The role of serotonin in learning and decision-making: a behavioural study*

Meta-decision making, or 'deciding how to decide', involves arbitrating how
much time and effort (both physical and cognitive) to invest into making a
decision. Recently, it has been suggested that these meta-decisions could be
governed by assessing the costs and potential benefits associated with each
behavioural strategy. This trade-off between costs and benefits would
incorporate readily internal and external variables, like availability of time
and other resources, reward history, motivation and confidence, to name a few.

A potential neural implementation of these variables is through neuromodulators
known to be involved in value-based decision-making: dopamine and serotonin.
The influence of serotonin appears to be particularly complex, with findings
implicating serotonin in aversive inhibition, waiting and patience, heuristic
responding, effort and information cost. In this study, we aim to reconcile
these different computations attributed to serotonin and elucidate serotonin*s
role in decision-making, by modulating serotonin using the selective serotonin
reuptake inhibitor escitalopram.

It is important to clarify the mechanistic basis of the role of serotonin in
these cognitive processes for a better understanding of human brain
functioning.

The purpose of this study is to determine and clarify the role of serotonin in
cognitive processes that support decision-making. The neural processes being
studied are reward learning, patience, aversive inhibition, investing cognitive
effort and other resources, and computational measures of the controllability
of the environment. Serotonin has been implicated in all of these processes,
but its precise role in them is not clear in humans.

We will employ a double-blind placebo-controlled design, using with a
between-subject approach, and two measurements per participant for a
within-subject component. All participants will participate in one screening
session and two testing sessions where behavioural tasks will be performed on a
computer. The two testing sessions will take place at the following points
during the study: on the first testing day before first oral intake of
escitalopram/placebo, and on the second testing day following a 2-3 week course
of escitalopram/placebo. The purpose of this manipulation is to increase
serotonin levels in the brain in one arm of the study population, by inhibiting
serotonin reuptake. Similar pharmacological studies, although with other
pharmacological agents, are regularly conducted within our research group.
Additionally, this dose of escitalopram has been used frequently in studies
where a similar (healthy) population was studied, without the occurrence of
serious side effects.

Subjects will participate in three research sessions: an intake session (3
hours), and two behavioural sessions (5 hrs each). In addition, subjects will
complete a set of online questionnaires at home (1 hour), and will keep a daily
diary to record side effects, via a smartphone application (2 minutes per day).
The intake session will consist of a medical and psychiatric screening
interview, neuropsychological testing, and training for the tasks during the
behavioural sessions. Between the first and second testing session, subjects
will take an oral dose of escitalopram or placebo daily for a period of 14 to
21 days, depending on their availability for the second testing session. The
first 5 days of the intervention, participants will take one capsule (dose
escitalopram: 10mg). The next 9-16 days, participants will take 2 capsules
(dose escitalopram: 20mg). By taking a lower dose the first few days, the
occurrence and intensity of side-effects will decrease. During this period,
subjects must adhere to some simple restrictions regarding medication, alcohol,
and drug use. During the behavioural sessions, subjects are asked to complete
some questionnaires and perform tasks related to decision-making. Escitalopram
can be safely administered in healthy individuals without any relevant risk of
serious serious side effects, and is approved for clinical use in the
Netherlands.