Clinical trial NCT04701866: Music as an Intervention to Improve Hemodynamic Tolerability of Ketamine in Depression
Official title: Music as a Potential Intervention to Improve Hemodynamic Tolerability of Repetitive Sub-Anesthetic IV Ketamine Infusions in Bipolar and Unipolar Depression: A Pilot Study
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Depressive Disorder, Treatment-Resistant
Depressive Disorder, Major
Unipolar Depression
Depression, Bipolar
Keywords: Treatment-Resistant Depression
Ketamine
Music
Hemodynamic Changes
Lead sponsor: Douglas Mental Health University Institute
Sponsor class: OTHER
Collaborators: name: Réseau québécois sur le suicide, les troubles de l'humeur et les troubles associés
First posted: 2021-01-08
Enrollment: 32
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to assess the impact of music on patients receiving a course of intravenous (IV) ketamine for treatment-resistant depression (TRD), both unipolar and bipolar. The primary outcome is changes in in systolic blood pressure throughout each 40-minute infusion. Secondary outcomes include repeated measures of mood, anxiety, suicidality, and psychological/physical pain. Aspects of the treatment experience, with and without music, will also be explored.

Detailed description: Depression is the first cause of disability worldwide, and approximately 1 in 3 patients will fail to respond to current treatments. Intravenous (IV) low-dose ketamine has remarkable efficacy in even the most treatment-resistant depression (here defined as failure to at least two adequate trials of Level 1-evidence psychiatric medications), inducing remission in 25-50%.

Over 100 randomized clinical trials (RCTs) show that music can mitigate hemodynamic and psychological stress caused by even highly invasive medical procedures. Though never studied, music may similarly improve ketamine tolerability.

In this randomized, single-blind (assessors will not know whether participants receive music or not) single-center trial, 20 participants with TRD will receive 1) curated music or 2) no music during their course of 6 IV ketamine treatments (0.50mg/kg bodyweight) over 4 weeks. The primary aim is to compare changes in systolic blood pressure from the beginning to the end (40 minutes, peak plasma concentration) of each infusion between groups.

Eligibility criteria: Inclusion Criteria:

* Bipolar and unipolar depressive episode, current episode of depression (DSM-V) despite at least two adequate trials of Level 1-evidence psychiatric medications.
* No active substance use disorder (beyond nicotine use disorder);
* No contraindication of ketamine;
* Not of childbearing potential, defined as: Postmenopausal (defined as no menses for 12 months without an alternative medical cause). A high follicle stimulating hormone (FSH) level (\>40 IU/L or mIU/mL in the postmenopausal range) will be used to confirm a postmenopausal state in women not using hormonal contraception or hormonal replacement therapy, however in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient;
* Permanently sterile: permanent sterilization methods include hysterectomy, bilateral salpingectomy, bilateral tubal occlusion/ligation procedures, and bilateral oophorectomy.
* Female subjects of childbearing potential must have a negative urine pregnancy test at the beginning and be willing to use a highly effective method of contraception during the treatment and after the last ketamine infusion.
* Female subjects of childbearing potential must practice a highly effective method of contraception (failure rate of \<1percent per year when used consistently and correctly) beginning at least two weeks before and continued while receiving ketamine infusions;
* Male subjects who are sexually active with a woman of childbearing potential must agree to use a double-barrier method of contraception (eg, diaphragm or cervical/vault caps plus condom with spermicidal foam/gel/film/cream/suppository).
* Male subjects who are sexually active with a woman who is pregnant must agree to use a condom. Male subjects must also agree to not donate sperm during the treatment and for a minimum of 1 spermatogenesis cycle (defined as approximately 90 days) after receiving the last dose of ketamine;
* Abstention from consuming grapefruit juice (a potent 3A4 cytochrome inhibitor) on the day of the ketamine infusions as it may alter the metabolism of ketamine;
* Provision of written informed consent after reading the participant information handout;

Exclusion Criteria:

* Baseline blood pressure within normal limits, i.e. below 140/90 mmHg, when measured thrice in a quiet room.
* Significant hearing impairment not improved with hearing aids and/or sound amplification or unwillingness to listen to music during treatment;
* The subject's depressive symptoms have previously demonstrated non-response to esketamine or ketamine in the current major depressive episode;
* Known intellectual deficiency or autism spectrum disorder;
* Unable to accommodate regular visits to the Depressive Disorders Program at the Douglas Mental Health University Institute, Montreal, QC;
* Depression evaluated as secondary to stroke, cancer or other severe medical illnesses;
* Known risk factors for intracranial hemorrhage, including previous significant trauma, known aneurysm, or previous neurosurgery;
* Evidence of clinically relevant disease, e.g., renal or hepatic impairment, significant coronary artery disease (myocardial infarct within a year prior to initial randomization), cerebrovascular disease, viral hepatitis B or C, acquired immunodeficiency syndrome;
* Prior or current substance abuse or dependence (except for caffeine or nicotine dependence) and/or recent history (last 12 months) of alcohol or cannabis abuse or dependence, as defined by DSM-5 criteria. (Cannabis will be considered similarly to alcohol for the purpose of this study, as it is clinically, in the context of its legalization in Canada. That is, recreational use that does not meet criteria for a substance use disorder and/or is not deemed to be negatively impacting participants' physical and mental health will not justify exclusion from the study just as it does not justify exclusion from purely clinical treatment by ketamine.)
* A positive toxicology screen for drugs that are not prescribed;
* Unwilling, or unable to receive treating physician's agreement, or unable to hold benzodiazepines from the evening prior to the infusion of ketamine;
* Unwilling, or unable to receive treating physician's agreement, to discontinue any narcotic beginning a minimum of 5 drug half-lives prior to infusion;
* Unwilling, or unable to receive treating physician's agreement, to discontinue memantine (an NMDA antagonist) during infusions, beginning a minimum of 5 drug half-lives prior to infusions;
* Pregnant, lactating, or of childbearing potential and not willing to use an approved method of contraception during the ketamine infusion, as per above;
* A clinical finding that is unstable or that, in the opinion of the treating clinician(s), would be negatively affected by, or would affect, the medication (e.g., diabetes mellitus, unstable angina);
* Liver function tests AST and ALT three times the upper normal limit at screening.
* Uncorrected hypothyroidism or hyperthyroidism: Subjects needing a thyroid hormone supplement to treat hypothyroidism must have been on a stable dose of the medication for 3 months prior to beginning infusions;
* Clinically significant deviation from the reference range in clinical laboratory test results as judged by the clinician(s);
* ECG results considered significantly abnormal as determined by the clinician(s);
* History of seizure disorder, except febrile convulsions;
* Known history of intolerance or hypersensitivity to ketamine;
* Acute psychotic symptoms, as judged by the initial clinical interview or reported by referring clinicians;
* Any significant, recent, acute decline in exercise tolerance.

Primary outcomes:
measure: Changes in Systolic Blood Pressure
timeFrame: From 0 to 40 minutes of each infusion.
Secondary outcomes:
measure: Change From Baseline in MADRS Total Score to Last Treatment
timeFrame: Baseline, Day 23
measure: Change From Baseline in MADRS Total Score to Follow-up
timeFrame: Baseline, 1-month follow-up (8 weeks)
measure: Change From Baseline in Beck Depression Inventory (BDI-II) Total Score to Last Treatment
timeFrame: Baseline, Day 23
measure: Change From Baseline in Beck Depression Inventory (BDI-II) Total Score to Follow-up
timeFrame: Baseline, 1-month follow-up (8 weeks)
measure: Change From Baseline in Clinician-Rated Global Impression Improvement Score to Last Treatment
timeFrame: Baseline, Day 23
measure: Change From Baseline in Clinician-Rated Global Impression Severity Score to Last Treatment
timeFrame: Baseline, Day 23
measure: Change From Baseline in Clinician-Rated Global Impression Suicidality Severity Score to Last Treatment
timeFrame: Baseline, Day 23
measure: Change From Baseline in Clinician-Rated Global Impression Suicidality Improvement Score to Last Treatment
timeFrame: Baseline, Day 23
measure: Change From Baseline in Clinician-Rated Global Impression Improvement Score to Follow-up
timeFrame: Baseline, 1-month follow-up (8 weeks)
measure: Change From Baseline in Clinician-Rated Global Impression Severity Score to Follow-up
timeFrame: Baseline, 1-month follow-up (8 weeks)
measure: Change From Baseline in Clinician-Rated Global Impression Suicidality Severity Score to Follow-up
timeFrame: Baseline, 1-month follow-up (8 weeks)
measure: Change From Baseline in Clinician-Rated Global Impression Suicidality Improvement Score to Follow-up
timeFrame: Baseline, 1-month follow-up (8 weeks)
measure: Change From Baseline in PSQI Total and Subscores to Last Treatment
timeFrame: Baseline, Day 23
measure: Change From Baseline in PSQI Total and Subscores to Follow-up
timeFrame: Baseline, 1-month follow-up (8 weeks)
measure: Change From Baseline in Beck Scale for Suicide Ideation (SSI) Total to Last Treatment
timeFrame: Baseline, Day 23
measure: Change From Baseline in Beck Scale for Suicide Ideation (SSI) Total to Follow-up
timeFrame: Baseline, 1-month follow-up (8 weeks)
measure: Change From Baseline in Psychological and Physical Pain to Last Treatment
timeFrame: Baseline, Day 23
measure: Change From Baseline in Psychological and Physical Pain to Follow-up
timeFrame: Baseline, 1-month follow-up (8 weeks)
measure: Change From Baseline in STAI-Y A to Last Treatment
timeFrame: Baseline, Day 23
measure: Change From Baseline in STAI-Y A to Follow-up
timeFrame: Baseline, 1-month follow-up (8 weeks)
measure: Change From Baseline in STAI-Y B to Last Treatment
timeFrame: Baseline, 1-month follow-up (8 weeks)
measure: Change From Baseline in STAI-Y B to Follow-up
timeFrame: Baseline, 1-month follow-up (8 weeks)
measure: The Mystical Experience Questionnaire (MEQ) after each treatment
timeFrame: Immediately after the interventions
measure: The Psychedelic Music Questionnaire Short-Form (PMQ-SF) after each treatment
timeFrame: Immediately after the interventions
measure: Inflammatory markers before and after the first and last treatment
timeFrame: Treatment 1 and 6 (day 23)
Other outcomes:
Locations:
city: Montreal
country: Canada
facility: Jewish General Hospital
state: Quebec
city: Montreal
country: Canada
facility: Douglas Mental Health University Institute
state: Quebec
Study officials:
affiliation: Douglas Mental Health University Insitute
name: Stéphane Richard-Devantoy, MD, PhD
role: PRINCIPAL_INVESTIGATOR
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