Skip to content
2000
  1. Home
  2. A-Z Publications
  3. Current Psychiatry Research and Reviews
  4. Volume 21, Issue 3
  5. Article
Volume 21, Issue 3
  • ISSN: 2666-0822
  • E-ISSN: 2666-0830
file format pdf download PDF
file format text download EPUB
side by side viewer icon HTML

Abstract

While the number of treatment options for major depressive disorder (MDD) has grown in recent years, the lack of quality data to guide optimal modality selection has lessened the potential impact of having a more diverse set of mechanistic approaches to treatment. The last attempt to investigate treatment sequencing for MDD was the Sequenced Treatment Alternatives for Relief of Depression Study (STAR*D), which gave rise to the concept of treatment-resistant depression (TRD) as a failure to respond to two or more monoaminergic antidepressants. However, a recent reanalysis of the STAR*D data indicates that most patients do not remit even when treated with multiple traditional antidepressants. Given these new results, labeling the majority of patients as treatment-resistant is not appropriate or useful. If monoamine-based drugs are not that effective for the majority of MDD patients, then it is necessary to consider the mechanistically distinct pharmacological and non-pharmacological treatment options that have emerged recently, including brain stimulation, glutamate receptor modulators, and psychedelic medicines. While these new treatment modalities have the potential to enhance patient outcomes, clinicians and patients currently lack a framework to guide their choices other than cost, feasibility, personal preference, and certain medical contraindications. Here, we review alternative treatment modalities for monoamine non-responders and consider the possibility that there will be new first-line therapies for MDD. We will review how treatment decisions for these patients are currently being made and how developments in precision psychiatry may help guide rational treatment selection in the future.

© 2025 Bentham Science Publishers
© 2025 The Author(s). Published by Bentham Science Publisher. This is an open access article published under CC BY 4.0 https://creativecommons.org/licenses/by/4.0/legalcode
Loading

Article metrics loading...

/content/journals/cprr/10.2174/0126660822284575240130053259
2024-02-13
2025-04-22

  • From This Site

    /content/journals/cprr/10.2174/0126660822284575240130053259
    dcterms_title,dcterms_subject,pub_keyword
    -contentType:Contributor -contentType:Concept -contentType:Institution
    10
    5
The full text of this item is not currently available.

References

  1. RushA.J. FavaM. WisniewskiS.R. Sequenced treatment alternatives to relieve depression (STAR*D): Rationale and design.Control. Clin. Trials200425111914210.1016/S0197‑2456(03)00112‑0 15061154
     [Google Scholar]
  2. RushA.J. TrivediM.H. WisniewskiS.R. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: A STAR*D report.Am. J. Psychiatry2006163111905191710.1176/ajp.2006.163.11.1905 17074942
     [Google Scholar]
  3. PigottH.E. KimT. XuC. KirschI. AmsterdamJ. What are the treatment remission, response and extent of improvement rates after up to four trials of antidepressant therapies in real-world depressed patients? A reanalysis of the STAR*D study’s patient-level data with fidelity to the original research protocol.BMJ Open2023137e06309510.1136/bmjopen‑2022‑063095 37491091
     [Google Scholar]
  4. CosciF. FavaG.A. Staging of unipolar depression: Systematic review and discussion of clinical implications.Psychol. Med.20225291621162810.1017/S0033291722001507 35655409
     [Google Scholar]
  5. ArnaudA. SuthoffE. ZhangX. Frequent treatment changes in the course of antidepressant therapy: Real-world evidence of unmet needs in the pharmacotherapy of major depressive disorder.J. Manag. Care Spec. Pharm.201925S49S50
     [Google Scholar]
  6. VoigtJ. CarpenterL. LeuchterA. A systematic literature review of the clinical efficacy of repetitive Transcranial Magnetic Stimulation (rTMS) in non-treatment resistant patients with major depressive disorder.BMC Psychiatry20191911310.1186/s12888‑018‑1989‑z 30621636
     [Google Scholar]
  7. NygrenA. ReutforsJ. BrandtL. BodénR. NordenskjöldA. TigerM. Response to electroconvulsive therapy in treatment-resistant depression: Nationwide observational follow-up study.BJPsych Open202392e3510.1192/bjo.2023.5 36786152
     [Google Scholar]
  8. JelovacA. KolshusE. McLoughlinD.M. Relapse following successful electroconvulsive therapy for major depression: A meta-analysis.Neuropsychopharmacology201338122467247410.1038/npp.2013.149 23774532
     [Google Scholar]
  9. ConnollyK.R. HelmerA. CristanchoM.A. CristanchoP. O’ReardonJ.P. Effectiveness of transcranial magnetic stimulation in clinical practice post-FDA approval in the United States: Results observed with the first 100 consecutive cases of depression at an academic medical center.J. Clin. Psychiatry2012734e567e57310.4088/JCP.11m07413 22579164
     [Google Scholar]
  10. SackeimH.A. AaronsonS.T. CarpenterL.L. Clinical outcomes in a large registry of patients with major depressive disorder treated with Transcranial Magnetic Stimulation.J. Affect. Disord.2020277657410.1016/j.jad.2020.08.005 32799106
     [Google Scholar]
  11. CarpenterL. AaronsonS. HuttonT.M. Comparison of clinical outcomes with two transcranial magnetic stimulation treatment protocols for major depressive disorder.Brain Stimul.202114117318010.1016/j.brs.2020.12.003 33346068
     [Google Scholar]
  12. AaronsonS.T. CarpenterL.L. HuttonT.M. Comparison of clinical outcomes with left unilateral and sequential bilateral Transcranial Magnetic Stimulation (TMS) treatment of major depressive disorder in a large patient registry.Brain Stimul.202215232633610.1016/j.brs.2022.01.006 35074549
     [Google Scholar]
  13. SenovaS. CotovioG. Pascual-LeoneA. Oliveira-MaiaA.J. Durability of antidepressant response to repetitive transcranial magnetic stimulation: Systematic review and meta-analysis.Brain Stimul.201912111912810.1016/j.brs.2018.10.001 30344109
     [Google Scholar]
  14. MohamedS. JohnsonG.R. ChenP. Effect of antidepressant switching vs. augmentation on remission among patients with major depressive disorder unresponsive to antidepressant treatment.JAMA2017318213214510.1001/jama.2017.8036 28697253
     [Google Scholar]
  15. ZakiN. ChenL. LaneR. Long-term safety and maintenance of response with esketamine nasal spray in participants with treatment-resistant depression: Interim results of the SUSTAIN-3 study.Neuropsychopharmacology20234881225123310.1038/s41386‑023‑01577‑5 37173512
     [Google Scholar]
  16. DalyE.J. TrivediM.H. JanikA. Efficacy of esketamine nasal spray plus oral antidepressant treatment for relapse prevention in patients with treatment-resistant depression.JAMA Psychiatry201976989390310.1001/jamapsychiatry.2019.1189 31166571
     [Google Scholar]
  17. McInnesL.A. QianJ.J. GargeyaR.S. DeBattistaC. HeifetsB.D. A retrospective analysis of ketamine intravenous therapy for depression in real-world care settings.J. Affect. Disord.202230148649510.1016/j.jad.2021.12.097 35027209
     [Google Scholar]
  18. HietamiesT.M. McInnesL.A. KliseA.J. The effects of ketamine on symptoms of depression and anxiety in real-world care settings: A retrospective controlled analysis.J. Affect. Disord.202333548449210.1016/j.jad.2023.04.141 37201900
     [Google Scholar]
  19. KellnerC.H. GeduldigE.T. KnappR.G. More data on speed of remission with ECT in geriatric depression.Br. J. Psychiatry2015206216710.1192/bjp.206.2.167 25644884
     [Google Scholar]
  20. O’ReardonJ.P. SolvasonH.B. JanicakP.G. Efficacy and safety of transcranial magnetic stimulation in the acute treatment of major depression: A multisite randomized controlled trial.Biol. Psychiatry200762111208121610.1016/j.biopsych.2007.01.018 17573044
     [Google Scholar]
  21. d’AndreaG. MancusiG. SantovitoM.C. Investigating the role of maintenance TMS protocols for major depression: Systematic review and future perspectives for personalized interventions.J. Pers. Med.202313469710.3390/jpm13040697 37109083
     [Google Scholar]
  22. BrunoniA.R. MoffaA.H. FregniF. Transcranial direct current stimulation for acute major depressive episodes: Meta-analysis of individual patient data.Br. J. Psychiatry2016208652253110.1192/bjp.bp.115.164715 27056623
     [Google Scholar]
  23. PereraT. GeorgeM.S. GrammerG. JanicakP.G. Pascual-LeoneA. WireckiT.S. The clinical TMS society consensus review and treatment recommendations for TMS therapy for major depressive disorder.Brain Stimul.20169333634610.1016/j.brs.2016.03.010 27090022
     [Google Scholar]
  24. StultzD.J. OsburnS. BurnsT. Pawlowska-WajswolS. WaltonR. Transcranial Magnetic Stimulation (TMS) safety with respect to seizures: A literature review.Neuropsychiatr. Dis. Treat.2020162989300010.2147/NDT.S276635 33324060
     [Google Scholar]
  25. ChenL. KloosterD.C.W. TikM. Accelerated repetitive transcranial magnetic stimulation to treat major depression: The past, present, and future.Harv. Rev. Psychiatry202331314216110.1097/HRP.0000000000000364 37171474
     [Google Scholar]
  26. ColeE.J. PhillipsA.L. BentzleyB.S. Stanford Neuromodulation Therapy (SNT): A double-blind randomized controlled trial.Am. J. Psychiatry2022179213214110.1176/appi.ajp.2021.20101429 34711062
     [Google Scholar]
  27. VoigtJ. CarpenterL. LeuchterA. Cost effectiveness analysis comparing repetitive transcranial magnetic stimulation to antidepressant medications after a first treatment failure for major depressive disorder in newly diagnosed patients - A lifetime analysis.PLoS One20171210e018695010.1371/journal.pone.0186950 29073256
     [Google Scholar]
  28. MilevR.V. GiacobbeP. KennedyS.H. Canadian Network for Mood and Anxiety Treatments (CANMAT) 2016 clinical guidelines for the management of adults with major depressive disorder: Section 4.Can. J. Psychiatry201661956157510.1177/0706743716660033 27486154
     [Google Scholar]
  29. KennedyS.H. LamR.W. McIntyreR.S. Canadian Network for Mood and Anxiety Treatments (CANMAT) 2016 clinical guidelines for the management of adults with major depressive disorder: Section 3.Can. J. Psychiatry201661954056010.1177/0706743716659417 27486148
     [Google Scholar]
  30. McQuaidJ.R. BueltA. CapaldiV. The management of major depressive disorder: synopsis of the 2022 U.S. department of veterans affairs and U.S. department of defense clinical practice guideline.Ann. Intern. Med.2022175101440145110.7326/M22‑1603 36122380
     [Google Scholar]
  31. JhaM.K. MathewS.J. Pharmacotherapies for treatment-resistant depression: How antipsychotics fit in the rapidly evolving therapeutic landscape.Am. J. Psychiatry2023180319019910.1176/appi.ajp.20230025 36855876
     [Google Scholar]
  32. CarbonM. KaneJ.M. LeuchtS. CorrellC.U. Tardive dyskinesia risk with first‐ and second‐generation antipsychotics in comparative randomized controlled trials: A meta‐analysis.World Psychiatry201817333034010.1002/wps.20579 30192088
     [Google Scholar]
  33. YangS. WangJ. LiX. Adverse effects of esketamine for the treatment of major depression disorder: Findings from randomized controlled trials.Psychiatr. Q.2022931819510.1007/s11126‑020‑09871‑x 33411126
     [Google Scholar]
  34. GastaldonC. RaschiE. KaneJ.M. BarbuiC. SchoretsanitisG. Post-marketing safety concerns with esketamine: A disproportionality analysis of spontaneous reports submitted to the FDA adverse event reporting system.Psychother. Psychosom.2021901414810.1159/000510703 32854103
     [Google Scholar]
  35. BahjiA. ZarateC.A. VazquezG.H. Efficacy and safety of racemic ketamine and esketamine for depression: A systematic review and meta-analysis.Expert Opin. Drug Saf.202221685386610.1080/14740338.2022.2047928 35231204
     [Google Scholar]
  36. PopovaV. DalyE.J. TrivediM. Efficacy and safety of flexibly dosed esketamine nasal spray combined with a newly initiated oral antidepressant in treatment-resistant depression: A randomized double-blind active-controlled study.Am. J. Psychiatry2019176642843810.1176/appi.ajp.2019.19020172 31109201
     [Google Scholar]
  37. DumanR.S. AghajanianG.K. SanacoraG. KrystalJ.H. Synaptic plasticity and depression: New insights from stress and rapid-acting antidepressants.Nat. Med.201622323824910.1038/nm.4050 26937618
     [Google Scholar]
  38. KrystalJ.H. KarperL.P. SeibylJ.P. Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans. Psychotomimetic, perceptual, cognitive, and neuroendocrine responses.Arch. Gen. Psychiatry199451319921410.1001/archpsyc.1994.03950030035004 8122957
     [Google Scholar]
  39. BermanR.M. CappielloA. AnandA. Antidepressant effects of ketamine in depressed patients.Biol. Psychiatry200047435135410.1016/S0006‑3223(99)00230‑9 10686270
     [Google Scholar]
  40. ZarateC.A.Jr SinghJ.B. CarlsonP.J. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression.Arch. Gen. Psychiatry200663885686410.1001/archpsyc.63.8.856 16894061
     [Google Scholar]
  41. SinghJ.B. FedgchinM. DalyE.J. A double-blind, randomized, placebo-controlled, dose-frequency study of intravenous ketamine in patients with treatment-resistant depression.Am. J. Psychiatry2016173881682610.1176/appi.ajp.2016.16010037 27056608
     [Google Scholar]
  42. PhillipsJ.L. NorrisS. TalbotJ. Single, repeated, and maintenance ketamine infusions for treatment-resistant depression: A randomized controlled trial.Am. J. Psychiatry2019176540140910.1176/appi.ajp.2018.18070834 30922101
     [Google Scholar]
  43. AlnefeesiY. Chen-LiD. KraneE. Real-world effectiveness of ketamine in treatment-resistant depression: A systematic review & meta-analysis.J. Psychiatr. Res.202215169370910.1016/j.jpsychires.2022.04.037 35688035
     [Google Scholar]
  44. OliverP.A. SnyderA.D. FeinnR. Clinical effectiveness of intravenous racemic ketamine infusions in a large community sample of patients with treatment-resistant depression, suicidal ideation, and generalized anxiety symptoms: A retrospective chart review.J. Clin. Psychiatry20228314336
     [Google Scholar]
  45. FreedmanR. Ketamine and ECT in depression - risks and rewards.N. Engl. J. Med.2023388252389239010.1056/NEJMe2305130 37224235
     [Google Scholar]
  46. EkstrandJ. FattahC. PerssonM. Racemic ketamine as an alternative to electroconvulsive therapy for unipolar depression: A randomized, open-label, non-inferiority trial (KetECT).Int. J. Neuropsychopharmacol.202225533934910.1093/ijnp/pyab088 35020871
     [Google Scholar]
  47. AnandA. MathewS.J. SanacoraG. Ketamine versus ECT for nonpsychotic treatment-resistant major depression.N. Engl. J. Med.2023388252315232510.1056/NEJMoa2302399 37224232
     [Google Scholar]
  48. RodriguesN.B. SiegelA. LipsitzO. Effectiveness of intravenous ketamine in mood disorder patients with a history of neurostimulation.CNS Spectr.202227331532110.1017/S1092852920002187 33298225
     [Google Scholar]
  49. PayetteO. LespéranceP. Desbeaumes JodoinV. Intravenous ketamine for treatment-resistant depression patients who have failed to respond to transcranial magnetic stimulation: A case series.J. Affect. Disord.2023333182010.1016/j.jad.2023.04.019 37075822
     [Google Scholar]
  50. McIntyreR.S. RosenblatJ.D. NemeroffC.B. Synthesizing the evidence for ketamine and esketamine in treatment-resistant depression: An international expert opinion on the available evidence and implementation.Am. J. Psychiatry2021178538339910.1176/appi.ajp.2020.20081251 33726522
     [Google Scholar]
  51. YesavageJ.A. FairchildJ.K. MiZ. Effect of repetitive transcranial magnetic stimulation on treatment-resistant major depression in US veterans.JAMA Psychiatry201875988489310.1001/jamapsychiatry.2018.1483 29955803
     [Google Scholar]
  52. Ochs-RossR. DalyE.J. ZhangY. Efficacy and safety of esketamine nasal spray plus an oral antidepressant in elderly patients with treatment-resistant depression-TRANSFORM-3.Am. J. Geriatr. Psychiatry202028212114110.1016/j.jagp.2019.10.008 31734084
     [Google Scholar]
  53. PennybakerS. RoachB.J. FryerS.L. Age affects temporal response, but not durability, to serial ketamine infusions for treatment refractory depression.Psychopharmacology2021238113229323710.1007/s00213‑021‑05939‑z 34363507
     [Google Scholar]
  54. JeffreysM. Clinician’s Guide to Medications for PTSD. U.S. Department of Veterans Affairs.2017Available from: https://www.ptsd.va.gov/professional/treat/txessentials/clinician_guide_meds.asp#evidence
    [Google Scholar]
  55. ZhongM. LiuQ. LiL. TangV.M. WongA.H.C. LiuY. Evaluating the effect of Electroconvulsive Therapy (ECT) on Post-Traumatic Stress Disorder (PTSD): A systematic review and meta-analysis of five studies.J. Psychiatr. Res.2023164374510.1016/j.jpsychires.2023.05.080 37311402
     [Google Scholar]
  56. FederA. CostiS. RutterS.B. A randomized controlled trial of repeated ketamine administration for chronic posttraumatic stress disorder.Am. J. Psychiatry2021178219320210.1176/appi.ajp.2020.20050596 33397139
     [Google Scholar]
  57. ArtinH. BentleyS. MehaffeyE. Effects of intranasal (S)-ketamine on veterans with co-morbid treatment-resistant depression and PTSD: A retrospective case series.EClinicalMedicine20224810143910.1016/j.eclinm.2022.101439 35706484
     [Google Scholar]
  58. GrabskiM. McAndrewA. LawnW. Adjunctive ketamine with relapse prevention-based psychological therapy in the treatment of alcohol use disorder.Am. J. Psychiatry2022179215216210.1176/appi.ajp.2021.21030277 35012326
     [Google Scholar]
  59. BallardE.D. IonescuD.F. Vande VoortJ.L. Improvement in suicidal ideation after ketamine infusion: Relationship to reductions in depression and anxiety.J. Psychiatr. Res.20145816116610.1016/j.jpsychires.2014.07.027 25169854
     [Google Scholar]
  60. IonescuD.F. RosenbaumJ.F. AlpertJ.E. Pharmacological approaches to the challenge of treatment-resistant depression.Dialogues Clin. Neurosci.201517211112610.31887/DCNS.2015.17.2/dionescu 26246787
     [Google Scholar]
  61. WilkinsonS.T. BallardE.D. BlochM.H. The effect of a single dose of intravenous ketamine on suicidal ideation: A systematic review and individual participant data meta-analysis.Am. J. Psychiatry2018175215015810.1176/appi.ajp.2017.17040472 28969441
     [Google Scholar]
  62. JollantF. ColleR. NguyenT.M.L. Ketamine and esketamine in suicidal thoughts and behaviors: A systematic review.Ther. Adv. Psychopharmacol.2023132045125323115132710.1177/20451253231151327 36776623
     [Google Scholar]
  63. WilliamsL.M. HackL.M. Precision psychiatry: Using neuroscience insights to inform personally tailored, measurement-based care.1st edWashington, DCAmerican Psychiatric Association Publishing2022
     [Google Scholar]
  64. Diagnostic and statistical manual of mental disorders: DSM-5.5th edWashington, D.CAmerican Psychiatric Association2013
     [Google Scholar]
  65. Tornero-CostaR. Martinez-MillanaA. Azzopardi-MuscatN. LazeriL. TraverV. Novillo-OrtizD. Methodological and quality flaws in the use of artificial intelligence in mental health research: Systematic review.JMIR Ment. Health202310e4204510.2196/42045 36729567
     [Google Scholar]
  66. DrysdaleA.T. GrosenickL. DownarJ. Resting-state connectivity biomarkers define neurophysiological subtypes of depression.Nat. Med.2017231283810.1038/nm.4246 27918562
     [Google Scholar]
  67. DoughertyR.F. ClarkeP. AtliM. Psilocybin therapy for treatment resistant depression: Prediction of clinical outcome by natural language processing.Psychopharmacology20232210.1007/s00213‑023‑06432‑5 37606733
     [Google Scholar]
  68. AngY.S. KaiserR. DeckersbachT. Pretreatment reward sensitivity and frontostriatal resting-state functional connectivity are associated with response to bupropion after sertraline non-response.Biol. Psychiatry202088865766710.1016/j.biopsych.2020.04.009 32507389
     [Google Scholar]
/content/journals/cprr/10.2174/0126660822284575240130053259
Loading
Considering New and Emerging Treatment Strategies for Depression: Beyond STAR*D and the Monoamines
Curr Psyc Res Rev 21, 215 (2025); https://doi.org/10.2174/0126660822284575240130053259
/content/journals/cprr/10.2174/0126660822284575240130053259
/content/journals/cprr/10.2174/0126660822284575240130053259
Loading

Data & Media loading...


  • Article Type:     Review Article
Keyword(s): electroconvulsive therapy; esketamine; ketamine; precision psychiatry; transcranial magnetic stimulation; Treatment resistant depression

Most Cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error
Please enter a valid_number test