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Depressive DisorderPhase 3NCT06957704

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

A Phase 3 study testing ketamine and Midazolam in people with Depressive Disorder and Suicidal Ideas, run by Federal University of São Paulo.

Not yet recruiting

Opening soon. The study is approved but enrolment has not started yet. Sites may already take enquiries.

Sites and contacts
Official record
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Trial 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). Read more about this study

Who is it for?
Ages 12 to 19 years
Conditions the study is for
Depressive Disorder, Suicidal Ideas
What is being tested?
ketamine and Midazolam
Type of treatment
Injection or infusion
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
60 participants
Where
No sites listed yet
Study dates
May 2025to Apr 2028
Phase
Phase 3
Are there results?
Not yet: the study is under way

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 12 to 19 years
  • All sexes
  • No healthy volunteers
  • Child, Adult

Who may be able to join

  • Age between 12 and 19 years.
  • Diagnosis of Major Depressive Episode, unipolar, made through the Schedule for Affective Disorders and Schizophrenia for School-Age Children (K-SADS-PL) administered by experienced evaluators, using DSM-5 criteria.
  • Under usual treatment for Major Depressive Episode, including clinically indicated psychopharmacological treatment and/or psychosocial treatment at one of the two collaborating clinics (DICA and Conversas de Vida / Unifesp).
  • Score ≥ 25 on the MADRS (Montgomery-Åsberg Depression Rating Scale).
  • Score ≥ 28 on the CDRS (Children Depression Rating Scale).
  • Score ≥ 2 on the Columbia Suicide Severity Rating Scale (C-SSRS).
  • History of suicide attempt or significant suicidal ideation or planning with a plan or intention requiring emergency evaluation in the last 30 days.

Who cannot join

  • Presence of the following psychiatric comorbidities: Autism Spectrum Disorder, Bipolar Disorder, Schizophrenia, Schizoaffective Disorder, or psychiatric disorder secondary to physical illness, and history of ketamine or other substance abuse or dependence in the last 6 months.
  • Presence of Intellectual Disability (assessed by IQ testing).
  • Presence of the following clinical comorbidities: history of myocardial infarction, congenital heart disease, decompensated cardiac arrhythmia, decompensated hypertension, porphyria, stroke, brain trauma with loss of consciousness, intracranial hypertension, hydrocephalus, central nervous system tumors, or central nervous system abnormalities.
  • Previous treatment for depression with esketamine.
  • Allergy to esketamine.
  • If female: pregnancy or breastfeeding.

Trial locations and contacts

No sites are listed yet. Contact the study team or a site near you to ask about taking part.

Sheila C Caetano, Phd contact

551197824398

sheila.caetano@unifesp.br

About this study

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).

Read the detailed description

Depression affects approximately 8% of adolescents, with an estimated 60% showing inadequate response to current standard treatments. Ketamine, a glutamatergic modulator, has demonstrated efficacy in adults with treatment-resistant depression and has shown promising preliminary results in adolescent populations. This Phase III, randomized, double-blind, placebo-controlled clinical trial aims to evaluate the efficacy and safety of subcutaneous ketamine as an adjunctive treatment for adolescents experiencing a major depressive episode with active suicidal ideation and/or behavior.

Participants will be randomized into two parallel groups to receive either subcutaneous ketamine (0.5 to 1 mg/kg) or an active placebo (1 mg midazolam diluted in 5 ml of 0.9% saline), administered twice weekly for four weeks. All participants will continue their usual treatment regimens. A two-week post-treatment follow-up period will be conducted to assess the persistence of effects and monitor safety outcomes.

Clinical assessments include diagnostic and symptom severity scales validated for pediatric populations. The efficacy will be primarily measured by depression remission and response, while safety will be assessed via adverse event monitoring and clinical examination. The trial will include 30 participants per group, providing 80% power to detect a clinically significant difference of 8.7 points on the Montgomery-Åsberg Depression Rating Scale (MADRS) between groups.

Being tested
ketamine, Midazolam
Keywords
Adolescent, Ketamine, Major Depressive Disorder, Midazolam
Medical subject headings
Depressive Disorder, Depressive Disorder, Major

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • ketamineDrug

    Ketamine will be administered as adjunctive therapy at an initial dose of 0.5 mg/kg via subcutaneous injection, twice weekly for four weeks, under double-blind conditions. Dose adjustments between 0.5 and 1.0 mg/kg will be based on depressive symptoms, efficacy, and tolerability. All procedures will occur at the Ketamine Clinic of Federal University of São Paulo.

  • MidazolamDrug

    Midazolam will be administered subcutaneously twice weekly for four consecutive weeks, also under double-blind conditions. The subject will be monitored continuously during the procedure, and every hour for three hours after the infusion.

Study groups in NCT06957704
Study groupRoleWhat they receive
KetamineExperimentalParticipants were randomly by assigned. ketamine will be used as an adjunctive treatment at an initial dose of 0.5 mg/kg, administered subcutaneously twice weekly for four weeks under double-blind conditions. Dose adjustments between 0.5 to 1.0 mg/kg may occur based on patient response and tolerability.
Receives: Drug: ketamine
MidazolamPlacebo comparatorFor the placebo group, midazolam will be administered subcutaneously at a dose of 1 mg diluted in 5 ml of 0.9% saline, twice weekly for four consecutive weeks, also under double-blind conditions.
Receives: Drug: Midazolam

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Change From Baseline in Montgomery-Asberg Rating Scale (MADRS) Total Score at 24 Hours Post First Dose

    The Montgomery-Åsberg Depression Rating Scale (MADRS) has a minimum score of 0 and a maximum score of 60; higher scores indicate worse depression. The primary efficacy endpoint of ketamine will be evaluated as follows:

    • Remission: Total score on the MADRS ≤ 12
    • Response: A reduction of more than 50% in the total MADRS score.
    • Lack of response: A reduction of less than 50% in the baseline MADRS scores.

    Measured: Baseline (predose) and 24 hours post first dose

Secondary outcomes (1)
  1. Remission and Response of Suicidal Ideation and Behavior Assessed by the Columbia-Suicide Severity Rating Scale (C-SSRS)

    The Columbia-Suicide Severity Rating Scale (C-SSRS) has a range from 0 to 5, where higher scores indicate greater severity of suicidal ideation or behavior.

    Secondary Efficacy Endpoint:

    • Remission of Suicide Risk: C-SSRS score = 0
    • Response: A 50% or greater improvement in the C-SSRS score.

    Measured: Baseline (predose) and 24 hours post first dose

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted4 May 2025
  2. Study startMay 2025 (estimated)
  3. Primary completionApr 2028 (estimated)
  4. Study completionApr 2028 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 3
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
Double blind
Who is masked
Participant, Outcomes assessor
Enrolment
60 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT06957704
Sponsor's protocol ID
82712924300005505
Status last verified
Mar 2025
First submitted
29 Mar 2025
Last updated
4 May 2025
Results posted
No
Data monitoring committee
No
FDA-regulated drug
Yes
FDA-regulated device
No

Publications

  • 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.

    PubMed 37414272
  • 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.

    PubMed 28969441
  • Willner P, Hale AS, Argyropoulos S. Dopaminergic mechanism of antidepressant action in depressed patients. J Affect Disord. 2005 May;86(1):37-45. doi: 10.1016/j.jad.2004.12.010.

    PubMed 15820269
  • Vecchia DD, Kanazawa LKS, Wendler E, de Almeida Soares Hocayen P, Bruginski E, Campos FR, Stern CAJ, Vital MABF, Miyoshi E, Wohr M, Schwarting RKW, Andreatini R. Effects of ketamine on vocal impairment, gait changes, and anhedonia induced by bilateral 6-OHDA infusion into the substantia nigra pars compacta in rats: Therapeutic implications for Parkinson's disease. Behav Brain Res. 2018 Apr 16;342:1-10. doi: 10.1016/j.bbr.2017.12.041. Epub 2018 Jan 4.

    PubMed 29307665
  • 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

  • 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.

    PubMed 36044154
  • Snaith RP, Hamilton M, Morley S, Humayan A, Hargreaves D, Trigwell P. A scale for the assessment of hedonic tone the Snaith-Hamilton Pleasure Scale. Br J Psychiatry. 1995 Jul;167(1):99-103. doi: 10.1192/bjp.167.1.99.

    PubMed 7551619
  • Sheehan DV, Lecrubier Y, Sheehan KH, Amorim P, Janavs J, Weiller E, Hergueta T, Baker R, Dunbar GC. The Mini-International Neuropsychiatric Interview (M.I.N.I.): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. J Clin Psychiatry. 1998;59 Suppl 20:22-33;quiz 34-57.

    PubMed 9881538
  • Scheuing L, Chiu CT, Liao HM, Chuang DM. Antidepressant mechanism of ketamine: perspective from preclinical studies. Front Neurosci. 2015 Jul 21;9:249. doi: 10.3389/fnins.2015.00249. eCollection 2015.

    PubMed 26257598
  • 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.

    PubMed 26888470
  • 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.

    PubMed 17074942
  • Robbins TW, Everitt BJ. Neurobehavioural mechanisms of reward and motivation. Curr Opin Neurobiol. 1996 Apr;6(2):228-36. doi: 10.1016/s0959-4388(96)80077-8.

    PubMed 8725965
  • Rhee TG, Shim SR, Forester BP, Nierenberg AA, McIntyre RS, Papakostas GI, Krystal JH, Sanacora G, Wilkinson ST. Efficacy and Safety of Ketamine vs Electroconvulsive Therapy Among Patients With Major Depressive Episode: A Systematic Review and Meta-analysis. JAMA Psychiatry. 2022 Dec 1;79(12):1162-1172. doi: 10.1001/jamapsychiatry.2022.3352.

    PubMed 36260324
  • Poznanski EO, Cook SC, Carroll BJ. A depression rating scale for children. Pediatrics. 1979 Oct;64(4):442-50.

    PubMed 492809
  • Posner K, Brown GK, Stanley B, Brent DA, Yershova KV, Oquendo MA, Currier GW, Melvin GA, Greenhill L, Shen S, Mann JJ. The Columbia-Suicide Severity Rating Scale: initial validity and internal consistency findings from three multisite studies with adolescents and adults. Am J Psychiatry. 2011 Dec;168(12):1266-77. doi: 10.1176/appi.ajp.2011.10111704.

    PubMed 22193671

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing ketamine and Midazolam in people with Depressive Disorder and Suicidal Ideas, run by Federal University of São Paulo.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 7 inclusion and 6 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: opening soon, as of the sponsor's last update on 4 May 2025. Status can change between updates, so confirm with the study contact before making plans.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

This study is still under way. Results are not available in the source record yet.

How can a doctor refer a patient or contact the research team?

Contact Sheila C Caetano, Phd (551197824398, sheila.caetano@unifesp.br), or a site near the patient. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Change From Baseline in Montgomery-Asberg Rating Scale (MADRS) Total Score at 24 Hours Post First Dose (time frame: Baseline (predose) and 24 hours post first dose). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT06957704, which also lists 56 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 4 May 2025.

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