Main Article Content
Abstract
Depression, particularly major depressive disorder (MDD), is among the most widespread and disabling mental health conditions globally. Medication continues to be a key element in its treatment, and recent progress in the field has led to the development of new and more targeted therapeutic options. This review outlines the latest updates in pharmacological interventions, with emphasis on innovative treatments such as Esketamine, Zuranolone, and Brexanolone. These agents offer novel mechanisms of action and are especially effective in cases like treatment-resistant depression and postpartum depression. The paper also evaluates and contrasts the clinical performance, side effect profiles, and safety of traditional antidepressant classes including SSRIs, SNRIs, tricyclic antidepressants, MAOIs, and atypical agents. Furthermore, the significance of personalizing therapy based on individual factors such as symptom patterns, drug tolerance, and genetic variability is explored. By presenting an integrated overview of established and emerging treatments, this review aims to enhance clinical decision-making and support more precise, patient-centred care in depression management.
Keywords
Major Depressive Disorder
Antidepressant Medications
Esketamine
Zuranolone
Drug Comparison
Personalized Therapy
Recent Advances
Pharmacological Treatment
Brexanolone
Article Details
How to Cite
Pharmacotherapy for Depression - Updates and Comparative Effectiveness. (2025). International Journal of Research in Pharmacology & Pharmacotherapeutics, 14(3), 405-412. https://ijrpp.com/ijrpp/article/view/714
How to Cite
Pharmacotherapy for Depression - Updates and Comparative Effectiveness. (2025). International Journal of Research in Pharmacology & Pharmacotherapeutics, 14(3), 405-412. https://ijrpp.com/ijrpp/article/view/714
References
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1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. Arlington: APA; 2013.
2. World Health Organization. Depression and Other Common Mental Disorders: Global Health Estimates. WHO; 2017.
3. Greenberg PE, Fournier AA, Sisitsky T, Pike CT, Kessler RC. The economic burden of adults with major depressive disorder in the United States (2005 and 2010). J Clin Psychiatry. 2015 Feb;76(2):155–62.
4. Cuijpers P, Beekman AT, Reynolds CF. Preventing depression: a global priority. JAMA. 2012 Mar 14;307(10):1033–4.
5. Cipriani A, Furukawa TA, Salanti G, 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. Lancet. 2018;391(10128):1357–66.
6. Rush AJ, Trivedi MH, Wisniewski SR, 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.
7. Fava M. Diagnosis and definition of treatment-resistant depression. Biol Psychiatry. 2003;53(8):649–59.
8. Daly EJ, Trivedi MH, Janik A, et al. Efficacy of esketamine nasal spray plus oral antidepressant treatment for relapse prevention in patients with treatment-resistant depression. JAMA Psychiatry. 2019;76(9):893–903.
9. Krishnan V, Nestler EJ. The molecular neurobiology of depression. Nature. 2008;455(7215):894–902.
10. Duman RS, Monteggia LM. A neurotrophic model for stress-related mood disorders. Biol Psychiatry. 2006;59(12):1116–27.
11. Pariante CM, Lightman SL. The HPA axis in major depression: classical theories and new developments. Trends Neurosci. 2008 Sep;31(9):464–8.
12. Dowlati Y, Herrmann N, Swardfager W, et al. A meta-analysis of cytokines in major depression. Biol Psychiatry. 2010 Mar 1;67(5):446–57.
13. Miller AH, Raison CL. The role of inflammation in depression: from evolutionary imperative to modern treatment target. Nat Rev Immunol. 2016 Jan;16(1):22–34.
14. Foster JA, McVey Neufeld KA. Gut–brain axis: how the microbiome influences anxiety and depression. Trends Neurosci. 2013 May;36(5):305–12.
15. Zheng P, Zeng B, Zhou C, et al. Gut microbiome remodelling induces depressive-like behaviours through a pathway mediated by the host’s metabolism. Mol Psychiatry. 2016 Jun;21(6):786–96.
16. Gartlehner G, Hansen RA, Morgan LC, 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.
17. Taylor MJ, Freemantle N, Geddes JR, et al. Early onset of selective serotonin reuptake inhibitor antidepressant action: systematic review and meta-analysis. Arch Gen Psychiatry. 2006;63(11):1217–23.
18. Malhi GS, Mann JJ. Understanding depression: past, present and future. Lancet. 2018;392(10161):2299–2312.
19. Duman RS, Aghajanian GK. Investigating the biological mechanisms behind rapid-onset antidepressants, focusing on BDNF and GSK-3β. Neuropsychopharmacology. 2014;39(1):233–242.
20. Basso LA, Santos DS, Ferreira RS, et al. Exploring drug development targets for depressive disorders and the road ahead. Expert Opin Ther Targets. 2020;24(7):605–619.
21. Sanacora G, Frye MA, McDonald W, et al. Guidelines for the clinical use of ketamine in treating depression-related mood disorders. JAMA Psychiatry. 2017;74(4):399–405.
22. Papakostas GI, Stahl SM, Krishen A, et al. Combined data analysis showing aripiprazole improves symptoms when added to antidepressants. J Clin Psychiatry. 2015;76(3):e342–e348.
23. Meltzer-Brody S, Colquhoun H, Riesenberg R, et al. Results from two major trials showing brexanolone’s effectiveness in postpartum depression. Lancet. 2018;392(10152):1058–1070.
24. Citrome L. Introduction to brexanolone: the first-in-class treatment for postpartum depression. Drugs Today (Barc). 2019;55(9):559–568.
25. Deligiannidis KM, Meltzer-Brody S. An overview of novel treatment approaches for postpartum depression. J Clin Psychiatry. 2020;81(5):19r13078.
26. Griffiths RR, Johnson MW, Carducci MA, et al. Psilocybin therapy linked with significant and lasting reductions in depression and anxiety. J Psychopharmacol. 2016;30(12):1181–1197.
27. Carhart-Harris RL, Bolstridge M, Rucker J, et al. Psilocybin paired with therapy shows continued benefit for resistant depression after six months. Psychopharmacology (Berl). 2018;235(2):399–408.
28. McIntyre RS, Lophaven S, Olsen CK. A comprehensive analysis of vortioxetine's effects on cognitive dysfunction in depression. Eur Neuropsychopharmacol. 2014;24(12):1855–1863.
29. Gonda X, Dome P, Rihmer Z. Clinical perspectives on the use of bupropion in treating depressive symptoms. Neuropsychopharmacol Hung. 2020;22(2):93–99.
30. Thase ME. Clinical strategies for managing patients with treatment-resistant depression. CNS Spectr. 2011;16(S1):1–16.
31. Al-Harbi KS. An overview of current challenges and future paths in treating resistant depression. Patient Prefer Adherence. 2012;6:369–388.
32. O’Reardon JP, Solvason HB, Janicak PG, et al. Examining the outcomes of TMS therapy in acute episodes of depression. Biol Psychiatry. 2007;62(11):1208–1216.
33. Bschor T, Bauer M, Adli M. Approach to chronic and treatment-resistant forms of depression and how to manage them. Drugs. 2004;64(23):2671–2689.
34. Perlis RH. A clinical framework for predicting which patients are likely to be resistant to depression treatments. Biol Psychiatry. 2013;74(1):7–14.
35. Vieta E, Berk M, Schulze TG, et al. Summarizing the understanding and treatment challenges of bipolar disorders. Nat Rev Dis Primers. 2018;4:18008.
36. Monteggia LM, Gideons E, Kavalali ET. Molecular pathways involved in fast-acting antidepressant responses, highlighting eEF2 kinase. Biol Psychiatry. 2013;73(12):1199–1205.
37. Zunszain PA, Anacker C, Cattaneo A, et al. The role of inflammation and glucocorticoids in depressive brain changes. Prog Neuropsychopharmacol Biol Psychiatry. 2011;35(3):722–729.
38. Cipriani A, Furukawa TA, Salanti G, et al. Head-to-head comparison of 21 antidepressants for treating major depression in adults: a network meta-analysis. Lancet. 2018;391(10128):1357–1366.
References
1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. Arlington: APA; 2013.
2. World Health Organization. Depression and Other Common Mental Disorders: Global Health Estimates. WHO; 2017.
3. Greenberg PE, Fournier AA, Sisitsky T, Pike CT, Kessler RC. The economic burden of adults with major depressive disorder in the United States (2005 and 2010). J Clin Psychiatry. 2015 Feb;76(2):155–62.
4. Cuijpers P, Beekman AT, Reynolds CF. Preventing depression: a global priority. JAMA. 2012 Mar 14;307(10):1033–4.
5. Cipriani A, Furukawa TA, Salanti G, 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. Lancet. 2018;391(10128):1357–66.
6. Rush AJ, Trivedi MH, Wisniewski SR, 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.
7. Fava M. Diagnosis and definition of treatment-resistant depression. Biol Psychiatry. 2003;53(8):649–59.
8. Daly EJ, Trivedi MH, Janik A, et al. Efficacy of esketamine nasal spray plus oral antidepressant treatment for relapse prevention in patients with treatment-resistant depression. JAMA Psychiatry. 2019;76(9):893–903.
9. Krishnan V, Nestler EJ. The molecular neurobiology of depression. Nature. 2008;455(7215):894–902.
10. Duman RS, Monteggia LM. A neurotrophic model for stress-related mood disorders. Biol Psychiatry. 2006;59(12):1116–27.
11. Pariante CM, Lightman SL. The HPA axis in major depression: classical theories and new developments. Trends Neurosci. 2008 Sep;31(9):464–8.
12. Dowlati Y, Herrmann N, Swardfager W, et al. A meta-analysis of cytokines in major depression. Biol Psychiatry. 2010 Mar 1;67(5):446–57.
13. Miller AH, Raison CL. The role of inflammation in depression: from evolutionary imperative to modern treatment target. Nat Rev Immunol. 2016 Jan;16(1):22–34.
14. Foster JA, McVey Neufeld KA. Gut–brain axis: how the microbiome influences anxiety and depression. Trends Neurosci. 2013 May;36(5):305–12.
15. Zheng P, Zeng B, Zhou C, et al. Gut microbiome remodelling induces depressive-like behaviours through a pathway mediated by the host’s metabolism. Mol Psychiatry. 2016 Jun;21(6):786–96.
16. Gartlehner G, Hansen RA, Morgan LC, 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.
17. Taylor MJ, Freemantle N, Geddes JR, et al. Early onset of selective serotonin reuptake inhibitor antidepressant action: systematic review and meta-analysis. Arch Gen Psychiatry. 2006;63(11):1217–23.
18. Malhi GS, Mann JJ. Understanding depression: past, present and future. Lancet. 2018;392(10161):2299–2312.
19. Duman RS, Aghajanian GK. Investigating the biological mechanisms behind rapid-onset antidepressants, focusing on BDNF and GSK-3β. Neuropsychopharmacology. 2014;39(1):233–242.
20. Basso LA, Santos DS, Ferreira RS, et al. Exploring drug development targets for depressive disorders and the road ahead. Expert Opin Ther Targets. 2020;24(7):605–619.
21. Sanacora G, Frye MA, McDonald W, et al. Guidelines for the clinical use of ketamine in treating depression-related mood disorders. JAMA Psychiatry. 2017;74(4):399–405.
22. Papakostas GI, Stahl SM, Krishen A, et al. Combined data analysis showing aripiprazole improves symptoms when added to antidepressants. J Clin Psychiatry. 2015;76(3):e342–e348.
23. Meltzer-Brody S, Colquhoun H, Riesenberg R, et al. Results from two major trials showing brexanolone’s effectiveness in postpartum depression. Lancet. 2018;392(10152):1058–1070.
24. Citrome L. Introduction to brexanolone: the first-in-class treatment for postpartum depression. Drugs Today (Barc). 2019;55(9):559–568.
25. Deligiannidis KM, Meltzer-Brody S. An overview of novel treatment approaches for postpartum depression. J Clin Psychiatry. 2020;81(5):19r13078.
26. Griffiths RR, Johnson MW, Carducci MA, et al. Psilocybin therapy linked with significant and lasting reductions in depression and anxiety. J Psychopharmacol. 2016;30(12):1181–1197.
27. Carhart-Harris RL, Bolstridge M, Rucker J, et al. Psilocybin paired with therapy shows continued benefit for resistant depression after six months. Psychopharmacology (Berl). 2018;235(2):399–408.
28. McIntyre RS, Lophaven S, Olsen CK. A comprehensive analysis of vortioxetine's effects on cognitive dysfunction in depression. Eur Neuropsychopharmacol. 2014;24(12):1855–1863.
29. Gonda X, Dome P, Rihmer Z. Clinical perspectives on the use of bupropion in treating depressive symptoms. Neuropsychopharmacol Hung. 2020;22(2):93–99.
30. Thase ME. Clinical strategies for managing patients with treatment-resistant depression. CNS Spectr. 2011;16(S1):1–16.
31. Al-Harbi KS. An overview of current challenges and future paths in treating resistant depression. Patient Prefer Adherence. 2012;6:369–388.
32. O’Reardon JP, Solvason HB, Janicak PG, et al. Examining the outcomes of TMS therapy in acute episodes of depression. Biol Psychiatry. 2007;62(11):1208–1216.
33. Bschor T, Bauer M, Adli M. Approach to chronic and treatment-resistant forms of depression and how to manage them. Drugs. 2004;64(23):2671–2689.
34. Perlis RH. A clinical framework for predicting which patients are likely to be resistant to depression treatments. Biol Psychiatry. 2013;74(1):7–14.
35. Vieta E, Berk M, Schulze TG, et al. Summarizing the understanding and treatment challenges of bipolar disorders. Nat Rev Dis Primers. 2018;4:18008.
36. Monteggia LM, Gideons E, Kavalali ET. Molecular pathways involved in fast-acting antidepressant responses, highlighting eEF2 kinase. Biol Psychiatry. 2013;73(12):1199–1205.
37. Zunszain PA, Anacker C, Cattaneo A, et al. The role of inflammation and glucocorticoids in depressive brain changes. Prog Neuropsychopharmacol Biol Psychiatry. 2011;35(3):722–729.
38. Cipriani A, Furukawa TA, Salanti G, et al. Head-to-head comparison of 21 antidepressants for treating major depression in adults: a network meta-analysis. Lancet. 2018;391(10128):1357–1366.
2. World Health Organization. Depression and Other Common Mental Disorders: Global Health Estimates. WHO; 2017.
3. Greenberg PE, Fournier AA, Sisitsky T, Pike CT, Kessler RC. The economic burden of adults with major depressive disorder in the United States (2005 and 2010). J Clin Psychiatry. 2015 Feb;76(2):155–62.
4. Cuijpers P, Beekman AT, Reynolds CF. Preventing depression: a global priority. JAMA. 2012 Mar 14;307(10):1033–4.
5. Cipriani A, Furukawa TA, Salanti G, 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. Lancet. 2018;391(10128):1357–66.
6. Rush AJ, Trivedi MH, Wisniewski SR, 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.
7. Fava M. Diagnosis and definition of treatment-resistant depression. Biol Psychiatry. 2003;53(8):649–59.
8. Daly EJ, Trivedi MH, Janik A, et al. Efficacy of esketamine nasal spray plus oral antidepressant treatment for relapse prevention in patients with treatment-resistant depression. JAMA Psychiatry. 2019;76(9):893–903.
9. Krishnan V, Nestler EJ. The molecular neurobiology of depression. Nature. 2008;455(7215):894–902.
10. Duman RS, Monteggia LM. A neurotrophic model for stress-related mood disorders. Biol Psychiatry. 2006;59(12):1116–27.
11. Pariante CM, Lightman SL. The HPA axis in major depression: classical theories and new developments. Trends Neurosci. 2008 Sep;31(9):464–8.
12. Dowlati Y, Herrmann N, Swardfager W, et al. A meta-analysis of cytokines in major depression. Biol Psychiatry. 2010 Mar 1;67(5):446–57.
13. Miller AH, Raison CL. The role of inflammation in depression: from evolutionary imperative to modern treatment target. Nat Rev Immunol. 2016 Jan;16(1):22–34.
14. Foster JA, McVey Neufeld KA. Gut–brain axis: how the microbiome influences anxiety and depression. Trends Neurosci. 2013 May;36(5):305–12.
15. Zheng P, Zeng B, Zhou C, et al. Gut microbiome remodelling induces depressive-like behaviours through a pathway mediated by the host’s metabolism. Mol Psychiatry. 2016 Jun;21(6):786–96.
16. Gartlehner G, Hansen RA, Morgan LC, 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.
17. Taylor MJ, Freemantle N, Geddes JR, et al. Early onset of selective serotonin reuptake inhibitor antidepressant action: systematic review and meta-analysis. Arch Gen Psychiatry. 2006;63(11):1217–23.
18. Malhi GS, Mann JJ. Understanding depression: past, present and future. Lancet. 2018;392(10161):2299–2312.
19. Duman RS, Aghajanian GK. Investigating the biological mechanisms behind rapid-onset antidepressants, focusing on BDNF and GSK-3β. Neuropsychopharmacology. 2014;39(1):233–242.
20. Basso LA, Santos DS, Ferreira RS, et al. Exploring drug development targets for depressive disorders and the road ahead. Expert Opin Ther Targets. 2020;24(7):605–619.
21. Sanacora G, Frye MA, McDonald W, et al. Guidelines for the clinical use of ketamine in treating depression-related mood disorders. JAMA Psychiatry. 2017;74(4):399–405.
22. Papakostas GI, Stahl SM, Krishen A, et al. Combined data analysis showing aripiprazole improves symptoms when added to antidepressants. J Clin Psychiatry. 2015;76(3):e342–e348.
23. Meltzer-Brody S, Colquhoun H, Riesenberg R, et al. Results from two major trials showing brexanolone’s effectiveness in postpartum depression. Lancet. 2018;392(10152):1058–1070.
24. Citrome L. Introduction to brexanolone: the first-in-class treatment for postpartum depression. Drugs Today (Barc). 2019;55(9):559–568.
25. Deligiannidis KM, Meltzer-Brody S. An overview of novel treatment approaches for postpartum depression. J Clin Psychiatry. 2020;81(5):19r13078.
26. Griffiths RR, Johnson MW, Carducci MA, et al. Psilocybin therapy linked with significant and lasting reductions in depression and anxiety. J Psychopharmacol. 2016;30(12):1181–1197.
27. Carhart-Harris RL, Bolstridge M, Rucker J, et al. Psilocybin paired with therapy shows continued benefit for resistant depression after six months. Psychopharmacology (Berl). 2018;235(2):399–408.
28. McIntyre RS, Lophaven S, Olsen CK. A comprehensive analysis of vortioxetine's effects on cognitive dysfunction in depression. Eur Neuropsychopharmacol. 2014;24(12):1855–1863.
29. Gonda X, Dome P, Rihmer Z. Clinical perspectives on the use of bupropion in treating depressive symptoms. Neuropsychopharmacol Hung. 2020;22(2):93–99.
30. Thase ME. Clinical strategies for managing patients with treatment-resistant depression. CNS Spectr. 2011;16(S1):1–16.
31. Al-Harbi KS. An overview of current challenges and future paths in treating resistant depression. Patient Prefer Adherence. 2012;6:369–388.
32. O’Reardon JP, Solvason HB, Janicak PG, et al. Examining the outcomes of TMS therapy in acute episodes of depression. Biol Psychiatry. 2007;62(11):1208–1216.
33. Bschor T, Bauer M, Adli M. Approach to chronic and treatment-resistant forms of depression and how to manage them. Drugs. 2004;64(23):2671–2689.
34. Perlis RH. A clinical framework for predicting which patients are likely to be resistant to depression treatments. Biol Psychiatry. 2013;74(1):7–14.
35. Vieta E, Berk M, Schulze TG, et al. Summarizing the understanding and treatment challenges of bipolar disorders. Nat Rev Dis Primers. 2018;4:18008.
36. Monteggia LM, Gideons E, Kavalali ET. Molecular pathways involved in fast-acting antidepressant responses, highlighting eEF2 kinase. Biol Psychiatry. 2013;73(12):1199–1205.
37. Zunszain PA, Anacker C, Cattaneo A, et al. The role of inflammation and glucocorticoids in depressive brain changes. Prog Neuropsychopharmacol Biol Psychiatry. 2011;35(3):722–729.
38. Cipriani A, Furukawa TA, Salanti G, et al. Head-to-head comparison of 21 antidepressants for treating major depression in adults: a network meta-analysis. Lancet. 2018;391(10128):1357–1366.