Depression
Conditions
Keywords
Electroconvulsive therapy, ECT, electrode placement, effectiveness, cognition, autobiographical memory
Brief summary
Electroconvulsive therapy (ECT) is the most powerful antidepressant treatment available and is often life-saving. There are concerns, however, that standard bitemporal ECT (the most commonly used form of ECT worldwide) causes persisting retrograde amnesia. However, clinical trials have indicated that high-dose unilateral ECT may be as effective as bitemporal ECT but have much less cognitive side-effects. The trial aims to test the primary experimental hypothesis: High-dose (6 x ST) right unilateral ECT is as effective as (i.e. not inferior to) standard (1.5 x ST) bitemporal ECT for severe depression in terms of Hamilton Depression Rating Score (HDRS) at the end of the treatment course.
Detailed description
The study is a two-group parallel design randomised controlled non-inferiority trial and has been registered (ISRCTN23577151). Consented patients with major depressive disorder (DSM-IV) will be randomly allocated to a course of bitemporal (BT) ECT (1.5 x ST) or high-dose right unilateral (RUL) ECT (6.0 x ST). To facilitate generalizability of results, the trial takes place under real world conditions and so both groups continue usual care and medications during the treatment phase and thereafter. Patients are followed-up for 12 months after completing their allocated course of ECT. Completion of the primary outcome depression-rating measure (i.e. HDRS) and the secondary outcome of most interest (autobiographical memory, using the AMI-SF) will be prioritised in the data collection. Patients, their treating clinicians and raters are blind to treatment; clinicians administering ECT are not involved in post randomisation assessments or formal data analysis. Success of blinding for patients and raters will be assessed after the second and final treatments. The trial statistician is also blinded to allocation status. Sample size: In a large series (n = 253) of depressed patients, Petrides et al. (2001) found a mean (SD) reduction in 24-item HDRS of 25.6 (9.4) after treatment with bitemporalT ECT (1.5 x ST). We therefore estimate that 69 patients will be required per treatment group to have 80% power to demonstrate, using a one-sided equivalence t-test at 5% level, that mean reduction in 24-item HDRS achieved using high-dose RUL ECT is no more than 4 points (i.e. equivalent to 3 points on 17-item HDRS) less than that achieved using standard BT ECT, assuming a common within-group SD of change scores of 9.4 and equal expected group mean change scores.
Interventions
DEVICEECT Mecta 5000M
ECT is administered twice weekly with hand-held electrodes using the Mecta 5000M device following a standard stimulus dosing protocol. Seizure duration is measured by EEG monitoring. Methohexitone (0.75-1.0 mg/kg) is used for anaesthesia with suxamethonium (0.5-1.0 mg/kg) as muscle relaxant. Seizure threshold (ST) is established by a method of limits at the first session and subsequent treatments will be given at 1.5 x ST for BT ECT and 6.0 x ST for RUL ECT. To reflect routine clinical practice, number of ECT treatments is determined by referring physicians who will be blind to randomisation. The treatment period varies between patients to allow up to 12 administrations of ECT, i.e. up to 6 weeks.
DRUGMethohexitone
Methohexitone (0.75-1.0 mg/kg) is used for anaesthesia along with suxamethonium (0.5-1.0 mg/kg)for muscle relaxation. Anesthesia is the same for both arms of the trial.
DRUGSuxamethonium
Suxamethonium (0.5-1.0 mg/kg)is used for muscle relaxation along with Methohexitone (0.75-1.0 mg/kg) for anaesthesia. Anesthesia is the same for both arms of the trial.
Sponsors
Health Research Board, Ireland
St Patrick's Hospital, Ireland
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients ≥18 years diagnosed with major depressive episode (DSM-IV) and referred for ECT
Exclusion criteria
* Any condition rendering patients medically unfit for general anaesthesia or ECT; treatment with ECT in previous six months; dementia or other Axis 1 diagnosis; alcohol/other substance abuse in previous six months; inability/refusal to consent.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Hamilton Depression Rating Scale (HDRS) | HDRS scores were obtained at baseline, end of allocated ECT treatment, and at 3 and 6 month follow-up timepoints. | The HDRS was originally designed to assess severity of depressive symptoms in patients with a primary depressive illness and is now the most commonly used measure of depression severity. It was first published in a 17-item format with the optional addition of 4 items making up the 21-item version. In addition to the original 21 items, the 24-item HDRS includes items on helplessness, hopelessness and worthlessness; its score range is 0-77, with higher scores reflecting greater burden of depressive symptoms. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Columbia Autobiographical Memory Interview-Short Form (AMI-SF) | end of allocated ECT course | The AMI-SF is used to assess retrospective autobiographical memory function. It has six categories, which involve five questions each, about a family member, most recent travel, last New Year's Eve, last birthday, most recent employment and last visit to a doctor for a physical complaint. At baseline interviewers encourage the participant to recall as much information as they can. Responses at baseline can be scored either two points, for a recognisable real memory, or zero for no memory or too little information to constitute a proper memory. Only those questions for which a memory had been retrieved at baseline are examined at follow-up. Follow-up assessments are scored as percentage recall of baseline score, which is scored as 100% irrespective of actual performance.. |
Countries
Ireland
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Bilateral ECT Mecta 5000M Twice-weekly modified bilateral ECT (bitemporal electrode positions) twice weekly at 1.5 times the seizure threshold. Methohexitone (0.75-1.0 mg/kg) is used for anaesthesia with suxamethonium (0.5-1.0mg/kg) for muscle relaxation.
Seizure threshold (ST) is established by a method of limits at the first session and subsequent treatments will be given at 1.5 x ST for BT ECT and 6.0 x ST for RUL ECT. To reflect routine clinical practice, number of ECT treatments is determined by referring physicians who will be blind to randomisation. The treatment period varies between patients to allow up to 12 administrations of ECT, i.e. up to 6 weeks. | 69 |
| High-dose Unilateral ECT Mecta 5000M Twice-weekly high-dose right modified unilateral ECT twice weekly at 6 times the seizure threshold. Methohexitone (0.75-1.0 mg/kg) is used for anaesthesia with suxamethonium (0.5-1.0mg/kg) for muscle relaxation.
Seizure threshold (ST) is established by a method of limits at the first session and subsequent treatments will be given at 6.0 x ST for RUL ECT. To reflect routine clinical practice, number of ECT treatments is determined by referring physicians who will be blind to randomisation. The treatment period varies between patients to allow up to 12 administrations of ECT, i.e. up to 6 weeks. | 69 |
| Total | 138 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Withdrawal by Subject | 0 | 2 |
Baseline characteristics
| Characteristic | Bilateral ECT Mecta 5000M | Total | High-dose Unilateral ECT Mecta 5000M |
|---|---|---|---|
| Age, Continuous | 56.8 years STANDARD_DEVIATION 14.4 | 56.7 years STANDARD_DEVIATION 14.8 | 56.6 years STANDARD_DEVIATION 15.3 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 69 Participants | 138 Participants | 69 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment Ireland | 69 participants | 138 participants | 69 participants |
| Sex: Female, Male Female | 47 Participants | 87 Participants | 40 Participants |
| Sex: Female, Male Male | 22 Participants | 51 Participants | 29 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 33 / 69 | 37 / 69 |
| serious Total, serious adverse events | 9 / 69 | 7 / 69 |
Outcome results
Primary
Hamilton Depression Rating Scale (HDRS)
The HDRS was originally designed to assess severity of depressive symptoms in patients with a primary depressive illness and is now the most commonly used measure of depression severity. It was first published in a 17-item format with the optional addition of 4 items making up the 21-item version. In addition to the original 21 items, the 24-item HDRS includes items on helplessness, hopelessness and worthlessness; its score range is 0-77, with higher scores reflecting greater burden of depressive symptoms.
Time frame: HDRS scores were obtained at baseline, end of allocated ECT treatment, and at 3 and 6 month follow-up timepoints.
Population: Intention to treat analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Bilateral ECT Mecta 5000M | Hamilton Depression Rating Scale (HDRS) | Baseline | 29.5 units on a scale | Standard Deviation 6.3 |
| Bilateral ECT Mecta 5000M | Hamilton Depression Rating Scale (HDRS) | End-of-treatment | 12.5 units on a scale | Standard Deviation 9.2 |
| Bilateral ECT Mecta 5000M | Hamilton Depression Rating Scale (HDRS) | 3 months follow-up | 15.0 units on a scale | Standard Deviation 10.2 |
| Bilateral ECT Mecta 5000M | Hamilton Depression Rating Scale (HDRS) | 6 months follow-up | 13.0 units on a scale | Standard Deviation 8.6 |
| High-dose Unilateral ECT Mecta 5000M | Hamilton Depression Rating Scale (HDRS) | 6 months follow-up | 12.6 units on a scale | Standard Deviation 10.9 |
| High-dose Unilateral ECT Mecta 5000M | Hamilton Depression Rating Scale (HDRS) | Baseline | 30.4 units on a scale | Standard Deviation 6.1 |
| High-dose Unilateral ECT Mecta 5000M | Hamilton Depression Rating Scale (HDRS) | 3 months follow-up | 11.5 units on a scale | Standard Deviation 9.1 |
| High-dose Unilateral ECT Mecta 5000M | Hamilton Depression Rating Scale (HDRS) | End-of-treatment | 11.1 units on a scale | Standard Deviation 7.5 |
Comparison: Based on a large bitemporal ECT series, we estimated that 69 patients were required per group to have 80% power to demonstrate, using a one-sided equivalence t test at 5% level, that the mean reduction in the 24-item HAM-D score following high-dose unilateral ECT was no more than 4 points (i.e., equivalent to 3 points on the 17-item HAM-D, deemed to be clinically relevant \[30\]) less than that achieved using bitemporal ECT.p-value: <0.0595% CI: [-1.67, 3.84]Regression, Linear
Secondary
Columbia Autobiographical Memory Interview-Short Form (AMI-SF)
The AMI-SF is used to assess retrospective autobiographical memory function. It has six categories, which involve five questions each, about a family member, most recent travel, last New Year's Eve, last birthday, most recent employment and last visit to a doctor for a physical complaint. At baseline interviewers encourage the participant to recall as much information as they can. Responses at baseline can be scored either two points, for a recognisable real memory, or zero for no memory or too little information to constitute a proper memory. Only those questions for which a memory had been retrieved at baseline are examined at follow-up. Follow-up assessments are scored as percentage recall of baseline score, which is scored as 100% irrespective of actual performance..
Time frame: end of allocated ECT course
Population: Not all patients completed this cognitive task.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Bilateral ECT Mecta 5000M | Columbia Autobiographical Memory Interview-Short Form (AMI-SF) | 56.8 % of baseline performance | Standard Deviation 17.3 |
| High-dose Unilateral ECT Mecta 5000M | Columbia Autobiographical Memory Interview-Short Form (AMI-SF) | 67.1 % of baseline performance | Standard Deviation 16.3 |
Comparison: The AMI-SF at end of treatment was analyzed using generalized linear models with a binomial distribution and logit-link. Post treatment AMI-SF measures provide the number of baseline items recalled after ECT; such number of items recalled variables were therefore modeled as arising from binomial distributions, with maximum number of possible recalls set to the number of items obtained at baseline.p-value: 0.00195% CI: [0.51, 0.85]generalized linear models with a binomia
Secondary
Columbia Autobiographical Memory Interview-Short Form (AMI-SF)
The AMI-SF is used to assess retrospective autobiographical memory function. It has six categories, which involve five questions each, about a family member, most recent travel, last New Year's Eve, last birthday, most recent employment and last visit to a doctor for a physical complaint. At baseline interviewers encourage the participant to recall as much information as they can. Responses at baseline can be scored either two points, for a recognisable real memory, or zero for no memory or too little information to constitute a proper memory. Only those questions for which a memory had been retrieved at baseline are examined at follow-up. Follow-up assessments are scored as percentage recall of baseline score, which is scored as 100% irrespective of actual performance..
Time frame: 3 months follow-up
Population: Not all patients completed this cognitive task.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Bilateral ECT Mecta 5000M | Columbia Autobiographical Memory Interview-Short Form (AMI-SF) | 56.2 % of baseline performance | Standard Deviation 18.1 |
| High-dose Unilateral ECT Mecta 5000M | Columbia Autobiographical Memory Interview-Short Form (AMI-SF) | 67.3 % of baseline performance | Standard Deviation 14.2 |
p-value: 0.00195% CI: [0.45, 0.78]Regression, Linear
Secondary
Columbia Autobiographical Memory Interview-Short Form (AMI-SF)
The AMI-SF is used to assess retrospective autobiographical memory function. It has six categories, which involve five questions each, about a family member, most recent travel, last New Year's Eve, last birthday, most recent employment and last visit to a doctor for a physical complaint. At baseline interviewers encourage the participant to recall as much information as they can. Responses at baseline can be scored either two points, for a recognisable real memory, or zero for no memory or too little information to constitute a proper memory. Only those questions for which a memory had been retrieved at baseline are examined at follow-up. Follow-up assessments are scored as percentage recall of baseline score, which is scored as 100% irrespective of actual performance..
Time frame: 6 months follow-up
Population: Not all patients completed this cognitive task.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Bilateral ECT Mecta 5000M | Columbia Autobiographical Memory Interview-Short Form (AMI-SF) | 52.9 % of baseline performance | Standard Deviation 16.4 |
| High-dose Unilateral ECT Mecta 5000M | Columbia Autobiographical Memory Interview-Short Form (AMI-SF) | 63.4 % of baseline performance | Standard Deviation 17.7 |
p-value: 0.00195% CI: [0.45, 0.79]Regression, Linear