Prediction of ECT treatment response and reduction of Cognitive Side-effects using EEG and Rivastigmine

Electroconvulsive therapy (ECT) is the most potent psychiatric treatment, with
an effect size of 1.5 for severe and refractory unipolar and bipolar
depression. ECT convincingly outperforms pharmacotherapy such as tricyclic
antidepressants and monoamine oxidase inhibitors and any form of psychotherapy.
Despite its outstanding performance in reducing depressive symptoms up to the
point of full remission, it is used only frugal. A recent Dutch study
calculated that currently only 1.2% of chronic depressive patients are offered
ECT, while 26% could actually benefit from this treatment. Unfortunately, the
response to ECT is largely unpredictable, while cognitive side-effects occur
frequently.
In a previous study, we found that multiple cognitive tests showed a
significant decline immediately post-ECT, which resolved within 6 months after
the last ECT session. Even though cognitive side-effects are mostly
short-lasting, patients and doctors see this as a great drawback of ECT. If
these disturbing side-effects could be prevented, more patients and
psychiatrists would choose ECT as a treatment option for this severely ill
group. This would lead to a more effective treatment and hence shorter duration
of chronic severe depression and improvement in quality of life, while costs
for health care and loss of productivity would decrease. A potential way of
ameliorating side effects, could be to add a cholinesterase inhibitor to ECT
treatment. Recent rodent studies show that the loss of cholinergic fibers
specifically correlated to the cognitive side effects of rodents after
electroconvulsive stimulation (ECS). We select rivastigmine (a cholinesterase
inhibitor) as a potential candidate in counteracting cognitive side effects
induced by cholinergic fiber loss due to ECT. Rivastigmine patches are very
well tolerated and widely used for Alzheimer*s Disease.
Tailoring treatment to patients that are likely to respond while
cognitive side-effects are unlikely to occur, would be another important
improvement of clinical care for patients with otherwise treatment-resistant
depression. Currently, ECT treatment outcome is unpredictable. Factors that
favor response include older age, psychotic depression, shorter duration of the
depressive episode, rapid response (if patients respond before the 6th session,
the chance of remission is higher) and smaller dentate gyrus volumes. However,
these predictors are insufficiently accurate to make individual response
profiles. Accurately classifying specifically non-responders will prevent
application of ineffective treatment with potential iatrogenic damage, while
more accurately predicted response will increase the applicability of ECT as
treatment option. A potentially powerful way which is easy to implement in the
clinic is prediction of ECT treatment response using EEG characteristics in
addition to clinical information.

This study has been transitioned to CTIS with ID 2024-518047-37-01 check the CTIS register for the current data.

The aim of our study is two folded: first, we aim to improve cognition after
ECT, improving its acceptability and tolerability and hence increase its
application. If ECT would be used for the calculated 26% of patients who have
chronic severe depression, morbidity and mortality of this disorder would
decrease steeply. Second, we aim to develop a prediction method based on
clinical and EEG characteristics, to accurately predict who will respond to
ECT. If it is possible to accurately predict ECT response (and non-response),
it could be prevented that patients with a low chance of recovery receives ECT
without response but with the associated risks.

Patients with a severe depressive episode indicated for ECT and treated as
outpatient at or admitted to the University Medical Centre Utrecht (UMCU; or
nearby center) or University Medical Centre Groningen (UMCG), between May 2021
and January 2025 will be asked to participate by the treating
psychiatrist/nurse/psychologist.

Rivastigmine add-on treatment during ECT treatment.
Patients will receive either placebo or rivastigmine, randomised in a 1:1
ratio. Rivastigmine will be added to the ECT course: in the first two weeks
patients will receive a 4.5mg rivastigmine patch per day, and after the first
weeks a 9.6mg catch will be given each day.
When ECT treatment stops, rivastigmine treatment will stop as well.

Rivastigmine is well tolerated and safe. It has been shown that rivastigmine
administered as patches has a more favorable side effect profile than
rivastigmine in oral capsule form [incidence of side effect are about three
times fewer. Rivastigmine is effective for mild to moderate AD and PDD for
several cognitive measures. The side effects associated to rivastigmine in
patches are for the majority gastrointestinal (about 6-7%: vomiting, nausea,
diarrhea), which is expected for cholinesterase inhibitors. Less frequent side
effects for rivastigmine patches are headaches (3%) and dizziness (2%). The
side effects were usually present during the titration phase (i.e. during the
first weeks at 4.5 mg) and gradually disappear during maintenance phase. Urine
incontinence is a rare but disturbing side effect. In addition, mild skin
reactions may occur at the location of the patch. No serious adverse events
that needed treatment are reported for rivastigmine in clinical trials.

No direct pharmacokinetic drug-drug interactions are observed for rivastigmine,
including common drugs like digoxin, warfarin, diazepam, and fluoxetine. And no
contraindications exist for rivastigmine use, except for an allergic reaction
to rivastigmine (Summary of Product Characteristics). Note that patients
receiving ECT are usually given succinylcholine for muscle relaxation.
Rivastigmine may exaggerate the effects of succinylcholine leading to prolonged
muscle relaxation. However, succinylcholine causes rapid and short muscle
duration of muscle relaxation (~ 4-6 minutes) whereas the alternative to
succinylcholine would be rocuronium which has a duration of action of 30-60
minutes (half-life of 66-80 minutes). So even if rivastigmine increases the
time of muscle relaxation by 4-5 times, it will be on average shorter than the
alternative rocuronium. However, we will carefully monitor the extent of
(prolonged) muscle relaxation using the clinically validated Train of Four
(TOF) assessment. In addition, we will administer the patches the evening
before each ECT session, aiming for the Cmax of rivastigmine to be achieved
during the night instead of during administration of succinylcholine.

In view of possible additive effects (possibly leading to bradycardia) no
concomitant cholinomimetic drugs should be given next to rivastigmine. In
addition, caution is warranted when administering rivastigmine with
betablockers and torsades de pointes inducing drugs [such as antipsychotics
like chlorpromazine (section 4.5 SPC rivastigmine, patch)].

Of note, one study investigating the addition of rivastigmine to haloperidol
treatment in the management of delirium in critically ill patients was
terminated early due to increased mortality in the rivastigmine group. The
population of that study (critically ill patients admitted to the intensive
care unit) is significantly different from the population of our study.
Furthermore, the method of administration in the current study (transdermally)
is different from that of the study by van Eijk et al., (2010; as a solution).
Transdermal administration of rivastigmine leads to slower release and uptake
of rivastigmine. Furthermore, in post-hoc analyses, the authors were unable to
exclude the possibility that the increased mortality in the rivastigmine group
was due to chance. Given the fact that these patients were critically ill,
which is not the case in the current study, and the absence of other reports on
increased mortality with rivastigmine use, we do not expect that rivastigmine
in the current study would pose a serious risk to the patients.