Exploration of Neuroscience

From: Novel treatments of depression: bridging the gap in current therapeutic approaches

Table 1. Evidence base and FDA approval for novel treatments of depression

Treatment modalities	Major depressive disorder	Treatment-resistant depression	Pediatric depression	Geriatric depression	Disadvantages	FDA approval
Intravenous ketamine	+	+	+/-	+/-	Limited availability	No
Esketamine	-	+	-	-	Limited indications	Yes^a
Anti-inflammatory agents	+	-	-	-	Limited evidence base	No
Brexanolone	-	-	-	-	Only approved for PPD, intravenous use only	Yes^c
Psychedelic-assisted psychotherapy	+/-	+/-	-	-	Regulatory constraints, limited evidence base
Probiotics/prebiotics	+/-	-	-	-	Limited evidence base	No
Anti-inflammatory diet	+/-	-	-	-	Limited evidence base	No
Ketamine-assisted ECT	+	-	-	-	Conflicting evidence of efficacy	No
rTMS	+	+	+/-	+	Limited availability	Yes^a,b
MST	-	+	-	-	Limited availability and indications; poorly defined treatment parameters	No
tDCS	+	-	-	-	Limited availability; poorly defined treatment parameters	No^*
DBS	-	+	-	-	Invasive, poor acceptability, limited indications	No
VNS	-	+	-	-	Invasive, poor acceptability, limited indications	Yes^a

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+: Evidence present; -: no evidence; +/-: limited evidence; ^a approved in adult TRD; ^b cleared in adolescent MDD; ^c approved in Postpartum depression (PPD); ^* approved for clinical trials. ECT: electroconvulsive therapy; rTMS: repetitive transcranial magnetic stimulation; MST: magnetic seizure therapy; tDCS: transcranial direct current stimulation; DBS: deep brain stimulation; VNS: vagal nerve stimulation

Declarations

Author contributions

AJ: Conceptualization, Investigation, Writing—original draft, Writing—review & editing

Conflicts of interest

The author declares that he has no conflicts of interest.

Ethical approval

Not applicable.

Consent to participate

Not applicable.

Consent for publication

Not applicable.

Availability of data and materials

Not applicable.

Funding

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References

Depressive Disorder (depression). Geneva: WHO; c2024 [cited 2024 May 26]. Available from: https://www.who.int/news-room/fact-sheets/detail/depression

Delgado PL. Depression: the case for a monoamine deficiency. J Clin Psychiatry. 2000;61:7–11. [PubMed]

Valenstein M. Keeping our eyes on STAR*D. Am J Psychiatry. 2006;163:1484–6. [DOI] [PubMed]

Al-Harbi KS. Treatment-resistant depression: therapeutic trends, challenges, and future directions. Patient Prefer Adherence. 2012;6:369–88. [DOI] [PubMed] [PMC]

Berman RM, Cappiello A, Anand A, Oren DA, Heninger GR, Charney DS, et al. Antidepressant effects of ketamine in depressed patients. Biol Psychiatry. 2000;47:351–4. [DOI] [PubMed]

Pal MM. Glutamate: The Master Neurotransmitter and Its Implications in Chronic Stress and Mood Disorders. Front Hum Neurosci. 2021;15:722323. [DOI] [PubMed] [PMC]

Miranda M, Morici JF, Zanoni MB, Bekinschtein P. Brain-Derived Neurotrophic Factor: A Key Molecule for Memory in the Healthy and the Pathological Brain. Front Cell Neurosci. 2019;13:363. [DOI] [PubMed] [PMC]

Jagtiani A, Khurana H, Malhotra N. Comparison of efficacy of ketamine versus thiopentone-assisted modified electroconvulsive therapy in major depression. Indian J Psychiatry. 2019;61:258–64. [DOI] [PubMed] [PMC]

Andrade C. Ketamine for Depression, 4: In What Dose, at What Rate, by What Route, for How Long, and at What Frequency? J Clin Psychiatry. 2017;78:e852–7. [DOI] [PubMed]

10.

Jr CAZ, 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;63:856–64. [DOI] [PubMed]

11.

Bahji A, Zarate CA, Vazquez GH. Efficacy and safety of racemic ketamine and esketamine for depression: a systematic review and meta-analysis. Expert Opin Drug Saf. 2022;21:853–66. [DOI] [PubMed] [PMC]

12.

Vincenzo JDD, Siegel A, Lipsitz O, Ho R, Teopiz KM, Ng J, et al. The effectiveness, safety and tolerability of ketamine for depression in adolescents and older adults: A systematic review. J Psychiatr Res. 2021;137:232–41. [DOI] [PubMed]

13.

Kim J, Farchione T, Potter A, Chen Q, Temple R. Esketamine for Treatment-Resistant Depression - First FDA-Approved Antidepressant in a New Class. N Engl J Med. 2019;381:1–4. [DOI] [PubMed]

14.

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. Focus (Am Psychiatr Publ). 2019;17:55–65. [DOI] [PubMed] [PMC]

15.

Daly EJ, Singh JB, Fedgchin M, Cooper K, Lim P, Shelton RC, et al. Efficacy and Safety of Intranasal Esketamine Adjunctive to Oral Antidepressant Therapy in Treatment-Resistant Depression: A Randomized Clinical Trial. JAMA Psychiatry. 2018;75:139–48. [DOI] [PubMed] [PMC]

16.

Daly EJ, Trivedi MH, Janik A, Li H, Zhang Y, Li X, et al. Efficacy of Esketamine Nasal Spray Plus Oral Antidepressant Treatment for Relapse Prevention in Patients With Treatment-Resistant Depression: A Randomized Clinical Trial. JAMA Psychiatry. 2019;76:893–903. [DOI] [PubMed] [PMC]

17.

Spravato^® (esketamine) nasal spray. Singapore: Janssen Global Services; c2012–2024 [cited 2024 May 26]. Available from: https://www.janssenlabels.com/package-insert/product-monograph/prescribing-information/SPRAVATO-pi.pdf

18.

Bahji A, Vazquez GH, Jr CAZ. Comparative efficacy of racemic ketamine and esketamine for depression: A systematic review and meta-analysis. J Affect Disord. 2021;278:542–55. Erratum in: J Affect Disord. 2021;281:1001. [DOI] [PubMed] [PMC]

19.

Acevedo-Diaz EE, Cavanaugh GW, Greenstein D, Kraus C, Kadriu B, Zarate CA, et al. Comprehensive assessment of side effects associated with a single dose of ketamine in treatment-resistant depression. J Affect Disord. 2020;263:568–75. [DOI] [PubMed] [PMC]

20.

Felger JC, Lotrich FE. Inflammatory cytokines in depression: neurobiological mechanisms and therapeutic implications. Neuroscience. 2013;246:199–229. [DOI] [PubMed] [PMC]

21.

Bai S, Guo W, Feng Y, Deng H, Li G, Nie H, et al. Efficacy and safety of anti-inflammatory agents for the treatment of major depressive disorder: a systematic review and meta-analysis of randomised controlled trials. J Neurol Neurosurg Psychiatry. 2020;91:21–32. [DOI] [PubMed]

22.

Cutler AJ, Mattingly GW, Maletic V. Understanding the mechanism of action and clinical effects of neuroactive steroids and GABAergic compounds in major depressive disorder. Transl Psychiatry. 2023;13:228. [DOI] [PubMed] [PMC]

23.

Edinoff AN, Odisho AS, Lewis K, Kaskas A, Hunt G, Cornett EM, et al. Brexanolone, a GABA_A Modulator, in the Treatment of Postpartum Depression in Adults: A Comprehensive Review. Front Psychiatry. 2021;12:699740. [DOI] [PubMed] [PMC]

24.

Schüle C, Nothdurfter C, Rupprecht R. The role of allopregnanolone in depression and anxiety. Prog Neurobiol. 2014;113:79–87. [DOI] [PubMed]

25.

Patatanian E, Nguyen DR. Brexanolone: A Novel Drug for the Treatment of Postpartum Depression. J Pharm Pract. 2022;35:431–6. [DOI] [PubMed]

26.

Zheng W, Cai D, Zheng W, Sim K, Ungvari GS, Peng X, et al. Brexanolone for postpartum depression: A meta-analysis of randomized controlled studies. Psychiatry Res. 2019;279:83–9. [DOI] [PubMed]

27.

George DR, Hanson R, Wilkinson D, Garcia-Romeu A. Ancient Roots of Today’s Emerging Renaissance in Psychedelic Medicine. Cult Med Psychiatry. 2022;46:890–903. [DOI] [PubMed] [PMC]

28.

Gattuso JJ, Perkins D, Ruffell S, Lawrence AJ, Hoyer D, Jacobson LH, et al. Default Mode Network Modulation by Psychedelics: A Systematic Review. Int J Neuropsychopharmacol. 2023;26:155–88. [DOI] [PubMed] [PMC]

29.

Ko K, Kopra EI, Cleare AJ, Rucker JJ. Psychedelic therapy for depressive symptoms: A systematic review and meta-analysis. J Affect Disord. 2023;322:194-204. Erratum in: J Affect Disord. 2024;348:409. [DOI] [PubMed]

30.

Reiff CM, Richman EE, Nemeroff CB, Carpenter LL, Widge AS, Rodriguez CI, et al.; Work Group on Biomarkers and Novel Treatments; a Division of the American Psychiatric Association Council of Research. Psychedelics and Psychedelic-Assisted Psychotherapy. Focus (Am Psychiatr Publ). 2021;19:95–115. [DOI] [PubMed] [PMC]

31.

Saravanan D, Khatoon BS, Winner GJ Sr. Unraveling the Interplay: Exploring the Links Between Gut Microbiota, Obesity, and Psychological Outcomes. Cureus. 2023;15:e49271. [DOI] [PubMed] [PMC]

32.

Mason BL, Li Q, Minhajuddin A, Czysz AH, Coughlin LA, Hussain SK, et al. Reduced anti-inflammatory gut microbiota are associated with depression and anhedonia. J Affect Disord. 2020;266:394–401. [DOI] [PubMed]

33.

Kim CS, Cha L, Sim M, Jung S, Chun WY, Baik HW, et al. Probiotic Supplementation Improves Cognitive Function and Mood with Changes in Gut Microbiota in Community-Dwelling Older Adults: A Randomized, Double-Blind, Placebo-Controlled, Multicenter Trial. J Gerontol A Biol Sci Med Sci. 2021;76:32–40. [DOI] [PubMed] [PMC]

34.

Schaub A, Schneider E, Vazquez-Castellanos JF, Schweinfurth N, Kettelhack C, Doll JPK, et al. Clinical, gut microbial and neural effects of a probiotic add-on therapy in depressed patients: a randomized controlled trial. Transl Psychiatry. 2022;12:227. [DOI] [PubMed] [PMC]

35.

Detopoulou P, Panagiotakos DB, Antonopoulou S, Pitsavos C, Stefanadis C. Dietary choline and betaine intakes in relation to concentrations of inflammatory markers in healthy adults: the ATTICA study. Am J Clin Nutr. 2008;87:424–30. [DOI] [PubMed]

36.

Tolkien K, Bradburn S, Murgatroyd C. An anti-inflammatory diet as a potential intervention for depressive disorders: A systematic review and meta-analysis. Clin Nutr. 2019;38:2045–52. [DOI] [PubMed]

37.

Fusar-Poli L, Vozza L, Gabbiadini A, Vanella A, Concas I, Tinacci S, et al. Curcumin for depression: a meta-analysis. Crit Rev Food Sci Nutr. 2020;60:2643–53. [DOI] [PubMed]

38.

Machado-Vieira R, Baumann J, Wheeler-Castillo C, Latov D, Henter ID, Salvadore G, et al. The Timing of Antidepressant Effects: A Comparison of Diverse Pharmacological and Somatic Treatments. Pharmaceuticals (Basel). 2010;3:19–41. [DOI] [PubMed] [PMC]

39.

Nagi T, Jagtiani A, Somvanshi S, Seegobin SA, Singh J, Bachu AK, et al. Ketamine Augmentation of Electroconvulsive Therapy: A Scoping Review of Dose-Dependent Effects in Major Depressive Disorder. Cureus. 2023;15:e40087. [DOI] [PubMed] [PMC]

40.

Ren L, Deng J, Min S, Peng L, Chen Q. Ketamine in electroconvulsive therapy for depressive disorder: A systematic review and meta-analysis. J Psychiatr Res. 2018;104:144–156. Erratum in: J Psychiatr Res. 2019;104:1. [DOI] [PubMed]

41.

Noda Y, Silverstein WK, Barr MS, Vila-Rodriguez F, Downar J, Rajji TK, et al. Neurobiological mechanisms of repetitive transcranial magnetic stimulation of the dorsolateral prefrontal cortex in depression: a systematic review. Psychol Med. 2015;45:3411–32. [DOI] [PubMed]

42.

George MS. Whither TMS: A One-Trick Pony or the Beginning of a Neuroscientific Revolution? Am J Psychiatry. 2019;176:904–10. [DOI] [PubMed] [PMC]

43.

Perera T, George MS, Grammer G, Janicak PG, Pascual-Leone A, Wirecki TS. The Clinical TMS Society Consensus Review and Treatment Recommendations for TMS Therapy for Major Depressive Disorder. Brain Stimul. 2016;9:336–46. [DOI] [PubMed] [PMC]

44.

Blumberger DM, Vila-Rodriguez F, Thorpe KE, Feffer K, Noda Y, Giacobbe P, et al. Effectiveness of theta burst versus high-frequency repetitive transcranial magnetic stimulation in patients with depression (THREE-D): a randomised non-inferiority trial. Lancet. 2018;391:1683–92. Erratum in: Lancet. 2018;391:e24. [DOI] [PubMed]

45.

Kang JI, Lee H, Jhung K, Kim KR, An SK, Yoon KJ, et al. Frontostriatal Connectivity Changes in Major Depressive Disorder After Repetitive Transcranial Magnetic Stimulation: A Randomized Sham-Controlled Study. J Clin Psychiatry. 2016;77:e1137–43. [DOI] [PubMed]

46.

Li C, Hsieh J, Huang H, Chen M, Juan C, Tu P, et al. Cognition-Modulated Frontal Activity in Prediction and Augmentation of Antidepressant Efficacy: A Randomized Controlled Pilot Study. Cereb Cortex. 2016;26:202–10. [DOI] [PubMed]

47.

Theleritis C, Sakkas P, Paparrigopoulos T, Vitoratou S, Tzavara C, Bonaccorso S, et al. Two Versus One High-Frequency Repetitive Transcranial Magnetic Stimulation Session per Day for Treatment-Resistant Depression: A Randomized Sham-Controlled Trial. J ECT. 2017;33:190–7. [DOI] [PubMed]

48.

Health Quality Ontario. Repetitive Transcranial Magnetic Stimulation for Treatment-Resistant Depression: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Ont Health Technol Assess Ser. 2016;16:1–66. [PubMed] [PMC]

49.

Valiengo L, Maia A, Cotovio G, Gordon PC, Brunoni AR, Forlenza OV, et al. Repetitive Transcranial Magnetic Stimulation for Major Depressive Disorder in Older Adults: Systematic Review and Meta-analysis. J Gerontol A Biol Sci Med Sci. 2022;77:851–860. [DOI] [PubMed]

50.

Sigrist C, Vöckel J, MacMaster FP, Farzan F, Croarkin PE, Galletly C, et al. Transcranial magnetic stimulation in the treatment of adolescent depression: a systematic review and meta-analysis of aggregated and individual-patient data from uncontrolled studies. Eur Child Adolesc Psychiatry. 2022;31:1501–25. [DOI] [PubMed] [PMC]

51.

NeuroStar® Advanced Therapy Receives FDA Clearance as a First-Line Add-On Treatment for Adolescents with Depression. Malvern: Neuronetics Inc.; c2024 [cited 2024 May 26]. Available from: https://ir.neuronetics.com/news-releases/news-release-details/neurostarr-advanced-therapy-receives-fda-clearance-first-line.

52.

Majumder P, Balan S, Gupta V, Wadhwa R, Perera TD. The Safety and Efficacy of Repetitive Transcranial Magnetic Stimulation in the Treatment of Major Depression Among Children and Adolescents: A Systematic Review. Cureus. 2021;13:e14564. [DOI] [PubMed] [PMC]

53.

Cretaz E, Brunoni AR, Lafer B. Magnetic Seizure Therapy for Unipolar and Bipolar Depression: A Systematic Review. Neural Plast. 2015;2015:521398. [DOI] [PubMed] [PMC]

54.

Bellini H, Cretaz E, Carneiro AM, Silva PHRd, Santos LAD, Gallucci-Neto J, et al. Magnetic Waves vs. Electric Shocks: A Non-Inferiority Study of Magnetic Seizure Therapy and Electroconvulsive Therapy in Treatment-Resistant Depression. Biomedicines. 2023;11:2150. [DOI] [PubMed] [PMC]

55.

Stagg CJ, Nitsche MA. Physiological basis of transcranial direct current stimulation. Neuroscientist. 2011;17:37–53. [DOI] [PubMed]

56.

Moffa AH, Martin D, Alonzo A, Bennabi D, Blumberger DM, Benseñor IM, et al. Efficacy and acceptability of transcranial direct current stimulation (tDCS) for major depressive disorder: An individual patient data meta-analysis. Prog Neuropsychopharmacol Biol Psychiatry. 2020;99:109836. [DOI] [PubMed]

57.

Bikson M, Grossman P, Thomas C, Zannou AL, Jiang J, Adnan T, et al. Safety of Transcranial Direct Current Stimulation: Evidence Based Update 2016. Brain Stimul. 2016;9:641–61. [DOI] [PubMed] [PMC]

58.

Morishita T, Fayad SM, Higuchi M, Nestor KA, Foote KD. Deep brain stimulation for treatment-resistant depression: systematic review of clinical outcomes. Neurotherapeutics. 2014;11:475–84. [DOI] [PubMed] [PMC]

59.

Kisely S, Li A, Warren N, Siskind D. A systematic review and meta-analysis of deep brain stimulation for depression. Depress Anxiety. 2018;35:468–80. [DOI] [PubMed]

60.

Schermer M. Ethical issues in deep brain stimulation. Front Integr Neurosci. 2011;5:17. [DOI] [PubMed] [PMC]

61.

Nemeroff CB, Mayberg HS, Krahl SE, McNamara J, Frazer A, Henry TR, et al. VNS therapy in treatment-resistant depression: clinical evidence and putative neurobiological mechanisms. Neuropsychopharmacology. 2006;31:1345–55. [DOI] [PubMed]

62.

Martin JLR, Martín-Sánchez E. Systematic review and meta-analysis of vagus nerve stimulation in the treatment of depression: variable results based on study designs. Eur Psychiatry. 2012;27:147–55. [DOI] [PubMed]

63.

Rush AJ, Marangell LB, Sackeim HA, George MS, Brannan SK, Davis SM, et al. Vagus nerve stimulation for treatment-resistant depression: a randomized, controlled acute phase trial. Biol Psychiatry. 2005;58:347–54. [DOI] [PubMed]

64.

Bajbouj M, Merkl A, Schlaepfer TE, Frick C, Zobel A, Maier W, et al. Two-year outcome of vagus nerve stimulation in treatment-resistant depression. J Clin Psychopharmacol. 2010;30:273–81. [DOI] [PubMed]

65.

Tan C, Qiao M, Ma Y, Luo Y, Fang J, Yang Y. The efficacy and safety of transcutaneous auricular vagus nerve stimulation in the treatment of depressive disorder: A systematic review and meta-analysis of randomized controlled trials. J Affect Disord. 2023;337:37–49. [DOI] [PubMed]

66.

Berry SM, Broglio K, Bunker M, Jayewardene A, Olin B, Rush AJ. A patient-level meta-analysis of studies evaluating vagus nerve stimulation therapy for treatment-resistant depression. Med Devices (Auckl). 2013;6:17–35. [DOI] [PubMed] [PMC]