{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,16]],"date-time":"2026-04-16T00:50:06Z","timestamp":1776300606140,"version":"3.50.1"},"reference-count":119,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2019,2,22]],"date-time":"2019-02-22T00:00:00Z","timestamp":1550793600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["Collaborative Research Center 1193"],"award-info":[{"award-number":["Collaborative Research Center 1193"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004836","name":"Det Frie Forskningsr\u00e5d","doi-asserted-by":"publisher","award":["DFF-5053-00103"],"award-info":[{"award-number":["DFF-5053-00103"]}],"id":[{"id":"10.13039\/501100004836","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100011958","name":"Danmarks Frie Forskningsfond","doi-asserted-by":"publisher","award":["8020-00310B"],"award-info":[{"award-number":["8020-00310B"]}],"id":[{"id":"10.13039\/501100011958","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002739","name":"Aarhus Universitets Forskningsfond","doi-asserted-by":"publisher","award":["AU-IDEAS initiative (eMOOD)"],"award-info":[{"award-number":["AU-IDEAS initiative (eMOOD)"]}],"id":[{"id":"10.13039\/501100002739","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010661","name":"Horizon 2020","doi-asserted-by":"publisher","award":["ExEDE"],"award-info":[{"award-number":["ExEDE"]}],"id":[{"id":"10.13039\/100010661","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000874","name":"Brain and Behavior Research Foundation","doi-asserted-by":"publisher","award":["NARSAD Young Investigator 22752"],"award-info":[{"award-number":["NARSAD Young Investigator 22752"]}],"id":[{"id":"10.13039\/100000874","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Gender differences play a pivotal role in the pathophysiology and treatment of major depressive disorder. This is strongly supported by a mean 2:1 female-male ratio of depression consistently observed throughout studies in developed nations. Considering the urgent need to tailor individualized treatment strategies to fight depression more efficiently, a more precise understanding of gender-specific aspects in the pathophysiology and treatment of depressive disorders is fundamental. However, current treatment guidelines almost entirely neglect gender as a potentially relevant factor. Similarly, the vast majority of animal experiments analysing antidepressant treatment in rodent models exclusively uses male animals and does not consider gender-specific effects. Based on the growing interest in innovative and rapid-acting treatment approaches in depression, such as the administration of ketamine, its metabolites or electroconvulsive therapy, this review article summarizes the evidence supporting the importance of gender in modulating response to rapid acting antidepressant treatment. We provide an overview on the current state of knowledge and propose a framework for rodent experiments to ultimately decode gender-dependent differences in molecular and behavioural mechanisms involved in shaping treatment response.<\/jats:p>","DOI":"10.3390\/ijms20040949","type":"journal-article","created":{"date-parts":[[2019,2,22]],"date-time":"2019-02-22T03:49:44Z","timestamp":1550807384000},"page":"949","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":35,"title":["Decoding the Mechanism of Action of Rapid-Acting Antidepressant Treatment Strategies: Does Gender Matter?"],"prefix":"10.3390","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6406-7990","authenticated-orcid":false,"given":"David P.","family":"Herzog","sequence":"first","affiliation":[{"name":"Department of Psychiatry and Psychotherapy, Johannes Gutenberg University Medical Center Mainz, Untere Zahlbacher Stra\u00dfe 8, 55131 Mainz, Germany"},{"name":"Focus Program Translational Neurosciences, Johannes Gutenberg University Medical Center Mainz, Langenbeckstra\u00dfe 1, 55131 Mainz, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0081-0068","authenticated-orcid":false,"given":"Gregers","family":"Wegener","sequence":"additional","affiliation":[{"name":"Translational Neuropsychiatry Unit, Department of Clinical Medicine, Aarhus University, Skovagervej 2, 8240 Risskov, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Klaus","family":"Lieb","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Psychotherapy, Johannes Gutenberg University Medical Center Mainz, Untere Zahlbacher Stra\u00dfe 8, 55131 Mainz, Germany"},{"name":"Focus Program Translational Neurosciences, Johannes Gutenberg University Medical Center Mainz, Langenbeckstra\u00dfe 1, 55131 Mainz, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marianne B.","family":"M\u00fcller","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Psychotherapy, Johannes Gutenberg University Medical Center Mainz, Untere Zahlbacher Stra\u00dfe 8, 55131 Mainz, Germany"},{"name":"Focus Program Translational Neurosciences, Johannes Gutenberg University Medical Center Mainz, Langenbeckstra\u00dfe 1, 55131 Mainz, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giulia","family":"Treccani","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Psychotherapy, Johannes Gutenberg University Medical Center Mainz, Untere Zahlbacher Stra\u00dfe 8, 55131 Mainz, Germany"},{"name":"Focus Program Translational Neurosciences, Johannes Gutenberg University Medical Center Mainz, Langenbeckstra\u00dfe 1, 55131 Mainz, Germany"},{"name":"Translational Neuropsychiatry Unit, Department of Clinical Medicine, Aarhus University, Skovagervej 2, 8240 Risskov, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2019,2,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1672","DOI":"10.1016\/S0140-6736(15)00390-6","article-title":"Addressing the burden of mental, neurological and substance use disorders: Key messages from Disease Control Priorities","volume":"387","author":"Patel","year":"2016","journal-title":"Lancet"},{"key":"ref_2","unstructured":"WHO (2018, October 10). World Health Organization Factsheet: Depression. Available online: www.who.int\/news-room\/fact-sheets\/detail\/depression."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"593","DOI":"10.1001\/archpsyc.62.6.593","article-title":"Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication","volume":"62","author":"Kessler","year":"2005","journal-title":"Arch. Gen. Psychiatry"},{"key":"ref_4","unstructured":"NICE (2019, January 02). Depression in Adults: Recognition and Management\u2014National Institute for Health and Care Excellence Guidelines [CG90]. Available online: www.nice.org.uk\/guidance\/cg90."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1001\/jamapsychiatry.2013.2819","article-title":"Longitudinal pattern of depressive symptoms around natural menopause","volume":"71","author":"Freeman","year":"2014","journal-title":"JAMA Psychiatry"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1124\/pr.109.002071","article-title":"Estrogen actions in the brain and the basis for differential action in men and women: A case for sex-specific medicines","volume":"62","author":"Gillies","year":"2010","journal-title":"Pharmacol. Rev."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1485","DOI":"10.1038\/aps.2013.160","article-title":"The neuroprotective effects of progesterone on traumatic brain injury: Current status and future prospects","volume":"34","author":"Wei","year":"2013","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1016\/0165-0327(93)90026-G","article-title":"Sex and depression in the National Comorbidity Survey. I: Lifetime prevalence, chronicity and recurrence","volume":"29","author":"Kessler","year":"1993","journal-title":"J. Affect. Disord."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S0165-0327(99)00158-5","article-title":"Gender differences in chronic major and double depression","volume":"60","author":"Kornstein","year":"2000","journal-title":"J. Affect. Disord."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1016\/j.jad.2004.09.008","article-title":"Gender differences in depression: findings from the STAR*D study","volume":"87","author":"Marcus","year":"2005","journal-title":"J. Affect. Disord."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1007\/s40572-017-0172-x","article-title":"Sex-Specific Epigenetics: Implications for Environmental Studies of Brain and Behavior","volume":"4","author":"Kundakovic","year":"2017","journal-title":"Curr. Environ. Health Rep."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"LeGates, T.A., Kvarta, M.D., and Thompson, S.M. (2018). Sex differences in antidepressant efficacy. Neuropsychopharmacology.","DOI":"10.1038\/s41386-018-0156-z"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"373","DOI":"10.31887\/DCNS.2016.18.4\/jmarrocco","article-title":"Sex in the brain: Hormones and sex differences","volume":"18","author":"Marrocco","year":"2016","journal-title":"Dial. Clin. Neurosci."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"447","DOI":"10.31887\/DCNS.2016.18.4\/ncutler","article-title":"Sex differences in the psychopharmacological treatment of depression","volume":"18","author":"Sramek","year":"2016","journal-title":"Dial. Clin. Neurosci."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1176\/appi.ajp.158.4.587","article-title":"Gender differences in the rates of exposure to stressful life events and sensitivity to their depressogenic effects","volume":"158","author":"Kendler","year":"2001","journal-title":"Am. J. Psychiatry"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Bundy, J.L., Vied, C., and Nowakowski, R.S. (2017). Sex differences in the molecular signature of the developing mouse hippocampus. BMC Genom., 18.","DOI":"10.1186\/s12864-017-3608-7"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1186\/s13059-015-0815-x","article-title":"The estrous cycle surpasses sex differences in regulating the transcriptome in the rat medial prefrontal cortex and reveals an underlying role of early growth response 1","volume":"16","author":"Duclot","year":"2015","journal-title":"Genome Biol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1102","DOI":"10.1038\/nm.4386","article-title":"Sex-specific transcriptional signatures in human depression","volume":"23","author":"Labonte","year":"2017","journal-title":"Nat. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1412745","DOI":"10.1080\/20008198.2017.1412745","article-title":"Dissecting the molecular mechanisms of gene x environment interactions: Implications for diagnosis and treatment of stress-related psychiatric disorders","volume":"8","author":"Binder","year":"2017","journal-title":"Eur. J. Psychotraumatol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"454","DOI":"10.1001\/jamapsychiatry.2013.4291","article-title":"Epigenetic mechanisms of depression","volume":"71","author":"Nestler","year":"2014","journal-title":"JAMA Psychiatry"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"690","DOI":"10.1038\/nn.3988","article-title":"Brain feminization requires active repression of masculinization via DNA methylation","volume":"18","author":"Nugent","year":"2015","journal-title":"Nat. Neurosci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1016\/j.yhbeh.2006.06.033","article-title":"Stress sensitivity and the development of affective disorders","volume":"50","author":"Bale","year":"2006","journal-title":"Horm. Behav."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"607","DOI":"10.1055\/s-0032-1312592","article-title":"Sex, stress and mood disorders: At the intersection of adrenal and gonadal hormones","volume":"44","author":"Fiedler","year":"2012","journal-title":"Horm. Metab. Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"664","DOI":"10.3109\/10253890.2013.840282","article-title":"Stressor-specific effects of sex on HPA axis hormones and activation of stress-related neurocircuitry","volume":"16","author":"Babb","year":"2013","journal-title":"Stress (Amsterdam, Netherlands)"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.psyneuen.2014.10.026","article-title":"Hippocampal gene expression induced by cold swim stress depends on sex and handling","volume":"52","author":"Bohacek","year":"2015","journal-title":"Psychoneuroendocrinology"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"689","DOI":"10.1016\/S0306-4522(97)00233-9","article-title":"Sex differences in dendritic atrophy of CA3 pyramidal neurons in response to chronic restraint stress","volume":"81","author":"Galea","year":"1997","journal-title":"Neuroscience"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1045","DOI":"10.1016\/j.neuroscience.2005.06.083","article-title":"Chronic stress enhances spatial memory in ovariectomized female rats despite CA3 dendritic retraction: Possible involvement of CA1 neurons","volume":"135","author":"McLaughlin","year":"2005","journal-title":"Neuroscience"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"448","DOI":"10.1016\/j.biopsych.2015.12.025","article-title":"Sex Differences in Effects of Ketamine on Behavior, Spine Density and Synaptic Proteins in Socially Isolated Rats","volume":"80","author":"Sarkar","year":"2016","journal-title":"Biol. Psychiatry"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1121","DOI":"10.1152\/physrev.1986.66.4.1121","article-title":"Adrenal steroid receptors and actions in the nervous system","volume":"66","author":"McEwen","year":"1986","journal-title":"Physiol. Rev."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2549","DOI":"10.1523\/JNEUROSCI.12-07-02549.1992","article-title":"Estradiol mediates fluctuation in hippocampal synapse density during the estrous cycle in the adult rat","volume":"12","author":"Woolley","year":"1992","journal-title":"J. Neurosci."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1016\/0006-8993(95)01059-9","article-title":"LTP varies across the estrous cycle: Enhanced synaptic plasticity in proestrus rats","volume":"703","author":"Warren","year":"1995","journal-title":"Brain Res."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Hagemann, G., Ugur, T., Schleussner, E., Mentzel, H.J., Fitzek, C., Witte, O.W., and Gaser, C. (2011). Changes in brain size during the menstrual cycle. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0014655"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1176\/appi.ajp.2012.11081302","article-title":"Premenstrual dysphoric disorder: Evidence for a new category for DSM-5","volume":"169","author":"Epperson","year":"2012","journal-title":"Am. J. Psychiatry"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/j.psyneuen.2011.04.015","article-title":"Chronic juvenile stress produces corticolimbic dendritic architectural remodeling and modulates emotional behavior in male and female rats","volume":"37","author":"Eiland","year":"2012","journal-title":"Psychoneuroendocrinology"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1177\/1534582305277152","article-title":"Effect of estrogen-serotonin interactions on mood and cognition","volume":"4","author":"Amin","year":"2005","journal-title":"Behav. Cogn. Neurosci. Rev."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"438","DOI":"10.1136\/jnnp.43.5.438","article-title":"Tryptophan, 5-hydroxyindoleacetic acid and indoleacetic acid in human cerebrospinal fluid: Interrelationships and the influence of age, sex, epilepsy and anticonvulsant drugs","volume":"43","author":"Young","year":"1980","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1002\/syn.1084","article-title":"Sex differences in [123I]beta-CIT SPECT measures of dopamine and serotonin transporter availability in healthy smokers and nonsmokers","volume":"41","author":"Staley","year":"2001","journal-title":"Synapse"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"231","DOI":"10.4306\/pi.2010.7.4.231","article-title":"The roles of BDNF in the pathophysiology of major depression and in antidepressant treatment","volume":"7","author":"Lee","year":"2010","journal-title":"Psychiatry Investig."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1037\/a0026708","article-title":"Estrogen effects on the brain: Actions beyond the hypothalamus via novel mechanisms","volume":"126","author":"McEwen","year":"2012","journal-title":"Behav. Neurosci."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"485","DOI":"10.3109\/09540261.2010.496448","article-title":"Gender differences in antidepressant drug response","volume":"22","author":"Keers","year":"2010","journal-title":"Int. Rev. Psychiatry"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"370","DOI":"10.1176\/appi.ajp.161.2.370","article-title":"Response to tricyclic antidepressants: Independent of gender?","volume":"161","author":"Wohlfarth","year":"2004","journal-title":"Am. J. Psychiatry"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1097\/01.jcp.0000168879.03169.ce","article-title":"Sex differences in antidepressant response in recent antidepressant clinical trials","volume":"25","author":"Khan","year":"2005","journal-title":"J. Clin. Psychopharmacol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1445","DOI":"10.1176\/appi.ajp.157.9.1445","article-title":"Gender differences in treatment response to sertraline versus imipramine in chronic depression","volume":"157","author":"Kornstein","year":"2000","journal-title":"Am. J. Psychiatry"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1439","DOI":"10.1176\/ps.2009.60.11.1439","article-title":"What did STAR*D teach us? Results from a large-scale, practical, clinical trial for patients with depression","volume":"60","author":"Gaynes","year":"2009","journal-title":"Psychiatr. Serv."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1016\/j.jad.2006.04.029","article-title":"Different gender response to serotonergic and noradrenergic antidepressants. A comparative study of the efficacy of citalopram and reboxetine","volume":"95","author":"Berlanga","year":"2006","journal-title":"J. Affect. Disord."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"508","DOI":"10.4088\/JCP.v60n0802","article-title":"The long-term outcome of dysthymia in private practice: Clinical features, temperament and the art of management","volume":"60","author":"Haykal","year":"1999","journal-title":"J. Clin. Psychiatry"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1097\/00019442-199721520-00002","article-title":"Estrogen replacement and response to fluoxetine in a multicenter geriatric depression trial. Fluoxetine Collaborative Study Group","volume":"5","author":"Schneider","year":"1997","journal-title":"Am. J. Geriatr. Psychiatry"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"609","DOI":"10.1089\/jwh.2005.14.609","article-title":"Relative antidepressant efficacy of venlafaxine and SSRIs: Sex-age interactions","volume":"14","author":"Thase","year":"2005","journal-title":"J. Womens Health (Larchmt)"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"941","DOI":"10.1002\/da.22328","article-title":"Gender as predictor and moderator of outcome in cognitive behavior therapy and pharmacotherapy for adult depression: An \u201cindividual patient data\u201d meta-analysis","volume":"31","author":"Cuijpers","year":"2014","journal-title":"Depress. Anxiety"},{"key":"ref_50","unstructured":"NIMH (2019, February 13). RDoC Matrix, Available online: https:\/\/www.nimh.nih.gov\/research-priorities\/rdoc\/constructs\/rdoc-matrix.shtml."},{"key":"ref_51","first-page":"241","article-title":"Clomipramine metabolism. Model-based analysis of variability factors from drug monitoring data","volume":"19","author":"Balant","year":"1990","journal-title":"Clin. Pharmacokinet."},{"key":"ref_52","first-page":"276","article-title":"Plasma levels of amitriptyline: Effect of age and sex","volume":"46","author":"Preskorn","year":"1985","journal-title":"J. Clin. Psychiatry"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"735","DOI":"10.1007\/s40261-015-0332-4","article-title":"Patterns of antidepressant use in Italy: Therapy duration, adherence and switching","volume":"35","author":"Piccinni","year":"2015","journal-title":"Clin. Drug Investig."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1016\/j.jad.2018.02.085","article-title":"Clinical and psychopathological features associated with treatment-emergent mania in bipolar-II depressed outpatients exposed to antidepressants","volume":"234","author":"Fornaro","year":"2018","journal-title":"J. Affect. Disord."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"494","DOI":"10.1016\/j.phrs.2018.10.025","article-title":"The emergence of loss of efficacy during antidepressant drug treatment for major depressive disorder: An integrative review of evidence, mechanisms and clinical implications","volume":"139","author":"Fornaro","year":"2019","journal-title":"Pharmacol. Res."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1155\/2013\/984845","article-title":"Biomarkers predicting antidepressant treatment response: How can we advance the field?","volume":"35","author":"Labermaier","year":"2013","journal-title":"Dis. Mark."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"512","DOI":"10.3389\/fpsyt.2018.00512","article-title":"Understanding and Predicting Antidepressant Response: Using Animal Models to Move Toward Precision Psychiatry","volume":"9","author":"Herzog","year":"2018","journal-title":"Front. Psychiatry"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"pyv124","DOI":"10.1093\/ijnp\/pyv124","article-title":"Effects of Low-Dose and Very Low-Dose Ketamine among Patients with Major Depression: A Systematic Review and Meta-Analysis","volume":"19","author":"Xu","year":"2016","journal-title":"Int. J. Neuropsychopharmacol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"856","DOI":"10.1001\/archpsyc.63.8.856","article-title":"A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression","volume":"63","author":"Zarate","year":"2006","journal-title":"Arch. Gen. Psychiatry"},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"De Berardis, D., Fornaro, M., Valchera, A., Cavuto, M., Perna, G., Di Nicola, M., Serafini, G., Carano, A., Pompili, M., and Vellante, F. (2018). Eradicating Suicide at Its Roots: Preclinical Bases and Clinical Evidence of the Efficacy of Ketamine in the Treatment of Suicidal Behaviors. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19102888"},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Tomasetti, C., Iasevoli, F., Buonaguro, E.F., De Berardis, D., Fornaro, M., Fiengo, A.L., Martinotti, G., Orsolini, L., Valchera, A., and Di Giannantonio, M. (2017). Treating the Synapse in Major Psychiatric Disorders: The Role of Postsynaptic Density Network in Dopamine-Glutamate Interplay and Psychopharmacologic Drugs Molecular Actions. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18010135"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"959","DOI":"10.1126\/science.1190287","article-title":"mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists","volume":"329","author":"Li","year":"2010","journal-title":"Science"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1038\/nature10130","article-title":"NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses","volume":"475","author":"Autry","year":"2011","journal-title":"Nature"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/j.neuroscience.2015.01.008","article-title":"Sex differences in the rapid and the sustained antidepressant-like effects of ketamine in stress-naive and \u201cdepressed\u201d mice exposed to chronic mild stress","volume":"290","author":"Franceschelli","year":"2015","journal-title":"Neuroscience"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1124\/jpet.118.251652","article-title":"Sex Differences in the Pharmacokinetics of Low-dose Ketamine in Plasma and Brain of Male and Female Rats","volume":"367","author":"Saland","year":"2018","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1016\/j.bcp.2018.03.032","article-title":"Ketamine and ketamine metabolites as novel estrogen receptor ligands: Induction of cytochrome P450 and AMPA glutamate receptor gene expression","volume":"152","author":"Ho","year":"2018","journal-title":"Biochem. Pharmacol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1016\/j.neuropharm.2017.11.022","article-title":"Behavioral and biochemical sensitivity to low doses of ketamine: Influence of estrous cycle in C57BL\/6 mice","volume":"130","author":"Dossat","year":"2018","journal-title":"Neuropharmacology"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"576","DOI":"10.1016\/j.bbr.2016.09.056","article-title":"Lack of effect of chronic ketamine administration on depression-like behavior and frontal cortex autophagy in female and male ICR mice","volume":"317","author":"Kara","year":"2017","journal-title":"Behav. Brain Res."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1038\/nature17998","article-title":"NMDAR inhibition-independent antidepressant actions of ketamine metabolites","volume":"533","author":"Zanos","year":"2016","journal-title":"Nature"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"1900","DOI":"10.1038\/s41386-018-0084-y","article-title":"(2R,6R)-Hydroxynorketamine is not essential for the antidepressant actions of (R)-ketamine in mice","volume":"43","author":"Yamaguchi","year":"2018","journal-title":"Neuropsychopharmacology"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1007\/s40263-018-0492-x","article-title":"Convergent Mechanisms Underlying Rapid Antidepressant Action","volume":"32","author":"Zanos","year":"2018","journal-title":"CNS Drugs"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.neuropharm.2018.06.033","article-title":"(2R,6R)-hydroxynorketamine rescues chronic stress-induced depression-like behavior through its actions in the midbrain periaqueductal gray","volume":"139","author":"Chou","year":"2018","journal-title":"Neuropharmacology"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"e3","DOI":"10.1016\/j.biopsych.2017.10.020","article-title":"Common Neurotransmission Recruited in (R,S)-Ketamine and (2R,6R)-Hydroxynorketamine-Induced Sustained Antidepressant-like Effects","volume":"84","author":"Pham","year":"2018","journal-title":"Biol. Psychiatry"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"812","DOI":"10.1038\/mp.2017.241","article-title":"Ketamine enhances structural plasticity in mouse mesencephalic and human iPSC-derived dopaminergic neurons via AMPAR-driven BDNF and mTOR signaling","volume":"23","author":"Cavalleri","year":"2018","journal-title":"Mol. Psychiatry"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"1425","DOI":"10.1097\/WNR.0000000000001131","article-title":"(2R,6R)-Hydroxynorketamine promotes dendrite outgrowth in human inducible pluripotent stem cell-derived neurons through AMPA receptor with timing and exposure compatible with ketamine infusion pharmacokinetics in humans","volume":"29","author":"Collo","year":"2018","journal-title":"Neuroreport"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"2066","DOI":"10.1038\/mp.2017.239","article-title":"Ketamine and its metabolite (2R,6R)-hydroxynorketamine induce lasting alterations in glutamatergic synaptic plasticity in the mesolimbic circuit","volume":"23","author":"Yao","year":"2017","journal-title":"Mol. Psychiatry"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1093\/ijnp\/pyx108","article-title":"Lack of Antidepressant Effects of (2R,6R)-Hydroxynorketamine in a Rat Learned Helplessness Model: Comparison with (R)-Ketamine","volume":"21","author":"Shirayama","year":"2018","journal-title":"Int. J. Neuropsychopharmacol."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"e43","DOI":"10.1016\/j.biopsych.2016.12.020","article-title":"(R)-Ketamine Shows Greater Potency and Longer Lasting Antidepressant Effects Than Its Metabolite (2R,6R)-Hydroxynorketamine","volume":"82","author":"Yang","year":"2017","journal-title":"Biol. Psychiatry"},{"key":"ref_79","doi-asserted-by":"crossref","unstructured":"Thomas, A.M., and Duman, R.S. (2017). Novel rapid-acting antidepressants: Molecular and cellular signaling mechanisms. Neuronal Signal., 1.","DOI":"10.1042\/NS20170010"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"2556","DOI":"10.2174\/1381612824666180730104707","article-title":"Rapid-Acting Antidepressants","volume":"24","author":"Witkin","year":"2018","journal-title":"Curr. Pharm. Des."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"1121","DOI":"10.1001\/archpsyc.63.10.1121","article-title":"Antidepressant efficacy of the antimuscarinic drug scopolamine: A randomized, placebo-controlled clinical trial","volume":"63","author":"Furey","year":"2006","journal-title":"Arch. Gen. Psychiatry"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1177\/0269881108094300","article-title":"Mystical-type experiences occasioned by psilocybin mediate the attribution of personal meaning and spiritual significance 14 months later","volume":"22","author":"Griffiths","year":"2008","journal-title":"J. Psychopharmacol."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"47","DOI":"10.2174\/1570159X14666160321122703","article-title":"The Development of Rapastinel (Formerly GLYX-13); A Rapid Acting and Long Lasting Antidepressant","volume":"15","author":"Moskal","year":"2017","journal-title":"Curr. Neuropharmacol."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1097\/01.pra.0000462606.17725.93","article-title":"Randomized proof of concept trial of GLYX-13, an N-methyl-D-aspartate receptor glycine site partial agonist, in major depressive disorder nonresponsive to a previous antidepressant agent","volume":"21","author":"Preskorn","year":"2015","journal-title":"J. Psychiatr. Pract."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1016\/j.coph.2018.02.001","article-title":"mGlu receptors as potential targets for novel antidepressants","volume":"38","author":"Chaki","year":"2018","journal-title":"Curr. Opin. Pharmacol."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"10974","DOI":"10.1021\/acs.jmedchem.6b01119","article-title":"Discovery of (1S,2R,3S,4S,5R,6R)-2-Amino-3-[(3,4-difluorophenyl)sulfanylmethyl]-4-hydroxy-bicy clo[3.1.0]hexane-2,6-dicarboxylic Acid Hydrochloride (LY3020371.HCl): A Potent, Metabotropic Glutamate 2\/3 Receptor Antagonist with Antidepressant-Like Activity","volume":"59","author":"Chappell","year":"2016","journal-title":"J. Med. Chem."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1016\/j.neuropharm.2015.12.021","article-title":"In vitro pharmacological and rat pharmacokinetic characterization of LY3020371, a potent and selective mGlu2\/3 receptor antagonist","volume":"115","author":"Witkin","year":"2017","journal-title":"Neuropharmacology"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"2499","DOI":"10.1038\/npp.2015.112","article-title":"Rapid Antidepressant Action and Restoration of Excitatory Synaptic Strength After Chronic Stress by Negative Modulators of Alpha5-Containing GABAA Receptors","volume":"40","author":"Fischell","year":"2015","journal-title":"Neuropsychopharmacology"},{"key":"ref_89","doi-asserted-by":"crossref","unstructured":"Zanos, P., Nelson, M.E., Highland, J.N., Krimmel, S.R., Georgiou, P., Gould, T.D., and Thompson, S.M. (2017). A Negative Allosteric Modulator for alpha5 Subunit-Containing GABA Receptors Exerts a Rapid and Persistent Antidepressant-Like Action without the Side Effects of the NMDA Receptor Antagonist Ketamine in Mice. eNeuro, 4.","DOI":"10.1523\/ENEURO.0285-16.2017"},{"key":"ref_90","doi-asserted-by":"crossref","unstructured":"Sales, A.J., Fogaca, M.V., Sartim, A.G., Pereira, V.S., Wegener, G., Guimaraes, F.S., and Joca, S.R.L. (2018). Cannabidiol Induces Rapid and Sustained Antidepressant-Like Effects Through Increased BDNF Signaling and Synaptogenesis in the Prefrontal Cortex. Mol. Neurobiol.","DOI":"10.1007\/s12035-018-1143-4"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1016\/j.bbr.2016.01.033","article-title":"Antidepressant-like effect of cannabidiol injection into the ventral medial prefrontal cortex-Possible involvement of 5-HT1A and CB1 receptors","volume":"303","author":"Sartim","year":"2016","journal-title":"Behav. Brain Res."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1016\/j.physbeh.2018.12.019","article-title":"Effects of cannabidiol in males and females in two different rat models of depression","volume":"201","author":"Shbiro","year":"2018","journal-title":"Physiol. Behav."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1159\/000443890","article-title":"Prohedonic Effect of Cannabidiol in a Rat Model of Depression","volume":"73","author":"Shoval","year":"2016","journal-title":"Neuropsychobiology"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"3170","DOI":"10.1016\/j.celrep.2018.05.022","article-title":"Psychedelics Promote Structural and Functional Neural Plasticity","volume":"23","author":"Ly","year":"2018","journal-title":"Cell Rep."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1016\/S0006-8993(99)01152-X","article-title":"Autoradiographic localization of alpha5 subunit-containing GABAA receptors in rat brain","volume":"822","author":"Sur","year":"1999","journal-title":"Brain Res."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"558","DOI":"10.1007\/BF02244012","article-title":"Antianxiety effect of cannabidiol in the elevated plus-maze","volume":"100","author":"Guimaraes","year":"1990","journal-title":"Psychopharmacology"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1111\/j.1476-5381.2009.00521.x","article-title":"Antidepressant-like effects of cannabidiol in mice: Possible involvement of 5-HT1A receptors","volume":"159","author":"Zanelati","year":"2010","journal-title":"Br. J. Pharmacol."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1016\/j.jad.2004.05.006","article-title":"Electroconvulsive therapy in depressive illness that has not responded to drug treatment","volume":"83","author":"Husain","year":"2004","journal-title":"J. Affect. Disord."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1038\/nrneurol.2010.30","article-title":"Brain stimulation in psychiatry and its effects on cognition","volume":"6","author":"Hoy","year":"2010","journal-title":"Nat. Rev. Neurol."},{"key":"ref_100","unstructured":"NIMH (2018, October 29). National Institute of Mental Health Information: Brain Stimulation Therapies, Available online: https:\/\/www.nimh.nih.gov\/health\/topics\/brain-stimulation-therapies\/brain-stimulation-therapies.shtml."},{"key":"ref_101","doi-asserted-by":"crossref","unstructured":"The UK ECT Review Group (2003). Efficacy and safety of electroconvulsive therapy in depressive disorders: A systematic review and meta-analysis. Lancet, 361, 799\u2013808.","DOI":"10.1016\/S0140-6736(03)12705-5"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"732","DOI":"10.1016\/j.biopsych.2008.11.029","article-title":"Inflammation and its discontents: The role of cytokines in the pathophysiology of major depression","volume":"65","author":"Miller","year":"2009","journal-title":"Biol. Psychiatry"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"823","DOI":"10.1016\/j.imbio.2016.07.001","article-title":"The role of macrophages in anti-inflammatory activity of antidepressant drugs","volume":"222","author":"Nazimek","year":"2017","journal-title":"Immunobiology"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1097\/YCT.0000000000000127","article-title":"The immune system and electroconvulsive therapy for depression","volume":"30","author":"Guloksuz","year":"2014","journal-title":"J. ECT"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/j.brs.2017.10.013","article-title":"Electroconvulsive therapy, depression, the immune system and inflammation: A systematic review","volume":"11","author":"Yrondi","year":"2018","journal-title":"Brain Stimul."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"2741","DOI":"10.1038\/npp.2016.86","article-title":"Relationship Between Hippocampal Volume, Serum BDNF and Depression Severity Following Electroconvulsive Therapy in Late-Life Depression","volume":"41","author":"Bouckaert","year":"2016","journal-title":"Neuropsychopharmacology"},{"key":"ref_107","first-page":"551","article-title":"Changes in serial dexamethasone suppression tests among unipolar depressive receiving electroconvulsive treatment","volume":"16","author":"Albala","year":"1981","journal-title":"Biol. Psychiatry"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1111\/j.1600-0447.2005.00625.x","article-title":"HPA axis normalization, estimated by DEX\/CRH test but less alteration on cerebral glucose metabolism in depressed patients receiving ECT after medication treatment failures","volume":"112","author":"Yuuki","year":"2005","journal-title":"Acta Psychiatr. Scand."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1111\/j.1600-0447.1990.tb03053.x","article-title":"Corticotropin, cortisol and beta-endorphin responses to the human corticotropin-releasing hormone during melancholia and after unilateral electroconvulsive therapy","volume":"82","author":"Dored","year":"1990","journal-title":"Acta Psychiatr. Scand."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"793","DOI":"10.4088\/JCP.08m04746blu","article-title":"Electroconvulsive therapy decreases dopamine D(2)receptor binding in the anterior cingulate in patients with depression: A controlled study using positron emission tomography with radioligand [(1)(1)C]FLB 457","volume":"71","author":"Saijo","year":"2010","journal-title":"J. Clin. Psychiatry"},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"1043","DOI":"10.1016\/S0006-3223(00)00228-6","article-title":"Increased neurogenesis in a model of electroconvulsive therapy","volume":"47","author":"Madsen","year":"2000","journal-title":"Biol. Psychiatry"},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1016\/j.euroneuro.2008.12.007","article-title":"Repeated electroconvulsive seizures increase the total number of synapses in adult male rat hippocampus","volume":"19","author":"Chen","year":"2009","journal-title":"Eur. Neuropsychopharmacol."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1017\/neu.2016.62","article-title":"Structural-functional brain changes in depressed patients during and after electroconvulsive therapy","volume":"30","author":"Yrondi","year":"2018","journal-title":"Acta Neuropsychiatr."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1002\/hup.2531","article-title":"Genetic mechanisms of electroconvulsive therapy response in depression","volume":"31","author":"Stein","year":"2016","journal-title":"Hum. Psychopharmacol."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1097\/YCT.0000000000000141","article-title":"Epigenetic effects of electroconvulsive seizures","volume":"30","author":"Arts","year":"2014","journal-title":"J. ECT"},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"pyw040","DOI":"10.1093\/ijnp\/pyw040","article-title":"Acute and Chronic Electroconvulsive Seizures (ECS) Differentially Regulate the Expression of Epigenetic Machinery in the Adult Rat Hippocampus","volume":"19","author":"Pusalkar","year":"2016","journal-title":"Int. J. Neuropsychopharmacol."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1016\/j.jad.2004.10.002","article-title":"Gender differences in electroconvulsive therapy: A retrospective chart review","volume":"84","author":"Bloch","year":"2005","journal-title":"J. Affect. Disord."},{"key":"ref_118","first-page":"32","article-title":"Is There a Role of Gender in Electroconvulsive Therapy Response?","volume":"26","author":"Bolu","year":"2016","journal-title":"Klinik Psikofarmakoloji B\u00fclteni-Bull. Clin. Psychopharmacol."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1097\/YCT.0000000000000170","article-title":"Effects of COMT, DRD2, BDNF and APOE Genotypic Variation on Treatment Efficacy and Cognitive Side Effects of Electroconvulsive Therapy","volume":"31","author":"Bousman","year":"2015","journal-title":"J. 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