Ketamine for Relapse Prevention in Recurrent Depressive Disorder (KINDRED)

Ketamine for Relapse Prevention in Recurrent Depressive Disorder: a Randomised, Controlled, Pilot Trial: the KINDRED Trial

Randomised, controlled, parallel-group, pilot clinical trial of ketamine vs. midazolam for depression relapse prevention in persons at high risk. The main purpose of the pilot study is to assess trial processes to help inform a future definitive trial.

Study Overview

• Status: Terminated
• Conditions: Depression; Major Depressive Disorder; Relapse; Recurrent Depressive Disorder
• Intervention / Treatment: Drug: Ketamine; Drug: Midazolam

Detailed Description

Participants will be recruited at admission to St Patrick's University Hospital for treatment of the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV)-diagnosed recurrent unipolar depression and followed-up weekly to assess recovery according to standard criteria. Blood samples for epigenetic studies will be taken at baseline. Treatment-as-usual will continue throughout the entire trial. Participants who meet standardised response criteria will then be invited to be randomised to course of four two-weekly ketamine or midazolam (active comparator) infusions. Block randomisation will be independently performed. Physical, psychotomimetic and cognitive outcomes will be monitored before, during and after infusions. Blood samples will be taken at four time-points in the first infusion session and before the final infusion for neuroplasticity biomarker studies.Trial Interventions: participants will receive four two-weekly infusions of either ketamine at 0.05mg/kg or midazolam at 0.045mg/kg. All infusions will be administered by a consultant anaesthetist. Repeated infusions of ketamine have been shown to be safe and well-tolerated by patients with mental illness. Minor haemodynamic changes and psychotomimetic side-effects can occur and will be assessed regularly during infusions and for 200 minutes afterwards.

Participants will be followed up over six months to assess for relapse according to standardised criteria. This is the highest-risk period for relapse and investigators hypothesize that ketamine will provide additional neurotrophic support (assessed by the laboratory biomarker project) which will result in lower relapse rates when compared to midazolam.

• Study Type: Interventional
• Enrollment (Actual): 9
• Phase: Phase 1

Contacts and Locations

Study Locations

• Ireland
  • Dublin, Ireland, 8
    • St Patrick's University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• ≥18 years old
• Hamilton Rating Scale for Depression, 24-item (HRSD-24) score of ≥21
• Voluntary admission for treatment of acute depressive episode
• Meet DSM-IV criteria for recurrent depressive disorder (RDD): ≥2 previous depressive episodes with at least 2-months(consecutive) subthreshold or no symptoms in between PLUS(to enrich the sample for those at high risk for relapse) must also have experienced ≥3 major depressive episodes(including index episode) within the previous 2 years

For the randomised pilot trial, RDD patients must have:

• received antidepressant treatment for the acute depressive episode(pharmacological, psychotherapeutic or multidisciplinary)
• ≥60% decrease from baseline HRSD-24 score and score ≤16
• Standardised Mini-Mental State Examination (sMMSE) score of ≥24
• able to provide informed consent

Exclusion Criteria:

• Current involuntary admission
• Medical condition rendering unfit for ketamine/midazolam
• Active suicidal intention
• Dementia
• History of Axis 1 diagnosis other than RDD
• Electroconvulsive therapy (ECT) for treatment of current depressive episode
• Alcohol/substance abuse in previous six months
• Pregnancy or inability to confirm use of adequate contraception during the trial

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Ketamine; Trial Interventions: participants will receive four two-weekly infusions of ketamine at 0.05mg/kg. All infusions will be administered by a consultant anaesthetist.	Drug: Ketamine; A sub-anaesthetic dose of ketamine will be administered in four infusions, each two weeks apart.; Other Names: Ketalar
Active Comparator: Midazolam; Trial Interventions: participants will receive four two-weekly infusions of midazolam at 0.045mg/kg. All infusions will be administered by a consultant anaesthetist.	Drug: Midazolam; A sub-anaesthetic dose of midazolam will be administered in four infusions, each two weeks apart.; Other Names: Hypnovel

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Completion Rate for Randomised Treatment Phase	The outcomes for this pilot trial are process outcomes, primarily rates of recruitment and retention. Thus, the completion rate for the randomised treatment phase is the primary outcome. The study is not designed to assess efficacy.	2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Depression Relapse Rate During Treatment and Follow-up Phase	Clinical outcomes are secondary in this pilot trial. The 24-item Hamilton Rating Scale for Depression (HRSD-24) was used to assess for the main clinical outcome, the relapse rate over six months. Criteria for relapse are ≥10 point increase in HRSD-24 compared to baseline score plus HRSD ≥16; in addition, increase in the HRSD should be maintained one week later (if indicated, additional follow-ups will be arranged). Hospital admission, and deliberate self-harm/suicide also constitute relapse. Relapse may also occur during the eight-week treatment phase and is captured here.	8 months

Collaborators and Investigators

• Sponsor: St Patrick's Hospital, Ireland
• Investigators: Principal Investigator: Declan McLoughlin, University of Dublin, Trinity College

Study record dates

Study Major Dates

• Study Start: December 1, 2015
• Primary Completion (Actual): May 23, 2018
• Study Completion (Actual): May 23, 2018

Study Registration Dates

• First Submitted: December 10, 2015
• First Submitted That Met QC Criteria: January 18, 2016
• First Posted (Estimate): January 22, 2016

Study Record Updates

• Last Update Posted (Actual): January 13, 2020
• Last Update Submitted That Met QC Criteria: January 7, 2020
• Last Verified: January 1, 2020

More Information

Terms related to this study

• Keywords: relapse prevention; ketamine; glutamate
• Additional Relevant MeSH Terms: Behavioral Symptoms; Mental Disorders; Pathologic Processes; Mood Disorders; Disease Attributes; Depression; Depressive Disorder; Disease; Recurrence; Depressive Disorder, Major; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Anesthetics, Dissociative; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Excitatory Amino Acid Antagonists; Excitatory Amino Acid Agents; Tranquilizing Agents; Psychotropic Drugs; Hypnotics and Sedatives; Adjuvants, Anesthesia; Anti-Anxiety Agents; GABA Modulators; GABA Agents; Ketamine; Midazolam
• Other Study ID Numbers: 20/15; 2015-002020-37 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: None envisaged: data will be anonymised