ECT With Ketamine Anesthesia vs High Intensity Ketamine With ECT Rescue for Treatment-Resistant Depression

Treatment Resistant Depression Clinical Trial

Official title:

A Prospective Randomized Controlled Trial of Electroconvulsive Therapy With Ketamine Anesthesia (Standard Therapy) and High Intensity Ketamine With Electroconvulsive Therapy Rescue for Treatment-Resistant Depression - EAST HIKER Trial

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03272698
• Other study ID #: 123456
• Status: Recruiting
• Phase: Phase 4
• Start date: September 1, 2017
• Est. completion date: December 30, 2024

Study information

• Verified date: December 2023
• Source: University of Saskatchewan
• Contact: Una Goncin
• Phone: 3066551183
• Email: ung039[@]usask.ca
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

To determine if an high intensity ketamine with ECT rescue (HIKER) approach for treatment resistant depression will: 1) reduce patient suffering by hastening disease remission, 2) have fewer side effects, 3) reduce the need for ECT, and 4) be preferred by most patients. Half of participants will be randomized to the HIKER arm and receive high intensity ketamine treatment for eight consecutive days, and the other half will be assigned to the ECT with ketamine anesthesia (EAST) arm and receive 8 ECT treatments (2-3 treatment/week)

Description:

Major depressive disorder (MDD) is a common psychiatric illness that will affect at least 15% of the population. The burden of MDD is staggering, considered by the World Health Organization to be the leading cause of disability in developed countries for people aged 15-44.

Oral antidepressant therapy for MDD is notoriously ineffective. At least 3 weeks of treatment is usually required to achieve response rates that rarely exceed 40% (only 10% better than placebo); furthermore, treatment can be complicated by serious side effects serious (e.g. falls, weight gain) including increased suicidality. Up to 15% of patients will eventually be diagnosed as having treatment-resistant depressions (TRD), defined as the failure to respond to at least two antidepressants from different pharmacologic classes after adequate treatment duration at therapeutic dosages. The gold standard therapy for TRD is electroconvulsive therapy (ECT) with general anaesthesia (GA), which produces rapid antidepressant effects after only a few sessions. Propofol is the traditional anaesthetic agent used in GA for ECT, although recently this research group showed that ECT with ketamine as the primary anaesthetic produced faster depression remission compared to ECT with propofol.

Despite its efficacy, ECT is associated with considerable problems. More than 10% of patients will experience amnesia and confusion, which can persist for weeks. These cognitive side effects limit the frequency of ECT treatments to two or three times per week. There is also a risk of rare but devastating cardiorespiratory adverse events, at least part of which can be attributed to the need to induce chemical paralysis (for safety) and administer opioids (for pain control) during ECT with GA. Lastly, ECT requires specialized psychiatric expertise, dedicated resources, specially trained nurses, and an anaesthesiologist - requirements that are both costly and not readily available in many settings.

In contrast to ECT, daily short-acting anaesthesia, including ketamine, is well tolerated. A recent study found that only three treatments of intravenous ketamine produced a greater early improvement in depression scores compared to ECT under non-ketamine-based GA. This suggests a possibility of achieving early disease remission in TRD with ketamine-only infusions while avoiding the safety risks and treatment delays associated with ECT under GA.

The efficacy, feasibility, and improved side-effect profile of frequent successive ketamine treatments suggest it may be the preferred treatment for TRD compared to ECT with ketamine-based GA. There may, however, be a small subgroup of TRD patients who do not respond to ketamine alone and require ECT, although with a daily treatment regimen, ketamine non-responders could be quickly identified and given a standard course of ECT. The researchers propose that a treatment protocol of daily High Intensity Ketamine with ECT Rescue (HIKER) will be superior to ECT Therapy with ketamine anesthesia standard therapy (EAST) in facilitating early disease remission, while at the same time yielding similar overall remission rates by allowing ketamine non-responders to be quickly identified and given ECT.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 62
• Est. completion date: December 30, 2024
• Est. primary completion date: December 30, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Montgomery Asberg Depression Rating Scale (MADRS) score of greater than 20) planned for ECT therapy.

• Subjects must meet clinical criteria for TRD defined as failure to respond to at least 2 standard-of-care drug therapies of adequate treatment duration.

Exclusion Criteria:

• Subjects will be ineligible if they cannot provide informed consent

• American Society of Anesthesiology physical status score of four or greater

• Implanted medical device with electronic parts (e.g. pacemaker, defibrillator, intrathecal pump, spinal cord stimulator, deep brain stimulator)

• Schizoaffective disorder

• Women of child-bearing potential will be asked to undergo a commercial urine pregnancy screening test. Those who refuse or screen positive will be excluded.

• Allergic to any of the study drugs or their carrier components

• Any serious physical condition prior to randomization deemed by the attending psychiatrist or consulting anesthetist to be a contraindication to ECT such as cardiovascular disease (including untreated hypertension), respiratory disease, cerebrovascular disease, intracranial hypertension (including glaucoma), or seizures.

Related Conditions & MeSH terms

• Depression
• Depressive Disorder
• Depressive Disorder, Treatment-Resistant
• Ketamine
• Treatment Resistant Depression

Intervention

Drug:
• Ketamine
IV Ketamine 0.50 mg/kg

Procedure:
• ECT
ECT with unilateral or bilateral electrode placement and monitoring of seizure threshold by the half-age method

Locations

Country	Name	City	State
Canada	Royal University Hospital	Saskatoon	Saskatchewan

Sponsors (2)

Lead Sponsor	Collaborator
University of Saskatchewan	Royal University Hospital Foundation

Country where clinical trial is conducted

Canada, 

References & Publications (17)

Atkinson MJ, Kumar R, Cappelleri JC, Hass SL. Hierarchical construct validity of the treatment satisfaction questionnaire for medication (TSQM version II) among outpatient pharmacy consumers. Value Health. 2005 Nov-Dec;8 Suppl 1:S9-S24. doi: 10.1111/j.1524-4733.2005.00066.x. — View Citation

Berlim MT, Turecki G. Definition, assessment, and staging of treatment-resistant refractory major depression: a review of current concepts and methods. Can J Psychiatry. 2007 Jan;52(1):46-54. doi: 10.1177/070674370705200108. — View Citation

Bundy BD, Hewer W, Andres FJ, Gass P, Sartorius A. Influence of anesthetic drugs and concurrent psychiatric medication on seizure adequacy during electroconvulsive therapy. J Clin Psychiatry. 2010 Jun;71(6):775-7. doi: 10.4088/JCP.08m04971gre. Epub 2009 Dec 29. — View Citation

Comparing Ketamine and Propofol Anesthesia for Electroconvulsive Therapy [database on the Internet]. 2013 [cited 2017 Jan 1]

Datto CJ. Side effects of electroconvulsive therapy. Depress Anxiety. 2000;12(3):130-4. doi: 10.1002/1520-6394(2000)12:33.0.CO;2-C. — View Citation

Diamond PR, Farmery AD, Atkinson S, Haldar J, Williams N, Cowen PJ, Geddes JR, McShane R. Ketamine infusions for treatment resistant depression: a series of 28 patients treated weekly or twice weekly in an ECT clinic. J Psychopharmacol. 2014 Jun;28(6):536-44. doi: 10.1177/0269881114527361. Epub 2014 Apr 3. — View Citation

Fink M. Is Catatonia a Primary Indication for ECT? Convuls Ther. 1990;6(1):1-4. No abstract available. — View Citation

Ghasemi M, Kazemi MH, Yoosefi A, Ghasemi A, Paragomi P, Amini H, Afzali MH. Rapid antidepressant effects of repeated doses of ketamine compared with electroconvulsive therapy in hospitalized patients with major depressive disorder. Psychiatry Res. 2014 Feb 28;215(2):355-61. doi: 10.1016/j.psychres.2013.12.008. Epub 2013 Dec 13. — View Citation

Gipson PY, Agarwala P, Opperman KJ, Horwitz A, King CA. Columbia-suicide severity rating scale: predictive validity with adolescent psychiatric emergency patients. Pediatr Emerg Care. 2015 Feb;31(2):88-94. doi: 10.1097/PEC.0000000000000225. — View Citation

Guy W. Clinical global impression scale. The ECDEU Assessment Manual for Psychopharmacology-Revised Volume DHEW Publ No ADM. 1976;76(338):218-22

Irwin SA, Iglewicz A, Nelesen RA, Lo JY, Carr CH, Romero SD, Lloyd LS. Daily oral ketamine for the treatment of depression and anxiety in patients receiving hospice care: a 28-day open-label proof-of-concept trial. J Palliat Med. 2013 Aug;16(8):958-65. doi: 10.1089/jpm.2012.0617. Epub 2013 Jun 27. — View Citation

Kessler RC, Berglund P, Demler O, Jin R, Merikangas KR, Walters EE. Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry. 2005 Jun;62(6):593-602. doi: 10.1001/archpsyc.62.6.593. Erratum In: Arch Gen Psychiatry. 2005 Jul;62(7):768. Merikangas, Kathleen R [added]. — View Citation

Kirsch I, Deacon BJ, Huedo-Medina TB, Scoboria A, Moore TJ, Johnson BT. Initial severity and antidepressant benefits: a meta-analysis of data submitted to the Food and Drug Administration. PLoS Med. 2008 Feb;5(2):e45. doi: 10.1371/journal.pmed.0050045. — View Citation

Mathers C, Fat DM, Boerma JT. The global burden of disease: 2004 update: World Health Organization; 2008.

Metriyakool K. Methohexital as alternative to propofol for intravenous anesthesia in children undergoing daily radiation treatment: a case report. Anesthesiology. 1998 Mar;88(3):821-2. doi: 10.1097/00000542-199803000-00035. No abstract available. — View Citation

Rush AJ, Blacker D. Handbook of psychiatric measures: American Psychiatric Pub; 2008

Skolnick P, Layer RT, Popik P, Nowak G, Paul IA, Trullas R. Adaptation of N-methyl-D-aspartate (NMDA) receptors following antidepressant treatment: implications for the pharmacotherapy of depression. Pharmacopsychiatry. 1996 Jan;29(1):23-6. doi: 10.1055/s-2007-979537. — View Citation

* Note: There are 17 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of treatments required to reach disease remission	The primary outcome is number of treatments required to reach disease remission, as defined by a reduction of MADRS score to under 10	From date of randomization until the date of disease remission or after 8 treatments, assessed up to 4 weeks
Secondary	Rate of rescue ECT in the HIKER arm	Percent of patients in the HIKER arm who do not achieve a 25% reduction in the Montgomery-Asberg Depression Rating Scale (MADRS) after the third treatment.	From date of randomization up to 6 days
Secondary	Suicidal ideation	Suicidal ideation as measured by the Columbia Suicide Severity Rating Scale	From date of randomization until the date of disease remission or after 8 treatments and at 30 days following last treatment, assessed up to 8 weeks
Secondary	Cognitive Impairment	Cognitive Impairment as measured by Mini-Mental State Exam (MMSE)	MMSE will be assessed at baseline, final treatment, and 30 day post-treatment follow-up
Secondary	Self- and clinician rated improvement	Patients will rate their condition on the patient-rated clinical global impression - improvement scale (PGI-I)	From date of randomization until the date of disease remission or after 8 treatments and at 30 days following last treatment, assessed up to 8 weeks
Secondary	Patient satisfaction with treatment	Satisfaction with treatment will be assessed by the 2-item treatment satisfaction questionnaire for medication-version II (TSQM-GS-II).	From date of randomization until the date of disease remission or after 8 treatments and at 30 days following last treatment, assessed up to 8 weeks