A randomized, parallel, double-blind, placebo controlled trial to investigate HPA-axis activation before and after electro-convulsive therapy in patients with a major depressive episode using an orally administered 5-HTP challenge test

The relevance of assessment of serotonergic stimulation of HPA-axis in major
unipolar or bipolar depressive disorder.
There is compelling evidence that among the biological factors predisposing a
person to major depression, alterations in presynaptic 5-HT activity,
alterations in postsynaptic 5-HT2 and 5-HT1A receptors in the brain, and
reciprocal relationships between dysfunctions in these systems and the
hypothalamus-pituitary-adrenal (HPA)-axis play an important role. Major
depression is characterized by an increased number, affinity, or responsivity
of central postsynaptic 5-HT2 receptors. This is associated with an increased
HPA-axis (cortisol, ACTH) response to 5-HT precursors L-TRP and 5-HTP. Although
oral administration of 5-Hydroxytryptophane (5-HTP) is a commonly used
serotonergic challenge of the HPA-axis, there is little standardization of
5-HTP-challenge tests, and its use has been hampered by unclear
pharmacokinetics. Furthermore, a narrow window exists between neuroendocrine
responses and side effects, which limits its usefulness in patient studies.

The need for the development of a reproducible well-tolerated 5-HTP-challenge
Recently, several studies were performed in healthy volunteers at CHDR to
develop a reproducible well-tolerated serotonergic challenge of the HPA-axis.
This oral challenge test consists of several drugs:
-the serotonin precursor 5-hydroxytryptophan (5-HTP) at a dose of 100 mg, to
stimulate serotonergic activity of the central nervous system
-the L-aromatic decarboxylase-inhibitor carbidopa at two doses of 100 and 50
mg, to inhibit peripheral conversion of 5-HTP with the aims of reducing
peripheral gastrointestinal and cardiovascular adverse effects, enhancing brain
exposure and diminishing the doses of 5-HTP
-the selective 5HT3-antagonist granisetron at a dose of 2 mg, to prevent nausea
and vomiting

Recently a challenge test consisting of 5-HTP 100 mg, 200mg and 300mg combined
with CBD 100 mg + 50 mg (5-HTP100/CBD100+50) was investigated and found to
produce a reliable dose-dependent release of cortisol. Its pharmacokinetics
were predictable and variability was acceptable, but its applicability was
limited due to the frequent occurrence of nausea and vomiting. Therefore,
maximal stimulation of the serotonergic system was precluded. Since suboptimal
stimulation of central serotonergic pathways may lead to minimilization of
differences between treatment effects (eg. healthy volunteers vs. patients)
this challenge was combined with an anti-emetic. 5-HTP 200 mg combined with CBD
100mg + 50mg (5-HTP200/CBD100+50) challenge test was combined with 2 mg
granisetron and found to be effective in curbing its side-effects (figure 2)
with maintenance of a predictable serum cortisol response and pharmacokinetics.

This challenge test was found to produce reproducible stimulations of the
HPA-axis, evidenced by dose-dependent increases in (both plasma and salivary)
cortisol and (more variably) of ACTH. The challenge did not lead to any
increases in prolactin (contrary to 5-HTP-challenges without granisetron) and
limited nausea without vomiting.

Other serotonergic challenges (like mCPP, 5-HTP alone, or SSRIs) are often
characterized by low tolerability, poor reproducibility and/or limited HPA-axis
stimulation. This 5-HTP-challenge developed at CHDR offers the most balanced
serotonergic challenge that is available today.[3-5] This makes this challenge
suitable for studies in patients, where assessment of serotonergic activation
can provide important pathophysiological information about abnormalities of the
HPA-axis in (subsets of) disease, and responses to treatments. Restoration from
HPA-axis abnormalities with clinical responses to treatment has been
documented, particularly in depressed patients who underwent electroconvulsive
therapy (ECT). Commonly, HPA-axis abnormalities and their restoration after
treatment is assessed with the dexamethasone suppression test (DST) or the
dexamethasone/corticotropin-releasing hormone (DEX/CRH) test. Currently there
are no studies available that evaluate HPA-axis function before and after ECT
treatment with a challenge of endogenous serotonergic activity. This study aims
to apply this newly developed challenge in patients with major depressive
disorder, before and after ECT.

Primary:
1. to investigate the serotonergic HPA-axis activation (cortisol, ACTH,
prolactin) in patients with a major depressive episode, using a newly developed
oral 5-HTP-challenge administered before the first ECT treatment.
2. to investigate the effects of an ECT course on serotonergic HPA-axis
activition (cortisol, ACTH, prolactin) in patients with a major depressive
episode, using a newly developed oral 5-HTP-challenge administered before the
first and after the last ECT treatment.
3. to investigate the tolerability of a newly developed oral 5-HTP-challenge in
patients with a major depressive episode (Visual Analogue Scales).
4. to investigate the safety of a newly developed oral 5-HTP-challenge in
patients with a major depressive episode (in terms of Adverse Events).

Secondary:
1. to investigate the kinetics of 5-HTP in patients with a major depressive
episode.
2. to investigate the autonomic effects (temperature, blood pressure, heart
rate) of a newly developed oral 5-HTP-challenge in patients with a major
depressive episode
3. to explore the relationship between plasma and salivary cortisol profiles in
patients with a major depressive episode receiving a newly developed 5-HTP
challenge.
4. to explore the relationship between clinical response (CPRS) and
neuroendocrine 5-HTP-challenge response (ACTH, cortisol, prolactin) before and
after a course of ECT.

Pilot study:
In order to assess practical feasibility of the study and the burden of the
study procedures for the patients, a pilot study (consisting of the first 5
patients or the first 6 months of study duration, whichever comes first) will
be performed. The results will be presented to the ethics committee for review,
prior to execution of the rest of the study

Randomized, parallel, double-blind, placebo controlled administration of an
oral 5-HTP challenge test before and after electroconvulsive therapy (ECT).

The trial will consist of two parts separated by an interim analysis:

Part 1: Randomization in the first part will be asymmetrical with a 2:1 ratio
of active:placebo treatment. 10 patients will receive 5-HTP and 5 patients will
receive placebo.

Part 2: Randomization for the second part will be performed after the interim
analysis. If decided to proceed with the second part, 10 more patients will
receive 5-HTP and 5 more patients will receive placebo.

At the start of part 1 of the trial, a pilot study will be performed with 5
patients or during 6 months (whatever occurs first). The randomisation ratio of
active:placebo treatment is 2:1, so after inclusion of 5 patients, at least 3
patients will have received the active treatment.

The results of the pilot study will be submitted to the Medical Ethics
Committee of Leiden University Medical Centre prior to continuing the study.
This will include the burden to patients, adverse events, the number of
screened patients and the percentage of excluded patients after screening will
be calculated, to evaluate the feasibility of the study. Based on the results
of this interim analysis and the subsequent evaluation by the Medical Ethics
Committee, the trial will either cease, continue or an amendment will be
submitted before continuing in the case of change in the ethical nature of the
original protocol.

- 2 days prior to the first and 1 day after the last ECT treatment patients
will receive either a 5-HTP challenge or a placebo challenge.
- Patients are medication free since they are indicated for electroconvulsive
therapy (ECT)
- Questionnaires are administered as part of routine patient care and do not
signify additional burden to the patients.
- The 5-HTP challenge has been developed at CHDR and the PD effects, PK
characteristics and safety have been studied well in at least 5 healthy
volunteer trials.
- During the challenge patients are required to remain on bed (in total 4.5
hours).
- Patients receive an intravenous cannula on each study day for blood sampling.
- Patients may develop self limiting and short lasting nausea as side-effect of
orally adminsitered 5-HTP.