Evaluation of the Efficacy and Safety of Subcutaneous Ketamine in the Treatment of Depressive Episode With Suicidal Ideation and/or Behavior in Adolescents

Summary

Evaluate the efficacy and safety of subcutaneous ketamine added to usual treatment in the management of depressive episodes with suicidal ideation or behavior in adolescent patients, compared to usual treatment added to placebo (midazolam).

Timeline

Start

2025-05

Primary completion

2028-04

Completion

2028-04

Publications

• Background Zhou Y, Lan X, Wang C, Zhang F, Liu H, Fu L, Li W, Ye Y, Hu Z, Chao Z, Ning Y. Effect of Repeated Intravenous Esketamine on Adolescents With Major Depressive Disorder and Suicidal Ideation: A Randomized Active-Placebo-Controlled Trial. J Am Acad Child Adolesc Psychiatry. 2024 May;63(5):507-518. doi: 10.1016/j.jaac.2023.05.031. Epub 2023 Jul 4.
• Background Wilkinson ST, Ballard ED, Bloch MH, Mathew SJ, Murrough JW, Feder A, Sos P, Wang G, Zarate CA Jr, Sanacora G. The Effect of a Single Dose of Intravenous Ketamine on Suicidal Ideation: A Systematic Review and Individual Participant Data Meta-Analysis. Am J Psychiatry. 2018 Feb 1;175(2):150-158. doi: 10.1176/appi.ajp.2017.17040472. Epub 2017 Oct 3.
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• Background Vazquez, D. A., Caetano, S., Schlegel, R., Lourenço, E., Nemi, A., Slemian, A., & Sanchez, Z. M. (2021). Schoolless life and the mental health of public-school students during the Covid-19 pandemic. In SciELO Preprints. https://doi.org/10.1590/SciELOPreprints.2329
• Background Surjan J, Grossi JD, Del Porto JA, Delfino RS, de Oliveira Cerqueira R, Lucchese AC, Magalhaes E, Del Sant LC, Tuena MA, Nakahira C, Fava VAR, Steglich MS, Abdo GL, Barbosa MG, Sarin LM, Lacerda ALT. Efficacy and Safety of Subcutaneous Esketamine in the Treatment of Suicidality in Major Depressive Disorder and Bipolar Depression. Clin Drug Investig. 2022 Oct;42(10):865-873. doi: 10.1007/s40261-022-01193-z. Epub 2022 Aug 31.
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• Background Saland SK, Schoepfer KJ, Kabbaj M. Hedonic sensitivity to low-dose ketamine is modulated by gonadal hormones in a sex-dependent manner. Sci Rep. 2016 Feb 18;6:21322. doi: 10.1038/srep21322.
• Background Rush AJ, Trivedi MH, Wisniewski SR, Nierenberg AA, Stewart JW, Warden D, Niederehe G, Thase ME, Lavori PW, Lebowitz BD, McGrath PJ, Rosenbaum JF, Sackeim HA, Kupfer DJ, Luther J, Fava M. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry. 2006 Nov;163(11):1905-17. doi: 10.1176/ajp.2006.163.11.1905.
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• Background Parsaik AK, Singh B, Khosh-Chashm D, Mascarenhas SS. Efficacy of Ketamine in Bipolar Depression: Systematic Review and Meta-analysis. J Psychiatr Pract. 2015 Nov;21(6):427-35. doi: 10.1097/PRA.0000000000000106.
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• Background Maguire L, Bullard T, Papa L. Ketamine for acute suicidality in the emergency department: A systematic review. Am J Emerg Med. 2021 May;43:54-58. doi: 10.1016/j.ajem.2020.12.088. Epub 2021 Jan 14.
• Background Lucchese AC, Sarin LM, Magalhaes EJM, Del Sant LC, B Puertas C, Tuena MA, Nakahira C, Fava VA, Delfino R, Surjan J, Steiglich MS, Barbosa M, Abdo G, Cohrs FM, Liberatori A, Del Porto JA, Lacerda AL, B Andreoli S. Repeated subcutaneous esketamine for treatment-resistant depression: Impact of the degree of treatment resistance and anxiety comorbidity. J Psychopharmacol. 2021 Feb;35(2):142-149. doi: 10.1177/0269881120978398. Epub 2021 Jan 9.
• Background Loo CK, Galvez V, O'Keefe E, Mitchell PB, Hadzi-Pavlovic D, Leyden J, Harper S, Somogyi AA, Lai R, Weickert CS, Glue P. Placebo-controlled pilot trial testing dose titration and intravenous, intramuscular and subcutaneous routes for ketamine in depression. Acta Psychiatr Scand. 2016 Jul;134(1):48-56. doi: 10.1111/acps.12572. Epub 2016 Mar 30.
• Background Li N, Liu RJ, Dwyer JM, Banasr M, Lee B, Son H, Li XY, Aghajanian G, Duman RS. Glutamate N-methyl-D-aspartate receptor antagonists rapidly reverse behavioral and synaptic deficits caused by chronic stress exposure. Biol Psychiatry. 2011 Apr 15;69(8):754-61. doi: 10.1016/j.biopsych.2010.12.015. Epub 2011 Feb 3.
• Background Lally N, Nugent AC, Luckenbaugh DA, Niciu MJ, Roiser JP, Zarate CA Jr. Neural correlates of change in major depressive disorder anhedonia following open-label ketamine. J Psychopharmacol. 2015 May;29(5):596-607. doi: 10.1177/0269881114568041. Epub 2015 Feb 17.
• Background Lally N, Nugent AC, Luckenbaugh DA, Ameli R, Roiser JP, Zarate CA. Anti-anhedonic effect of ketamine and its neural correlates in treatment-resistant bipolar depression. Transl Psychiatry. 2014 Oct 14;4(10):e469. doi: 10.1038/tp.2014.105.
• Background Kokkinou M, Ashok AH, Howes OD. The effects of ketamine on dopaminergic function: meta-analysis and review of the implications for neuropsychiatric disorders. Mol Psychiatry. 2018 Jan;23(1):59-69. doi: 10.1038/mp.2017.190. Epub 2017 Oct 3.
• Background Kim S, Rush BS, Rice TR. A systematic review of therapeutic ketamine use in children and adolescents with treatment-resistant mood disorders. Eur Child Adolesc Psychiatry. 2021 Oct;30(10):1485-1501. doi: 10.1007/s00787-020-01542-3. Epub 2020 May 8.
• Background Kessler RC, Berglund P, Demler O, Jin R, Koretz D, Merikangas KR, Rush AJ, Walters EE, Wang PS; National Comorbidity Survey Replication. The epidemiology of major depressive disorder: results from the National Comorbidity Survey Replication (NCS-R). JAMA. 2003 Jun 18;289(23):3095-105. doi: 10.1001/jama.289.23.3095.
• Background Kaufman J, Birmaher B, Brent D, Rao U, Flynn C, Moreci P, Williamson D, Ryan N. Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version (K-SADS-PL): initial reliability and validity data. J Am Acad Child Adolesc Psychiatry. 1997 Jul;36(7):980-8. doi: 10.1097/00004583-199707000-00021.
• Background Jaen-Varas D, Mari JJ, Asevedo E, Borschmann R, Diniz E, Ziebold C, Gadelha A. The association between adolescent suicide rates and socioeconomic indicators in Brazil: a 10-year retrospective ecological study. Braz J Psychiatry. 2019 Feb 18;41(5):389-395. doi: 10.1590/1516-4446-2018-0223. eCollection 2019.
• Background 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. doi: 10.4088/JCP.14m09298.
• Background Glue P, Medlicott NJ, Harland S, Neehoff S, Anderson-Fahey B, Le Nedelec M, Gray A, McNaughton N. Ketamine's dose-related effects on anxiety symptoms in patients with treatment refractory anxiety disorders. J Psychopharmacol. 2017 Oct;31(10):1302-1305. doi: 10.1177/0269881117705089. Epub 2017 Apr 26.
• Background George D, Galvez V, Martin D, Kumar D, Leyden J, Hadzi-Pavlovic D, Harper S, Brodaty H, Glue P, Taylor R, Mitchell PB, Loo CK. Pilot Randomized Controlled Trial of Titrated Subcutaneous Ketamine in Older Patients with Treatment-Resistant Depression. Am J Geriatr Psychiatry. 2017 Nov;25(11):1199-1209. doi: 10.1016/j.jagp.2017.06.007. Epub 2017 Jun 13.
• Background Garcia LS, Comim CM, Valvassori SS, Reus GZ, Barbosa LM, Andreazza AC, Stertz L, Fries GR, Gavioli EC, Kapczinski F, Quevedo J. Acute administration of ketamine induces antidepressant-like effects in the forced swimming test and increases BDNF levels in the rat hippocampus. Prog Neuropsychopharmacol Biol Psychiatry. 2008 Jan 1;32(1):140-4. doi: 10.1016/j.pnpbp.2007.07.027. Epub 2007 Aug 8.
• Background Garcia LS, Comim CM, Valvassori SS, Reus GZ, Stertz L, Kapczinski F, Gavioli EC, Quevedo J. Ketamine treatment reverses behavioral and physiological alterations induced by chronic mild stress in rats. Prog Neuropsychopharmacol Biol Psychiatry. 2009 Apr 30;33(3):450-5. doi: 10.1016/j.pnpbp.2009.01.004. Epub 2009 Jan 21.
• Background Galvez V, O'Keefe E, Cotiga L, Leyden J, Harper S, Glue P, Mitchell PB, Somogyi AA, DeLory A, Loo CK. Long-lasting effects of a single subcutaneous dose of ketamine for treating melancholic depression: a case report. Biol Psychiatry. 2014 Aug 1;76(3):e1-2. doi: 10.1016/j.biopsych.2013.12.010. Epub 2014 Jan 3. No abstract available.
• Background Friedrich MJ. Depression Is the Leading Cause of Disability Around the World. JAMA. 2017 Apr 18;317(15):1517. doi: 10.1001/jama.2017.3826. No abstract available.
• Background Fava VAR, Sarin LM, Lucchese AC, Del Sant L, Magalhaes E, Delfino RS, Tuena MA, Nakahira C, Jackowski AP, Abdo G, Surjan J, Steiglich M, Barbosa MG, Porto JAD, Lacerda ALT, Cogo-Moreira H. The probability of response after each subcutaneous injection of esketamine in treatment-resistant depression. Rev Psiquiatr Salud Ment (Engl Ed). 2020 Oct 16:S1888-9891(20)30117-8. doi: 10.1016/j.rpsm.2020.10.003. Online ahead of print. English, Spanish.
• Background Dwyer JB, Landeros-Weisenberger A, Johnson JA, Londono Tobon A, Flores JM, Nasir M, Couloures K, Sanacora G, Bloch MH. Efficacy of Intravenous Ketamine in Adolescent Treatment-Resistant Depression: A Randomized Midazolam-Controlled Trial. Am J Psychiatry. 2021 Apr 1;178(4):352-362. doi: 10.1176/appi.ajp.2020.20010018. Epub 2021 Mar 3.
• Background Duman RS, Aghajanian GK. Synaptic dysfunction in depression: potential therapeutic targets. Science. 2012 Oct 5;338(6103):68-72. doi: 10.1126/science.1222939.
• Background Del Sant LC, Sarin LM, Magalhaes EJM, Lucchese AC, Tuena MA, Nakahira C, Fava VAR, Delfino R, Surjan J, Steiglich MS, Barbosa M, Abdo G, Cohrs FM, Liberatori A, Del Porto JA, Lacerda ALT, de Jesus Mari J. Effects of subcutaneous esketamine on blood pressure and heart rate in treatment-resistant depression. J Psychopharmacol. 2020 Oct;34(10):1155-1162. doi: 10.1177/0269881120922955. Epub 2020 Jul 8.
• Background Delfino RS, Del-Porto JA, Surjan J, Magalhaes E, Sant LCD, Lucchese AC, Tuena MA, Nakahira C, Fava VAR, Steglich MS, Barbosa MG, Sarin LM, Lacerda ALT. Comparative effectiveness of esketamine in the treatment of anhedonia in bipolar and unipolar depression. J Affect Disord. 2021 Jan 1;278:515-518. doi: 10.1016/j.jad.2020.09.056. Epub 2020 Sep 15.
• Background Cullen KR, Amatya P, Roback MG, Albott CS, Westlund Schreiner M, Ren Y, Eberly LE, Carstedt P, Samikoglu A, Gunlicks-Stoessel M, Reigstad K, Horek N, Tye S, Lim KO, Klimes-Dougan B. Intravenous Ketamine for Adolescents with Treatment-Resistant Depression: An Open-Label Study. J Child Adolesc Psychopharmacol. 2018 Sep;28(7):437-444. doi: 10.1089/cap.2018.0030. Epub 2018 Jul 13.
• Background Caye A, Kieling RR, Rocha TB, Graeff-Martins AS, Geyer C, Krieger F, Manfro GG, Brentani H, Isolan L, Rosario MC, Grassi-Oliveira R, Caetano SC, Moriyama T, Rohde LA, Kieling C. Schedule for Affective Disorders and Schizophrenia for School-Age Children - Present and Lifetime Version (K-SADS-PL), DSM-5 update: translation into Brazilian Portuguese. Braz J Psychiatry. 2017 Oct-Dec;39(4):384-386. doi: 10.1590/1516-4446-2017-2317. No abstract available.
• Background Cavenaghi VB, da Costa LP, Lacerda ALT, Hirata ES, Miguel EC, Fraguas R. Subcutaneous Ketamine in Depression: A Systematic Review. Front Psychiatry. 2021 May 28;12:513068. doi: 10.3389/fpsyt.2021.513068. eCollection 2021.
• Background Boletim Epidemiológico número 33 da Coordenação-Geral de Doenças e Agravos Não Transmissíveis do Departamento de Análise em Saúde e Vigilância das Doenças Não Transmissíveis da Secretaria de Vigilância em Saúde (CGDANT/DASNT/SVS/MS): Oliveira RV. Coordenação-Geral de Saúde Mental Álcool e outras Drogas do Departamento de Ações Programáticas Estratégicas da Secretaria de Atenção Primária à Saúde (CGMAD/ DAPES/SAPS/MS): Ribeiro RB, Santos AF, Almeida L, Juliani LW. Coordenação de Saúde do Homem do Departamento de Ações Programáticas Estratégicas (COSAH/DAPES/SAPS/MS): Albuquerque FP. Universidade Federal de São Paulo (Unifesp): Caetano SC.
• Background Bodden DHM, Stikkelbroek Y, Dirksen CD. Societal burden of adolescent depression, an overview and cost-of-illness study. J Affect Disord. 2018 Dec 1;241:256-262. doi: 10.1016/j.jad.2018.06.015. Epub 2018 Jul 18.
• Background Beck AT, Steer RA, Ranieri WF. Scale for Suicide Ideation: psychometric properties of a self-report version. J Clin Psychol. 1988 Jul;44(4):499-505. doi: 10.1002/1097-4679(198807)44:43.0.co;2-6.
• Background Ballard ED, Wills K, Lally N, Richards EM, Luckenbaugh DA, Walls T, Ameli R, Niciu MJ, Brutsche NE, Park L, Zarate CA Jr. Anhedonia as a clinical correlate of suicidal thoughts in clinical ketamine trials. J Affect Disord. 2017 Aug 15;218:195-200. doi: 10.1016/j.jad.2017.04.057. Epub 2017 Apr 25.
• Background Argyropoulos SV, Nutt DJ. Anhedonia revisited: is there a role for dopamine-targeting drugs for depression? J Psychopharmacol. 2013 Oct;27(10):869-77. doi: 10.1177/0269881113494104. Epub 2013 Jul 31.
• Background Andrews G, Issakidis C, Sanderson K, Corry J, Lapsley H. Utilising survey data to inform public policy: comparison of the cost-effectiveness of treatment of ten mental disorders. Br J Psychiatry. 2004 Jun;184:526-33. doi: 10.1192/bjp.184.6.526.
• Background 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 Jul;78(7):e852-e857. doi: 10.4088/JCP.17f11738.
• Background Alnefeesi Y, Chen-Li D, Krane E, Jawad MY, Rodrigues NB, Ceban F, Di Vincenzo JD, Meshkat S, Ho RCM, Gill H, Teopiz KM, Cao B, Lee Y, McIntyre RS, Rosenblat JD. Real-world effectiveness of ketamine in treatment-resistant depression: A systematic review & meta-analysis. J Psychiatr Res. 2022 Jul;151:693-709. doi: 10.1016/j.jpsychires.2022.04.037. Epub 2022 May 25.
• Background Abdallah CG, Jackowski A, Salas R, Gupta S, Sato JR, Mao X, Coplan JD, Shungu DC, Mathew SJ. The Nucleus Accumbens and Ketamine Treatment in Major Depressive Disorder. Neuropsychopharmacology. 2017 Jul;42(8):1739-1746. doi: 10.1038/npp.2017.49. Epub 2017 Mar 8.
• Background Abbar M, Demattei C, El-Hage W, Llorca PM, Samalin L, Demaricourt P, Gaillard R, Courtet P, Vaiva G, Gorwood P, Fabbro P, Jollant F. Ketamine for the acute treatment of severe suicidal ideation: double blind, randomised placebo controlled trial. BMJ. 2022 Feb 2;376:e067194. doi: 10.1136/bmj-2021-067194.

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