Antidepressant medications: a comprehensive review of efficacy, safety, and future directions
DOI:
https://doi.org/10.18203/2394-6040.ijcmph20253726Keywords:
Antidepressant drugs, Depression, Efficacy, Mechanism of action, Personalized medicine, Safety profile, Treatment-resistant depression, Future directionsAbstract
Depression is a disabling psychiatric disorder that affects emotional, cognitive, and physical functioning worldwide. Pharmacotherapy remains the cornerstone of treatment; however, limitations such as delayed onset, adverse effects, and treatment resistance continue to challenge clinical management. Recent advances in psychopharmacology, including rapid-acting agents, multimodal antidepressants, and pharmacogenomic-guided therapy, offer new possibilities for improving outcomes. A systematic review of PubMed, Scopus, and Web of Science databases was conducted for studies published between 2000 and 2024. Using preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines, 35 peer-reviewed articles—including randomized controlled trials, meta-analyses, and systematic reviews—were selected. Data on mechanisms, efficacy, safety, and emerging therapies were qualitatively analyzed to synthesize current evidence on antidepressant pharmacotherapy. Conventional antidepressants such as selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) remain effective first-line agents, though approximately 30–40% of patients exhibit inadequate response. Recent findings highlight the efficacy of novel treatments like ketamine, esketamine, and vortioxetine, which demonstrate rapid symptom relief and cognitive benefits. Personalized medicine and pharmacogenomics are emerging as valuable tools to optimize drug selection and minimize side effects. Additionally, controlled psychedelic-assisted therapies show promise for treatment-resistant depression. Antidepressant therapy is undergoing a paradigm shift toward precision psychiatry. Integration of rapid-acting agents, multimodal mechanisms, and personalized approaches may enhance efficacy, tolerability, and patient-centered outcomes. Continued research into novel targets and individualized treatment strategies is essential to advance the management of depressive disorders.
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References
World Health Organization. Depression and other common mental disorders: global health estimates. 2017. Available at: https://www.who.int/publications /i/item/depression-global-health-estimates. Accessed on 25 August 2025.
GBD 2019 Mental Disorders Collaborators. Global, regional, and national burden of 12 mental disorders in 204 countries and territories, 1990-2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet Psychiatr. 2022;9(2):137-50. DOI: https://doi.org/10.1016/S2215-0366(21)00395-3
Kessler RC, Bromet EJ. The epidemiology of depression across cultures. Annual Rev Public Health. 2013;34:119-38. DOI: https://doi.org/10.1146/annurev-publhealth-031912-114409
Blier P, de Montigny C. Current advances and trends in the treatment of depression. Trends in Pharmacol Sci. 2004;25(7):351-7.
Aan Het Rot M, Mathew SJ, Charney DS. Neurobiological mechanisms in major depressive disorder. Can Med Assoc J. 2009;180(3):305-13.
Cipriani A, Furukawa TA, Salanti G, Chaimani A, Atkinson LZ, Ogawa Y, et al. Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a systematic review and network meta-analysis. The Lancet. 2018;391(10128):1357-66. DOI: https://doi.org/10.1016/S0140-6736(17)32802-7
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. DOI: https://doi.org/10.1176/ajp.2006.163.11.1905
Ferguson JM. SSRI antidepressant medications: adverse effects and tolerability. Primary Care Companion. J Clin Psychiatry. 2001;3(1):22-7. DOI: https://doi.org/10.4088/PCC.v03n0105
Montgomery SA, Baldwin DS, Blier P, Fineberg NA, Kasper S, Lader M, et al. Which antidepressants have demonstrated superior efficacy? A review of the evidence. Int Clin Psychopharmacol. 2007;22(6):323-9. DOI: https://doi.org/10.1097/YIC.0b013e3282eff7e0
Murrough JW, Iosifescu DV, Chang LC, Al Jurdi RK, Green CE, Perez AM, et al. Antidepressant efficacy of ketamine in treatment-resistant major depression: a two-site randomized controlled trial. Am J Psychiatry. 2013;170(10):1134-42. DOI: https://doi.org/10.1176/appi.ajp.2013.13030392
McIntyre RS, Lophaven S, Olsen CK. A randomized, double-blind, placebo-controlled study of vortioxetine on cognitive function in depressed adults. Int J Neuropsychopharmacol. 2014;17(10):1557-67. DOI: https://doi.org/10.1017/S1461145714000546
Tan G, Ward J, Luedtke A, et al. Pharmacogenomics in depression: a systematic review of clinical studies. The Pharmacogenomics Journal. 2020;20(2):141-53.
Carhart-Harris RL, Bolstridge M, Rucker J, Day CM, 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. DOI: https://doi.org/10.1016/S2215-0366(16)30065-7
Carhart-Harris RL, Roseman L, Bolstridge M, Demetriou L, Pannekoek JN, et al. Psilocybin for treatment-resistant depression: fMRI-measured brain mechanisms. Sci Rep. 2017;7(1):13187. DOI: https://doi.org/10.1038/s41598-017-13282-7
Duman RS, Aghajanian GK, Sanacora G, Krystal JH. Synaptic plasticity and depression: new insights from stress and rapid-acting antidepressants. Nature Med. 2016;22(3):238-49. DOI: https://doi.org/10.1038/nm.4050
Trivedi MH, Rush AJ, Wisniewski SR, Nierenberg AA, Warden D, Ritz L, et al. Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: implications for clinical practice. Am J Psychiatry. 2006;163(1):28-40. DOI: https://doi.org/10.1176/appi.ajp.163.1.28
Moher D, Liberati A, Tetzlaff J, Altman DG; PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med. 2009;6(7):e1000097. DOI: https://doi.org/10.1371/journal.pmed.1000097
aan het Rot M, Mathew SJ, Charney DS. Neurobiological mechanisms in major depressive disorder. Can Med Assoc J. 2009;180(3):305-13. DOI: https://doi.org/10.1503/cmaj.080697
Malberg JE, Eisch AJ, Nestler EJ, Duman RS. Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. J Neurosci. 2000;20(24):9104-10. DOI: https://doi.org/10.1523/JNEUROSCI.20-24-09104.2000
Anderson IM. Selective serotonin reuptake inhibitors versus tricyclic antidepressants: a meta-analysis of efficacy and tolerability. J Affect Disord. 2000;58(1):19-36. DOI: https://doi.org/10.1016/S0165-0327(99)00092-0
Stahl SM. Mechanism of action of serotonin selective reuptake inhibitors: serotonin receptors and pathways mediate therapeutic effects and side effects. J Affect Disord. 1998;51(3):215-35. DOI: https://doi.org/10.1016/S0165-0327(98)00221-3
Duman RS, Heninger GR, Nestler EJ. A molecular and cellular theory of depression. Arch Gen Psychiatry. 1997;54(7):597-606. DOI: https://doi.org/10.1001/archpsyc.1997.01830190015002
Kennedy SH, Lam RW, McIntyre RS, Tourjman SV, Bhat V, Blier P, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) 2016 Clinical Guidelines for the Management of Adults with Major Depressive Disorder: Section 3. Pharmacological Treatments. Can J Psychiatry. 2016;61(9):540-60. DOI: https://doi.org/10.1177/0706743716659417
Fava M, Rush AJ, Alpert JE, Balasubramani GK, Wisniewski SR, Carmin CN, et al. Difference in treatment outcome in outpatients with anxious versus nonanxious depression: a STAR*D report. Am J Psychiatry. 2008;165(3):342-51. DOI: https://doi.org/10.1176/appi.ajp.2007.06111868
Bauer M, Bschor T, Pfennig A, Whybrow PC, Angst J, Versiani M, et al. World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for Biological Treatment of Unipolar Depressive Disorders in Primary Care. World J Biol Psychiatry. 2007;8(2):67-104. DOI: https://doi.org/10.1080/15622970701227829
Aan Het Rot M, Zarate CA Jr, Charney DS, Mathew SJ. Ketamine for depression: where do we go from here? Biol Psychiatry. 2012;72(7):537-47. DOI: https://doi.org/10.1016/j.biopsych.2012.05.003
Krystal JH, Sanacora G, Duman RS. Rapid-acting glutamatergic antidepressants: the path to ketamine and beyond. Biol Psychiatry. 2013;73(12):1133-41. DOI: https://doi.org/10.1016/j.biopsych.2013.03.026
Li N, Lee B, Liu RJ, Banasr M, Dwyer JM, Iwata M, et al. mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science. 2010;329(5994):959-64. DOI: https://doi.org/10.1126/science.1190287
Alvarez E, Perez V, Dragheim M, Loft H, Artigas F. A double-blind, randomized, placebo-controlled, active reference study of Lu AA21004 in patients with major depressive disorder. Int J Neuropsychopharmacol. 2012;15(5):589-600. DOI: https://doi.org/10.1017/S1461145711001027
Fabbri C, Serretti A. Pharmacogenetics of major depressive disorder: top genes and pathways toward clinical applications. Curr Psychiatr Rep. 2015;17(7):50. DOI: https://doi.org/10.1007/s11920-015-0594-9
Bousman CA, Arandjelovic K, Mancuso SG, Eyre HA, Dunlop BW. Pharmacogenetic tests and depressive symptom remission: a meta-analysis of randomized controlled trials. Pharmacogenomics. 2019;20(1):37-47. DOI: https://doi.org/10.2217/pgs-2018-0142
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. DOI: https://doi.org/10.1016/j.biopsych.2008.11.029
Duman RS, Monteggia LM. A neurotrophic model for stress-related mood disorders. Biol Psychiatry. 2006;59(12):1116-27. DOI: https://doi.org/10.1016/j.biopsych.2006.02.013
Thase ME, Haight BR, Richard N, Rockett CB, Mitton M, Modell JG, et al. Remission rates following antidepressant therapy with bupropion or selective serotonin reuptake inhibitors: a meta-analysis of original data from 7 randomized controlled trials. J Clin Psychiatry. 2005;66(8):974-81. DOI: https://doi.org/10.4088/JCP.v66n0803
Papakostas GI, Fava M. Does the probability of receiving placebo influence clinical trial outcome? A meta-regression of double-blind, randomized clinical trials in MDD. Eur Neuropsychopharmacol. 2009;19(1):34-40. DOI: https://doi.org/10.1016/j.euroneuro.2008.08.009
Kirsch I, Deacon BJ, Huedo-Medina TB, Scoboria A, Moore TJ, Johnson BT. Initial severity and antidepressant benefits: a meta-analysis of data submitted to the Food and Drug Administration. PLoS Med. 2008;5(2):e45. DOI: https://doi.org/10.1371/journal.pmed.0050045
Mulrow CD, Williams JW Jr, Chiquette E, Aguilar C, Hitchcock-Noel P, Lee S, et al. Efficacy of newer medications for treating depression in primary care patients. Am J Med. 2000;108(1):54-64. DOI: https://doi.org/10.1016/S0002-9343(99)00316-2
Zarate CA Jr, Singh JB, Carlson PJ, Brutsche NE, Ameli R, Luckenbaugh DA, et al. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry. 2006;63(8):856-64. DOI: https://doi.org/10.1001/archpsyc.63.8.856
Hammad TA, Laughren T, Racoosin J. Suicidality in pediatric patients treated with antidepressant drugs. Arch Gen Psychiatry. 2006;63(3):332-9. DOI: https://doi.org/10.1001/archpsyc.63.3.332
Gartlehner G, Hansen RA, Morgan LC, Thaler K, Lux L, Van Noord M, et al. Comparative benefits and harms of second-generation antidepressants for treating major depressive disorder: an updated meta-analysis. Ann Intern Med. 2011;155(11):772-85. DOI: https://doi.org/10.7326/0003-4819-155-11-201112060-00009
Trivedi MH, Rush AJ, Carmody TJ, Donahue RM, Bolden-Watson C, Houser TL, et al. Do bupropion SR and sertraline differ in their effects on anxiety in depressed patients? J Clin Psychiatry. 2001;62(10):776-81. DOI: https://doi.org/10.4088/JCP.v62n1005
Clayton AH, McGarvey EL, Clavet GJ. The changes in sexual functioning questionnaire (CSFQ): development, reliability, and validity. Psychopharmacol Bull. 1997;33(4):731-45.
Glassman AH, Bigger JT Jr. Antidepressant drugs and cardiovascular risk: a review of the evidence. J Clin Psychiatry. 2001;62:28-33.
Canuso CM, Singh JB, Fedgchin M, Alphs L, Lane R, Lim P, et al. Efficacy and Safety of Intranasal Esketamine for the Rapid Reduction of Symptoms of Depression and Suicidality in Patients at Imminent Risk for Suicide: Results of a Double-Blind, Randomized, Placebo-Controlled Study. Am J Psychiatry. 2018;175(7):620-30. DOI: https://doi.org/10.1176/appi.ajp.2018.17060720
Baldwin DS, Chrones L, Florea I, Nielsen RZ, Nomikos GG, Palo W, et al. The safety and tolerability of vortioxetine. J Psychopharmacol. 2016;30(3):242-52. DOI: https://doi.org/10.1177/0269881116628440
Rush AJ, Trivedi MH, Stewart JW, Nierenberg AA, Fava M, Kurian BT, et al. Combining medications to enhance depression outcomes (CO-MED). Am J Psychiatry. 2011;168(7):689-701. DOI: https://doi.org/10.1176/appi.ajp.2011.10111645
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. Am J Psychiatry. 2021;178(5):383-99. DOI: https://doi.org/10.1176/appi.ajp.2020.20081251
Popova V, Daly EJ, Trivedi M, Cooper K, Lane R, Lim P, et al. Efficacy and safety of flexibly dosed esketamine nasal spray. Am J Psychiatry. 2019;176(6):428-38. DOI: https://doi.org/10.1176/appi.ajp.2019.19020172
Zeier Z, Carpenter LL, Kalin NH, Rodriguez CI, McDonald WM, Widge AS, et al. Clinical implementation of pharmacogenomics for treatment-resistant depression. Mol Psychiatry. 2018;23(5):1181-93.
Davis AK, Barrett FS, May DG, Cosimano MP, Sepeda ND, Johnson MW, et al. Effects of psilocybin-assisted therapy on major depressive disorder: a randomized clinical trial. JAMA Psychiatry. 2021;78(5):481-9. DOI: https://doi.org/10.1001/jamapsychiatry.2020.3285
Sanacora G, Frye MA, McDonald W, Mathew SJ, Turner MS, Schatzberg AF, et al. A consensus statement on the use of ketamine in the treatment of mood disorders. JAMA Psychiatry. 2017;74(4):399-405. DOI: https://doi.org/10.1001/jamapsychiatry.2017.0080
Fava M, Davidson KG. Definition and epidemiology of treatment-resistant depression. Psychiatr Clin North Am. 1996;19(2):179-200. DOI: https://doi.org/10.1016/S0193-953X(05)70283-5
Köhler CA, Freitas TH, Maes M, de Andrade NQ, Liu CS, Fernandes BS, et al. Peripheral cytokine and chemokine alterations in depression: a meta-analysis of 82 studies. Acta Psychiatr Scand. 2017;135(5):373-87. DOI: https://doi.org/10.1111/acps.12698
Thase ME, Mahableshwarkar AR, Dragheim M, Loft H, Vieta E, Häggström L, et al. Meta-analysis of randomized, placebo-controlled trials of vortioxetine for major depressive disorder. Ann Gen Psychiatry. 2016;15:33. DOI: https://doi.org/10.1016/j.euroneuro.2016.03.007
Bousman CA, Bengesser SA, Aitchison KJ, Amare AT, Aschauer H, Baune BT, et al. Review and Consensus on Pharmacogenomic Testing in Psychiatry. Pharmacopsychiatry. 2021;54(1):5-17. DOI: https://doi.org/10.1055/a-1288-1061