Depressive Disorder, Major Clinical Trial
Official title:
A Randomized Controlled Non-inferiority Trial Comparing Ketamine With ECT in Patients With Major Depressive Disorder
Developing more effective and faster acting antidepressant is of outmost clinical importance. Available antidepressant therapies have a delayed therapeutic effect. It typically takes several weeks before symptom relief is evident. Furthermore, antidepressants are relatively ineffective - as many as 30% of patients do not respond to any medication at all. In this study the investigators evaluate the NMDA-receptor antagonist ketamine as a potentially new antidepressant treatment for severely depressed patients and compare its effectiveness with that of electroconvulsive therapy (ECT).
In line with the PICO model, patient selection and procedures for experimental and control
treatments and outcome measures are rigorously defined. Inpatients, aged 18-85, diagnosed
with major depressive disorder (MDD, according to DSM-IV), that have been offered and have
accepted ECT, are eligible to participate. Patients must be proficient in spoken and written
Swedish, and score ≥ 20 points on the Montgomery Åsberg Depression Rating Scale (MADRS).
Exclusion criteria are known allergy to the active substance; co-morbid conditions that could
interfere with the treatment (e.g. primary psychosis); habitual difficulties to speak, hear,
remember or reason; on-going or recent (6 months) drug abuse; treatment according to LPT
(Lagen om psykiatrisk tvångsvård; Compulsory Psychiatric Care Act); and a number of
cardiovascular conditions.
Patients randomized to the experimental treatment receive intravenous infusions of racemic
ketamine (0.5 mg/kg), delivered over a period of forty minutes thrice weekly (Monday,
Wednesday, Friday). Patients in the control group receive ECT in line with standard
procedures (including anesthesia, muscle relaxation and oxygenation) thrice weekly. ECT was
chosen as the reference treatment as it is the most effective treatment for patients
suffering from moderate to severe depression.
Primary outcome is the proportion of patients in remission after 4 weeks of treatment in each
arm. Remission is defined as a MADRS ≤ 10.
The study uses a non-inferiority design. Demonstrating superiority of ketamine was not an
option based on the number of patients needed to gain sufficient power with such a design.
Also, the investigators do not believe that ketamine treatment needs to be more effective, at
least not in terms of the primary outcome. ECT is associated with side effects (in particular
amnesia during the treatment period, but some patients also report persistent memory
problems) and patients need to be anaesthetised under the supervision of a anaesthesiologist.
The treatment is thus fairly demanding and expensive. A significant amount of patients are
also unwilling to undergo ECT. Given non- inferiority of ketamine regarding the primary
outcome, and given that it is associated with fewer side effects or shorter time to remission
and does not involve the need for anaesthesia, in a risk-benefit analysis the scale might be
tipped in favour of ketamine, even if it is not superior per se.
Secondary outcomes include proportion of patients in re mission and /or response and
symptomatic relief at follow-up time points (3, 6 and 12 months after treatment cessation).
Also addressed is how the two treatments affect cognition. A computerized test battery, the
Cambridge Automated Neuropsychological Test Automated Battery (CANTAB) is administered prior
to the first treatment, after two weeks, shortly after remission and at three additional time
points (3, 6 and 12 months) after conclusion of the treatment. See figure for specification
and description of cognitive tests.
Blood samples are drawn before the first treatment and 2-3 months after finishing treatment.
Apart from plasma and serum samples (which will be used for later analysis of potential
biomarkers such as IL 6 and D-serine), additional blood is collected for genomic DNA
analysis. A total of 4 x 6 mL are taken at each occasion. Blood samples are stored at the
regional biobank.
Time to response will be analysed with parametric survival analysis (for changes in MADRS
score) or with non-parametric analysis of two-way ordinal data with repeated measurements34
(for ordinal data). Cognitive data and biological samples will be analysed with t-tests
(paired or unpaired as appropriate) or with analysis of variance ANOVA.
Study sample size was calculated based on actual or assumed remission rates, the primary
outcome parameter of the study. A remission rate of 60% was set for the reference treatment
(ECT). A non-inferiority limit of 40% was set for the experimental intervention (ketamine).
This is an arbitrary level, based on an assumption of fewer and milder side effects, faster
antidepressant effect and the fact that the patients do not need to be anaesthetized and
given muscle relaxants. With the above limits, a power of 80% and a significance level of 5%,
97 patients are required in each arm, according to: n = (2 * 8,4 * p(1-p) / difference2),
where "2" and "8,4" are derived from significance and power levels, p are the (actual and
assumed) levels for the proportion of patients reaching remission for ECT and ketamine (60%
and 40% respectively). The size of the cohort is calculated to be sufficiently large to
detect ECT-associated cognitive side effects.
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