Original Research Difficult to Treat Depression September 12, 2022

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

Patrick A. Oliver, MD; Andrew D. Snyder, MD; Richard Feinn, PhD; Stanislav Malov, MD; Gray McDiarmid, BSc; Albert J. Arias, MD, MS

J Clin Psychiatry 2022;83(6):21m14336

ABSTRACT

Introduction: Few studies have been published to date exploring the effectiveness of ketamine for treatment-resistant depression (TRD) in large clinical samples. We report on the clinical outcomes of a large cohort treated with ketamine as part of clinical practice.

Methods: Deidentified electronic chart data were obtained from a multisite private ketamine infusion clinic for 424 patients with TRD seen from November 9, 2017, to May 4, 2021. Ketamine infusions were administered at a starting dose of 0.5 mg/kg/40 minutes for 6 infusions within 21 days. Maintenance infusions were offered based on clinical response. Changes in outcome measures (scores on the Patient Health Questionnaire-9 [PHQ-9] and Generalized Anxiety Disorder-7 [GAD-7]) within subjects were analyzed using longitudinal multilevel modeling with Kaplan-Meier estimates. Logistic regression was used to analyze for a priori theorized potential moderators of response.

Results: Significant improvements from baseline were observed over time on the main outcomes (all P < .001). Based on PHQ-9 self-report data, within 6 weeks of infusion initiation, a 50% response rate and 20% remission rate for depressive symptoms were observed. Response and remission rates were 72% and 38%, respectively, after 10 infusions, and there was a 50% reduction in self-harm/suicidal ideation (SI) symptom scores within 6 weeks. Half of patients with SI at baseline no longer had it after 6 infusions. A 30% reduction in anxiety symptoms (per the GAD-7) was observed.

Conclusions: Ketamine was effective at reducing symptoms of SI, depression, and anxiety. The high rates of response and remission were similar to those for interventional treatments in community samples of TRD. Comparative efficacy trials with other interventions and randomized controlled trials of racemic ketamine infusion as the primary treatment for SI are needed.

Continue Reading...

Did you know members enjoy unlimited free PDF downloads as part of their subscription? Subscribe today for instant access to this article and our entire library in your preferred format. Alternatively, you can purchase the PDF of this article individually.

Subscribe Now

Already a member? Login

Purchase PDF for $40

Members enjoy free PDF downloads on all articles. Join today

  1. Fava M. Diagnosis and definition of treatment-resistant depression. Biol Psychiatry. 2003;53(8):649–659. PubMed CrossRef
  2. CDC. National Center for Health Statistics. Suicide mortality in the United States, 1999–2017. Hyattsville, MD. CDC website. https://www.cdc.gov/nchs/products/databriefs/db330.htm. 2018. Accessed April 23, 2022.
  3. Wang J, Sumner SA, Simon TR, et al. Trends in the incidence and lethality of suicidal acts in the United States, 2006 to 2015. JAMA Psychiatry. 2020;77(7):684–693. PubMed CrossRef
  4. Centers for Disease Control and Prevention. Web-based Injury Statistics Query and Reporting System (WISQARS). Atlanta, GA: National Centers for Injury Prevention and Control, Centers for Disease Control and Prevention. https://www.cdc.gov/injury/wisqars/index.html. 2022. Accessed April 23, 2022.
  5. Substance Abuse and Mental Health Services Administration. Key substance use and mental health indicators in the United States: Results from the 2020 National Survey on Drug Use and Health (HHS Publication No. PEP21-07-01-003, NSDUH Series H-56). Rockville, MD: Center for Behavioral Health Statistics and Quality, Substance Abuse and Mental Health Services Administration. https://www.samhsa.gov/data/report/2020-nsduh-annual-national-report. 2021. Accessed April 23, 2022.
  6. Friedrich MJ. Depression is the leading cause of disability around the world. JAMA. 2017;317(15):1517. PubMed CrossRef
  7. Bergfeld IO, Mantione M, Figee M, et al. Treatment-resistant depression and suicidality. J Affect Disord. 2018;235:362–367. PubMed CrossRef
  8. Kishimoto T, Chawla JM, Hagi K, et al. Single-dose infusion ketamine and non-ketamine N-methyl-d-aspartate receptor antagonists for unipolar and bipolar depression: a meta-analysis of efficacy, safety and time trajectories. Psychol Med. 2016;46(7):1459–1472. PubMed CrossRef
  9. Lapidus KAB, Levitch CF, Perez AM, et al. A randomized controlled trial of intranasal ketamine in major depressive disorder. Biol Psychiatry. 2014;76(12):970–976. PubMed CrossRef
  10. McGirr A, Berlim MT, Bond DJ, et al. A systematic review and meta-analysis of randomized, double-blind, placebo-controlled trials of ketamine in the rapid treatment of major depressive episodes. Psychol Med. 2015;45(4):693–704. PubMed CrossRef
  11. Fedgchin M, Trivedi M, Daly EJ, et al. Efficacy and safety of fixed-dose esketamine nasal spray combined with a new oral antidepressant in treatment-resistant depression: results of a randomized, double-blind, active-controlled study (TRANSFORM-1). Int J Neuropsychopharmacol. 2019;22(10):616–630. PubMed CrossRef
  12. Popova V, Daly EJ, Trivedi M, et al. 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 Psychiatry. 2019;176(6):428–438. PubMed CrossRef
  13. Ochs-Ross R, Daly EJ, Zhang Y, et al. Efficacy and safety of esketamine nasal spray plus an oral antidepressant in elderly patients with treatment-resistant depression—TRANSFORM-3. Am J Geriatr Psychiatry. 2020;28(2):121–141. PubMed CrossRef
  14. 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: a randomized clinical trial. JAMA Psychiatry. 2019;76(9):893–903. PubMed CrossRef
  15. O’Brien B, Lijffijt M, Lee J, et al. Distinct trajectories of antidepressant response to intravenous ketamine. J Affect Disord. 2021;286:320–329. PubMed CrossRef
  16. Judd LL, Schettler PJ, Akiskal HS. The prevalence, clinical relevance, and public health significance of subthreshold depressions. Psychiatr Clin North Am. 2002;25(4):685–698. PubMed CrossRef
  17. 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):1905–1917. PubMed CrossRef
  18. Trivedi MH, Rush AJ, Wisniewski SR, et al; STAR*D Study Team. 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. PubMed CrossRef
  19. De Jonghe F, Hendricksen M, van Aalst G, et al. Psychotherapy alone and combined with pharmacotherapy in the treatment of depression. Br J Psychiatry. 2004;185(1):37–45. PubMed CrossRef
  20. de Maat SM, Dekker J, Schoevers RA, et al. Relative efficacy of psychotherapy and combined therapy in the treatment of depression: a meta-analysis. Eur Psychiatry. 2007;22(1):1–8. PubMed CrossRef
  21. Thase ME, Greenhouse JB, Frank E, et al. Treatment of major depression with psychotherapy or psychotherapy-pharmacotherapy combinations. Arch Gen Psychiatry. 1997;54(11):1009–1015. PubMed CrossRef
  22. Warden D, Rush AJ, Trivedi MH, et al. The STAR*D Project results: a comprehensive review of findings. Curr Psychiatry Rep. 2007;9(6):449–459. PubMed CrossRef
  23. Benard V, Vaiva G, Masson M, et al. Lithium and suicide prevention in bipolar disorder. Encephale. 2016;42(3):234–241. PubMed CrossRef
  24. Yerevanian BI, Koek RJ, Mintz J. Lithium, anticonvulsants and suicidal behavior in bipolar disorder. J Affect Disord. 2003;73(3):223–228. PubMed CrossRef
  25. Undurraga J, Sim K, Tondo L, et al. Lithium treatment for unipolar major depressive disorder: systematic review. J Psychopharmacol. 2019;33(2):167–176. PubMed CrossRef
  26. Brodaty H, Berle D, Hickie I, et al. “Side effects” of ECT are mainly depressive phenomena and are independent of age. J Affect Disord. 2001;66(2-3):237–245. PubMed CrossRef
  27. Consoli A, Cohen J, Bodeau N, et al. Electroconvulsive therapy in adolescents with intellectual disability and severe self-injurious behavior and aggression: a retrospective study. Eur Child Adolesc Psychiatry. 2013;22(1):55–62. PubMed CrossRef
  28. Ittasakul P, Vora-Arporn S, Waleeprakhon P, et al. Number of electroconvulsive therapy sessions required for thai psychiatric patients: a retrospective study. Neuropsychiatr Dis Treat. 2020;16:673–679. PubMed CrossRef
  29. McClintock SM, Reti IM, Carpenter LL, et al; National Network of Depression Centers rTMS Task Group; American Psychiatric Association Council on Research Task Force on Novel Biomarkers and Treatments. Consensus recommendations for the clinical application of repetitive transcranial magnetic stimulation (rTMS) in the treatment of depression. J Clin Psychiatry. 2018;79(1):16cs10905. PubMed CrossRef
  30. Eranti S, Mogg A, Pluck G, et al. A randomized, controlled trial with 6-month follow-up of repetitive transcranial magnetic stimulation and electroconvulsive therapy for severe depression. Am J Psychiatry. 2007;164(1):73–81. PubMed CrossRef
  31. Feffer K, Lee HH, Mansouri F, et al. Early symptom improvement at 10 sessions as a predictor of rTMS treatment outcome in major depression. Brain Stimul. 2018;11(1):181–189. PubMed CrossRef
  32. Ren J, Li H, Palaniyappan L, et al. Repetitive transcranial magnetic stimulation versus electroconvulsive therapy for major depression: a systematic review and meta-analysis. Prog Neuropsychopharmacol Biol Psychiatry. 2014;51:181–189. PubMed CrossRef
  33. Bobo WV, Vande Voort JL, Croarkin PE, et al. Ketamine for treatment-resistant unipolar and bipolar major depression: critical review and implications for clinical practice. Depress Anxiety. 2016;33(8):698–710. PubMed CrossRef
  34. Calabrese L. Titrated serial ketamine infusions stop outpatient suicidality and avert er visits and hospitalizations. Int J Psychiatry Res. 2019;2(6):2–12. CrossRef
  35. Marcantoni WS, Akoumba BS, Wassef M, et al. A systematic review and meta-analysis of the efficacy of intravenous ketamine infusion for treatment resistant depression: January 2009–January 2019. J Affect Disord. 2020;277:831–841. PubMed CrossRef
  36. Daly EJ, Singh JB, Fedgchin M, 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(2):139–148. PubMed CrossRef
  37. Fedgchin M, Trivedi M, Daly EJ, et al. Efficacy and safety of fixed-dose esketamine nasal spray combined with a new oral antidepressant in treatment-resistant depression: results of a randomized, double-blind, active-controlled study (TRANSFORM-1). Int J Neuropsychopharmacol. 2019;22(10):616–630. PubMed CrossRef
  38. Fu DJ, Ionescu DF, Li X, et al. Esketamine nasal spray for rapid reduction of major depressive disorder symptoms in patients who have active suicidal ideation with intent: double-blind, randomized study (ASPIRE I). J Clin Psychiatry. 2020;81(3):19m3191. PubMed CrossRef
  39. Olié E, Nobile B, Courtet P. The antisuicidal effect of esketamine should be further investigated. J Clin Psychiatry. 2020;81(6):20l13482. PubMed CrossRef
  40. Wilkinson ST, Katz RB, Toprak M, et al. Acute and longer-term outcomes using ketamine as a clinical treatment at the Yale Psychiatric Hospital. J Clin Psychiatry. 2018;79(4):17m11731. PubMed CrossRef
  41. Short B, Fong J, Galvez V, et al. Side-effects associated with ketamine use in depression: a systematic review. Lancet Psychiatry. 2018;5(1):65–78. PubMed CrossRef
  42. Wajs E, Aluisio L, Holder R, et al. Esketamine nasal spray plus oral antidepressant in patients with treatment-resistant depression: assessment of long-term safety in a phase 3, open-label study (SUSTAIN-2). J Clin Psychiatry. 2020;81(3):19m12891. PubMed CrossRef
  43. Bremner JD, Krystal JH, Putnam FW, et al. Measurement of dissociative states with the Clinician-Administered Dissociative States Scale (CADSS). J Trauma Stress. 1998;11(1):125–136. PubMed CrossRef
  44. Kroenke K, Spitzer RL, Williams JB. The PHQ-9: validity of a brief depression severity measure. J Gen Intern Med. 2001;16(9):606–613. PubMed CrossRef
  45. Spitzer RL, Kroenke K, Williams JB, et al. A brief measure for assessing generalized anxiety disorder: the GAD-7. Arch Intern Med. 2006;166(10):1092–1097. PubMed CrossRef
  46. Somani A, Kar SK. Efficacy of repetitive transcranial magnetic stimulation in treatment-resistant depression: the evidence thus far. Gen Psychiatr. 2019;32(4):e100074. PubMed CrossRef
  47. Brus O, Cao Y, Gustafsson E, et al. Self-assessed remission rates after electroconvulsive therapy of depressive disorders. Eur Psychiatry. 2017;45:154–160. PubMed CrossRef
  48. Prudic J, Olfson M, Marcus SC, et al. Effectiveness of electroconvulsive therapy in community settings. Biol Psychiatry. 2004;55(3):301–312. PubMed CrossRef
  49. Pagnin D, de Queiroz V, Pini S, et al. Efficacy of ECT in depression: a meta-analytic review. Focus. 2008;6(1):155–162. CrossRef
  50. Abdelnaim MA, Langguth B, Deppe M, et al. Anti-suicidal efficacy of repetitive transcranial magnetic stimulation in depressive patients: a retrospective analysis of a large sample. Front Psychiatry. 2020;10:929. PubMed CrossRef
  51. Weissman CR, Blumberger DM, Brown PE, et al. Bilateral repetitive transcranial magnetic stimulation decreases suicidal ideation in depression. J Clin Psychiatry. 2018;79(3):17m11692. PubMed CrossRef
  52. Niciu MJ, Luckenbaugh DA, Ionescu DF, et al. Clinical predictors of ketamine response in treatment-resistant major depression. J Clin Psychiatry. 2014;75(5):e417–e423. PubMed CrossRef
  53. Ionescu DF, Fu DJ, Qiu X, et al. Esketamine nasal spray for rapid reduction of depressive symptoms in patients with major depressive disorder who have active suicide ideation with intent: results of a phase 3, double-blind, randomized study (ASPIRE II). Int J Neuropsychopharmacol. 2021;24(1):22–31. PubMed CrossRef
  54. Rossom RC, Coleman KJ, Ahmedani BK, et al. Suicidal ideation reported on the PHQ9 and risk of suicidal behavior across age groups. J Affect Disord. 2017;215:77–84. PubMed CrossRef
  55. McInnes LA, Qian JJ, Gargeya RS, et al. A retrospective analysis of ketamine intravenous therapy for depression in real-world care settings. J Affect Disord. 2022;301:486–495. PubMed CrossRef