Bringing computational psychiatry to clinical practice: Patient stratification for successful administration of intranasal s-ketamine in treatment-resistant depression

Depression is one of the most prevalent (globally ~5% of adults) psychiatric
disorders due to its incidence and chronicity rates. It is a leading cause of
disability world-wide and contributes greatly to the global burden of disease.
Although different psychological and pharmacological treatments are available,
about 25% of depressed patients remain clinically symptomatic, even after
several conventional treatment steps, making treatment resistant depression
(TRD) an extremely debilitating and costly condition. Finding the right
treatment is often a long and painful search of trial and error. We are thus in
direct need of more efficacious and efficient treatment regimens. Understanding
why some people do respond to a certain treatment and why others don*t, is a
key step in the roadmap towards more efficacious and efficient treatment
regimens.
Moreover, understanding a depressive condition as a corollary of disturbed
neural circuitry related to relatively well-understood value-based decision
making, gives us a stepping-stone for advancing our knowledge on the mode of
action of effective treatments, which in turn will enable us to address
variability in treatment effects.
Esketamine was the first new treatment in decades to be approved for the
treatment of TRD in 2021. This treatment has an estimated response rate of
~50% after four weeks in TRD patients, which makes this treatment an asset for
this patient group and leaves much room for improvement. Esketamine has an
innovative, yet still marginally understood, mode of action in terms of
neurotransmission (primarily via down-stream effects of NMDA-receptors instead
of monoaminergic reuptake inhibition) and time scale (in terms of hours
compared to weeks) compared to conventional antidepressants. There is thus a
need to better understand the mode of action of esketamine and its relation to
variability in treatment effects.
Thus, in the current proposal we will assess how basic learning task
performance, probing value-based decision making, and associated neural
activity in regions which are also likely to be involved in the effect of
esketamine, differ between patients with TRD who respond to esketamine and
those who do not respond to esketamine.
To do this we will invite TRD patients to two neuroimaging sessions
respectively before and after 4 weeks of their treatment. This latter point is
chosen as this is the point in clinical practice when the first choice of
treatment prolongation is taken (thus, when the first differentiation between
responders and non-responders is made).

Primary objective:
(1) Assess baseline (i.e., before treatment) differences between
esketamine-responders and non-responders on key elements of value-based
decision making (including reward- and punishment sensitivity,
approach-avoidance tendencies, motivation and effort-investments) and related
neural pathways (including the activation/connectivity of the habenula, raphe
nucleus, ventral tegmental area, (ventral) striatum, anterior cingulate cortex,
insula, ventromedial prefrontal cortex and hippocampus/amygdala).

Secondary objectives:
(2) Establish difference in neurobehavioral changes between responders and
non-responders from pre-to-post treatment.
(3) Contribute to neurobiological validation of clinical change by relating
clinical change to change in key nodes of habenula-related monoaminergic
pathways from pre-to-post treatment.
(4) Contribute neurobiological validation of clinical predictors/risk factors
by relating these to key nodes of habenula-related monoaminergic pathways.

Observational, prospective, longitudinal cohort study.

Participants will have to attend two meetings at the MRI labs for
neurocognitive measurements and will also have to answer multiple
questionnaires as part of clinical assessments (see study design). The
neurocognitive measurements include feedback on performance that might be
frustrating or uncomfortable (e.g., shock).
All other procedures that the patients will undergo, are clinical routine and
would have been carried out regardless whether patients would participate in
our study.
Considering the extensive exclusion criteria, the screening procedure, and
constant monitoring of the subjects we do not expect (S)AE side effects for MRI
measurements. MRI measurements themselves do not pose any risk if appropriate
precautions are made. However, the noise and the relative confined space of the
MRI scanner may cause discomfort to some subjects.