7]]}},"alternative-id":["ijms22147421"],"URL":"https:\/\/doi.org\/10.3390\/ijms22147421","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,7,10]]}}}