Tools for Practice Outils pour la pratique

#360 Ketamine for Depression

What are the benefits and harms of ketamine/esketamine for depression?

Ketamine/esketamine appears effective for moderate-severe depression (helping 10-20% more people respond over placebo at 1-4 weeks).  However, biases are very common and large effects are likely exaggerated.  Adverse events are common (example: 20% more nausea/vomiting). Considerable uncertainty remains (treating mid/long-term, misuse risk, and long-term harms) and treatment is costly.

CFPCLearn Logo

Reading Tools for Practice Article can earn you MainPro+ Credits

La lecture d'articles d'outils de pratique peut vous permettre de gagner des crédits MainPro+

Join Now S’inscrire maintenant

Already a CFPCLearn Member? Log in

Déjà abonné à CMFCApprendre? Ouvrir une session

  • 11 systematic reviews with meta-analyses (3-49 randomized controlled trials (RCTs), 703-3299 moderately-severely, mostly treatment-resistant, depressed patients) in last 3 years.1-11 Typically, ketamine single-dose intravenously 0.5mg/kg over 40 minutes or esketamine intranasally 28mg (1-3 puffs) twice weekly (less frequent when stable). Results statistically significant unless noted.
  • Efficacy:
    • Response rate (highest-quality review) versus placebo:1
      • Ketamine (4-7 RCTs, 185-202 patients):
        • Day 1: 27% versus 9%, number needed to treat (NNT)=6.
        • Day 28: Not statistically different (week 1-2 becomes non-significant).
      • Esketamine (5 RCTs, 1071-1117 patients):
        • Day 1: 27% versus 15%, NNT=9.
        • Day 28: 57% versus 42%, NNT=7.
      • Others found similar.2-8,10
    • Changes in depression scale:
      • Meta-analysis (3 RCTs, 703 patients):4 MADRS depression scale (scale 0-60, ≤6 normal), baseline ≥28:
        • Mean improvement esketamine=18 versus placebo=14, difference=4 at 4 weeks. Minimal important difference12=3-6.
        • Other found similar7 or statistics not clinically interpretable.1-3,5,6,9,11
  • Versus active control:
    • Electroconvulsive Therapy (ECT): One RCT favored ECT (186 more-severe patients),13 one favored ketamine (403 less-severe).14
    • Anti-depressant augmentation with esketamine versus quetiapine (150-300mg):15 Remission (8 weeks), 27% versus 18%, NNT=11.
  • Stopping: 297 esketamine responders (after 16 weeks) randomized to continue or placebo:16
    • At 18 weeks, relapse 26% (continued esketamine) versus 50% (discontinued/placebo), NNT=5.
  • Adverse Events:
    • Esketamine: Dissociation (29% versus 4%); dizziness (32% versus 11%); nausea/vomiting (36% versus 15%); and more. Ketamine similar.1
    • Serious events (examples: mortality, substance misuse) inadequately studied.17,18
  • Ketamine research issues: Mostly small/short, single-dose RCTs;1,2,5-11 publication bias;2,5,6 benefit halved in higher-quality RCTs;5,6,11 unblinding common.19
    • RCT: 40 depressed patients given ketamine or placebo under-anesthesia. No difference in depression efficacy.20

  • Mechanism of action remains uncertain.1,21-23
  • Guidelines:23,24 Ketamine potential option for severe, treatment-resistant depression with awareness of risk mitigation, adequate delivery standards and uncertainty regarding medium/long-term management.
  • Cost of intranasal esketamine:25 $15,000-45,000/year. Ketamine generally in-hospital or related outpatient IV clinic.

shamsuddin chaudhry March 4, 2024

good topic

shamsuddin chaudhry March 4, 2024

very heigh risk of abuse

tia renouf March 4, 2024

evidence not compelling

johannes malan March 4, 2024

will probably not use it

johannes malan March 4, 2024

will probably not use it
will not use it

Latest Tools for Practice
Derniers outils pour la pratique

#370 Antibiotics or no antibiotics for acute diverticulitis, that is the question!

Do antibiotics change clinical outcomes for patients with acute uncomplicated diverticulitis?
Read Lire 0.25 credits available Crédits disponibles

#369 Remind me, do medications that target brain amyloid improve my dementia?

Are amyloid-targeting monoclonal antibodies safe and effective for mild cognitive impairment or Alzheimer’s dementia?
Read Lire 0.25 credits available Crédits disponibles

#368 Sodium Restriction in Heart Failure: Beneficial or pouring salt in the wound?

Does sodium restriction improve outcomes in patients with chronic heart failure?
Read Lire 0.25 credits available Crédits disponibles

This content is certified for MainPro+ Credits, log in to access

Ce contenu est certifié pour les crédits MainPro+, Ouvrir une session

  • G. Michael Allan MD CCFP
  • Jessica Kirkwood MD CCFP (AM)
  • Jennifer Young MD CCFP-EM

1. Dean RL, Hurducas C, Hawton K, et al. Cochrane Database Syst Rev. 2021; 9(9): CD011612.

2. Nikolin S, Rodgers A, Schwaab A, et al. eClinicalMedicine. 2023; 62: 102127.

3. Jawad MY, Di Vincenzo JD, Ceban F, et al. Expert Opin Drug Saf. 2022; 21(6):841-52.

4. Floriano I, Silvinato A, Bernardo WA. Rev Assoc Med Bras (1992). 2023; 69(6):e2023D696.

5. Bahji A, Zarate CA, Vazquez GH. Expert Opin Drug Saf. 2022; 21(6):853-66.

6. Marcantoni WS, Akoumba BS, Wassef M, et al. J Affect Disord. 2020; 277:831-41.

7. Hock RS, Feeney A, Iovieno N, et al. J Clin Psychiatry. 2022; 84(1):21r14086.

8. Meiering MS, Weigner D, Gärtner M, et al. J Psychiatr Res. 2022 Dec; 156:639-646.

9. McIntyre RS, Carvalho IP, Lui LMW, et al. J Affect Disord. 2020; 276:576-84.

10. Price RB, Kissel N, Baumeister A, et al. Molecular Psychiatry. 2022; 27:5096–5112.

11. Conley AA, Norwood AEQ, Hatvany TC, et al. Psychopharmacology (Berl). 2021; 238(7):1737-52.

12. Hengartner MP, Plöderl M. BMJ Evid Based Med. 2022; 27(2):69-73.

13. Ekstrand J, Fattah C, Persson M, et al. Int J Neuropsychopharmacol. 2022; 25:339-49.

14. Anand A, Mathew SJ, Sanacora G, et al. N Engl J Med. 2023; 388(25):2315-25.

15. Reif A, Bitter I, Buyze J, et al. N Engl J Med. 2023; 389:1298-309.

16. Daly EJ, Trivedi MH, Janik A, et al. JAMA Psychiatry. 2019; 76(9):893-903.

17. Orsolini L, Salvi V, Volpe U. Expert Opin Drug Saf. 2022;21(6):803-812.

18. Nikayin S, Murphy E, Krystal JH, et al. Expert Opin Drug Saf. 2022; 21(6):777-787.

19. Muthukumaraswamy SD, Forsyth A, Lumley T. Expert Rev Clin Pharmacol. 2021; 14(9):1133-1152.

20. Lii TR, Smith AE, Flohr JR, et al. Nat Mental Health. 2023; 1: 876–86.

21. Williams NR, Schatzberg AF. Curr Opin Neurobiol. 2016; 36:112–117.

22. Williams NR, Heifets BD, Blasey C, et al. Am J Psychiatry. 2018 Dec 1; 175(12):1205-1215.

23. Swainson J, McGirr A, Blier P, et al. Can J Psychiatry. 2021 Feb; 66(2):113-125.

24. McQuaid JR, Buelt A, Capaldi V, et al. Ann Intern Med. 2022 Oct; 175(10):1440-1451.

25. Drug reimbursement recommendation: Esketamine (Spravato) — CDEC Meeting — June 17, 2020; CDEC Reconsideration Meeting — December 9, 2020; Notice of Final Recommendation – December 16, 2020. Available at: Accessed January 24, 2024.

Authors do not have any conflicts of interest to declare.