Treatment-resistant depression: molecular mechanisms and management.

Réus GZ, de Moura AB, Borba LA, Abelaira HM, Quevedo J. Strategies for treatment-resistant depression: lessons learned from animal models. Complex Psychiatry. 2019;5(4):178–89. https://doi.org/10.1159/000500324 .

doi: 10.1159/000500324

Jakobsen JC, Gluud C, Kirsch I. Should antidepressants be used for major depressive disorder? BMJ Evidence-Based Med. 2020;25(4):130–6. https://doi.org/10.1136/bmjebm-2019-111238 .

doi: 10.1136/bmjebm-2019-111238

Lee B, Wang Y, Carlson SA, Greenlund KJ, Lu H, Liu Y, et al. National, state-level, and county-level prevalence estimates of adults aged ≥18 years self-reporting a lifetime diagnosis of depression - United States, 2020. MMWR Morb Mortal Wkly Rep. 2023;72(24):644–50. https://doi.org/10.15585/mmwr.mm7224a1 .

doi: 10.15585/mmwr.mm7224a1 pubmed: 37318995 pmcid: 10328468

Krystal JH, Kavalali ET, Monteggia LM. Ketamine and rapid antidepressant action: new treatments and novel synaptic signaling mechanisms. Neuropsychopharmacology. 2024;49(1):41–50. https://doi.org/10.1038/s41386-023-01629-w .

doi: 10.1038/s41386-023-01629-w pubmed: 37488280

Edinoff AN, Fort JM, Woo JJ, Causey CD, Burroughs CR, Cornett EM, et al. Selective serotonin reuptake inhibitors and clozapine: clinically relevant interactions and considerations. Neurol Int. 2021;13(3):445–63. https://doi.org/10.3390/neurolint13030044 .

doi: 10.3390/neurolint13030044 pubmed: 34564289 pmcid: 8482107

Kamran M, Bibi F, Ur Rehman A, Morris DW. Major depressive disorder: existing hypotheses about pathophysiological mechanisms and new genetic findings. Genes (Basel). 2022;13(4). https://doi.org/10.3390/genes13040646 .

Vázquez GH, Bahji A, Undurraga J, Tondo L, Baldessarini RJ. Efficacy and tolerability of combination treatments for major depression: antidepressants plus second-generation Antipsychotics vs. Esketamine vs Lithium J Psychopharmacol. 2021;35(8):890–900. https://doi.org/10.1177/02698811211013579 .

doi: 10.1177/02698811211013579 pubmed: 34238049

Thase ME. Preventing relapse and recurrence of depression: a brief review of therapeutic options. CNS Spectr. 2016;11(S15):12–21. https://doi.org/10.1017/s1092852900015212 .

doi: 10.1017/s1092852900015212

Hillhouse TM, Porter JH. A brief history of the development of antidepressant drugs: from monoamines to glutamate. Exp Clin Psychopharmacol. 2015;23(1):1–21. https://doi.org/10.1037/a0038550 .

doi: 10.1037/a0038550 pubmed: 25643025 pmcid: 4428540

Akil H, Gordon J, Hen R, Javitch J, Mayberg H, McEwen B, et al. Treatment resistant depression: a multi-scale, systems biology approach. Neurosci Biobehav Rev. 2018;84(May):272–88. https://doi.org/10.1016/j.neubiorev.2017.08.019 .

doi: 10.1016/j.neubiorev.2017.08.019 pubmed: 28859997

Pessina E, Martini A, Raffone F, Martiadis V. Cariprazine augmentation in patients with treatment resistant unipolar depression who failed to respond to previous atypical antipsychotic add-on. A case-series. Front Psychiatry. 2023;14(November):1–5. https://doi.org/10.3389/fpsyt.2023.1299368 .

doi: 10.3389/fpsyt.2023.1299368

Culpepper L, Muskin PR, Stahl SM. Major depressive disorder: understanding the significance of residual symptoms and balancing efficacy with tolerability. Am J Med. 2015;128(9 Suppl):S1-15. https://doi.org/10.1016/j.amjmed.2015.07.001 .

doi: 10.1016/j.amjmed.2015.07.001 pubmed: 26337210

Tundo A, de Filippis R, Proietti L. Pharmacologic approaches to treatment resistant depression: evidences and personal experience. World J Psychiatry. 2015;5(3):330. https://doi.org/10.5498/wjp.v5.i3.330 .

doi: 10.5498/wjp.v5.i3.330 pubmed: 26425446 pmcid: 4582308

Bartova L, Dold M, Kautzky A, Fabbri C, Spies M, Serretti A, et al. Results of the European Group for the Study of Resistant Depression (GSRD) - basis for further research and clinical practice. World J Biol Psychiatry. 2019;20(6):427–48. https://doi.org/10.1080/15622975.2019.1635270 .

doi: 10.1080/15622975.2019.1635270 pubmed: 31340696

Veraart JKE, Smith-Apeldoorn SY, Bakker IM, Visser BAE, Kamphuis J, Schoevers RA, et al. Pharmacodynamic interactions between ketamine and psychiatric medications used in the treatment of depression: a systematic review. Int J Neuropsychopharmacol. 2021;24(10):808–31. https://doi.org/10.1093/ijnp/pyab039 .

doi: 10.1093/ijnp/pyab039 pubmed: 34170315 pmcid: 8538895

Gabriel FC, Stein AT, de Oliveira Melo D, Fontes-Mota GCH, dos Santos IB, da Silva Rodrigues S, et al. Guidelines’ recommendations for the treatment-resistant depression: a systematic review of their quality. PLoS One. 2023;18(2 February):1–10. https://doi.org/10.1371/journal.pone.0281501 .

doi: 10.1371/journal.pone.0281501

Ercis M, Ozerdem A, Singh B. When and how to use lithium augmentation for treating major depressive disorder. J Clin Psychiatry. 2023;84(2):22–7. https://doi.org/10.4088/JCP.23ac14813 .

doi: 10.4088/JCP.23ac14813

Zhang J, Ming S, Chen X, Zhang T, Qian H, Peng S, et al. Herbal medicine as adjunctive therapy with antidepressants for post-stroke depression: a systematic review and network meta-analysis of randomized controlled trials. Front Pharmacol. 2023;14(July):1–9. https://doi.org/10.3389/fphar.2023.1180071 .

doi: 10.3389/fphar.2023.1180071

Dang C, Wang Q, Li Q, Xiong Y, Lu Y. Chinese herbal medicines for the treatment of depression: a systematic review and network meta-analysis. Front Pharmacol. 2024;15(April):1–19. https://doi.org/10.3389/fphar.2024.1295564 .

doi: 10.3389/fphar.2024.1295564

Tor PC, Amir N, Fam J, Ho R, Ittasakul P, Maramis MM, et al. A southeast asia consensus on the definition and management of treatment-resistant depression. Neuropsychiatr Dis Treat. 2022;18(October):2747–57. https://doi.org/10.2147/NDT.S380792 .

doi: 10.2147/NDT.S380792 pubmed: 36444218 pmcid: 9700522

Cusin C, Peyda S. The Massachusetts general hospital guide to depression. Cham: Springer International Publishing; 2019. https://doi.org/10.1007/978-3-319-97241-1 .

doi: 10.1007/978-3-319-97241-1

Dale E, Bang-Andersen B, Sánchez C. Emerging mechanisms and treatments for depression beyond SSRIs and SNRIs. Biochem Pharmacol. 2015;95(2):81–97. https://doi.org/10.1016/j.bcp.2015.03.011 .

doi: 10.1016/j.bcp.2015.03.011 pubmed: 25813654

Wijesinghe R. Emerging therapies for treatment resistant depression. Ment Heal Clin. 2014;4(5):226–30. https://doi.org/10.9740/mhc.n207179 .

doi: 10.9740/mhc.n207179

Luscher B, Shen Q, Sahir N. The GABAergic deficit hypothesis of major depressive disorder. Mol Psychiatry. 2011;16(4):383–406. https://doi.org/10.1038/mp.2010.120 .

doi: 10.1038/mp.2010.120 pubmed: 21079608

Vecera CM, C Courtes A, Jones G, Soares JC, Machado-Vieira R. Pharmacotherapies targeting GABA-Glutamate neurotransmission for treatment-resistant depression. Pharmaceuticals (Basel). 2023;16(11):1–32. https://doi.org/10.3390/ph16111572 .

Menke A. Is the HPA axis as target for depression outdated, or is there a new hope? Front Psychiatry. 2019;10(FEB):1–8. https://doi.org/10.3389/fpsyt.2019.00101 .

doi: 10.3389/fpsyt.2019.00101

Pochwat B, Krupa AJ, Siwek M, Szewczyk B. New investigational agents for the treatment of major depressive disorder. Expert Opin Investig Drugs. 2022;31(10):1053–66. https://doi.org/10.1080/13543784.2022.2113376 .

doi: 10.1080/13543784.2022.2113376 pubmed: 35975761

Biernacka JM, Sangkuhl K, Jenkins G, Whaley RM, Barman P, Batzler A, et al. The International SSRI Pharmacogenomics Consortium (ISPC): a genome-wide association study of antidepressant treatment response. Transl Psychiatry. 2015;5(4):9. https://doi.org/10.1038/tp.2015.47 .

doi: 10.1038/tp.2015.47

Nemeroff CB. Prevalence and management of treatment-resistant depression. J Clin Psychiatry. 2007;68(SUPPL. 8):17–25 WOS:000248487100003.

pubmed: 17640154

Fava M. Diagnosis and definition of treatment-resistant depression. Biol Psychiatry. 2003;53(8):649–59. https://doi.org/10.1016/S0006-3223(03)00231-2 .

doi: 10.1016/S0006-3223(03)00231-2 pubmed: 12706951

Voineskos D, Daskalakis ZJ, Blumberger DM. Management of treatment-resistant depression: challenges and strategies. Neuropsychiatr Dis Treat. 2020;16:221–34. https://doi.org/10.2147/NDT.S198774 .

doi: 10.2147/NDT.S198774 pubmed: 32021216 pmcid: 6982454

Lullau APM, Haga EMW, Ronold EH, Dwyer GE. Antidepressant mechanisms of ketamine: a review of actions with relevance to treatment-resistance and neuroprogression. Front Neurosci. 2023;17(August):1–20. https://doi.org/10.3389/fnins.2023.1223145 .

doi: 10.3389/fnins.2023.1223145

Liu CH, Zhang GZ, Li B, Li M, Woelfer M, Walter M, et al. Role of inflammation in depression relapse. J Neuroinflammation. 2019;16(1):1–11. https://doi.org/10.1186/s12974-019-1475-7 .

doi: 10.1186/s12974-019-1475-7 pubmed: 30606213 pmcid: 6317220

Ali ZA, Nuss S, El-Mallakh RS. Antidepressant discontinuation in treatment resistant depression. Contemp Clin Trials Commun. 2019;15(March):100383. https://doi.org/10.1016/j.conctc.2019.100383 .

doi: 10.1016/j.conctc.2019.100383 pubmed: 31193850 pmcid: 6543016

Papakostas GI. Dopaminergic-based pharmacotherapies for depression. Eur Neuropsychopharmacol. 2006;16(6):391–402. https://doi.org/10.1016/j.euroneuro.2005.12.002 .

doi: 10.1016/j.euroneuro.2005.12.002 pubmed: 16413172

Padala PR, Padala KP, Majagi AS, Garner KK, Dennis RA, Sullivan DH. Selective serotonin reuptake inhibitors-associated apathy syndrome: A cross sectional study. Medicine (Baltimore). 2020;99(33):e21497. https://doi.org/10.1097/MD.0000000000021497 .

doi: 10.1097/MD.0000000000021497 pubmed: 32871995

Israel JA. The impact of residual symptoms in major depression. Pharmaceuticals. 2010;3(8):2426–40. https://doi.org/10.3390/ph3082426 .

doi: 10.3390/ph3082426 pubmed: 27713362 pmcid: 4033933

Fabbri C, Kasper S, Kautzky A, Bartova L, Dold M, Zohar J, et al. Genome-wide association study of treatment-resistance in depression and meta-analysis of three independent samples. Br J Psychiatry. 2019;214(1):36–41. https://doi.org/10.1192/bjp.2018.256 .

doi: 10.1192/bjp.2018.256 pubmed: 30468137

Fabbri C, Hagenaars SP, John C, Williams AT, Shrine N, Moles L, et al. Genetic and clinical characteristics of treatment-resistant depression using primary care records in two UK cohorts. Mol Psychiatry. 2021;26(7):3363–73. https://doi.org/10.1038/s41380-021-01062-9 .

doi: 10.1038/s41380-021-01062-9 pubmed: 33753889 pmcid: 8505242

Fava GA. Clinical use of staging in psychiatry. Psychother Psychosom. 2024;93(3):143–50. https://doi.org/10.1159/000538526 .

doi: 10.1159/000538526 pubmed: 38636469

Souery D, Amsterdam J, de Montigny C, Lecrubier Y, Montgomery S, Lipp O, et al. Treatment resistant depression: methodological overview and operational criteria. Eur Neuropsychopharmacol. 1999;9(1–2):83–91. https://doi.org/10.1016/s0924-977x(98)00004-2 .

doi: 10.1016/s0924-977x(98)00004-2 pubmed: 10082232

McIntyre RS, Alsuwaidan M, Baune BT, Berk M, Demyttenaere K, Goldberg JF, et al. Treatment-resistant depression: definition, prevalence, detection, management, and investigational interventions. World Psychiatry. 2023;22(3):394–412. https://doi.org/10.1002/wps.21120 .

doi: 10.1002/wps.21120 pubmed: 37713549 pmcid: 10503923

Brown S, Rittenbach K, Cheung S, McKean G, MacMaster FP, Clement F. Current and common definitions of treatment-resistant depression: findings from a systematic review and qualitative interviews. Can J Psychiatry. 2019;64(6):380–7. https://doi.org/10.1177/0706743719828965 .

doi: 10.1177/0706743719828965 pubmed: 30763119 pmcid: 6591751

Wang G, Han C, Liu C-Y, Chan S, Kato T, Tan W, et al. Management of treatment-resistant depression in real-world clinical practice settings across asia. Neuropsychiatr Dis Treat. 2020;16:2943–59. https://doi.org/10.2147/NDT.S264813 .

doi: 10.2147/NDT.S264813 pubmed: 33299316 pmcid: 7721287

Dooley LN, Kuhlman KR, Robles TF, Eisenberger NI, Craske MG, Bower JE. The role of inflammation in core features of depression: Insights from paradigms using exogenously-induced inflammation. Neurosci Biobehav Rev. 2018;94(July):219–37. https://doi.org/10.1016/j.neubiorev.2018.09.006 .

doi: 10.1016/j.neubiorev.2018.09.006 pubmed: 30201219 pmcid: 6192535

Fried EI, Nesse RM. Depression is not a consistent syndrome: an investigation of unique symptom patterns in the STAR∗D study. J Affect Disord. 2015;172:96–102. https://doi.org/10.1016/j.jad.2014.10.010 .

doi: 10.1016/j.jad.2014.10.010 pubmed: 25451401

Dean J, Keshavan M. The neurobiology of depression: an integrated view. Asian J Psychiatr. 2017;2017(27):101–11. https://doi.org/10.1016/j.ajp.2017.01.025 .

doi: 10.1016/j.ajp.2017.01.025

Barbon A, Orlandi C, La Via L, Caracciolo L, Tardito D, Musazzi L, et al. Antidepressant treatments change 5-HT2C receptor mRNA expression in rat prefrontal/frontal cortex and hippocampus. Neuropsychobiology. 2011;63(3):160–8. https://doi.org/10.1159/000321593 .

doi: 10.1159/000321593 pubmed: 21228608

Di Matteo V, Di Giovanni G, Pierucci M, Esposito E. Serotonin control of central dopaminergic function: focus on in vivo microdialysis studies. Prog Brain Res. 2008;172:7–44. https://doi.org/10.1016/S0079-6123(08)00902-3 .

doi: 10.1016/S0079-6123(08)00902-3 pubmed: 18772026

Alex KD, Pehek EA. Pharmacologic mechanisms of serotonergic regulation of dopamine neurotransmission. Pharmacol Ther. 2007;113(2):296–320. https://doi.org/10.1016/j.pharmthera.2006.08.004 .

doi: 10.1016/j.pharmthera.2006.08.004 pubmed: 17049611

Howell LL, Cunningham KA. Serotonin 5-HT2 receptor interactions with dopamine function: implications for therapeutics in cocaine use disorder. Pharmacol Rev. 2015;67(1):176–97. https://doi.org/10.1124/pr.114.009514 .

doi: 10.1124/pr.114.009514 pubmed: 25505168 pmcid: 4279075

Maletic V, Eramo A, Gwin K, Offord SJ, Duffy RA. The role of norepinephrine and its α-adrenergic receptors in the pathophysiology and treatment of major depressive disorder and schizophrenia: a systematic review. Front Psychiatry. 2017;8(MAR):42. https://doi.org/10.3389/fpsyt.2017.00042 .

doi: 10.3389/fpsyt.2017.00042 pubmed: 28367128 pmcid: 5355451

Devoto P, Flore G. On the origin of cortical dopamine: is it a co-transmitter in noradrenergic neurons? Curr Neuropharmacol. 2006;4(2):115–25. https://doi.org/10.2174/157015906776359559 .

doi: 10.2174/157015906776359559 pubmed: 18615131 pmcid: 2430672

Morón JA, Brockington A, Wise RA, Rocha BA, Hope BT. Dopamine uptake through the norepinephrine transporter in brain regions with low levels of the dopamine transporter: evidence from knock-out mouse lines. J Neurosci. 2002;22(2):389–95. https://doi.org/10.1523/jneurosci.22-02-00389.2002 .

doi: 10.1523/jneurosci.22-02-00389.2002 pubmed: 11784783 pmcid: 6758674

Borgkvist A, Malmlöf T, Feltmann K, Lindskog M, Schilström B. Dopamine in the hippocampus is cleared by the norepinephrine transporter. Int J Neuropsychopharmacol. 2012;15(4):531–40. https://doi.org/10.1017/S1461145711000812 .

doi: 10.1017/S1461145711000812 pubmed: 21669025

Strauss M, O’Donovan B, Ma Y, Xiao Z, Lin S, Bardo MT, et al. [3H]Dopamine uptake through the dopamine and norepinephrine transporters is decreased in the prefrontal cortex of transgenic mice expressing HIV-1 transactivator of transcription protein. J Pharmacol Exp Ther. 2020;374(2):241–51. https://doi.org/10.1124/jpet.120.266023 .

doi: 10.1124/jpet.120.266023 pubmed: 32461322 pmcid: 7366287

Himmerich H, Patsalos O, Lichtblau N, Ibrahim MAA, Dalton B. Cytokine research in depression: principles, challenges, and open questions. Front Psychiatry. 2019;10(FEB). https://doi.org/10.3389/fpsyt.2019.00030 .

Gurevich I, Englander MT, Adlersberg M, Siegal NB, Schmauss C. Modulation of serotonin 2C receptor editing by sustained changes in serotonergic neurotransmission. J Neurosci. 2002;22(24):10529–32. https://doi.org/10.1523/jneurosci.22-24-10529.2002 .

doi: 10.1523/jneurosci.22-24-10529.2002 pubmed: 12486144 pmcid: 6758441

Termorshuizen F, Palmen SJM, Heerdink ER. Suicide behavior before and after the start with antidepressants: a high persistent risk in the first month of treatment among the young. Int J Neuropsychopharmacol. 2016;19(2):1–10. https://doi.org/10.1093/ijnp/pyv081 .

doi: 10.1093/ijnp/pyv081

Masdrakis VG, Markianos M, Baldwin DS. Apathy associated with antidepressant drugs: a systematic review. Acta Neuropsychiatr. 2023;35(4):189–204. https://doi.org/10.1017/neu.2023.6 .

doi: 10.1017/neu.2023.6 pubmed: 36644883

Browne CJ, Abela AR, Chu D, Li Z, Ji X, Lambe EK, et al. Dorsal raphe serotonin neurons inhibit operant responding for reward via inputs to the ventral tegmental area but not the nucleus accumbens: evidence from studies combining optogenetic stimulation and serotonin reuptake inhibition. Neuropsychopharmacology. 2019;44(4):793–804. https://doi.org/10.1038/s41386-018-0271-x .

doi: 10.1038/s41386-018-0271-x pubmed: 30420603

Sanders AC, Hussain AJ, Hen R, Zhuang X. Chronic blockade or constitutive deletion of the serotonin transporter reduces operant responding for food reward. Neuropsychopharmacology. 2007;32(11):2321–9. https://doi.org/10.1038/sj.npp.1301368 .

doi: 10.1038/sj.npp.1301368 pubmed: 17356573

Di Giovanni G, Esposito E, Di Matteo V. Role of serotonin in central dopamine dysfunction. CNS Neurosci Ther. 2010;16(3):179–94. https://doi.org/10.1111/j.1755-5949.2010.00135.x .

doi: 10.1111/j.1755-5949.2010.00135.x pubmed: 20557570 pmcid: 6493878

Blier P, El-Mansari M. Serotonin and beyond: therapeutics for major depression. Philos Trans R Soc B Biol Sci. 2013;368(1615):1–7. https://doi.org/10.1098/rstb.2012.0536 .

doi: 10.1098/rstb.2012.0536

Sarawagi A, Soni ND, Patel AB. Glutamate and GABA homeostasis and neurometabolism in major depressive disorder. Front Psychiatry. 2021;12(5):637863. https://doi.org/10.3389/fpsyt.2021.637863 .

doi: 10.3389/fpsyt.2021.637863 pubmed: 33986699 pmcid: 8110820

Höflich A, Michenthaler P, Kasper S, Lanzenberger R. Circuit mechanisms of reward, anhedonia, and depression. Int J Neuropsychopharmacol. 2019;22(2):105–18. https://doi.org/10.1093/ijnp/pyy081 .

doi: 10.1093/ijnp/pyy081 pubmed: 30239748

Han MH, Nestler EJ. Neural substrates of depression and resilience. Neurotherapeutics. 2017;14(3):677–86. https://doi.org/10.1007/s13311-017-0527-x .

doi: 10.1007/s13311-017-0527-x pubmed: 28397115 pmcid: 5509625

Wong AHC, Liu F. Uncoupling the dopamine D1–D2 receptor complex: A novel target for antidepressant treatment. Clin Pharmacol Ther. 2012;91(2):298–302. https://doi.org/10.1038/clpt.2011.311 .

doi: 10.1038/clpt.2011.311 pubmed: 22205193

Tundo A, Betro’ S, de Filippis R, Marchetti F, Nacca D, Necci R, et al. Pramipexole augmentation for treatment-resistant unipolar and bipolar depression in the real world: a systematic review and meta-analysis. Life. 2023;13(4):1043. https://doi.org/10.3390/life13041043 .

doi: 10.3390/life13041043 pubmed: 37109571 pmcid: 10141126

Li J, Lu C, Gao Z, Feng Y, Luo H, Lu T, et al. SNRIs achieve faster antidepressant effects than SSRIs by elevating the concentrations of dopamine in the forebrain. Neuropharmacology. 2020;177(July):108237. https://doi.org/10.1016/j.neuropharm.2020.108237 .

doi: 10.1016/j.neuropharm.2020.108237 pubmed: 32710978

Page ME, Lucki I. Effects of acute and chronic reboxetine treatment on stress-induced monoamine efflux in the rat frontal cortex. Neuropsychopharmacology. 2002;27(2):237–47. https://doi.org/10.1016/S0893-133X(02)00301-9 .

doi: 10.1016/S0893-133X(02)00301-9 pubmed: 12093597

De Bundel D, Femenía T, Dupont CM, Konradsson-Geuken A, Feltmann K, Schilström B, et al. Hippocampal and prefrontal dopamine D1/5 receptor involvement in the memory-enhancing effect of reboxetine. Int J Neuropsychopharmacol. 2013;16(9):2041–51. https://doi.org/10.1017/S1461145713000370 .

doi: 10.1017/S1461145713000370 pubmed: 23672849

Hostinar CE, Nusslock R, Miller GE. Future directions in the study of early-life stress and physical and emotional health: implications of the neuroimmune network hypothesis. J Clin Child Adolesc Psychol. 2018;47(1):142–56. https://doi.org/10.1080/15374416.2016.1266647 .

doi: 10.1080/15374416.2016.1266647 pubmed: 28107039

Felger JC, Treadway MT. Inflammation effects on motivation and motor activity: role of dopamine. Neuropsychopharmacology. 2017;42(1):216–41. https://doi.org/10.1038/npp.2016.143 .

doi: 10.1038/npp.2016.143 pubmed: 27480574

Capuron L, Miller AH. Immune system to brain signaling: neuropsychopharmacological implications. Pharmacol Ther. 2011;130(2):226–38. https://doi.org/10.1016/j.pharmthera.2011.01.014 .

doi: 10.1016/j.pharmthera.2011.01.014 pubmed: 21334376 pmcid: 3072299

Goldsmith DR, Rapaport MH, Miller BJ. A meta-analysis of blood cytokine network alterations in psychiatric patients: comparisons between schizophrenia, bipolar disorder and depression. Mol Psychiatry. 2016;21(12):1696–709. https://doi.org/10.1038/mp.2016.3 .

doi: 10.1038/mp.2016.3 pubmed: 26903267 pmcid: 6056174

Jeon SW, Kim YK. Molecular neurobiology and promising new treatment in depression. Int J Mol Sci. 2016;17(3). https://doi.org/10.3390/ijms17030381 .

Miller AH, Maletic V, Raison CL. Inflammation and its discontents: the role of cytokines in the pathophysiology of major depression. Biol Psychiatry. 2009;65(9):732–41. https://doi.org/10.1016/j.biopsych.2008.11.029 .

doi: 10.1016/j.biopsych.2008.11.029 pubmed: 19150053 pmcid: 2680424

Raison CL, Rutherford RE, Woolwine BJ, Shuo C, Schettler P, Drake DF, et al. A randomized controlled trial of the tumor necrosis factor antagonist infliximab for treatment-resistant depression: the role of baseline inflammatory biomarkers. JAMA Psychiat. 2013;70(1):31–41. https://doi.org/10.1001/2013.jamapsychiatry.4 .

doi: 10.1001/2013.jamapsychiatry.4

Raison CL, Miller AH. Do cytokines really sing the blues?. Cerebrum. 2013;2013(August):10.

pubmed: 24116267 pmcid: 3788165

Levite M, Marino F, Cosentino M. Dopamine, T cells and multiple sclerosis (MS). J Neural Transm. 2017;124(5):525–42. https://doi.org/10.1007/s00702-016-1640-4 .

doi: 10.1007/s00702-016-1640-4 pubmed: 28283756

Vidal PM, Pacheco R. The cross-talk between the dopaminergic and the immune system involved in schizophrenia. Front Pharmacol. 2020;11(March):1–18. https://doi.org/10.3389/fphar.2020.00394 .

doi: 10.3389/fphar.2020.00394

Matt SM, Gaskill PJ. Where Is Dopamine and how do Immune Cells See it?: dopamine-mediated immune cell function in health and disease. J Neuroimmune Pharmacol. 2020;15(1):114–64. https://doi.org/10.1007/s11481-019-09851-4 .

doi: 10.1007/s11481-019-09851-4 pubmed: 31077015

Arreola R, Alvarez-Herrera S, Pérez-Sánchez G, Becerril-Villanueva E, Cruz-Fuentes C, Flores-Gutierrez EO, et al. Immunomodulatory effects mediated by dopamine. J Immunol Res. 2016;2016:1–31. https://doi.org/10.1155/2016/3160486 .

doi: 10.1155/2016/3160486

Broome ST, Louangaphay K, Keay K, Leggio G, Musumeci G, Castorina A. Dopamine: an immune transmitter. Neural Regen Res. 2020;15(12):2173–85. https://doi.org/10.4103/1673-5374.284976 .

doi: 10.4103/1673-5374.284976

Ransohoff RM, Perry VH. Microglial physiology: unique stimuli, specialized responses. Annu Rev Immunol. 2009;27(1):119–45. https://doi.org/10.1146/annurev.immunol.021908.132528 .

doi: 10.1146/annurev.immunol.021908.132528 pubmed: 19302036

Afridi R, Suk K. Microglial responses to stress-induced depression: causes and consequences. Cells. 2023;12(11):1–15. https://doi.org/10.3390/cells12111521 .

doi: 10.3390/cells12111521

Pacheco R. Targeting dopamine receptor D3 signalling in inflammation. Oncotarget. 2017;8(5):7224–5. https://doi.org/10.18632/oncotarget.14601 .

doi: 10.18632/oncotarget.14601 pubmed: 28086229 pmcid: 5352314

Channer B, Matt SM, Nickoloff-Bybel EA, Pappa V, Agarwal Y, Wickman J, et al. Dopamine, immunity, and disease. Pharmacol Rev. 2023;75(1):62–158. https://doi.org/10.1124/pharmrev.122.000618 .

doi: 10.1124/pharmrev.122.000618 pubmed: 36757901 pmcid: 9832385

Kalkman HO, Feuerbach D. Antidepressant therapies inhibit inflammation and microglial M1-polarization. Pharmacol Ther. 2016;163:82–93. https://doi.org/10.1016/j.pharmthera.2016.04.001 .

doi: 10.1016/j.pharmthera.2016.04.001 pubmed: 27101921

Chu AL, Stochl J, Lewis G, Zammit S, Jones PB, Khandaker GM. Longitudinal association between inflammatory markers and specific symptoms of depression in a prospective birth cohort. Brain Behav Immun. 2018;2019(76):74–81. https://doi.org/10.1016/j.bbi.2018.11.007 .

doi: 10.1016/j.bbi.2018.11.007

Rittmannsberger H. Amisulpride as an augmentation agent in treatment resistant depression: a case series and review of the literature. Psychiatr Danub. 2019;31(2):148–56. https://doi.org/10.24869/psyd.2019.148 .

doi: 10.24869/psyd.2019.148 pubmed: 31291218

Haase J, Brown E. Integrating the monoamine, neurotrophin and cytokine hypotheses of depression–a central role for the serotonin transporter? Pharmacol Ther. 2015;147:1–11. https://doi.org/10.1016/j.pharmthera.2014.10.002 .

doi: 10.1016/j.pharmthera.2014.10.002 pubmed: 25444754

Malynn S, Campos-Torres A, Moynagh P, Haase J. The pro-inflammatory cytokine TNF-α regulates the activity and expression of the serotonin transporter (SERT) in astrocytes. Neurochem Res. 2013;38(4):694–704. https://doi.org/10.1007/s11064-012-0967-y .

doi: 10.1007/s11064-012-0967-y pubmed: 23338678

Liu C-H, Zhang G-Z, Li B, Li M, Woelfer M, Walter M, et al. Role of inflammation in depression relapse. J Neuroinflammation. 2019;16(1):90. https://doi.org/10.1186/s12974-019-1475-7 .

doi: 10.1186/s12974-019-1475-7 pubmed: 30995920 pmcid: 6472093

Bridwell DA, Steele VR, Maurer JM, Kiehl KA, Calhoun VD. The relationship between somatic and cognitive-affective depression symptoms and error-related ERPs. J Affect Disord. 2015;172:89–95. https://doi.org/10.1016/j.jad.2014.09.054 .

doi: 10.1016/j.jad.2014.09.054 pubmed: 25451400

Steer RA, Ball R, Ranieri WF, Beck AT. Dimensions of the Beck Depression Inventory-II in clinically depressed outpatients. J Clin Psychol. 1999;55(1):117–28. https://doi.org/10.1002/(SICI)1097-4679(199901)55:1%3c117::AID-JCLP12%3e3.0.CO;2-A .

doi: 10.1002/(SICI)1097-4679(199901)55:1<117::AID-JCLP12>3.0.CO;2-A pubmed: 10100838

Capuron L, Castanon N. Role of inflammation in the development of neuropsychiatric symptom domains: evidence and mechanisms. Curr Top Behav Neurosci. 2016;31:31–44. https://doi.org/10.1007/7854_2016_14 .

doi: 10.1007/7854_2016_14

Maydych V. The interplay between stress, inflammation, and emotional attention: Relevance for depression. Front Neurosci. 2019;13(APR):1–8. https://doi.org/10.3389/fnins.2019.00384 .

doi: 10.3389/fnins.2019.00384

Hammar Å. Cognitive functioning in major depression – a summary. Front Hum Neurosci. 2009;3(SEP):1–7. https://doi.org/10.3389/neuro.09.026.2009 .

doi: 10.3389/neuro.09.026.2009

Jokela M, Virtanen M, David Batty G, Kivimaki M. Research letter. JAMA Psychiat. 2016;73(1):87–8. https://doi.org/10.1001/jamapsychiatry.2015.1977 .

doi: 10.1001/jamapsychiatry.2015.1977

White J, Kivimäki M, Jokela M, Batty GD. Association of inflammation with specific symptoms of depression in a general population of older people: the english longitudinal study of ageing. Brain Behav Immun. 2017;61:27–30. https://doi.org/10.1016/j.bbi.2016.08.012 .

doi: 10.1016/j.bbi.2016.08.012 pubmed: 27562420

Carstens L, Popp M, Keicher C, Hertrampf R, Weigner D, Meiering MS, et al. Effects of a single dose of amisulpride on functional brain changes during reward- and motivation-related processing using task-based fMRI in healthy subjects and patients with major depressive disorder — study protocol for a randomized clinical trial. Trials. 2023;24(1):761. https://doi.org/10.1186/s13063-023-07788-x .

doi: 10.1186/s13063-023-07788-x pubmed: 38012795 pmcid: 10683198

Blier P, Briley M. The noradrenergic symptom cluster: Clinical expression and neuropharmacology. Neuropsychiatr Dis Treat. 2011;7(SUPPL.):15–20. https://doi.org/10.2147/NDT.S19613 .

doi: 10.2147/NDT.S19613 pubmed: 21750624 pmcid: 3131097

Dantzer R, O’Connor JC, Freund GG, Johnson RW, Kelley KW. From inflammation to sickness and depression: when the immune system subjugates the brain. Nat Rev Neurosci. 2008;9(1):46–56. https://doi.org/10.1038/nrn2297 .

doi: 10.1038/nrn2297 pubmed: 18073775 pmcid: 2919277

Nutt D, Demyttenaere K, Janka Z, Aarre T, Bourin M, Canonico PL, et al. The other face of depression, reduced positive affect: The role of catecholamines in causation and cure. J Psychopharmacol. 2007;21(5):461–71. https://doi.org/10.1177/0269881106069938 .

doi: 10.1177/0269881106069938 pubmed: 17050654

Jaracz J, Gattner K, Jaracz K, G??rna K. Unexplained painful physical symptoms in patients with major depressive disorder: prevalence, pathophysiology and management. CNS Drugs. 2016;30(4):293–304. https://doi.org/10.1007/s40263-016-0328-5 .

Papakostas GI, Thase ME, Fava M, Nelson JC, Shelton RC. Are antidepressant drugs that combine serotonergic and noradrenergic mechanisms of action more effective than the selective serotonin reuptake inhibitors in treating major depressive disorder? A meta-analysis of studies of newer agents. Biol Psychiatry. 2007;62(11):1217–27. https://doi.org/10.1016/j.biopsych.2007.03.027 .

doi: 10.1016/j.biopsych.2007.03.027 pubmed: 17588546

Vancassel S, Capuron L, Castanon N. Brain Kynurenine and BH4 pathways: relevance to the pathophysiology and treatment of inflammation-driven depressive symptoms. Front Neurosci. 2018;12(July):1–16. https://doi.org/10.3389/fnins.2018.00499 .

doi: 10.3389/fnins.2018.00499

Wichers MC, Maes M. The role of indoleamine 2,3-dioxygenase (IDO) in the pathophysiology of interferon-α-induced depression. J Psychiatry Neurosci. 2004;29(1):11–7.

pubmed: 14719046 pmcid: 305266

Pastis I, Santos MG, Paruchuri A. Exploring the role of inflammation in major depressive disorder: beyond the monoamine hypothesis. Front Behav Neurosci. 2023;17(January). https://doi.org/10.3389/fnbeh.2023.1282242 .

Li Y, Wang L, Huang J, Zhang P, Zhou Y, Tong J, et al. Serum neuroactive metabolites of the tryptophan pathway in patients with acute phase of affective disorders. Front Psychiatry. 2024;15(April):1–10. https://doi.org/10.3389/fpsyt.2024.1357293 .

doi: 10.3389/fpsyt.2024.1357293

Park HJ, Shim HS, An K, Starkweather A, Kim KS, Shim I. IL-4 inhibits IL-1 β-Induced depressive-like behavior and central neurotransmitter alterations. Mediators Inflamm. 2015;2015. https://doi.org/10.1155/2015/941413 .

Zhu C Bin, Blakely RD, Hewlett WA. The proinflammatory cytokines interleukin-1beta and tumor necrosis factor-alpha activate serotonin transporters. Neuropsychopharmacology. 2006;31(10):2121–31. https://doi.org/10.1038/sj.npp.1301029 .

Miller AH, Haroon E, Raison CL, Felger JC. Cytokine targets in the brain: impact on neurotransmitters and neurocircuits. Depress Anxiety. 2013;30(4):297–306. https://doi.org/10.1002/da.22084 .

doi: 10.1002/da.22084 pubmed: 23468190 pmcid: 4141874

Raison CL, Dantzer R, Kelley KW, Lawson MA, Woolwine BJ, Vogt G, et al. CSF concentrations of brain tryptophan and kynurenines during immune stimulation with IFN-α: Relationship to CNS immune responses and depression. Mol Psychiatry. 2010;15(4):393–403. https://doi.org/10.1038/mp.2009.116 .

doi: 10.1038/mp.2009.116 pubmed: 19918244

Troubat R, Barone P, Leman S, Desmidt T, Cressant A, Atanasova B, et al. Neuroinflammation and depression: a review. Eur J Neurosci. 2021;53(1):151–71. https://doi.org/10.1111/ejn.14720 .

doi: 10.1111/ejn.14720 pubmed: 32150310

Chen J, Zou J, Huang P, Gao X, Lun J, Li Y, et al. KYNA ameliorates glutamate toxicity of HAND by enhancing glutamate uptake in A2 astrocytes. Int J Mol Sci. 2024;25(8). https://doi.org/10.3390/ijms25084286 .

Roszkowicz-Ostrowska K, Młotkowska P, Kowalczyk P, Marciniak E, Barszcz M, Misztal T. Central stimulatory effect of kynurenic acid on BDNF-TrkB signaling and BER enzymatic activity in the Hippocampal CA1 field in sheep. Int J Mol Sci. 2022;24(1):136. https://doi.org/10.3390/ijms24010136 .

doi: 10.3390/ijms24010136 pubmed: 36613581 pmcid: 9820639

Tanaka M, Szabó Á, Lőrinczi B, Szatmári I, Fülöp F, Vécsei L. Antidepressant-like Effects of Kynurenic Acid Analogues. Proc. 1st Int. Electron. Conf. Biomed., Basel, Switzerland: MDPI; 2022; p. 10301. https://doi.org/10.3390/ecb2021-10301 .

Bai MY, Lovejoy DB, Guillemin GJ, Kozak R, Stone TW, Koola MM. Galantamine-memantine combination and kynurenine pathway enzyme inhibitors in the treatment of neuropsychiatric disorders. Complex Psychiatry. 2021;7(1–2):19–33. https://doi.org/10.1159/000515066 .

doi: 10.1159/000515066 pubmed: 35141700 pmcid: 8443947

Sell SL, Boone DR, Weisz HA, Cardenas C, Willey HE, Bolding IJ, et al. MicroRNA profiling identifies a novel compound with antidepressant properties. PLoS ONE. 2019;14(8):e0221163. https://doi.org/10.1371/journal.pone.0221163 .

doi: 10.1371/journal.pone.0221163 pubmed: 31442236 pmcid: 6707633

Erabi H, Okada G, Shibasaki C, Setoyama D, Kang D, Takamura M, et al. Kynurenic acid is a potential overlapped biomarker between diagnosis and treatment response for depression from metabolome analysis. Sci Rep. 2020;10(1):16822. https://doi.org/10.1038/s41598-020-73918-z .

doi: 10.1038/s41598-020-73918-z pubmed: 33033336 pmcid: 7545168

Santana-Martínez RA, Silva-Islas CA, Fernández-Orihuela YY, Barrera-Oviedo D, Pedraza-Chaverri J, Hernández-Pando R, et al. The Therapeutic effect of curcumin in quinolinic acid-induced neurotoxicity in rats is associated with BDNF, ERK1/2, Nrf2, and antioxidant enzymes. Antioxidants. 2019;8(9):388. https://doi.org/10.3390/antiox8090388 .

doi: 10.3390/antiox8090388 pubmed: 31514267 pmcid: 6769626

Ge X, Zheng M, Hu M, Fang X, Geng D, Liu S, et al. Butyrate ameliorates quinolinic acid–induced cognitive decline in obesity models. J Clin Invest. 2023;133(4):1–15. https://doi.org/10.1172/JCI154612 .

doi: 10.1172/JCI154612

Hestad K, Alexander J, Rootwelt H, Aaseth JO. The role of tryptophan dysmetabolism and quinolinic acid in depressive and neurodegenerative diseases. Biomolecules. 2022;12(7):1–13. https://doi.org/10.3390/biom12070998 .

doi: 10.3390/biom12070998

Zheng H, Teague TK, Yeh FC, Burrows K, Figueroa-Hall LK, Aupperle RL, et al. C-Reactive protein and the kynurenic acid to quinolinic acid ratio are independently associated with white matter integrity in major depressive disorder. Brain Behav Immun. 2022;105:180–9. https://doi.org/10.1016/j.bbi.2022.07.011 .

doi: 10.1016/j.bbi.2022.07.011 pubmed: 35853557 pmcid: 9983279

Lugo-Huitrón R, Ugalde Muñiz P, Pineda B, Pedraza-Chaverrí J, Ríos C, Pérez-de la Cruz V. Quinolinic acid: an endogenous neurotoxin with multiple targets. Oxid Med Cell Longev. 2013;2013:104024. https://doi.org/10.1155/2013/104024 .

doi: 10.1155/2013/104024 pubmed: 24089628 pmcid: 3780648

Hughes MM, Connor TJ, Harkin A. Stress-related immune markers in depression: implications for treatment. Int J Neuropsychopharmacol. 2016;19(6):1–19. https://doi.org/10.1093/ijnp/pyw001 .

doi: 10.1093/ijnp/pyw001

Haruki H, Hovius R, Pedersen MG, Johnsson K. Tetrahydrobiopterin biosynthesis as a potential target of the kynurenine pathway metabolite xanthurenic acid. J Biol Chem. 2016;291(2):652–7. https://doi.org/10.1074/jbc.C115.680488 .

doi: 10.1074/jbc.C115.680488 pubmed: 26565027

Fanet H, Capuron L, Castanon N, Calon F, Vancassel S. Tetrahydrobioterin (BH4) pathway: from metabolism to neuropsychiatry. Curr Neuropharmacol. 2021;19(5):591–609. https://doi.org/10.2174/1570159X18666200729103529 .

doi: 10.2174/1570159X18666200729103529 pubmed: 32744952 pmcid: 8573752

Neurauter G, Schrocksnadel K, Scholl-Burgi S, Sperner-Unterweger B, Schubert C, Ledochowski M, et al. Chronic immune stimulation correlates with reduced phenylalanine turnover. Curr Drug Metab. 2008;9(7):622–7. https://doi.org/10.2174/138920008785821738 .

doi: 10.2174/138920008785821738 pubmed: 18781914

Adzic M, Brkic Z, Mitic M, Francija E, Jovicic MJ, Radulovic J, et al. Therapeutic strategies for treatment of inflammation-related depression. Curr Neuropharmacol. 2017;16(2):176–209. https://doi.org/10.2174/1570159x15666170828163048 .

doi: 10.2174/1570159x15666170828163048

Treadway MT, Cooper JA, Miller AH. Can’t or Won’t? Immunometabolic constraints on dopaminergic drive. Trends Cogn Sci. 2019;23(5):435–48. https://doi.org/10.1016/j.tics.2019.03.003 .

doi: 10.1016/j.tics.2019.03.003 pubmed: 30948204 pmcid: 6839942

Yohn SE, Arif Y, Haley A, Tripodi G, Baqi Y, Müller CE, et al. Effort-related motivational effects of the pro-inflammatory cytokine interleukin-6: pharmacological and neurochemical characterization. Psychopharmacology. 2016;233(19–20):3575–86. https://doi.org/10.1007/s00213-016-4392-9 .

doi: 10.1007/s00213-016-4392-9 pubmed: 27497935

Van Heesch F, Prins J, Korte-Bouws GAH, Westphal KGC, Lemstra S, Olivier B, et al. Systemic tumor necrosis factor-alpha decreases brain stimulation reward and increases metabolites of serotonin and dopamine in the nucleus accumbens of mice. Behav Brain Res. 2013;253:191–5. https://doi.org/10.1016/j.bbr.2013.07.038 .

doi: 10.1016/j.bbr.2013.07.038 pubmed: 23896053

Kaster MP, Gadotti VM, Calixto JB, Santos ARS, Rodrigues ALS. Depressive-like behavior induced by tumor necrosis factor-α in mice. Neuropharmacology. 2012;62(1):419–26. https://doi.org/10.1016/j.neuropharm.2011.08.018 .

doi: 10.1016/j.neuropharm.2011.08.018 pubmed: 21867719

Knezevic E, Nenic K, Milanovic V, Knezevic NN. The role of cortisol in chronic stress, neurodegenerative diseases, and psychological disorders. Cells. 2023;12(23). https://doi.org/10.3390/cells12232726 .

Hassamal S. Chronic stress, neuroinflammation, and depression: an overview of pathophysiological mechanisms and emerging anti-inflammatories. Front Psychiatry. 2023;14(May). https://doi.org/10.3389/fpsyt.2023.1130989 .

Halaris A, Sohl E, Whitham EA. Treatment-resistant depression revisited: a glimmer of hope. J Pers Med. 2021;11(2):155. https://doi.org/10.3390/jpm11020155 .

doi: 10.3390/jpm11020155 pubmed: 33672126 pmcid: 7927134

Sarapultsev A, Gusev E, Komelkova M, Utepova I, Luo S, Hu D. JAK-STAT signaling in inflammation and stress-related diseases: implications for therapeutic interventions. Mol Biomed. 2023;4(1):1–30. https://doi.org/10.1186/s43556-023-00151-1 .

doi: 10.1186/s43556-023-00151-1

Kurczewska E, Ferensztajn-Rochowiak E, Rybakowski F, Michalak M, Rybakowski J. Treatment-resistant depression: neurobiological correlates and the effect of sleep deprivation with sleep phase advance for the augmentation of pharmacotherapy. World J Biol Psychiatry. 2021;22(1):58–69. https://doi.org/10.1080/15622975.2020.1755449 .

doi: 10.1080/15622975.2020.1755449 pubmed: 32295463

Walsh CP, Bovbjerg DH, Marsland AL. Glucocorticoid resistance and β2-adrenergic receptor signaling pathways promote peripheral pro-inflammatory conditions associated with chronic psychological stress: a systematic review across species. Neurosci Biobehav Rev. 2021;128:117–35. https://doi.org/10.1016/j.neubiorev.2021.06.013 .

doi: 10.1016/j.neubiorev.2021.06.013 pubmed: 34116126 pmcid: 8556675

Seki K, Yoshida S, Jaiswal M. Molecular mechanism of noradrenaline during the stress-induced major depressive disorder. Neural Regen Res. 2018;13(7):1159–69. https://doi.org/10.4103/1673-5374.235019 .

doi: 10.4103/1673-5374.235019 pubmed: 30028316 pmcid: 6065220

Sakamoto S, Zhu X, Hasegawa Y, Karma S, Obayashi M, Alway E, et al. Inflamed brain: targeting immune changes and inflammation for treatment of depression. Psychiatry Clin Neurosci. 2021;75(10):304–11. https://doi.org/10.1111/pcn.13286 .

doi: 10.1111/pcn.13286 pubmed: 34227186 pmcid: 8683253

Valiuliene G, Valiulis V, Zentelyte A, Dapsys K, Germanavicius A, Navakauskiene R. Anti-neuroinflammatory microRNA-146a-5p as a potential biomarker for neuronavigation-guided rTMS therapy success in medication resistant depression disorder. Biomed Pharmacother. 2023;166(May):115313. https://doi.org/10.1016/j.biopha.2023.115313 .

doi: 10.1016/j.biopha.2023.115313 pubmed: 37572636

Candee R, Wilkenson R, Schreiber M, Decenzo M. The roles of neuroinflammation and glutamatergic excitotoxicity in treatment-resistant depression. J Am Acad Physician Assist. 2023;36(4):12–7. https://doi.org/10.1097/01.JAA.0000921252.57819.4b .

doi: 10.1097/01.JAA.0000921252.57819.4b

Ribeiro DE, Roncalho AL, Glaser T, Ulrich H, Wegener G, Joca S. P2X7 receptor signaling in stress and depression. Int J Mol Sci. 2019;20(11):1–26. https://doi.org/10.3390/ijms20112778 .

doi: 10.3390/ijms20112778

Zhao Y-F, Ren W-J, Zhang Y, He J-R, Yin H-Y, Liao Y, et al. High, in contrast to low levels of acute stress induce depressive-like behavior by involving astrocytic, in addition to Microglial P2X7 receptors in the rodent Hippocampus. Int J Mol Sci. 2022;23(3). https://doi.org/10.3390/ijms23031904 .

Calzaferri F, Ruiz-Ruiz C, de Diego AMG, de Pascual R, Méndez-López I, Cano-Abad MF, et al. The purinergic P2X7 receptor as a potential drug target to combat neuroinflammation in neurodegenerative diseases. Med Res Rev. 2020;40(6):2427–65. https://doi.org/10.1002/med.21710 .

doi: 10.1002/med.21710 pubmed: 32677086

Stokes L, Fuller SJ, Sluyter R, Skarratt KK, Gu BJ, Wiley JS. Two haplotypes of the P2X(7) receptor containing the Ala-348 to Thr polymorphism exhibit a gain-of-function effect and enhanced interleukin-1beta secretion. FASEB J. 2010;24(8):2916–27. https://doi.org/10.1096/fj.09-150862 .

doi: 10.1096/fj.09-150862 pubmed: 20360457

Urbina-Treviño L, von Mücke-Heim I-A, Deussing JM. P2X7 receptor-related genetic mouse models - tools for translational research in psychiatry. Front Neural Circuits. 2022;16(March):876304. https://doi.org/10.3389/fncir.2022.876304 .

doi: 10.3389/fncir.2022.876304 pubmed: 35422688 pmcid: 9001905

Facci L, Barbierato M, Marinelli C, Argentini C, Skaper SD, Giusti P. Toll-like receptors 2, -3 and -4 prime microglia but not astrocytes across central nervous system regions for ATP-dependent interleukin-1β release. Sci Rep. 2014;4:6824. https://doi.org/10.1038/srep06824 .

doi: 10.1038/srep06824 pubmed: 25351234 pmcid: 5381369

Shim HS, Park HJ, Woo J, Lee CJ, Shim I. Role of astrocytic GABAergic system on inflammatory cytokine-induced anxiety-like behavior. Neuropharmacology. 2019;160(September):107776. https://doi.org/10.1016/j.neuropharm.2019.107776 .

doi: 10.1016/j.neuropharm.2019.107776 pubmed: 31513788

Cuellar-Santoyo AO, Ruiz-Rodríguez VM, Mares-Barbosa TB, Patrón-Soberano A, Howe AG, Portales-Pérez DP, et al. Revealing the contribution of astrocytes to glutamatergic neuronal transmission. Front Cell Neurosci. 2023;16(January):1–15. https://doi.org/10.3389/fncel.2022.1037641 .

doi: 10.3389/fncel.2022.1037641

Bak LK, Schousboe A, Waagepetersen HS. The glutamate/GABA-glutamine cycle: aspects of transport, neurotransmitter homeostasis and ammonia transfer. J Neurochem. 2006;98(3):641–53. https://doi.org/10.1111/j.1471-4159.2006.03913.x .

doi: 10.1111/j.1471-4159.2006.03913.x pubmed: 16787421

Dalangin R, Kim A, Campbell RE. The role of amino acids in neurotransmission and fluorescent tools for their detection. Int J Mol Sci. 2020;21(17):1–36. https://doi.org/10.3390/ijms21176197 .

doi: 10.3390/ijms21176197

Schousboe A, Scafidi S, Bak LK, Waagepetersen HS, McKenna MC. Glutamate metabolism in the brain focusing on astrocytes. 2014. p. 13–30. https://doi.org/10.1007/978-3-319-08894-5_2 .

doi: 10.1007/978-3-319-08894-5_2

Caraci F, Calabrese F, Molteni R, Bartova L, Dold M, Leggio GM, et al. International Union of Basic and Clinical Pharmacology CIV: the Neurobiology of treatment-resistant depression: from antidepressant classifications to novel pharmacological targets. Pharmacol Rev. 2018;70(3):475–504. https://doi.org/10.1124/pr.117.014977 .

doi: 10.1124/pr.117.014977 pubmed: 29884653

Andersen JV, Jakobsen E, Westi EW, Lie MEK, Voss CM, Aldana BI, et al. Extensive astrocyte metabolism of γ-aminobutyric acid (GABA) sustains glutamine synthesis in the mammalian cerebral cortex. Glia. 2020;68(12):2601–12. https://doi.org/10.1002/glia.23872 .

doi: 10.1002/glia.23872 pubmed: 32584476

Andersen JV, Schousboe A. Milestone review: metabolic dynamics of glutamate and GABA mediated neurotransmission — The essential roles of astrocytes. J Neurochem. 2023;166(2):109–37. https://doi.org/10.1111/jnc.15811 .

doi: 10.1111/jnc.15811 pubmed: 36919769

Maurice N, Deniau JM, Menetrey A, Glowinski J, Thierry AM. Position of the ventral pallidum in the rat prefrontal cortex-basal ganglia circuit. Neuroscience. 1997;80(2):523–34. https://doi.org/10.1016/s0306-4522(97)00002-x .

doi: 10.1016/s0306-4522(97)00002-x pubmed: 9284354

Smith KS, Tindell AJ, Aldridge JW, Berridge KC. Ventral pallidum roles in reward and motivation. Behav Brain Res. 2009;196(2):155–67. https://doi.org/10.1016/j.bbr.2008.09.038 .

doi: 10.1016/j.bbr.2008.09.038 pubmed: 18955088

Faget L, Oriol L, Lee W-C, Zell V, Sargent C, Flores A, et al. Ventral pallidum GABA and glutamate neurons drive approach and avoidance through distinct modulation of VTA cell types. Nat Commun. 2024;15(1):4233. https://doi.org/10.1038/s41467-024-48340-y .

doi: 10.1038/s41467-024-48340-y pubmed: 38762463 pmcid: 11102457

Adachi M, Barrot M, Autry AE, Theobald D, Monteggia LM. Selective loss of brain-derived neurotrophic factor in the dentate gyrus attenuates antidepressant efficacy. Biol Psychiatry. 2008;63(7):642–9. https://doi.org/10.1016/j.biopsych.2007.09.019 .

doi: 10.1016/j.biopsych.2007.09.019 pubmed: 17981266

Kosanovic Rajacic B, Sagud M, Begic D, Nikolac Perkovic M, Dvojkovic A, Ganoci L, et al. Plasma brain-derived neurotrophic factor levels in first-episode and recurrent major depression and before and after bright light therapy in treatment-resistant depression. Biomolecules. 2023;13(9):1425. https://doi.org/10.3390/biom13091425 .

doi: 10.3390/biom13091425 pubmed: 37759825 pmcid: 10526351

Zelada MI, Garrido V, Liberona A, Jones N, Zúñiga K, Silva H, et al. Brain-Derived Neurotrophic Factor (BDNF) as a predictor of treatment response in Major Depressive Disorder (MDD): a systematic review. Int J Mol Sci. 2023;24(19). https://doi.org/10.3390/ijms241914810 .

Yao H, Wang X, Chi J, Chen H, Liu Y, Yang J, et al. Exploring novel antidepressants targeting G Protein-Coupled receptors and key membrane receptors based on molecular structures. Molecules. 2024;29(5). https://doi.org/10.3390/molecules29050964 .

Park JM, Jung SC, Eun SY. Long-term synaptic plasticity: circuit perturbation and stabilization. Korean J Physiol Pharmacol. 2014;18(6):457–60. https://doi.org/10.4196/kjpp.2014.18.6.457 .

doi: 10.4196/kjpp.2014.18.6.457 pubmed: 25598658 pmcid: 4296033

Pham TH, Gardier AM. Fast-acting antidepressant activity of ketamine: highlights on brain serotonin, glutamate, and GABA neurotransmission in preclinical studies. Pharmacol Ther. 2019;199:58–90. https://doi.org/10.1016/j.pharmthera.2019.02.017 .

doi: 10.1016/j.pharmthera.2019.02.017 pubmed: 30851296

Yang T, Nie Z, Shu H, Kuang Y, Chen X, Cheng J, et al. The role of BDNF on neural plasticity in depression. Front Cell Neurosci. 2020;14. https://doi.org/10.3389/fncel.2020.00082 .

Edelmann E, Cepeda-Prado E, Franck M, Lichtenecker P, Brigadski T, Leßmann V. Theta burst firing recruits BDNF release and signaling in postsynaptic CA1 neurons in spike-timing-dependent LTP. Neuron. 2015;86(4):1041–54. https://doi.org/10.1016/j.neuron.2015.04.007 .

doi: 10.1016/j.neuron.2015.04.007 pubmed: 25959732

Malenka RC, Nicoll RA. Long-term potentiation–a decade of progress? Science. 1999;285(5435):1870–4. https://doi.org/10.1126/science.285.5435.1870 .

doi: 10.1126/science.285.5435.1870 pubmed: 10489359

Li Z, Zhang Y, Wang Z, Chen J, Fan J, Guan Y, et al. The role of BDNF, NTRK2 gene and their interaction in development of treatment-resistant depression: data from multicenter, prospective, longitudinal clinic practice. J Psychiatr Res. 2013;47(1):8–14. https://doi.org/10.1016/j.jpsychires.2012.10.003 .

doi: 10.1016/j.jpsychires.2012.10.003 pubmed: 23137999

Party H, Dujarrier C, Hébert M, Lenoir S, Martinez De Lizarrondo S, Delépée R, et al. Plasminogen Activator Inhibitor-1 (PAI-1) deficiency predisposes to depression and resistance to treatments. Acta Neuropathol Commun. 2019;7(1):153. https://doi.org/10.1186/s40478-019-0807-2 .

doi: 10.1186/s40478-019-0807-2 pubmed: 31610810 pmcid: 6791031

Arango-Lievano M, Lambert WM, Bath KG, Garabedian MJ, Chao MV, Jeanneteau F. Neurotrophic-priming of glucocorticoid receptor signaling is essential for neuronal plasticity to stress and antidepressant treatment. Proc Natl Acad Sci U S A. 2015;112(51):15737–42. https://doi.org/10.1073/pnas.1509045112 .

doi: 10.1073/pnas.1509045112 pubmed: 26630005 pmcid: 4697403

Hayley S, Poulter MO, Merali Z, Anisman H. The pathogenesis of clinical depression: Stressor- and cytokine-induced alterations of neuroplasticity. Neuroscience. 2005;135(3):659–78. https://doi.org/10.1016/j.neuroscience.2005.03.051 .

doi: 10.1016/j.neuroscience.2005.03.051 pubmed: 16154288

Tsai S-J, Hong C-J, Liou Y-J. Effects of BDNF polymorphisms on antidepressant action. Psychiatry Investig. 2010;7(4):236. https://doi.org/10.4306/pi.2010.7.4.236 .

doi: 10.4306/pi.2010.7.4.236 pubmed: 21253406 pmcid: 3022309

Zhang J-C, Yao W, Hashimoto K. Brain-derived Neurotrophic Factor (BDNF)-TrkB signaling in inflammation-related depression and potential therapeutic targets. Curr Neuropharmacol. 2016;14(7):721–31. https://doi.org/10.2174/1570159x14666160119094646 .

doi: 10.2174/1570159x14666160119094646 pubmed: 26786147 pmcid: 5050398

Cubillos S, Engmann O, Brancato A. BDNF as a mediator of antidepressant response: recent advances and lifestyle interactions. Int J Mol Sci. 2022;23(22):14445. https://doi.org/10.3390/ijms232214445 .

doi: 10.3390/ijms232214445 pubmed: 36430921 pmcid: 9698349

Jermy BS, Glanville KP, Coleman JRI, Lewis CM, Vassos E. Exploring the genetic heterogeneity in major depression across diagnostic criteria. Mol Psychiatry. 2021;26(12):7337–45. https://doi.org/10.1038/s41380-021-01231-w .

doi: 10.1038/s41380-021-01231-w pubmed: 34290369 pmcid: 8872976

Fabbri C, Corponi F, Souery D, Kasper S, Montgomery S, Zohar J, et al. The genetics of treatment-resistant depression: a critical review and future perspectives. Int J Neuropsychopharmacol. 2019;22(2):93–104. https://doi.org/10.1093/ijnp/pyy024 .

doi: 10.1093/ijnp/pyy024 pubmed: 29688548

Horstmann S, Lucae S, Menke A, Hennings JM, Ising M, Roeske D, et al. Polymorphisms in GRIK4, HTR2A, and FKBP5 show interactive effects in predicting remission to antidepressant treatment. Neuropsychopharmacology. 2010;35(3):727–40. https://doi.org/10.1038/npp.2009.180 .

doi: 10.1038/npp.2009.180 pubmed: 19924111

Milanesi E, Bonvicini C, Congiu C, Bortolomasi M, Gainelli G, Gennarelli M, et al. The role of GRIK4 gene in treatment-resistant depression. Genet Res (Camb). 2015;97:e14. https://doi.org/10.1017/S0016672315000142 .

doi: 10.1017/S0016672315000142 pubmed: 26139080

Saez E, Erkoreka L, Moreno-Calle T, Berjano B, Gonzalez-Pinto A, Basterreche N, et al. Genetic variables of the glutamatergic system associated with treatment-resistant depression: a review of the literature. World J Psychiatry. 2022;12(7):884–96. https://doi.org/10.5498/wjp.v12.i7.884 .

doi: 10.5498/wjp.v12.i7.884 pubmed: 36051601 pmcid: 9331449

Zhang C, Li Z, Wu Z, Chen J, Wang Z, Peng D, et al. A study of N-methyl-D-aspartate receptor gene (GRIN2B) variants as predictors of treatment-resistant major depression. Psychopharmacology. 2014;231(4):685–93. https://doi.org/10.1007/s00213-013-3297-0 .

doi: 10.1007/s00213-013-3297-0 pubmed: 24114429

Amare AT, Schubert KO, Baune BT. Pharmacogenomics in the treatment of mood disorders: strategies and opportunities for personalized psychiatry. EPMA J. 2017;8(3):211–27. https://doi.org/10.1007/s13167-017-0112-8 .

doi: 10.1007/s13167-017-0112-8 pubmed: 29021832 pmcid: 5607053

Kendler KS, Kessler RC, Walters EE, MacLean C, Neale MC, Heath AC, et al. Stressful life events, genetic liability, and onset of an episode of major depression in women. Am J Psychiatry. 1995;152(6):833–42. https://doi.org/10.1176/ajp.152.6.833 .

doi: 10.1176/ajp.152.6.833 pubmed: 7755111

McLaughlin KA, Green JG, Gruber MJ, Sampson NA, Zaslavsky AM, Kessler RC. Childhood adversities and adult psychopathology in the National Comorbidity Survey Replication (NCS-R) III: associations with functional impairment related to DSM-IV disorders. Psychol Med. 2010;40(5):847–59. https://doi.org/10.1017/S0033291709991115 .

doi: 10.1017/S0033291709991115 pubmed: 19732483

Kessler RC, McLaughlin KA, Green JG, Gruber MJ, Sampson NA, Zaslavsky AM, et al. Childhood adversities and adult psychopathology in the WHO world mental health surveys. Br J Psychiatry. 2010;197(5):378–85. https://doi.org/10.1192/bjp.bp.110.080499 .

doi: 10.1192/bjp.bp.110.080499 pubmed: 21037215 pmcid: 2966503

Suntsova M, Garazha A, Ivanova A, Kaminsky D, Zhavoronkov A, Buzdin A. Molecular functions of human endogenous retroviruses in health and disease. Cell Mol Life Sci. 2015;72(19):3653–75. https://doi.org/10.1007/s00018-015-1947-6 .

doi: 10.1007/s00018-015-1947-6 pubmed: 26082181 pmcid: 11113533

Gröger V, Emmer A, Staege MS, Cynis H. Endogenous retroviruses in nervous system disorders. Pharmaceuticals (Basel). 2021;14(1):70. https://doi.org/10.3390/ph14010070 .

doi: 10.3390/ph14010070 pubmed: 33467098

Serati M, Esposito CM, Grassi S, Bollati V, Barkin JL, Buoli M. The Association between Plasma ERVWE1 concentrations and affective symptoms during pregnancy: is this a friendly alien? Int J Environ Res Public Health. 2020;17(24):1–7. https://doi.org/10.3390/ijerph17249217 .

doi: 10.3390/ijerph17249217

Levet S, Charvet B, Bertin A, Deschaumes A, Perron H, Hober D. Human endogenous retroviruses and type 1 diabetes. Curr Diab Rep. 2019;19(12):141. https://doi.org/10.1007/s11892-019-1256-9 .

doi: 10.1007/s11892-019-1256-9 pubmed: 31754894 pmcid: 6872510

Tamouza R, Meyer U, Foiselle M, Richard J-R, Wu C-L, Boukouaci W, et al. Identification of inflammatory subgroups of schizophrenia and bipolar disorder patients with HERV-W ENV antigenemia by unsupervised cluster analysis. Transl Psychiatry. 2021;11(1):377. https://doi.org/10.1038/s41398-021-01499-0 .

doi: 10.1038/s41398-021-01499-0 pubmed: 34230451 pmcid: 8260666

Weis S, Llenos IC, Sabunciyan S, Dulay JR, Isler L, Yolken R, et al. Reduced expression of human endogenous retrovirus (HERV)-W GAG protein in the cingulate gyrus and hippocampus in schizophrenia, bipolar disorder, and depression. J Neural Transm. 2007;114(5):645–55. https://doi.org/10.1007/s00702-006-0599-y .

doi: 10.1007/s00702-006-0599-y pubmed: 17219017

Durnaoglu S, Lee S-K, Ahnn J. Syncytin, envelope protein of human endogenous retrovirus (HERV): no longer ‘fossil’ in human genome. Animal Cells Syst (Seoul). 2021;25(6):358–68. https://doi.org/10.1080/19768354.2021.2019109 .

doi: 10.1080/19768354.2021.2019109

Canli T. A model of human endogenous retrovirus (HERV) activation in mental health and illness. Med Hypotheses. 2019;133(August):109404. https://doi.org/10.1016/j.mehy.2019.109404 .

doi: 10.1016/j.mehy.2019.109404 pubmed: 31557593

Duarte RRR, Pain O, Bendall ML, de Mulder RM, Marston JL, Selvackadunco S, et al. Integrating human endogenous retroviruses into transcriptome-wide association studies highlights novel risk factors for major psychiatric conditions. Nat Commun. 2024;15(1):3803. https://doi.org/10.1038/s41467-024-48153-z .

doi: 10.1038/s41467-024-48153-z pubmed: 38778015 pmcid: 11111684

Rangel SC, da Silva MD, Natrielli Filho DG, Santos SN, do Amaral JB, Victor JR, et al. HERV-W upregulation expression in bipolar disorder and schizophrenia: unraveling potential links to systemic immune/inflammation status. Retrovirology. 2024;21(1):7. https://doi.org/10.1186/s12977-024-00640-3 .

Duperray A, Barbe D, Raguenez G, Weksler BB, Romero IA, Couraud PO, et al. Inflammatory response of endothelial cells to a human endogenous retrovirus associated with multiple sclerosis is mediated by TLR4. Int Immunol. 2015;27(11):545–53. https://doi.org/10.1093/intimm/dxv025 .

doi: 10.1093/intimm/dxv025 pubmed: 25957268 pmcid: 4625887

Wang X, Huang J, Zhu F. Human endogenous retroviral envelope protein Syncytin-1 and inflammatory abnormalities in neuropsychological diseases. Front Psychiatry. 2018;9(SEP):422. https://doi.org/10.3389/fpsyt.2018.00422 .

doi: 10.3389/fpsyt.2018.00422 pubmed: 30245643 pmcid: 6137383

Baumeister D, Lightman SL, Pariante CM. The HPA axis in the pathogenesis and treatment of depressive disorders: integrating clinical and molecular findings. Psychopathol Rev. 2016;a3(1):64–76. https://doi.org/10.5127/pr.034413 .

doi: 10.5127/pr.034413

Yan Q, Wu X, Zhou P, Zhou Y, Li X, Liu Z, et al. HERV-W envelope triggers abnormal dopaminergic neuron process through DRD2/PP2A/AKT1/GSK3 for Schizophrenia Risk. Viruses. 2022;14(1):145. https://doi.org/10.3390/v14010145 .

doi: 10.3390/v14010145 pubmed: 35062349 pmcid: 8777930

Huang W, Li S, Hu Y, Yu H, Luo F, Zhang Q, et al. Implication of the env gene of the human endogenous retrovirus W family in the expression of BDNF and DRD3 and development of recent-onset schizophrenia. Schizophr Bull. 2011;37(5):988–1000. https://doi.org/10.1093/schbul/sbp166 .

doi: 10.1093/schbul/sbp166 pubmed: 20100784

Ahmad Dar M, Ahmad WR. Role of Amisulpride augmentation in treatment resistant major depressive disorder: an open label study from North India. Int J Emerg Ment Heal Hum Resil. 2015;17(2):538–43. https://doi.org/10.4172/1522-4821.1000209 .

doi: 10.4172/1522-4821.1000209

Guyon A, Assouly-Besse F, Biala G, Puech AJ, Thiébot MH. Potentiation by low doses of selected neuroleptics of food-induced conditioned place preference in rats. Psychopharmacology. 1993;110(4):460–6. https://doi.org/10.1007/BF02244653 .

doi: 10.1007/BF02244653 pubmed: 7870917

Szczypiński JJ, Gola M. Dopamine dysregulation hypothesis: the common basis for motivational anhedonia in major depressive disorder and schizophrenia? Rev Neurosci. 2018;29(7):727–44. https://doi.org/10.1515/revneuro-2017-0091 .

doi: 10.1515/revneuro-2017-0091 pubmed: 29573379

Mohamed S, Johnson GR, Chen P, Hicks PB, Davis LL, Yoon J, et al. Effect of antidepressant switching vs augmentation on remission among patients with major depressive disorder unresponsive to antidepressant treatment: the VAST-D randomized clinical trial. JAMA. 2017;318(2):132–45. https://doi.org/10.1001/jama.2017.8036 .

doi: 10.1001/jama.2017.8036 pubmed: 28697253 pmcid: 5817471

Ruberto VL, Jha MK, Murrough JW. Pharmacological treatments for patients with treatment-resistant depression. Pharmaceuticals. 2020;13(6):116. https://doi.org/10.3390/ph13060116 .

doi: 10.3390/ph13060116 pubmed: 32512768 pmcid: 7345023

von Mücke-Heim I-A, Pape JC, Grandi NC, Erhardt A, Deussing JM, Binder EB. Multiomics and blood-based biomarkers of electroconvulsive therapy in severe and treatment-resistant depression: study protocol of the DetECT study. Eur Arch Psychiatry Clin Neurosci. 2024;274(3):673–84. https://doi.org/10.1007/s00406-023-01647-1 .

doi: 10.1007/s00406-023-01647-1

Ruhé HG, van Rooijen G, Spijker J, Peeters FPML, Schene AH. Staging methods for treatment resistant depression. A systematic review. J Affect Disord. 2012;137(1–3):35–45. https://doi.org/10.1016/j.jad.2011.02.020 .

doi: 10.1016/j.jad.2011.02.020 pubmed: 21435727

Howes OD, Thase ME, Pillinger T. Treatment resistance in psychiatry: state of the art and new directions. Mol Psychiatry. 2022;27(1):58–72. https://doi.org/10.1038/s41380-021-01200-3 .

doi: 10.1038/s41380-021-01200-3 pubmed: 34257409

Bauer M, Pfennig A, Severus E, Whybrow PC, Angst J, Möller HJ, et al. World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for biological treatment of unipolar depressive disorders, Part 1: update 2013 on the acute and continuation treatment of unipolar depressive disorders. World J Biol Psychiatry. 2013;14(5):334–85. https://doi.org/10.3109/15622975.2013.804195 .

doi: 10.3109/15622975.2013.804195 pubmed: 23879318

Wang HR, Woo YS, Ahn HS, Ahn IM, Kim HJ, Bahk W-M. Can atypical antipsychotic augmentation reduce subsequent treatment failure more effectively among depressed patients with a higher degree of treatment resistance? A meta-analysis of randomized controlled trials. Int J Neuropsychopharmacol. 2015;18(8):1–10. https://doi.org/10.1093/ijnp/pyv023 .

doi: 10.1093/ijnp/pyv023

Little A. Treatment-resistant depression. Am Fam Physician. 2009;80(2):167–72. https://doi.org/10.1176/appi.ajp.2012.12050648 .

doi: 10.1176/appi.ajp.2012.12050648 pubmed: 19621857

Olgiati P, Bajo E, Bigelli M, Montgomery S, Serretti A. Challenging sequential approach to treatment resistant depression: cost-utility analysis based on the sequenced treatment alternatives to relieve depression (STAR⁎D) trial. Eur Neuropsychopharmacol. 2013;23(12):1739–46. https://doi.org/10.1016/j.euroneuro.2013.08.008 .

doi: 10.1016/j.euroneuro.2013.08.008 pubmed: 24075716

Andrade C. Antidepressant augmentation with anti-inflammatory agents. J Clin Psychiatry. 2014;75(9):975–7. https://doi.org/10.4088/JCP.14f09432 .

doi: 10.4088/JCP.14f09432 pubmed: 25295422

Pandarakalam JP. Challenges of treatment-resistant depression. Psychiatr Danub. 2018;30(3):273–84. https://doi.org/10.24869/psyd.2018.273 .

doi: 10.24869/psyd.2018.273 pubmed: 30267518

Gauthier C, Abdel-Ahad P, Gaillard R. Switching and stopping antidepressants. Encephale. 2018;44(4):379–86. https://doi.org/10.1016/j.encep.2018.08.001 .

doi: 10.1016/j.encep.2018.08.001 pubmed: 30177305

Sørensen A, Jørgensen KJ, Munkholm K. Clinical practice guideline recommendations on tapering and discontinuing antidepressants for depression : a systematic review. Ther Adv Psychopharmacol. 2022;12:1–16. https://doi.org/10.1177/20451253211067656 .

doi: 10.1177/20451253211067656

Rush AJ, Trivedi MH, Wisniewski SR, Nierenberg AA, Stewart JW, Warden D, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry. 2006;163(11):1905–17. https://doi.org/10.1176/ajp.2006.163.11.1905 .

doi: 10.1176/ajp.2006.163.11.1905 pubmed: 17074942

Souery D, Serretti A, Calati R, Oswald P, Massat I, Konstantinidis A, et al. Switching antidepressant class does not improve response or remission in treatment-resistant depression. J Clin Psychopharmacol. 2011;31(4):512–6. https://doi.org/10.1097/JCP.0b013e3182228619 .

doi: 10.1097/JCP.0b013e3182228619 pubmed: 21694617

Cuijpers P, Noma H, Karyotaki E, Vinkers CH, Cipriani A, Furukawa TA. A network meta-analysis of the effects of psychotherapies, pharmacotherapies and their combination in the treatment of adult depression. World Psychiatry. 2020;19(1):92–107. https://doi.org/10.1002/wps.20701 .

doi: 10.1002/wps.20701 pubmed: 31922679 pmcid: 6953550

Gloster AT, Rinner MTB, Ioannou M, Villanueva J, Block VJ, Ferrari G, et al. Treating treatment non-responders: a meta-analysis of randomized controlled psychotherapy trials. Clin Psychol Rev. 2019;2020(75).

van Bronswijk S, Moopen N, Beijers L, Ruhe HG, Peeters F. Effectiveness of psychotherapy for treatment-resistant depression: a meta-analysis and meta-regression. Psychol Med. 2019;49(3):366–79. https://doi.org/10.1017/S003329171800199X .

doi: 10.1017/S003329171800199X pubmed: 30139408

Valiuliene G, Valiulis V, Dapsys K, Vitkeviciene A, Gerulskis G, Navakauskiene R, et al. Brain stimulation effects on serum BDNF, VEGF, and TNFα in treatment-resistant psychiatric disorders. Eur J Neurosci. 2021;53(11):3791–802. https://doi.org/10.1111/ejn.15232 .

doi: 10.1111/ejn.15232 pubmed: 33861484

Rizvi S, Khan AM. Use of transcranial magnetic stimulation for depression. Cureus. 2019;28(9):1–4. https://doi.org/10.7759/cureus.4736 .

doi: 10.7759/cureus.4736

Massé-Leblanc C, Jodoin VD, Nguyen DK, Lespérance P, Miron J-P. Effectiveness of transcranial magnetic stimulation for treatment-resistant depression at a Canadian tertiary referral hospital. Brain Stimul. 2023;16(1):241. https://doi.org/10.1016/j.brs.2023.01.374 .

doi: 10.1016/j.brs.2023.01.374

Mathew SJ, Wilkinson ST, Altinay M, Asghar-Ali A, Chang LC, Collins KA, et al. ELEctroconvulsive therapy (ECT) vs. Ketamine in patients with treatment-resistant depression: the ELEKT-D study protocol. Contemp Clin Trials. 2019;77(August 2018):19–26. https://doi.org/10.1016/j.cct.2018.12.009 .

doi: 10.1016/j.cct.2018.12.009 pubmed: 30572160

Porter RJ, Baune BT, Morris G, Hamilton A, Bassett D, Boyce P, et al. Cognitive side-effects of electroconvulsive therapy: what are they, how to monitor them and what to tell patients. BJPsych Open. 2020;6(3):e40. https://doi.org/10.1192/bjo.2020.17 .

doi: 10.1192/bjo.2020.17 pubmed: 32301408 pmcid: 7191622

Andrade C, Arumugham SS, Thirthalli J. Adverse effects of electroconvulsive therapy. Psychiatr Clin North Am. 2016;39(3):513–30. https://doi.org/10.1016/j.psc.2016.04.004 .

doi: 10.1016/j.psc.2016.04.004 pubmed: 27514303

Pottkämper JCM, Verdijk JPAJ, Hofmeijer J, van Waarde JA, van Putten MJAM. Seizures induced in electroconvulsive therapy as a human epilepsy model: a comparative case study. Epilepsia Open. 2021;6(4):672–84. https://doi.org/10.1002/epi4.12532 .

doi: 10.1002/epi4.12532 pubmed: 34351710 pmcid: 8633469

Lespérance P, Desbeaumes JV, Drouin D, Racicot F, Miron J-P, Longpré-Poirier C, et al. Vagus nerve stimulation modulates inflammation in treatment-resistant depression patients: a pilot study. Int J Mol Sci. 2024;25(5):2679. https://doi.org/10.3390/ijms25052679 .

doi: 10.3390/ijms25052679 pubmed: 38473935 pmcid: 10931975

Zhang X, Guo YM, Ning YP, Cao LP, Rao YH, Sun JQ, et al. Adjunctive vagus nerve stimulation for treatment-resistant depression: a preliminary study. Int J Psychiatry Clin Pract. 2022;26(4):337–42. https://doi.org/10.1080/13651501.2021.2019789 .

doi: 10.1080/13651501.2021.2019789 pubmed: 35023429

Jongkees BJ, Immink MA, Finisguerra A, Colzato LS. Transcutaneous Vagus Nerve Stimulation (tVNS) enhances response selection during sequential action. Front Psychol. 2018;9(JUL):1–8. https://doi.org/10.3389/fpsyg.2018.01159 .

doi: 10.3389/fpsyg.2018.01159

Olsen LK, Solis E, McIntire LK, Hatcher-Solis CN. Vagus nerve stimulation: mechanisms and factors involved in memory enhancement. Front Hum Neurosci. 2023;17(June). https://doi.org/10.3389/fnhum.2023.1152064 .

Shah A, Carreno FR, Frazer A. Therapeutic modalities for treatment resistant depression: focus on vagal nerve stimulation and ketamine. Clin Psychopharmacol Neurosci. 2014;12(2):83–93. https://doi.org/10.9758/cpn.2014.12.2.83 .

doi: 10.9758/cpn.2014.12.2.83 pubmed: 25191499 pmcid: 4153868

Aaronson ST, Sears P, Ruvuna F, Bunker M, Conway CR, Dougherty DD, et al. A 5-year observational study of patients with treatment-resistant depression treated with vagus nerve stimulation or treatment as usual: comparison of response, remission, and suicidality. Am J Psychiatry. 2017;174(7):640–8. https://doi.org/10.1176/appi.ajp.2017.16010034 .

doi: 10.1176/appi.ajp.2017.16010034 pubmed: 28359201

Conway CR, Kumar A, Xiong W, Bunker M, Aaronson ST, Rush AJ. Chronic vagus nerve stimulation significantly improves quality of life in treatment-resistant major depression. J Clin Psychiatry. 2018;79(5):11–2. https://doi.org/10.4088/JCP.18m12178 .

doi: 10.4088/JCP.18m12178

Bonaz BL, Bernstein CN. Brain-gut interactions in inflammatory bowel disease. Gastroenterology. 2013;144(1):36–49. https://doi.org/10.1053/j.gastro.2012.10.003 .

doi: 10.1053/j.gastro.2012.10.003 pubmed: 23063970

Borbély É, Simon M, Fuchs E, Wiborg O, Czéh B, Helyes Z. Novel drug developmental strategies for treatment-resistant depression. Br J Pharmacol. 2022;179(6):1146–86. https://doi.org/10.1111/bph.15753 .

doi: 10.1111/bph.15753 pubmed: 34822719

Millen AM, Daniels WM, Baijnath S. Depression, an unmet health need in Africa: understanding the promise of ketamine. Heliyon. 2024;10(7):e28610. https://doi.org/10.1016/j.heliyon.2024.e28610 .

doi: 10.1016/j.heliyon.2024.e28610 pubmed: 38601594 pmcid: 11004535

Shim I. Distinct functions of S-ketamine and R-ketamine in mediating biobehavioral processes of drug dependency: comments on Bonaventura, et al. Mol Psychiatry. 2023;28(12):4939–40. https://doi.org/10.1038/s41380-022-01629-0 .

doi: 10.1038/s41380-022-01629-0 pubmed: 35595979

McIntyre RS, Rosenblat JD, Nemeroff CB, Sanacora G, Murrough JW, Berk M, et al. Synthesizing the evidence for ketamine and esketamine in treatment-resistant depression: an international expert opinion on the available evidence and implementation. Am J Psychiatry. 2021;178(5):383–99. https://doi.org/10.1176/appi.ajp.2020.20081251 .

doi: 10.1176/appi.ajp.2020.20081251 pubmed: 33726522 pmcid: 9635017

Herzog DP, Wegener G, Lieb K, Müller MB, Treccani G. Decoding the mechanism of action of rapid-acting antidepressant treatment strategies: Does gender matter? Int J Mol Sci. 2019;20(4):949. https://doi.org/10.3390/ijms20040949 .

doi: 10.3390/ijms20040949 pubmed: 30813226 pmcid: 6412361

Riggs LM, Gould TD. Ketamine and the future of rapid-acting antidepressants. Annu Rev Clin Psychol. 2021;17(1):207–31. https://doi.org/10.1146/annurev-clinpsy-072120-014126 .

doi: 10.1146/annurev-clinpsy-072120-014126 pubmed: 33561364 pmcid: 8170851

Medeiros GC, Gould TD, Prueitt WL, Nanavati J, Grunebaum MF, Farber NB, et al. Blood-based biomarkers of antidepressant response to ketamine and esketamine: a systematic review and meta-analysis. Mol Psychiatry. 2022;27(9):3658–69. https://doi.org/10.1038/s41380-022-01652-1 .

doi: 10.1038/s41380-022-01652-1 pubmed: 35760879 pmcid: 9933928

Medeiros GC, Matheson M, Demo I, Reid MJ, Matheson S, Twose C, et al. Brain-based correlates of antidepressant response to ketamine: a comprehensive systematic review of neuroimaging studies. Lancet Psychiatry. 2023;10(10):790–800. https://doi.org/10.1016/S2215-0366(23)00183-9 .

doi: 10.1016/S2215-0366(23)00183-9 pubmed: 37625426

Krystal JH, Abdallah CG, Sanacora G, Charney DS, Duman RS. Ketamine: a paradigm shift for depression research and treatment. Neuron. 2019;101(5):774–8. https://doi.org/10.1016/j.neuron.2019.02.005 .

doi: 10.1016/j.neuron.2019.02.005 pubmed: 30844397 pmcid: 6560624

Thase M, Connolly KR. etamine and esketamine for treating unipolar depression in adults : administration , efficacy , and adverse effects. 2024. https://www.uptodate.com/contents/ketamine-and-esk .

Alnefeesi Y, Chen-Li D, Krane E, Jawad MY, Rodrigues NB, Ceban F, et al. Real-world effectiveness of ketamine in treatment-resistant depression: a systematic review & meta-analysis. J Psychiatr Res. 2022;2022(151):693–709. https://doi.org/10.1016/j.jpsychires.2022.04.037 .

doi: 10.1016/j.jpsychires.2022.04.037

Arputhanantham SS. Managing treatment resistant depression and molecular mechanism of ketamine- an update. EC Pharmacol Toxicol. 2019;7(9):977–80.

Newport DJ, Carpenter LL, McDonald WM, Potash JB, Tohen M, Nemeroff CB. Ketamine and other NMDA antagonists: early clinical trials and possible mechanisms in depression. Am J Psychiatry. 2015;172(10):950–66. https://doi.org/10.1176/appi.ajp.2015.15040465 .

doi: 10.1176/appi.ajp.2015.15040465 pubmed: 26423481

Kishimoto T, Chawla JM, Hagi K, Zarate CA, Kane JM, Bauer M, et al. Single-dose infusion ketamine and non-ketamine N-methyl-d-aspartate receptor antagonists for unipolar and bipolar depression: a meta-analysis of efficacy, safety and time trajectories. Psychol Med. 2016;46(07):1459–72. https://doi.org/10.1017/S0033291716000064 .

doi: 10.1017/S0033291716000064 pubmed: 26867988 pmcid: 5116384

Matveychuk D, Thomas RK, Swainson J, Khullar A, MacKay MA, Baker GB, et al. Ketamine as an antidepressant: overview of its mechanisms of action and potential predictive biomarkers. Ther Adv Psychopharmacol. 2020;10:1–21. https://doi.org/10.1177/2045125320916657 .

doi: 10.1177/2045125320916657

Kalkman HO. Activation of σ1-Receptors by R-Ketamine may enhance the antidepressant effect of S-Ketamine. Biomedicines. 2023;11(10):1–8. https://doi.org/10.3390/biomedicines11102664 .

doi: 10.3390/biomedicines11102664

Thomas AM, Duman RS. Novel rapid-acting antidepressants: molecular and cellular signaling mechanisms. Neuronal Signal. 2017;1(4):1–10. https://doi.org/10.1042/ns20170010 .

doi: 10.1042/ns20170010

Chen MH, Li CT, Lin WC, Hong CJ, Tu PC, Bai YM, et al. Rapid inflammation modulation and antidepressant efficacy of a low-dose ketamine infusion in treatment-resistant depression: a randomized, double-blind control study. Psychiatry Res. 2018;269(January):207–11. https://doi.org/10.1016/j.psychres.2018.08.078 .

doi: 10.1016/j.psychres.2018.08.078 pubmed: 30153598

Bonaventura J, Lam S, Carlton M, Boehm MA, Gomez JL, Solís O, et al. Pharmacological and behavioral divergence of ketamine enantiomers: implications for abuse liability. Mol Psychiatry. 2021;26(11):6704–22. https://doi.org/10.1038/s41380-021-01093-2 .

doi: 10.1038/s41380-021-01093-2 pubmed: 33859356 pmcid: 8517038

Kokkinou M, Ashok AH, Howes OD. The effects of ketamine on dopaminergic function: meta-Analysis and review of the implications for neuropsychiatric disorders. Mol Psychiatry. 2018;23(1):59–69. https://doi.org/10.1038/mp.2017.190 .

doi: 10.1038/mp.2017.190 pubmed: 28972576

Wei Y, Chang L, Hashimoto K. A historical review of antidepressant effects of ketamine and its enantiomers. Pharmacol Biochem Behav. 2020;190(February):172870. https://doi.org/10.1016/j.pbb.2020.172870 .

doi: 10.1016/j.pbb.2020.172870 pubmed: 32035078

Hare BD, Shinohara R, Liu RJ, Pothula S, DiLeone RJ, Duman RS. Optogenetic stimulation of medial prefrontal cortex Drd1 neurons produces rapid and long-lasting antidepressant effects. Nat Commun. 2019;10(1):1–12. https://doi.org/10.1038/s41467-018-08168-9 .

doi: 10.1038/s41467-018-08168-9

Rincón-Cortés M, Grace AA. Antidepressant effects of ketamine on depression-related phenotypes and dopamine dysfunction in rodent models of stress. Behav Brain Res. 2020;379:112367. https://doi.org/10.1016/j.bbr.2019.112367 .

doi: 10.1016/j.bbr.2019.112367 pubmed: 31739001

Gould TD, Zarate CA, Thompson SM. Molecular pharmacology and neurobiology of rapid-acting antidepressants. Annu Rev Pharmacol Toxicol. 2019;59(1):213–36. https://doi.org/10.1146/annurev-pharmtox-010617-052811 .

doi: 10.1146/annurev-pharmtox-010617-052811 pubmed: 30296896

Browne CA, Lucki I. Antidepressant effects of ketamine: mechanisms underlying fast-acting novel antidepressants. Front Pharmacol. 2013;4 DEC(December):1–18. https://doi.org/10.3389/fphar.2013.00161 .

doi: 10.3389/fphar.2013.00161

Weleff J, Bryant K, Kovacevich A, Barnett BS. Suicide versus accidental death by autoerotic asphyxiation in a patient receiving intravenous ketamine for depression. Case Rep Psychiatry. 2022;2022:1–4. https://doi.org/10.1155/2022/1104668 .

doi: 10.1155/2022/1104668

Cusin C, Sakurai H, Bentley K, Pedrelli P, Foster S, Fava M, et al. All suicidal ideation is not created equal: two cases of suicide attempts during maintenance ketamine treatment. Am J Psychiatry. 2020;177(2):173–4. https://doi.org/10.1176/appi.ajp.2019.19050508 .

doi: 10.1176/appi.ajp.2019.19050508 pubmed: 32008389

Jelen LA, McShane R, Young AH. Guidelines for ketamine use in clinical psychiatry practice. BJPsych Open. 2024;10(3):1–3. https://doi.org/10.1192/bjo.2024.62 .

doi: 10.1192/bjo.2024.62

Breeksema JJ, Niemeijer A, Krediet E, Karsten T, Kamphuis J, Vermetten E, et al. Patient perspectives and experiences with psilocybin treatment for treatment-resistant depression: a qualitative study. Sci Rep. 2024;14(1):2929. https://doi.org/10.1038/s41598-024-53188-9 .

doi: 10.1038/s41598-024-53188-9 pubmed: 38316896 pmcid: 10844281

Carhart-Harris RL, Roseman L, Bolstridge M, Demetriou L, Pannekoek JN, Wall MB, et al. Psilocybin for treatment-resistant depression: fMRI-measured brain mechanisms. Sci Rep. 2017;7(1):13187. https://doi.org/10.1038/s41598-017-13282-7 .

doi: 10.1038/s41598-017-13282-7 pubmed: 29030624 pmcid: 5640601

Vollenweider FX, Hell D. Vollenweider FX, Vontobel P, Hell D, Leenders basal ganglia in psilocybin-induced 5-HT modulation of dopamine release in basal ganglia in psilocybin-induced psychosis in Man — A PET study with [11 C ] raclopride. Neuropharmacology. 1999;20(5):424–33.

Ishii T, Kimura Y, Ichise M, Takahata K, Kitamura S, Moriguchi S, et al. Anatomical relationships between serotonin 5-HT2A and dopamine D2 receptors in living human brain. PLoS ONE. 2017;12(12):e0189318. https://doi.org/10.1371/journal.pone.0189318 .

doi: 10.1371/journal.pone.0189318 pubmed: 29220382 pmcid: 5722317

Carhart-Harris RL, Bolstridge M, Rucker J, Day CMJ, Erritzoe D, Kaelen M, et al. Psilocybin with psychological support for treatment-resistant depression: an open-label feasibility study. Lancet Psychiatry. 2016;3(7):619–27. https://doi.org/10.1016/S2215-0366(16)30065-7 .

doi: 10.1016/S2215-0366(16)30065-7 pubmed: 27210031

Carhart-Harris RL, Bolstridge M, Day CMJ, Rucker J, Watts R, Erritzoe DE, et al. Psilocybin with psychological support for treatment-resistant depression: six-month follow-up. Psychopharmacology. 2018;235(2):399–408. https://doi.org/10.1007/s00213-017-4771-x .

doi: 10.1007/s00213-017-4771-x pubmed: 29119217

Gukasyan N, Davis AK, Barrett FS, Cosimano MP, Sepeda ND, Johnson MW, et al. Efficacy and safety of psilocybin-assisted treatment for major depressive disorder: prospective 12-month follow-up. J Psychopharmacol. 2022;36(2):151–8. https://doi.org/10.1177/02698811211073759 .

doi: 10.1177/02698811211073759 pubmed: 35166158 pmcid: 8864328

Cowen PJ. Backing into the future: pharmacological approaches to the management of resistant depression. Psychol Med. 2017;47(15):2569–77. https://doi.org/10.1017/S003329171700068X .

doi: 10.1017/S003329171700068X pubmed: 28838328 pmcid: 5635969

Kappelmann N, Lewis G, Dantzer R, Jones PB, Khandaker GM. Antidepressant activity of anti-cytokine treatment: a systematic review and meta-analysis of clinical trials of chronic inflammatory conditions. Mol Psychiatry. 2018;23(2):335–43. https://doi.org/10.1038/mp.2016.167 .

doi: 10.1038/mp.2016.167 pubmed: 27752078

Köhler-Forsberg O, N Lydholm C, Hjorthøj C, Nordentoft M, Mors O, Benros ME. Efficacy of anti-inflammatory treatment on major depressive disorder or depressive symptoms: meta-analysis of clinical trials. Acta Psychiatr Scand. 2019;139(5):404–19. https://doi.org/10.1111/acps.13016 .

Wessa C, Morrens M, De Picker LJ. Choice of outcome measure predicts anti-inflammatory treatment efficacy in major depressive disorder [Letter]. Neuropsychiatr Dis Treat. 2023;19(March):515–7. https://doi.org/10.2147/NDT.S407852 .

doi: 10.2147/NDT.S407852 pubmed: 36910332 pmcid: 9994662

Simon MS, Arteaga-Henríquez G, Fouad Algendy A, Siepmann T, Illigens BMW. Anti-inflammatory treatment efficacy in major depressive disorder: a systematic review of meta-analyses. Neuropsychiatr Dis Treat. 2023;19(January):1–25. https://doi.org/10.2147/NDT.S385117 .

doi: 10.2147/NDT.S385117 pubmed: 36636142 pmcid: 9830720

Qiu Y, Duan A, Yin Z, Xie M, Chen Z, Sun X, et al. Efficacy and tolerability of minocycline in depressive patients with or without treatment-resistant: a meta-analysis of randomized controlled trials. Front Psychiatry. 2023;14(Mdd). https://doi.org/10.3389/fpsyt.2023.1139273 .

Du Y, Dou Y, Wang M, Wang Y, Yan Y, Fan H, et al. Efficacy and acceptability of anti-inflammatory agents in major depressive disorder: a systematic review and meta-analysis. Front Psychiatry. 2024;15(May):1–11. https://doi.org/10.3389/fpsyt.2024.1407529 .

doi: 10.3389/fpsyt.2024.1407529

Ding Y, Wei Z, Yan H, Guo W. Efficacy of treatments targeting hypothalamic-pituitary-adrenal systems for major depressive disorder: a meta-analysis. Front Pharmacol. 2021;12(September):1–14. https://doi.org/10.3389/fphar.2021.732157 .

doi: 10.3389/fphar.2021.732157

Sigalas PD, Garg H, Watson S, McAllister-Williams RH, Ferrier IN. Metyrapone in treatment-resistant depression. Ther Adv Psychopharmacol. 2012;2(4):139–49. https://doi.org/10.1177/2045125312436597 .

doi: 10.1177/2045125312436597 pubmed: 23983967 pmcid: 3736936

Kostadinov I, Mihaylova A, Zlatanova H, Doncheva N, Delev D, Ivanovska M. P.414 Influence of the dopamine receptor agonist pramipexole on serum levels of pro- and anti-inflammatory cytokines. Eur Neuropsychopharmacol. 2019;29(December):S293-4. https://doi.org/10.1016/j.euroneuro.2019.09.427 .

doi: 10.1016/j.euroneuro.2019.09.427

De Kwaasteniet BP, Pinto C, Ruhé EHG, Van Wingen GA, Booij J, Denys D. Striatal dopamine D2/3 receptor availability in treatment resistant depression. PLoS ONE. 2014;9(11):1–6. https://doi.org/10.1371/journal.pone.0113612 .

doi: 10.1371/journal.pone.0113612

Kaur M, Sanches M. Experimental therapeutics in treatment-resistant major depressive disorder. J Exp Pharmacol. 2021;13:181–96. https://doi.org/10.2147/JEP.S259302 .

doi: 10.2147/JEP.S259302 pubmed: 33658867 pmcid: 7917305

Treatment-resistant depression: molecular mechanisms and management.

Journal

Informations de publication

Résumé

Identifiants

Substances chimiques

Types de publication

Langues

Sous-ensembles de citation

Pagination

Informations de copyright

Références

Auteurs

Mayanja M Kajumba (MM)

Angelina Kakooza-Mwesige (A)

Noeline Nakasujja (N)

Deborah Koltai (D)

Turhan Canli (T)

Articles similaires

[Redispensing of expensive oral anticancer medicines: a practical application].

Smoking Cessation and Incident Cardiovascular Disease.

Evaluation of Low-Value Services Across Major Medicare Advantage Insurers and Traditional Medicare.

Effectiveness of Virtual Yoga for Chronic Low Back Pain: A Randomized Clinical Trial.

Classifications MeSH