Intramuscular Ketamine Versus Aripiprazole and Escitalopram in the Treatment of Resistant Depression

Ketamine

Brief Summary

The treatment of resistant depression should be optimized aiming at complete remission of symptoms, a complex condition due to several factors. Approximately 1/3 of patients with depressive disorders do not even respond to available antidepressants. Consequently, new molecules with robust action, fast effects and sustained improvement are currently being researched worldwide. Ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, has emerged as a promising alternative due to its involvement in neurogenesis, synaptogenesis and consequent rapid improvement of depressive and suicidal symptoms with traditional intravenous (IV) use in sub dose (0.5 mg / kg). The therapeutic response of IV use has been short and requires monitoring in a hospital setting. There are no studies evaluating response to long-term ketamine use. Recent research has focused on identifying other routes of ketamine use such as intranasal and intramuscular (IM). The use of ketamine IM, despite the fact that there are few studies and small samples, can demonstrate efficacy in acute treatment and maintenance of depression, as well as low profile of side effects, greater accessibility potential, reduced costs and risks, patient comfort and possible expansion of resistant depression treatment capabilities in different settings.

Intervention / Treatment

Subjects will receive IM ketamine or IM saline applications as randomized. Applications will occur three times a week. It will be 4 weeks of IM application (12 initial applications). Injections will occur into the subjects' glutes (0.75 mg / kg). The ketamine group will use 2 placebo tablets and the parallel group escitalopram 15 mg and aripiprazole 5 mg. Thereafter, participants will receive weekly ketamine doses over 6 months as maintenance treatment. Research members will be submitted to Structured Clinical Interview for the DSM for diagnostic categorization and will be evaluated from other scales. Vital signs will be checked continuously for a period of 2 hours with each infusion. Patients will be observed in a quiet, comfortable room and subjected to medical monitoring for 2 hours. They will leave the environment in the company of a competent adult.
  • Ketamine (DRUG)
    (0,75 mg/kg) saline solution (15 mg) Escitalopram (5 mg) Aripiprazole
  • Cognition (DIAGNOSTIC_TEST)
    Composite tools
  • Suicide risk (OTHER)
    MADRS (10) and HAM-D (3)
  • Depression thoughts (OTHER)
    EPD
  • Quality of life and disability (OTHER)
  • Clinical and epidemiological factors (OTHER)
    Variables and categories
  • Safety of ketamine IM (DEVICE)
    Vital signs
  • Tolerability of ketamine IM (OTHER)
    UKU-SERS, YOUNG, CADSS and BPRS-12.

Condition or Disease

  • Depressive Disorder

Phase

  • Phase 4

    • Study Design

    Study type: INTERVENTIONAL
    Status: Unknown status
    Study results: No Results Available
    Age: 18 Years to 40 Years
    Enrollment: 88 (ESTIMATED)
    Funded by: Other
    Allocation: Randomized
    Primary Purpose: Treatment

    Masking

    QUADRUPLE:
    • Participant
    • Care Provider
    • Investigator
    • Outcomes Assessor

    Clinical Trial Dates

    Start date: Apr 03, 2018 ACTUAL
    Primary Completion: Jun 03, 2020 ESTIMATED
    Completion Date: Apr 03, 2021 ESTIMATED
    Study First Posted: Jan 21, 2020 ACTUAL
    Results First Posted: Aug 31, 2020
    Last Updated: Jan 15, 2020

    Sponsors / Collaborators

    Lead Sponsor: University of Sao Paulo
    Responsible Party: N/A

    Location

    Santa Catarina, Brazil
    Blumenau, Santa Catarina, Brazil

    Compare the response of ketamine IM versus active control in treatment-resistant depression (TRD \[primary outcome\]) and find safety and tolerability of ketamine IM, evaluate changes in life quality, cognition and suicidal risk (secondary outcomes)

    Participant Groups

    • Subjects eligible to participate in the study will receive IM ketamine and will use 2 placebo tablets as randomized.

    • Subjects eligible to participate in the study will receive IM saline and will use escitalopram 15 mg and aripiprazole 5 mg as randomized

    Eligibility Criteria

    Sex: All
    Minimum Age: 18
    Maximum Age: 40
    Age Groups: Adult
    Healthy Volunteers: Yes

    Inclusion Criteria:

    1. Diagnosis of TRD, according to clinical evaluation and confirmed by SCID-IV (Structured Clinical Interview for the DSM);
    2. Moderate to severe intensity of the disease;
    3. Female patients in fertile conditions should be using a clinically accepted contraceptive method (oral contraceptive and/or condom);

    a. Blood test will be requested at the diagnostic stage and in case of clinical doubt as to the patient's gestational status,
    4. Literate and able to understand the tasks requested;
    5. With clinical comorbidities, however compensated;
    6. Patients and/or legal representatives should understand the nature of the study and sign the Informed Consent Form.

    Exclusion Criteria:

    1. Imminent risk of suicide;
    2. Patients with psychoactive substance dependence;
    3. Intellectual deficit and psychotic symptoms;
    4. Bipolar spectrum disorders and other primary psychiatric diagnoses;
    5. Allergic to ketamine;
    6. Glaucoma;
    7. Treatment with reversible MAOI (monoamine oxidase inhibitor) in the week prior to visit 0;
    8. Treatment with irreversible MAOI in two weeks prior to visit 0;
    9. Fluoxetine treatment within 4 weeks prior to visit 0;
    10. Treatment with others antidepressants;
    11. Treatment with antipsychotics, lithium, benzodiazepines or other psychotropic drugs within 7 days prior to visit 0;

    a. Lorazepam and zolpidem may be used;
    12. Patients who become pregnant will be excluded from the study and referred for obstetric care.

    Primary Outcomes

    • Montomery-Åsberg Depression Rating Scale (\[0-60\] higher scores: worse outcome). No improvement: MADRS ≤ 25% Partial response: MADRS ≥ 25% and \< 50% Response: MADRS ≥ 50% Remission: MADRS ≤10

    • Montgomery-Åsberg Depression Rating Scale (\[0-60\] higher scores: worse outcome). Recovery: Maintenance ≥ 6-8 months Relapse: Full return of symptoms once remission has occurred or worsening ≤ 75% with lower percentage of improvement (HAM-D inclusion criteria)

    • Montgomery-Åsberg Depression Rating Scale (\[0-60\] higher scores: worse outcome). Relapse: Full return of symptoms once remission has occurred or worsening ≤ 75% with lower percentage of improvement (HAM-D inclusion criteria).

    Secondary Outcomes

    • Hamiltom Depression Ratins Scale (HAM-D \[0-50\] higher scores: worse outcome).

    • Clinical Global Impression Scale (CGI \[0-7\] higher scores: worse outcome).

    • Clinical Global Impression Scale (CGI \[0-7\] higher scores: worse outcome).

    • P wave, PR interval, QRS complex, J-point, ST segment, T wave, Corrected QT interval and U wave Rhythm (irregular rhythm: worse outcome).

    • BP low \<90/60 (systolic/diastolic) mmHg and high \>140/90 mmHg ( (systolic/diastolic).

    • Anormal HR \<60 bpm or \>100 bpm.

    • Low oxygen saturation \<95%.

    • Anormal RR \<10 cycles/min or \>20 cycles/min.

    • Montgomery-Åsberg Depression Rating Scale (item 10 \[0-6\] higher scores: worse outcome).

    • Hamilton Depression Rating Scale (item 3 \[0-4\] higher scores: worse outcome).

    • Ugvalg for Kliniske Undersgelser-Side Effect Rating Scale (UKU-SERS \[48 specific symptoms).

    • Young Mania Rating Scale (YOUNG \[0-58\] higher scores: worse outcome).

    • Clinician-Administered Dissociative State Scale (CADSS \[0-108\] higher scores: worse outcome)

    • Brief Psychiatric Rating Scale (item 12 \[0-6\] higher scores: worse outcome).

    • Depression Thoughts Scale (EPD \[1-78\] higher scores: worse outcome)

    • Wechsler Abreviated Scale of Intelligence (WASI \[70-160 percentille\] higher scores: better outcomes).

    • Wechsler Scale of Intelligence (WAIS III \[70-155 percentille\] higher scores: better outcomes).

    • Trial Making Test (5-95 percentille, higher scores: better outcomes).

    • Rey figures (10-100 percentille, higher scores: better outcomes)

    • Wisconsin Test (50-\>80 score, higher scores: better outcomes).

    • Stroop Color Word Test (5-95 percentille, higher scores: better outcomes)

    • Verbal Fluency Test (FAS \[10-90 percentille\], higher scores: better outcomes))

    • The Rey Auditory-Verbal Learning Test (RAVLT \[5-95 percentille\], higher scores: better outcomes).

    • World Health Organization Quality of Life (WHOQOL-brief \[4 domains, 26 questions higher scores: better outcome\]).

    • Sheehan Disability Scale (SDS \[0-30\] higher scores: worse outcome).

    • Weight and height (kg/m2).

    • Disease intensity (HAM-D \[% of patients\], moderate or severe)

    • Number of episodes (questionnaire \[incidence\])

    • Current episode duration (questionnaire \[years\])

    • Suicide attempts (questionnaire \[% of pacients\])

    • History of physical abuse (questionnaire \[% of pacients\])

    • History of sexual abuse (questionnaire \[% of pacients\])

    • Psychiatric hospitalizations (questionnaire \[% of pacients\])

    • Clinical comorbidities (questionnaire \[% of patients\]).

    • Family history of depression (questionnaire \[% of patients\])

    • Family history of bipolar disorders (questionnaire \[% of patients)

    • Family history of other mental disorders (questionnaire \[% of patients\]).

    • Age (questionnaire \[years\]).

    • Gender (questionnaire \[% of patients\]; male/female)

    • Marital status (questionnaire \[% of patients\] single, married, separated, divorced or widower).

    • Ethnicity (questionnaire \[% of patients\])

    • Religion (questionnaire \[% of patients\] protestant, pentecostal or neopentecostal, spiritism, afro-brazilian, no religion or atheism and others\]).

    • Occupation (questionnaire \[% of patients\])

    • Education (questionnaire \[years\])

    • Individual income (questionnaire \[dollars\]).

    • Family income (questionnaire \[dollars\]).

    More Details

    NCT Number: NCT04234776
    Acronym: KETProject
    Other IDs: rampty2805
    Study URL: https://clinicaltrials.gov/study/NCT04234776
    Last updated: Sep 29, 2023