Rivastigmine for ECT-induced Cognitive Adverse effects in Late Life Depression:
a multicenter, randomized, double-blind, placebo-controlled, crossover trial

Background:

Electroconvulsive therapy (ECT) is the most effective treatment for severe depressions. Unfortunately, several cognitive side effects with a large pallet of different manifestations and impact often occur. For instance, postictal agitation ((PIA) with ia motor restlessness and panic like behavior directly after ECT lasting 5 minutes till one hour), or more mildly general disorientation recovering within 1-2 hours after ECT, anterograde memory deficits and retrograde amnesia (both mostly reversible after a few weeks till several months) are well known. Finally, interictal delirium characterized by severe confusion which can appear separately form the postictal disorientation, taking several days to weeks to resolve, mostly in elderly individuals, has also been described (Selvaraj, 2012). In particular the latter may result in a premature abandoning of ECT, and hence failure to achieve remission of the depressive disorder.



Considering its beneficial effect on cognition in persons with mild to moderate Alzheimer’s dementia and the potential beneficial effect on memory deficits in ECT-treated persons with schizophrenia (Stryjer et al., 2012) and either major depressive disorder, bipolar or schizoaffective disorder (Matthews et al., 2013), treatment with an acetylcholinesterase inhibitor (ie rivastigmine) might be useful for the prevention or reversion of the interictal delirium as well. Therefore we designed a randomised double blind placebo controlled crossover trial embedded in a large cohort-study on ECT-patients, to investigate whether rivastigmine treatment has a positive effect on the severity and duration of the interictal delirium. We hypothesize, that rivastigmine addition during ECT can diminish the interictal delirium, induced by ECT.



Main objectives:

The main aim of this study is twofold. We aim to (1) investigate whether rivastigmine can be used as a novel treatment to reduce ECT-induced interictal delirium and (2) to gain further insight into differences in determinants between inter-ictal delirium and adjacent cognitive disturbances induced by ECT, including post-ictal agitation and mild general disorientation of short duration.



Methods:

All admitted depressed patients formally diagnosed with the Composite International Diagnostic Interview (CIDI) and indicated for ECT, will be screened for inclusion in a cohort of ECT patients (n=250). Next, regular ECT-treatment starts, with twice weekly ECT. Patients, who develop interictal delirium assessed by a decline of the Mini Mental State Examination (MMSE) of at least 4 points, or meeting the criteria of a delirium assessed by the Confusion Assessment Method (CAM) (Inouye et al., 1990), both measured once weekly, are eligible for inclusion in the multicenter, randomized, double-blind, placebo-controlled, crossover trial on rivastigmine (n=38).



Intervention:

When a patient fulfils the inclusion criteria for the trial, a transdermal rivastigmine patch (group A) or placebo patch (group B) will be applicated the evening before ECT treatment and will be removed 24hrs after application. After two ECT sessions, group A will receive placebo treatment for two sessions and group B will receive a rivastigmine patch for two sessions.

Electroconvulsive therapy (ECT) is the most effective treatment for severe depressions. Unfortunately, several cognitive side effects with a large pallet of different manifestations and impact often occur. For instance, postictal agitation ((PIA) with ia motor restlessness and panic like behavior directly after ECT lasting 5 minutes till one hour), or more mildly general disorientation recovering within 1-2 hours after ECT, anterograde memory deficits and retrograde amnesia (both mostly reversible after a few weeks till several months) are well known. Finally, interictal delirium characterized by severe confusion which can appear separately form the postictal disorientation, taking several days to weeks to resolve, mostly in elderly individuals, has also been described (Selvaraj, 2012). In particular the latter may result in a premature abandoning of ECT, and hence failure to achieve remission of the depressive disorder.



Considering its beneficial effect on cognition in persons with mild to moderate Alzheimer’s dementia and the potential beneficial effect on memory deficits in ECT-treated persons with schizophrenia (Stryjer et al., 2012) and either major depressive disorder, bipolar or schizoaffective disorder (Matthews et al., 2013), treatment with an acetylcholinesterase inhibitor (ie rivastigmine) might be useful for the prevention or reversion of the interictal delirium as well. Therefore we designed a randomised double blind placebo controlled crossover trial embedded in a large cohort-study on ECT-patients, to investigate whether rivastigmine treatment has a positive effect on the severity and duration of the interictal delirium. We hypothesize, that rivastigmine addition during ECT can diminish the interictal delirium, induced by ECT.

Major measurements: Baseline, T1 (=at inclusion in trila), T2=1 week trial, T3= after 2 week trial, T4: after ECT-course.

In addition: every week minor measurements of deperssion severity and cognition.

Note: target sample size=250 for cohort, in order to include n=38 for trial.



Intervention:

After inclusion (e.g. the occurrence of interictal delirium), the randomized, placebo-controlled cross-over trial starts. The randomization will be organized with a simple Williams design. Patients will be randomly assigned to either the order Rivastigmine (Riv)-Placebo (Pla) or the order Pla-Riv in the treatment periods. Each period lasts for 2 consecutive ECT-treatments. Nineteen patients will be treated with the Riv-Pla order (4.6 mg patch, the night prior to ECT), hence: during two consecutive ECTs rivastigmine is administered, followed by two consecutive ECTs with placebo (Group A), and nineteen patients, with the opposite order (Pla-Riv). (Group B) After 4 treatments (=2 weeks), the blinding is ended and the patients will be treated with – for him/her- the most effective procedure. Tmax of rivastigmine patch is 10-16 hours. Hence, application the night prior to ECT results in optimal dosage during ECT. The patch will be removed after 24 hours.