Depression, Major Depressive Disorder, Recurrent Depressive Disorder, Relapse
Conditions
Keywords
ketamine, glutamate, relapse prevention
Brief summary
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.
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.
Interventions
DRUGKetamine
A sub-anaesthetic dose of ketamine will be administered in four infusions, each two weeks apart.
DRUGMidazolam
A sub-anaesthetic dose of midazolam will be administered in four infusions, each two weeks apart.
Sponsors
St Patrick's Hospital, Ireland
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
OTHER
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Masking took place by sealed envelope random allocation and double blinding of participants and raters was assessed throughout. The anaesthesiologist administering infusions was aware of the allocation.
Intervention model description
A randomised, double-blind, placebo-controlled study designed to assess feasibility of recruitment, randomisation and retention.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Completion Rate for Randomised Treatment Phase | 2 years | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Depression Relapse Rate During Treatment and Follow-up Phase | 8 months | 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. |
Countries
Ireland
Participant flow
Recruitment details
Participants were inpatients at St Patrick's Mental Health Services admitted for treatment of an acute depressive episode with a previous history of depression
Pre-assignment details
Participants were randomised from n=28 participants in an observational phase, all of whom were receiving inpatient treatment for recurrent depressive disorder. Participants were monitored weekly for response to treatment and those who responded were invited to be randomised.
Participants by arm
| Arm | Count |
|---|---|
| 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.
Ketamine: A sub-anaesthetic dose of ketamine will be administered in four infusions, each two weeks apart. | 5 |
| 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.
Midazolam: A sub-anaesthetic dose of midazolam will be administered in four infusions, each two weeks apart. | 4 |
| Total | 9 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lack of Efficacy | 1 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 1 |
Baseline characteristics
| Characteristic | Midazolam | Total | Ketamine |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 1 Participants | 1 Participants |
| Age, Categorical Between 18 and 65 years | 4 Participants | 8 Participants | 4 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 4 Participants | 9 Participants | 5 Participants |
| Region of Enrollment Ireland | 4 participants | 9 participants | 5 participants |
| Sex: Female, Male Female | 3 Participants | 5 Participants | 2 Participants |
| Sex: Female, Male Male | 1 Participants | 4 Participants | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 5 | 0 / 4 |
| other Total, other adverse events | 1 / 5 | 1 / 4 |
| serious Total, serious adverse events | 0 / 5 | 0 / 4 |
Outcome results
Primary
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.
Time frame: 2 years
Population: All randomised participants who received one infusion were analysed (intention to treat)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ketamine | Completion Rate for Randomised Treatment Phase | 3 Participants |
| Midazolam | Completion Rate for Randomised Treatment Phase | 2 Participants |
Secondary
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.
Time frame: 8 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ketamine | Depression Relapse Rate During Treatment and Follow-up Phase | 2 Participants |
| Midazolam | Depression Relapse Rate During Treatment and Follow-up Phase | 3 Participants |