Efficacy of amantadine on behavioural and emotional problems and impairment of executive functioning
due to acquired brain injury to the frontal lobes: a series of single case experimental design studies.

Rationale: Brain injury due to different causes is common and can have severe
functional impact. Frontal lesions often lead to cognitive impairments, but
also to behavioural consequences, e.g. apathy, agitation, aggression, and
emotional lability.
Amantadine may be effective in the treatment of these cognitive and behavioural
consequences. Anatomical and neurochemical theory support these findings and
amantadine is clinically used albeit without the support of scientific
evidence.

Objective: The objective of this study is to establish the effectiveness and
safety of amantadine on emotional lability/irritability, aggression, apathy and
impaired executive functioning due to frontal lobe brain injury.

Study design:
This study is a series of Single Case Experimental Design (SCED) studies. Each
study has an A-A1-B-A, or A-B-A1-A double blind, randomized,
placebo-controlled, and multiple baseline design. (A=baseline/withdrawal;
A1=placebo; B=amantadine)

Intervention : Amantadine is the pharmaceutical intervention in each Single
Case experiment in this series.
Dosage schedule amantadine in the B phase:
Day 1-7, 100 mgs od
Day 8-28, 100 mgs bd
Day 29-35 100 mgs od
During baseline and withdrawal no amantadine is given. In the treatment phase
(amantadine or placebo) the subject takes two pills per day. Depending on the
randomisation schedule these will contain amantadine or placebo.

Amantadine has no major side effects and low risk of adverse events.
Amantadine's undesirable effects are often mild and transient, usually
appearing within the first 2 to 4 days of treatment and promptly disappearing
24 to 48 hours after discontinuation.
Although amantadine has been widely used in clinical practice for other
indications and was found safe, in the current study every precaution is taken,
on the one hand to monitor side effects constantly and on the other hand to
react immediately if side effects are forming a health risk for the patient.
Before treatment starts, risk factors are carefully established and if risk
factors emerge subjects will be excluded.
Side effects will be monitored weekly.
The subject can withdraw at any moment in time without any restriction if side
effects are too cumbersome for the patient.

So far the only adverse event reported in the literature is the association of
acute withdrawal from amantadine and a Malignant Neuroleptic Syndrome.
The study design does not include instant withdrawal. Subjects and significant
others will be warned explicitly against instant withdrawal.
Of the questionnaires only the MMSE and the side effect monitor will involve
the subject directly.
So the burden of medication and measurements to the patient is negligible.