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

Study Overview
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Brief Summary
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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
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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)

Official Title
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Intramuscular Ketamine Versus Escitalopram and Aripiprazole in Acute and Maintenance Treatment of Patients With Treatment-resistant Depression

Conditions
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Depressive Disorder

Intervention / Treatment
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* 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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of TRD, according to clinical evaluation and confirmed by SCID-IV (Structured Clinical Interview for the DSM); Moderate to severe intensity of the disease; 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, Literate and able to understand the tasks requested; With clinical comorbidities, however compensated; Patients and/or legal representatives should understand the nature of the study and sign the Informed Consent Form. Exclusion Criteria: Imminent risk of suicide; Patients with psychoactive substance dependence; Intellectual deficit and psychotic symptoms; Bipolar spectrum disorders and other primary psychiatric diagnoses; Allergic to ketamine; Glaucoma; Treatment with reversible MAOI (monoamine oxidase inhibitor) in the week prior to visit 0; Treatment with irreversible MAOI in two weeks prior to visit 0; Fluoxetine treatment within 4 weeks prior to visit 0; Treatment with others antidepressants; Treatment with antipsychotics, lithium, benzodiazepines or other psychotropic drugs within 7 days prior to visit 0; a. Lorazepam and zolpidem may be used; Patients who become pregnant will be excluded from the study and referred for obstetric care.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 40 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: 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.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Rapid-acting antidepressant<br>Subjects eligible to participate in the study will receive IM ketamine and will use 2 placebo tablets as randomized. | Drug: Ketamine<br>* (0,75 mg/kg) saline solution (15 mg) Escitalopram (5 mg) Aripiprazole<br>* Other names: Placebo;Diagnostic Test: Cognition<br>* Composite tools<br>Other: Suicide risk<br>* MADRS (10) and HAM-D (3)<br>Other: Depression thoughts<br>* EPD<br>Other: Quality of life and disability<br>* Quality of life and disability<br>Other: Clinical and epidemiological factors<br>* Variables and categories<br>Device: Safety of ketamine IM<br>* Vital signs<br>Other: Tolerability of ketamine IM<br>* UKU-SERS, YOUNG, CADSS and BPRS-12.<br>|
| Active Comparator: Comparator<br>Subjects eligible to participate in the study will receive IM saline and will use escitalopram 15 mg and aripiprazole 5 mg as randomized | Drug: Ketamine<br>* (0,75 mg/kg) saline solution (15 mg) Escitalopram (5 mg) Aripiprazole<br>* Other names: Placebo;Diagnostic Test: Cognition<br>* Composite tools<br>Other: Suicide risk<br>* MADRS (10) and HAM-D (3)<br>Other: Depression thoughts<br>* EPD<br>Other: Quality of life and disability<br>* Quality of life and disability<br>Other: Clinical and epidemiological factors<br>* Variables and categories<br>Device: Safety of ketamine IM<br>* Vital signs<br>Other: Tolerability of ketamine IM<br>* UKU-SERS, YOUNG, CADSS and BPRS-12.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in depressive symptoms | 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 | 3 times a week in once month (Phase II) | 
| Change in depressive symptoms | 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) | Once a week in six months (Phase III) | 
| Change in depressive symptoms | 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). | Once a week in once month (Phase IV) | 

Secondary Outcome Measures

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

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Ketamine, Treatment Resistant Depression