Depressive DisorderPhase 4NCT02579642
Effects of Low-dose Ketamine as an Adjunct to Propofol-based Anesthesia for Electroconvulsive Therapy
A Phase 4 study testing Ketamine in people with Depressive Disorder, run by University of Alberta at 2 sites in Canada.
Trial summary
Ketamine has been used successfully as the sole medication for anesthesia in the setting of electroconvulsive therapy (ECT), and has more recently been studied as an adjunct agent in combination with propofol (the most commonly used anesthetic agent) to induce anesthesia for ECT. Read more about this study
- Who is it for?
- Ages 18 to 70 years
- Conditions the study is for
- Depressive Disorder
- What is being tested?
- Ketamine
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 48 participants
- Where
- 2 sitesCanada
- Study dates
- Oct 2015to May 2019
- Phase
- Phase 4
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 70 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- referred for ECT with a Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) diagnosis of major depressive disorder
- considered American Society of Anesthesiologists (ASA) Physical Class I - III
- baseline MADRS score greater than 24 (i.e. at least moderate to severe depression)
- a "first" or "new" episode of depression which has lasted not more than 3 months and requires ECT treatment as judged by a psychiatrist
Who cannot join
- ASA Class IV or V as judged by the anesthesiologist
- Any ECT treatment in the previous three months
- Inability or refusal to provide informed consent
- A history of allergic reactions, hypersensitivity, or intolerance to anesthetics or their constituents used in the study (ketamine, propofol, egg phosphatide, soybean oil)
- Anyone taking medications considered contraindicated for ECT or for general anesthesia
- Presence of any of the following DSM-IV diagnoses: Substance or alcohol dependence at enrolment (except dependence in full remission, and except for caffeine or nicotine dependence), abuse of opiates, amphetamines, barbiturates, cocaine, cannabis, or hallucinogen abuse in the 4 weeks prior to enrolment, pervasive developmental disorder, dementia
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- Significant medical condition that would contraindicate the use of ketamine, propofol or that is untreated and would need urgent attention (as determined by treating physician)
- Medical conditions that would significantly affect absorption, distribution, metabolism, or excretion of ketamine or propofol
- Unstable or inadequately treated medical illness (e.g. congestive heart failure, angina pectoris, hypertension) as judged by the investigator
- Patients with increased risk of laryngospasm (such as active pulmonary infection, upper respiratory infection, asthma), increased intracranial pressure, glaucoma, thyroid disease/hyperthyroidism
- Any clinically significant deviation from the reference range in clinical laboratory test results as judged by the investigator
- Pregnancy (or female of child-bearing age not using adequate contraception) or lactation
- Participation in another drug trial within 4 weeks prior enrolment into this study or longer in accordance with local requirements
Trial locations and contacts
2 sites in 1 country.
Canada2 sites
Alberta Hospital Edmonton
Edmonton, Alberta, T5J 2J7
University of Alberta Hospital
Edmonton, Alberta, T6G 2B7
About this study
Ketamine has been used successfully as the sole medication for anesthesia in the setting of electroconvulsive therapy (ECT), and has more recently been studied as an adjunct agent in combination with propofol (the most commonly used anesthetic agent) to induce anesthesia for ECT. New literature postulates an anti-depressant effect of ketamine, which in ECT specifically may be helpful with regards to the overall goals of therapy (i.e. ECT indicated for severe or treatment-resistant depression).
Current research focusing on ketamine with respect to its anti-depressant effect suggests it may even represent an alternative to ECT. This study will seek to determine whether ketamine when used in low-doses as an adjunct to propofol-based anesthesia for ECT has anti-depressant effects and whether it influences the characteristics of recovery from anesthesia in the ECT setting (i.e. vital sign parameters such as blood pressure and heart rate, quality of recovery, etc.).
Read the detailed description
This is a proof-of-concept study to elucidate whether the use of low-dose ketamine as an adjunct to propofol-based anesthesia for electroconvulsive therapy has beneficial anti-depressant effects in a population of adults with major depressive disorder presenting for ECT.
Since thiopental is no longer widely available in North America as an induction agent for anesthesia, other agents have supplanted it for various uses, including for induction of anesthesia for electroconvulsive therapy (ECT). Induction is most commonly achieved using propofol in doses of 0.75 - 1 mg/kg IV bolus.
Propofol as an induction agent for ECT may not be the ideal agent in this setting as its anticonvulsant effects may result in less-than-ideal seizure quality and duration. Ketamine has been studied in the ECT setting but at full induction doses has well-known psychotomimetic and dissociative effects. However, the anti-depressant effects of ketamine, even at low-doses, may have a beneficial effect on depressive symptoms after ECT as compared with propofol alone.
Ketamine also has been used successfully as the sole induction agent for anesthesia in this setting, and has more recently been studied as an adjunct or co-induction agent in combination with propofol. Drawbacks of using ketamine as the sole induction agent are related to its hemodynamic and psychotomimetic effects (e.g. post-treatment hypertension and hallucinogenic activity).
New literature postulates a putative anti-depressant effect of ketamine via the N-Methyl-D-aspartate (NMDA) receptor, which in the ECT setting specifically may be helpful with regards to the overall goals of therapy (i.e. ECT indicated for severe or treatment-resistant depression). Current research focusing on the efficacy of ketamine with respect to anti-depressant effects suggests that ketamine may even represent an alternative to ECT.
As per the investigators' standard practice for ECT, treatment for each patient would be 3 times per week up to a total of 12 treatments (i.e. 4 weeks of treatment). The total study duration for each patient will be not more than 6 weeks. As discussed below, patients will be withdrawn from the study at anytime upon their own request or when the treating psychiatrist feels the clinical improvement is strong enough to justify doing so.
An interim analysis will be completed after the first 14 patients have completed treatment. If after these first 14 patients the investigators find a lower than expected difference in efficacy in favor of the ketamine group, able to achieve alpha error >0.2 and power <80%, all subsequently recruited patients will be randomized to receive either propofol at usual induction doses for ECT (0.75 - 1 mg/kg IV bolus) with placebo (normal saline), or with a slightly higher dose of ketamine of 0.5 mg/kg. Should this turn out to be the case, thirty new patients will be recruited from that point.
- Conditions
- Depressive Disorder
- Being tested
- Ketamine, Placebo
- Keywords
- Moderate to severe depression, Monopolar, Bipolar, Ketamine, ECT, Electroconvulsive therapy, NMDA
- Medical subject headings
- Depressive Disorder
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
KetamineDrug
Also called Ketalar
Low dose ketamine 0.2 mg/kg (or 0.5 mg/kg depending on results of interim analysis) administered with usual induction drugs for ECT
PlaceboDrug
Also called Normal saline, 0.9% NS
Normal saline administered with usual induction drugs for ECT
| Study group | Role | What they receive |
|---|---|---|
| Placebo | Placebo comparator | Propofol at usual induction doses for ECT (0.75 - 1 mg/kg IV bolus) with placebo (normal saline) Receives: Drug: Placebo |
| Ketamine | Experimental | Propofol at usual induction doses for ECT (0.75 - 1 mg/kg IV bolus) with the addition of low-dose ketamine 0.2 mg/kg (or 0.5 mg/kg - see interim analysis) Receives: Drug: Ketamine |
What is being measured
The primary outcome is the main question the study is designed to answer.
Number of treatments to achieve 50% change (reduction) in Montgomery Ashberg Depression Rating Scale (MADRS)
Defined a priori as "response". Assessed at baseline, 24 hours after ECT treatments for the duration of the study and then once at 6 weeks.
Measured: 6 weeks
Secondary outcomes (7)
Number of treatments to achieve 25% change (reduction) in MADRS
Defined a priori as "partial response". Assessed at baseline, 24 hours after ECT treatments for the duration of the study and then once at 6 weeks.
Measured: 6 weeks
Change in Clinical Global Impression - Severity (CGI-S) scores
Assessed at baseline, 24 hours after ECT treatments for the duration of the study and then once at 6 weeks.
Measured: 6 weeks
Changes in blood pressure seen during ECT
Measured during ECT treatments and in the post-ECT recovery room.
Measured: 4 weeks
Changes in heart rate seen during ECT
Measured during ECT treatments and in the post-ECT recovery room.
Measured: 4 weeks
Changes in oxygen saturation seen during ECT
Measured during ECT treatments and in the post-ECT recovery room.
Measured: 4 weeks
Changes in respiratory rate seen during ECT
Measured during ECT treatments and in the post-ECT recovery room.
Measured: 4 weeks
Changes in times to discharge from post-ECT recovery
Measured: 4 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted19 Oct 2015 (estimated)
- Study startOct 2015
- Primary completionMay 2019
- Study completionMay 2019
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (5)Papers the sponsor has linked to this study.
- Other trials for Depressive DisorderStudies of the same condition, open and under way.
- More trials run by University of AlbertaThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 48 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Alberta
- Sponsor type
- University, hospital or other
- Collaborators
- Alberta Health services
- Responsible party
- Principal investigator, Ferrante Gragasin, University of Alberta
- Investigators
- Ferrante S Gragasin, MD, PhD, Principal investigator, University of Alberta
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02579642
- Sponsor's protocol ID
- PRO00044771
- Status last verified
- Apr 2021
- First submitted
- 13 Oct 2015
- Last updated
- 28 Apr 2021
- Results posted
- No
- Data monitoring committee
- Yes
Publications
Okamoto N, Nakai T, Sakamoto K, Nagafusa Y, Higuchi T, Nishikawa T. Rapid antidepressant effect of ketamine anesthesia during electroconvulsive therapy of treatment-resistant depression: comparing ketamine and propofol anesthesia. J ECT. 2010 Sep;26(3):223-7. doi: 10.1097/YCT.0b013e3181c3b0aa.
PubMed 19935085Wang X, Chen Y, Zhou X, Liu F, Zhang T, Zhang C. Effects of propofol and ketamine as combined anesthesia for electroconvulsive therapy in patients with depressive disorder. J ECT. 2012 Jun;28(2):128-32. doi: 10.1097/YCT.0b013e31824d1d02.
PubMed 22622291Larkin GL, Beautrais AL. A preliminary naturalistic study of low-dose ketamine for depression and suicide ideation in the emergency department. Int J Neuropsychopharmacol. 2011 Sep;14(8):1127-31. doi: 10.1017/S1461145711000629. Epub 2011 May 5.
PubMed 21557878Murrough JW, Iosifescu DV, Chang LC, Al Jurdi RK, Green CE, Perez AM, Iqbal S, Pillemer S, Foulkes A, Shah A, Charney DS, Mathew SJ. Antidepressant efficacy of ketamine in treatment-resistant major depression: a two-site randomized controlled trial. Am J Psychiatry. 2013 Oct;170(10):1134-42. doi: 10.1176/appi.ajp.2013.13030392.
PubMed 23982301Woolsey AJ, Nanji JA, Moreau C, Sivapalan S, Bourque SL, Ceccherini-Nelli A, Gragasin FS. Low-dose ketamine does not improve the speed of recovery from depression in electroconvulsive therapy: a randomized controlled trial. Braz J Psychiatry. 2022 Jan-Feb;44(1):6-14. doi: 10.1590/1516-4446-2020-1705.
PubMed 34076068
Study at a glance
From the registry record, last updated by the sponsor on 28 Apr 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Effects of Low-dose Ketamine as an Adjunct to Propofol-based Anesthesia for Electroconvulsive Therapy
- ClinicalTrials.gov ID
- NCT02579642
- Acronym / sponsor ID
- PRO00044771
- Conditions
- Depressive Disorder
- Keywords
- Moderate to severe depression, Monopolar, Bipolar, Ketamine, ECT, Electroconvulsive therapy, NMDA
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 48 participants (actual)
- Lead sponsor
- University of AlbertaUniversity, hospital or other
- Collaborators
- Alberta Health services
- Study start
- Oct 2015
- Primary completion
- May 2019 (actual)
- Study completion
- May 2019 (actual)
- First posted
- 19 Oct 2015 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Ketamine has been used successfully as the sole medication for anesthesia in the setting of electroconvulsive therapy (ECT), and has more recently been studied as an adjunct agent in combination with propofol (the most commonly used anesthetic agent) to induce anesthesia for ECT. New literature postulates an anti-depressant effect of ketamine, which in ECT specifically may be helpful with regards to the overall goals of therapy (i.e. ECT indicated for severe or treatment-resistant depression).
Current research focusing on ketamine with respect to its anti-depressant effect suggests it may even represent an alternative to ECT. This study will seek to determine whether ketamine when used in low-doses as an adjunct to propofol-based anesthesia for ECT has anti-depressant effects and whether it influences the characteristics of recovery from anesthesia in the ECT setting (i.e. vital sign parameters such as blood pressure and heart rate, quality of recovery, etc.).
Detailed description
This is a proof-of-concept study to elucidate whether the use of low-dose ketamine as an adjunct to propofol-based anesthesia for electroconvulsive therapy has beneficial anti-depressant effects in a population of adults with major depressive disorder presenting for ECT.
Since thiopental is no longer widely available in North America as an induction agent for anesthesia, other agents have supplanted it for various uses, including for induction of anesthesia for electroconvulsive therapy (ECT). Induction is most commonly achieved using propofol in doses of 0.75 - 1 mg/kg IV bolus.
Propofol as an induction agent for ECT may not be the ideal agent in this setting as its anticonvulsant effects may result in less-than-ideal seizure quality and duration. Ketamine has been studied in the ECT setting but at full induction doses has well-known psychotomimetic and dissociative effects. However, the anti-depressant effects of ketamine, even at low-doses, may have a beneficial effect on depressive symptoms after ECT as compared with propofol alone.
Ketamine also has been used successfully as the sole induction agent for anesthesia in this setting, and has more recently been studied as an adjunct or co-induction agent in combination with propofol. Drawbacks of using ketamine as the sole induction agent are related to its hemodynamic and psychotomimetic effects (e.g. post-treatment hypertension and hallucinogenic activity).
New literature postulates a putative anti-depressant effect of ketamine via the N-Methyl-D-aspartate (NMDA) receptor, which in the ECT setting specifically may be helpful with regards to the overall goals of therapy (i.e. ECT indicated for severe or treatment-resistant depression). Current research focusing on the efficacy of ketamine with respect to anti-depressant effects suggests that ketamine may even represent an alternative to ECT.
As per the investigators' standard practice for ECT, treatment for each patient would be 3 times per week up to a total of 12 treatments (i.e. 4 weeks of treatment). The total study duration for each patient will be not more than 6 weeks. As discussed below, patients will be withdrawn from the study at anytime upon their own request or when the treating psychiatrist feels the clinical improvement is strong enough to justify doing so.
An interim analysis will be completed after the first 14 patients have completed treatment. If after these first 14 patients the investigators find a lower than expected difference in efficacy in favor of the ketamine group, able to achieve alpha error >0.2 and power <80%, all subsequently recruited patients will be randomized to receive either propofol at usual induction doses for ECT (0.75 - 1 mg/kg IV bolus) with placebo (normal saline), or with a slightly higher dose of ketamine of 0.5 mg/kg. Should this turn out to be the case, thirty new patients will be recruited from that point.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Placebo | Placebo comparator | Drug: PlaceboPropofol at usual induction doses for ECT (0.75 - 1 mg/kg IV bolus) with placebo (normal saline) |
| Ketamine | Experimental | Drug: KetaminePropofol at usual induction doses for ECT (0.75 - 1 mg/kg IV bolus) with the addition of low-dose ketamine 0.2 mg/kg (or 0.5 mg/kg - see interim analysis) |
Who may qualify
- Ages
- 18 to 70 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (4 listed)
- referred for ECT with a Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) diagnosis of major depressive disorder
- considered American Society of Anesthesiologists (ASA) Physical Class I - III
- baseline MADRS score greater than 24 (i.e. at least moderate to severe depression)
- a "first" or "new" episode of depression which has lasted not more than 3 months and requires ECT treatment as judged by a psychiatrist
Key exclusion criteria (13 listed)
- ASA Class IV or V as judged by the anesthesiologist
- Any ECT treatment in the previous three months
- Inability or refusal to provide informed consent
- A history of allergic reactions, hypersensitivity, or intolerance to anesthetics or their constituents used in the study (ketamine, propofol, egg phosphatide, soybean oil)
- Anyone taking medications considered contraindicated for ECT or for general anesthesia
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| KetamineAlso: KetalarLow dose ketamine 0.2 mg/kg (or 0.5 mg/kg depending on results of interim analysis) administered with usual induction drugs for ECT | Drug | Ketamine |
| PlaceboAlso: Normal saline, 0.9% NSNormal saline administered with usual induction drugs for ECT | Drug | Placebo |
Primary outcome
Number of treatments to achieve 50% change (reduction) in Montgomery Ashberg Depression Rating Scale (MADRS)
Time frame: 6 weeks
Defined a priori as "response". Assessed at baseline, 24 hours after ECT treatments for the duration of the study and then once at 6 weeks.
7 secondary outcomes
Number of treatments to achieve 25% change (reduction) in MADRS
Time frame: 6 weeks
Change in Clinical Global Impression - Severity (CGI-S) scores
Time frame: 6 weeks
Changes in blood pressure seen during ECT
Time frame: 4 weeks
Changes in heart rate seen during ECT
Time frame: 4 weeks
Changes in oxygen saturation seen during ECT
Time frame: 4 weeks
Changes in respiratory rate seen during ECT
Time frame: 4 weeks
Changes in times to discharge from post-ECT recovery
Time frame: 4 weeks
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 28 Apr 2021.
- Background: PubMed 19935085Okamoto N, Nakai T, Sakamoto K, Nagafusa Y, Higuchi T, Nishikawa T. Rapid antidepressant effect of ketamine anesthesia during electroconvulsive therapy of treatment-resistant depression: comparing ketamine and propofol anesthesia. J ECT. 2010 Sep;26(3):223-7. doi: 10.1097/YCT.0b013e3181c3b0aa.
- Background: PubMed 22622291Wang X, Chen Y, Zhou X, Liu F, Zhang T, Zhang C. Effects of propofol and ketamine as combined anesthesia for electroconvulsive therapy in patients with depressive disorder. J ECT. 2012 Jun;28(2):128-32. doi: 10.1097/YCT.0b013e31824d1d02.
- Background: PubMed 21557878Larkin GL, Beautrais AL. A preliminary naturalistic study of low-dose ketamine for depression and suicide ideation in the emergency department. Int J Neuropsychopharmacol. 2011 Sep;14(8):1127-31. doi: 10.1017/S1461145711000629. Epub 2011 May 5.
- Background: PubMed 23982301Murrough JW, Iosifescu DV, Chang LC, Al Jurdi RK, Green CE, Perez AM, Iqbal S, Pillemer S, Foulkes A, Shah A, Charney DS, Mathew SJ. Antidepressant efficacy of ketamine in treatment-resistant major depression: a two-site randomized controlled trial. Am J Psychiatry. 2013 Oct;170(10):1134-42. doi: 10.1176/appi.ajp.2013.13030392.
- Derived from this study: PubMed 34076068Woolsey AJ, Nanji JA, Moreau C, Sivapalan S, Bourque SL, Ceccherini-Nelli A, Gragasin FS. Low-dose ketamine does not improve the speed of recovery from depression in electroconvulsive therapy: a randomized controlled trial. Braz J Psychiatry. 2022 Jan-Feb;44(1):6-14. doi: 10.1590/1516-4446-2020-1705.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Ferrante S Gragasin, MD, PhD principal investigator
University of Alberta
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Ketamine in people with Depressive Disorder, run by University of Alberta at 2 sites in Canada.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 13 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 28 Apr 2021. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in Canada. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Number of treatments to achieve 50% change (reduction) in Montgomery Ashberg Depression Rating Scale (MADRS) (time frame: 6 weeks). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02579642, which also lists 5 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 28 Apr 2021.