Exploring the Pharmacomicrobiomics of Depression

The high prevalence of psychiatric disorders puts a burden on the society. A
disorder that greatly contributes to this burden is depression, with a
life-time prevalence of 16-20%. Beyond the societal impact, depression can have
a tremendous impact on the individual, as it affects, amongst others, cognitive
abilities, independency, and general well-being. If persistent, depression is
commonly treated with anti-depressant medication. Unfortunately, the treatment
efficacy for drug treatments is limited. Anti-depressants are prescribed in a
trial-and-error fashion, and patients* treatment response is highly variable,
with overall one-third of patients not responding to medication. Furthermore,
patients commonly experience debilitating side effects such as weight increase,
metabolic dysfunction, and gastrointestinal complaints. Ineffective treatment
and medication-induced health risks add significantly to the patients* as well
as to the societal disease burden. Therefore, to improve treatment efficacy, a
personalized treatment approach is desirable.

A promising but highly overlooked candidate contributing to variation in
treatment efficacy are the gut microbiota, residing in the human intestinal
tract in trillions. The gut microbiota are involved in myriad functions,
including digestion and absorption of nutrients. Preliminary evidence suggested
a modulating role for the gut microbiota in treatment response and side-effects
of anti-depressant medication. Several studies describe a reduction in overall
bacterial diversity and altered abundance of specific bacteria as a result of
anti-depressant medication, such as selective serotonin reuptake inhibitors
(SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs) and Tricyclic
Compounds (TCAs). Moreover, a recent study reports differences in the gut
microbial composition between treated and untreated patients with depression,
but also between treatment-resistant and -responding patients, suggesting a
role of the gut microbiota in the treatment efficacy.

Several mechanisms could underly such a modulating effect of the gut microbiota
on treatment efficacy. In terms of medication, the gut microbiota process oral
medication before uptake in circulation, potentially modulating drug metabolism
and absorption, and thereby to the treatment effect. A specific mechanism
originates from the observed reduction in the abundance of spore-forming taxa
such as T. sanguinis in animal and in-vitro studies. These are bacteria
regulating serotonin metabolism, one of the main neurotransmitters involved in
major depressive disorder. Interestingly, the majority of serotonin is produced
in the gut where it affects gut immunity and gut motility, processes related to
gastrointestinal side effects of SSRIs/SNRIs and TCAs. Hence, alterations in
the guts* serotonin metabolism may affect treatment efficacy, both in terms of
experienced symptoms and (gastrointestinal) side-effects.

Putting this all together, the gut microbiota are a plausible modulator for
treatment efficacy in patients with depression. Possibly, medication-induced
changes in the microbial community can explain part of the variability in the
antidepressant treatment efficacy between patients. Although preliminary
evidence is promising, longitudinal clinical data linking medication-induced
gut microbial effects to treatment success in patients with depression is
currently lacking, stressing the need for further research.

This study has been transitioned to CTIS with ID 2024-518101-18-02 check the CTIS register for the current data.

The main objective of this project is to associate the gut microbial community
with treatment efficacy (i.e., relieve in symptoms and side effects) in
patients with suspected treatment-resistant depression.
The secondary objective of this project is to clarify the role of drug
metabolism and absorption in the association between the gut microbial
community and treatment efficacy.

This is an observational, longitudinal study. Patients will come in for three
visits as a part of their regular treatment. During the first visit the intake
takes place. In between the first and second visit the current medication is
phased out, and the second visit takes place about seven days (~ 5 times the
half-life of the current medication) after stopping the current medication
treatment. The third visit takes place approximately six to eight weeks after
initiating the new medication treatment. All visits take place on site.

Patients have a prescription for an antidepressant in the class SSRI/SNRI or
TCA, prescribed as a part of regular care. Patients will start the treatment
after the second (baseline) visit, after the previous antidepressant has
completely phased out. The choice of antidepressant is determined using
national guidelines (farmacotherapeutisch kompas).

The burden for the participating patients consists of providing two stool
samples at home, six to eight weeks apart. Optionally, patients can consent to
an additional blood draw by venipuncture apart from their standard care (10ml;
six to eight weeks after starting a new medication). The risks, and physical
and psychological discomfort associated with participating in this study are
negligible. All other procedures are part of their regular treatment program.