Toward a Computationally-Informed, Personalized Treatment for Hallucinations

Rivastigmine doses will be administered transdermally using 9.5 mg/24 hr transdermal patches. Participants will be randomized to two treatments with oral rivastigmine vs. placebo separated by a 15-hour washout period (\>5 half-lives to eliminate any residual effects). This will require three separate visits: a baseline visit, a visit for the first transdermal treatment and a visit for the second transdermal treatment. All visits include fMRI scans. The first transdermal patch will be administered 8-14 hours before the scan. After the washout period, the second transdermal patch will be administered 8-14 hours before the scan. No study team member except for the unblinded team member will know which capsule the participant receives first. Because we are interested in rivastigmine as a probe for a pre-identified computational/physiological abnormality, we will median-split groups post-hoc for the purposes of analysis.

The authors have chosen to use scopolamine to determine the effects of cholinergic antagonism, as treatment with scopolamine demonstrates a dose-related increase in propensity toward conditioned hallucinations and in doses much higher than those proposed here, can cause spontaneous hallucinations. At the proposed dose, scopolamine has an excellent safety profile and has been used routinely for nearly 20 years for treatment of nausea due to surgery or motion sickness in adults and children. Scopolamine is available in the US only as a 1mg / 72 hours transdermal patch, and peak plasma levels are reached within 24 hours. This standard dosage level is very well tolerated in the general population.

Participants in Aim 2 will receive a placebo patch versus rivastigmine patch.

Participants in Aim 1 will receive a placebo patch versus scopolamine patch.