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

Phase 4

• Conditions: Depressive Disorder
• Interventions: Drug: Ketamine; Diagnostic Test: Cognition; Other: Suicide risk; Other: Depression thoughts; Other: Quality of life and disability; Other: Clinical and epidemiological factors; Device: Safety of ketamine IM; Other: Tolerability of ketamine IM

• Registration Number: NCT04234776
• Lead Sponsor: University of Sao Paulo

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.

Detailed Description

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)

Study Timeline

• Study Start: 2018-04-03
• Study First Submitted: 2019-10-07
• Status Verified: 2019-12
• Study First Submitted QC: 2020-01-15
• Last Update Submitted: 2020-01-15
• Study First Posted: 2020-01-21
• Last Update Posted: 2020-01-21
• Primary Completion: 2020-06-03
• Study Completion: 2021-04-03

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: All
• Target Recruitment: 88

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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Rapid-acting antidepressant	Ketamine	Subjects eligible to participate in the study will receive IM ketamine and will use 2 placebo tablets as randomized.
Rapid-acting antidepressant	Cognition	Subjects eligible to participate in the study will receive IM ketamine and will use 2 placebo tablets as randomized.
Rapid-acting antidepressant	Suicide risk	Subjects eligible to participate in the study will receive IM ketamine and will use 2 placebo tablets as randomized.
Rapid-acting antidepressant	Depression thoughts	Subjects eligible to participate in the study will receive IM ketamine and will use 2 placebo tablets as randomized.
Rapid-acting antidepressant	Quality of life and disability	Subjects eligible to participate in the study will receive IM ketamine and will use 2 placebo tablets as randomized.
Rapid-acting antidepressant	Clinical and epidemiological factors	Subjects eligible to participate in the study will receive IM ketamine and will use 2 placebo tablets as randomized.
Rapid-acting antidepressant	Safety of ketamine IM	Subjects eligible to participate in the study will receive IM ketamine and will use 2 placebo tablets as randomized.
Rapid-acting antidepressant	Tolerability of ketamine IM	Subjects eligible to participate in the study will receive IM ketamine and will use 2 placebo tablets as randomized.
Comparator	Cognition	Subjects eligible to participate in the study will receive IM saline and will use escitalopram 15 mg and aripiprazole 5 mg as randomized
Comparator	Suicide risk	Subjects eligible to participate in the study will receive IM saline and will use escitalopram 15 mg and aripiprazole 5 mg as randomized
Comparator	Depression thoughts	Subjects eligible to participate in the study will receive IM saline and will use escitalopram 15 mg and aripiprazole 5 mg as randomized
Comparator	Quality of life and disability	Subjects eligible to participate in the study will receive IM saline and will use escitalopram 15 mg and aripiprazole 5 mg as randomized
Comparator	Clinical and epidemiological factors	Subjects eligible to participate in the study will receive IM saline and will use escitalopram 15 mg and aripiprazole 5 mg as randomized
Comparator	Safety of ketamine IM	Subjects eligible to participate in the study will receive IM saline and will use escitalopram 15 mg and aripiprazole 5 mg as randomized
Comparator	Tolerability of ketamine IM	Subjects eligible to participate in the study will receive IM saline and will use escitalopram 15 mg and aripiprazole 5 mg as randomized
Comparator	Ketamine	Subjects eligible to participate in the study will receive IM saline and will use escitalopram 15 mg and aripiprazole 5 mg as randomized

Primary Outcome Measures

Name	Time	Method
Change in depressive symptoms	Once a week in once month (Phase IV)	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 Outcome Measures

Name	Time	Method
Body Mass Index (BMI)	Through study completion, an average of 1 year.	Weight and height (kg/m2).
Clinical impressions-S	Through study completion, an average of 1 year.	Clinical Global Impression Scale (CGI \[0-7\] higher scores: worse outcome).
Digital pulse oximetry (%).	3 times a week in once month (Fase II) and once a week in six months (Phase III)	Low oxygen saturation \<95%.
Clinical impressions-I	Through study completion, an average of 1 year.	Clinical Global Impression Scale (CGI \[0-7\] higher scores: worse outcome).
Blood Pressure (BP [mmHg]).	3 times a week in once month (Fase II) and once a week in six months (Phase III)	BP low \<90/60 (systolic/diastolic) mmHg and high \>140/90 mmHg ( (systolic/diastolic).
Respiratory rate (RR [cycles/min])	3 times a week in once month (Fase II) and once a week in six months (Phase III)	Anormal RR \<10 cycles/min or \>20 cycles/min.
Depression symptoms	Through study completion, an average of 1 year.	Hamiltom Depression Ratins Scale (HAM-D \[0-50\] higher scores: worse outcome).
Electrocardiographic monitoring	3 times a week in once month (Fase II) and once a week in six months (Phase III)	P wave, PR interval, QRS complex, J-point, ST segment, T wave, Corrected QT interval and U wave Rhythm (irregular rhythm: worse outcome).
Suicide risk 2	Through study completion, an average of 1 year.	Hamilton Depression Rating Scale (item 3 \[0-4\] higher scores: worse outcome).
General side effects	3 times a week in once month (Phase II) and once a week in six months (Phase III)	Ugvalg for Kliniske Undersgelser-Side Effect Rating Scale (UKU-SERS \[48 specific symptoms).
Hypo/maniac symptoms	3 times a week in once month (Phase II) and once a week in six months (Phase III)	Young Mania Rating Scale (YOUNG \[0-58\] higher scores: worse outcome).
Dissociative symptoms	3 times a week in once month (Phase II) and once a week in six months (Phase III)	Clinician-Administered Dissociative State Scale (CADSS \[0-108\] higher scores: worse outcome)
Psychotic symptoms	3 times a week in once month (Phase II) and once a week in six months (Phase III)	Brief Psychiatric Rating Scale (item 12 \[0-6\] higher scores: worse outcome).
Depression thoughts	Through study completion, an average of 1 year.	Depression Thoughts Scale (EPD \[1-78\] higher scores: worse outcome)
Stimate intelligence quocient	Through study completion, an average of 1 year.	Wechsler Abreviated Scale of Intelligence (WASI \[70-160 percentille\] higher scores: better outcomes).
Intelligence quocient	Through study completion, an average of 1 year.	Wechsler Scale of Intelligence (WAIS III \[70-155 percentille\] higher scores: better outcomes).
Attention	Through study completion, an average of 1 year.	Trial Making Test (5-95 percentille, higher scores: better outcomes).
Heart rate (HR [bpm]).	3 times a week in once month (Fase II) and once a week in six months (Phase III)	Anormal HR \<60 bpm or \>100 bpm.
Suicide risk 1	Through study completion, an average of 1 year.	Montgomery-Åsberg Depression Rating Scale (item 10 \[0-6\] higher scores: worse outcome).
Memory	Through study completion, an average of 1 year.	Rey figures (10-100 percentille, higher scores: better outcomes)
Executive functions 1	Through study completion, an average of 1 year.	Wisconsin Test (50-\>80 score, higher scores: better outcomes).
Executive functions 2	Through study completion, an average of 1 year.	Stroop Color Word Test (5-95 percentille, higher scores: better outcomes)
Verbal fluency 1	Through study completion, an average of 1 year.	Verbal Fluency Test (FAS \[10-90 percentille\], higher scores: better outcomes))
Verbal fluency 2	Through study completion, an average of 1 year.	The Rey Auditory-Verbal Learning Test (RAVLT \[5-95 percentille\], higher scores: better outcomes).
Functional recovery 1	Through study completion, an average of 1 year.	World Health Organization Quality of Life (WHOQOL-brief \[4 domains, 26 questions higher scores: better outcome\]).
Functional recovery 2	Through study completion, an average of 1 year.	Sheehan Disability Scale (SDS \[0-30\] higher scores: worse outcome).
Clinical and psychiatric features 1	Through study completion, an average of 1 year.	Disease intensity (HAM-D \[% of patients\], moderate or severe)
Clinical and psychiatric features 2	Through study completion, an average of 1 year.	Number of episodes (questionnaire \[incidence\])
Clinical and psychiatric features 3	Through study completion, an average of 1 year.	Current episode duration (questionnaire \[years\])
Clinical and psychiatric features 5	Through study completion, an average of 1 year.	History of physical abuse (questionnaire \[% of pacients\])
Clinical and psychiatric features 6	Through study completion, an average of 1 year.	History of sexual abuse (questionnaire \[% of pacients\])
Clinical and psychiatric features 8	Through study completion, an average of 1 year.	Clinical comorbidities (questionnaire \[% of patients\]).
Clinical and psychiatric features 9	Through study completion, an average of 1 year.	Family history of depression (questionnaire \[% of patients\])
Epidemiological features 8	Through study completion, an average of 1 year.	Individual income (questionnaire \[dollars\]).
Clinical and psychiatric features 4	Through study completion, an average of 1 year.	Suicide attempts (questionnaire \[% of pacients\])
Clinical and psychiatric features 11	Through study completion, an average of 1 year.	Family history of other mental disorders (questionnaire \[% of patients\]).
Epidemiological features 5	Through study completion, an average of 1 year.	Religion (questionnaire \[% of patients\] protestant, pentecostal or neopentecostal, spiritism, afro-brazilian, no religion or atheism and others\]).
Clinical and psychiatric features 7	Through study completion, an average of 1 year.	Psychiatric hospitalizations (questionnaire \[% of pacients\])
Clinical and psychiatric features 10	Through study completion, an average of 1 year.	Family history of bipolar disorders (questionnaire \[% of patients)
Epidemiological features 1	Through study completion, an average of 1 year.	Age (questionnaire \[years\]).
Epidemiological features 2	Through study completion, an average of 1 year.	Gender (questionnaire \[% of patients\]; male/female)
Epidemiological features 3	Through study completion, an average of 1 year.	Marital status (questionnaire \[% of patients\] single, married, separated, divorced or widower).
Epidemiological features 4	Through study completion, an average of 1 year.	Ethnicity (questionnaire \[% of patients\])
Epidemiological features 6	Through study completion, an average of 1 year.	Occupation (questionnaire \[% of patients\])
Epidemiological features 9	Through study completion, an average of 1 year.	Family income (questionnaire \[dollars\]).
Epidemiological features 7	Through study completion, an average of 1 year.	Education (questionnaire \[years\])

Trial Locations

Locations (1)

Núcleo de Pesquisas em Saúde Mental; 🇧🇷 Blumenau, Santa Catarina, Brazil