Clinical Predictors of Intravenous Ketamine Response in Treatment-Resistant Depression
Study Details
Study Description
Brief Summary
For patients with treatment-resistant depression (TRD), a single low dose of intravenous (IV) ketamine can help relieve symptoms as quickly as 24 hours later.
The main problem with IV ketamine for TRD is that the effect is short-lived, lasting only days to 1 or 2 weeks. Furthermore, IV ketamine is a resource-intensive treatment, and the safety of long-term, repeated use for depression is unknown. To provide this treatment in a safe and cost-effective way, Investigators must allocate it efficiently to those patients who have the greatest need and probability of benefit. Therefore, this project aims to find clinical features (signs, symptoms, and parts of a patient's history) that will help predict which patients are most likely to respond to a single dose of IV ketamine for TRD. This will help guide patient selection and triaging.
Investigators will recruit 40 participants with TRD over one year, and randomize them to one of two conditions (ketamine followed by an active placebo 3-weeks later, or vice versa). With clinical data collected through detailed interviews and questionnaires, this study design will let us evaluate how well such factors predict (A) rapid response at 24-hours, and (B) sustained response at 7 and 14 days.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
| Phase 3 |
Detailed Description
Study Design:
This will be a randomized, double-blinded, midazolam-controlled crossover trial. There is no perfect control agent for studies of subanaesthetic IV ketamine, but midazolam is generally thought to be superior to normal saline since it is not an antidepressant, yet is psychoactive and thus should better preserve blinding. Participants will undergo psychiatric assessment to establish diagnosis and determine suitability. After providing informed consent for participation, the day before infusion (Day -1), participants will complete a set of rating scales. The following day (Day 0), the participants will receive either a single infusion of IV ketamine (KET) (KET; 0.5mg/kg over 40 minutes) or midazolam (MID) (MID; 30μg/kg over 40 minutes). Investigators will randomize infusion sequences in a 1-to-1 ratio: KET followed by MID (K→M) or vice versa (M→K). Infusions will be administered on Day 0 and Day 21, separated by a 20-day washout period. This duration balances the need to establish comparable baselines at each crossover phase and the ethical consideration of not allowing depressive symptoms to remain untreated for an unreasonable amount of time. Investigators will obtain objective depression ratings with the Montgomery-Åsberg Depression Rating Scale (MADRS) on Days -1, 1, 7, 14, 20, 22, 28, 35, and 41. Participants will provide daily self-ratings of depressive symptoms (using the Quick Inventory of Depressive Symptoms 16-item self-rated version; QIDS 16-SR). Daily symptom monitoring will continue for 20 days following the second infusion.
Study Groups:
Participants will receive either (A) 0.5mg/kg of ketamine hydrochloride or (B) 30μg/kg of MID diluted in 0.9 percent Sodium chloride (NaCl) over 40 minutes by an intravenous pump. The KET and MID doses are similar to those used in previous studies, and selected to minimize the possibility of unblinding. Participants must abstain from consuming grapefruit juice or benzodiazepines for 24 hours preceding the infusion since the former is a potent CYP3A4 inhibitor that may reduce the rate of midazolam and ketamine elimination, and the latter reduces the response to ketamine.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Ketamine Participants will be randomly assigned to receive Ketamine or Midazolam |
Drug: Ketamine
IV Ketamine infusion 0.5mg/kg over 40 minutes
Other Names:
|
| Active Comparator: Midazolam Participants will receive either Ketamine or Midazolam based on what they initially received |
Drug: Midazolam
IV Midazolam infusion 30μg/kg over 40 minutes
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Change in Montgomery Åsberg Depression Rating Scale Score [24 hours, 7 days, 14 days]
Montgomery Åsberg Depression Rating Scale (MADRS) measures depressive symptoms. The scores for each item ranges from 0 to 6 and total scores range from 0 to 60, with higher scores indicating more severe depression. Researchers will investigate the degree to which each clinical feature predicts the 24h, 7 day, and 14 day post-infusion MADRS using a biomarker prediction model.
Secondary Outcome Measures
- Daily self-ratings of Generalized Anxiety Disorder 7 Scale [24 hours, 7 days, 14 days]
Generalized Anxiety Disorder 7 Scale (GAD-7) measures symptoms of anxiety. The scores for each item ranges from 0 to 3, and total scores range from 0 to 21 with higher scores indicating more severe anxiety. Researchers will investigate the degree to which clinical features predict change in participants' GAD-7 score.
Other Outcome Measures
- Migraine Severity Questionnaire [7 days]
The scores for some items range from 0 to 4 and others from 0 to 3, and total scores range from 4 to 15, with higher scores indicating more severe migraine. As an exploratory outcome, researchers will investigate the degree to which ketamine infusions affect migraine symptoms, and whether changes in migraine severity are associated with depressive symptom improvements.
Eligibility Criteria
Criteria
Inclusion Criteria:
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Able to fluently read in English with or without optical correction
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Native English speaker (to ensure appropriateness for neurocognitive paradigms)
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Ability to understand and comply with the study requirements
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This is determined by the investigators
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Provision of written informed consent
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Documented diagnosis of MDD meeting DSM-5 criteria (as confirmed by the Diagnostic Assessment Research Tool), currently in a single or recurrent episode without psychotic features
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Failure of at least two antidepressant medications from different pharmacological classes, as well as at least one augmentation agent, each of which must have been given at adequate doses for at least 6 weeks during the present episode (recorded using the Antidepressant Treatment History Form - Short Form).
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Augmentation strategies include those listed in the 2016 Canadian Network for Mood and Anxiety Treatments (CANMAT) depression guidelines, including a 12-week course of cognitive behavioural therapy or interpersonal therapy.
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MADRS score of ≥25 at initial assessment and randomization, and no more than 20% improvement between those visits.
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For premenopausal females who are currently sexually active with male partners:
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Negative urine pregnancy test at enrolment
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AND commitment to using an appropriate birth control method of their choice throughout the duration of the study, including
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intrauterine device
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oral contraceptive
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long-term injectable contraceptive
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double-barrier method
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implant
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dermal contraception
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tubal ligation
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Abstinence from grapefruit juice consumption on the day of infusion
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Abstinence from benzodiazepine use within 24 hours of infusion
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Adherence to maintaining current antidepressant management
Exclusion Criteria:
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Substance related exclusion criteria:
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Concomitant use of naltrexone or narcotics
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Positive urine drug screen or history of DSM-5 substance use disorder (except caffeine or nicotine)
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Psychiatric exclusion criteria:
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Previous ketamine use (therapeutic or recreational)
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Concurrent use of naltrexone
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History of electroconvulsive therapy
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Comorbid DSM-5 personality disorder with a major impact on mental status
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Secondary depressive disorders
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E.g. secondary to stroke, cancer, or other somatic pathology
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Subjects who will be starting psychotherapy during the trial period, or have only recently started psychotherapy within 2 months of the trial
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Medical comorbidity related exclusion criteria:
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Evidence on history or chart review of any of the following:
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Epilepsy
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Renal or hepatic impairment
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Myocardial infarct within a year prior to initial randomization
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Cerebrovascular disease,
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Viral hepatitis B or C
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Acquired immunodeficiency syndrome.
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Abnormal liver function tests.
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Liver enzymes three times the upper normal limit at screening
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Current uncorrected thyroid pathology or recent correction within 30 days (correction of thyroid function for longer than 1 month is admissible).
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Any unstable somatic pathology or clinically significant investigational abnormality (biochemical, ECG) that investigators believe would be negatively impacted by study procedures or that would negatively impact study procedures
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Mood Disorders Program | Halifax | Nova Scotia | Canada | B3H2E2 |
Sponsors and Collaborators
- Abraham Nunes
- Nova Scotia Health Authority
Investigators
- Principal Investigator: Abraham Nunes MD PhD MBA FRCPC, Nova Scotia Health Authority
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- DALKETCLIN