Differences in serotonin synthesis between patients with major depression and healthy controls, measured with [11C]5-HTP PET

In literature, depressive symptoms and antidepressant effects are often related
to serotonin (5-HT) neurotransmission in the brain. In addition, a possible
reason for the moderate effectiveness of antidepressants may be related to
serotonin synthesis rates. A reduction in serotonin synthesis could reduce
serotonin stores, resulting in insufficient availability of serotonin for
release. There are indications that serotonin synthesis is decreased in the
brain of depressed patients.
The measurement of serotonin synthesis in the brain is possible with positron
emission tomography (PET) and by using the tracer [11C]5-HTP. Previous studies
show, that the uptake of this tracer is reduced in depressed patients.
Although, actual synthesis rates have never been looked at, which can be
calculated by kinetic modeling. Therefore in this study, we look at the
difference in synthesis rate between healthy volunteers and depressed patients.

Primary: a) To asses whether there is a difference in patients with major
depression and healthy controls in serotonin synthesis rates.
Secondary: a) Do these rates correlate with severity of depression? b) Does
serotonin synthesis correlate with other factors like neuroticism or coping
style? c) Or is there a relation with glutamate levels or performance in fMRI
tasks?

The study design is a case-control study where we compare patients with major
depression with healthy controls, to see if they differ in baseline 5-HT
synthesis rates. Depressed patients will be recruited via the University
Medical Center Groningen (UMCG), via their treating physician, or through
Roden, GGZ Drenthe, and healthy controls will be recruited through
advertisement and distribution of flyers (E3_flyer_5-HTP). Only drug-naïve
patients are included in the study.
Patients will be asked by their physician whether they are interested to be
informed about the study. Next, they receive verbal and written information
(E1_informatie Vrijwilligers/patienten) from the investigator. They will be
asked whether they are interested to participate in the imaging study, during
which they will undergo a PET scan and a MRI scan. In addition, they are told
they will have to fill in a few questionnaires about personality traits and
coping style.
When the subjects received the information for participants, they have two
weeks to decide whether they want to participate in the study. When the subject
agrees, he can sign the informed consent and make an appointment with the
investigator which will subsequently fill in the informed consent.
All participants will receive a medical examination including: anamnesis and
physical examination. The medical examination together with a MINI-plus and a
questionnaire about their medical history (F1_medische vragenlijst) is
performed by the research psychiatrist to determine if the subject meets the
inclusion and exclusion criteria. If not, they wiil be excluded from the study
and their information will be discarded.

First, 5 healthy subjects and 5 depressed patients undergo a baseline scan to
validate the tracer for the use in our facilities and assess whether there is
an initial difference between the groups. When through power analysis it
becomes apparent that significant differences in serotonin synthesis rates will
be obtained between groups, another 2 x 5 subjects are included. A significant
difference would indicate a physiological condition that could contribute to
the pathophysiology of depression, but more importantly it suggests an
important target for antidepressants. When the scans are not like we expected
(low resolution, failure kinetic modeling), the study is not continued. A low
resolution would result in high variability between subjects, which we can
check in controls. The scans are analyzed by kinetic modeling, where a curve is
fitted through the activity data. By visual inspection of the curve fit one can
if this fit is appropriate for data analysis.

The only interventions are a [11C]5-HTP PET scans and a MRI scan. This tracer
is already produced in the department of Nuclear Medicine and Molecular Imaging
for the visualization of neuro-endocrine tumours, so we are familiar with the
procedure.
For kinetic modeling an arterial input function is needed, obtained by
continuous arterial blood sampling during the PET scan (185 ml). In addition,
blood samples for measurements of metabolites, tryptophan/ amino acid ratios,
and genetic polymorphisms are determined (5 ml). Prior to the scan, patients
and healthy controls will complete the IDS-RS questionnaire to assess severity
of depressive symptoms, the NEO-PI-R for personality traits, and the Utrechtse
Coping Lijst for coping style.

In total, there are two groups needed:
1) 10 Healthy controls
2) 10 Depressed patients

Patients: randomized treatment with a SSRI or CBT and 2 PET scans before and
after 8 weeks of treatment + 1 MRI; healthy controls: 1 PET scan + 1 MRI.

The risks in this study are limited as no new drug is being tested and all
procedures have been performed in human before. The PET scan procedure is being
performed at the department of Nuclear Medicine and Molecular Imaging on a
regular base by trained and skilled technicians. According to the International
Commission on Radiological Protection (ICRP62) the radiation level of 2 times
1.45 mSv (for 400 MBq, see IMPD of [11C]-5-HTP) is within category IIb (1-10
mSv, minor to moderate risk).
However, some of the procedures like arterial canulation are invasive and
possibly uncomfortable. This burden is in proportion with the potential value
of this study, because the outcome can be of great medical importance. The
mechanisms underlying depressive symptoms are unknown. In addition, there is no
fast acting antidepressant on the market, and differences in serotonin
synthesis rate at baseline or changes due to treatment may be associated with
therapeutic efficacy. Therefore, it is of great importance to know the
difference in 5-HT synthesis rate between healthy controls and depressive
patients at baseline levels, as hereafter we can investigate the effect of
antidepressant drugs on 5-HT synthesis.