A double blind, randomized, placebo controlled four way cross-over trial to investigate the effects of metoclopramide on central vasopressin release and HPA-axis activation

Major depressive disorder is a severely disabling medical illness that is
characterized by anhedonia, depressed mood, anxiety, cognitive dysfunction,
neurovegetative disturbances, psychomotor retardation or agitation and
increased suicide risk. The depressive disorders may be conceived of as being a
dysregulation of the physiological response to stress. Investigation of altered
regulation of the hypothalamus-pituitary-adrenal (HPA) axis is therefore one of
the main research strategies in depressive disorders. Increased activity of
arginine-vasopressin (AVP) might play a role in at least some forms of major
depression. AVP together with corticotrophin-release hormone (CRH) plays a
central regulatory role in the HPA-axis. These act synergistically on the
anterior pituitary to bring about release of adrenocorticotropin (ACTH), which
in turn stimulates the adrenal gland to produce cortisol. Recently, studies
have suggested that AVP could play a role in the pathogenesis of melancholic
depression, either directly or indirectly as a mediator of the HPA-axis.
Furthermore, studies performed with desmopressin, a synthetic analogue of
vasopressin, suggest that HPA axis regulation in depression shifts from primary
regulation by CRH towards a predominant AVP regulation by upregulation of the
V3 vasopressin receptor (V3-R). Thus, the development of V3-R-antagonists as
antidepressant could be a useful new strategy to treat these severe types of
depression. The development of such V3-R-antagonists could benefit greatly
from a reliable function test of the vasopressinergic drive and its effects on
the HPA-axis in humans. Such a function test could be used to characterize
abnormalities in vasopressinergic regulation in different groups of patients,
and to examine the effects of drugs acting on this system in healthy subjects
and patients. The aim of this study is to develop a challenge test with AVP
mediated HPA-axis activation as objective biomarker. Release of AVP by means of
a central mechanism leading to ACTH and cortisol release needs to be explored.
It has been shown that an anti-emetic agent, the D2-receptor antagonist
metoclopramide (MCP), also stimulates AVP-release from the hypothalamus and/or
the pituitary as measured peripherally in plasma. However, the nature of the
hypothesized central mechanism is not clear yet.

Arginine-vasopressin (AVP) is a physiological co-activator of the HPA-axis, and
would therefore be expected to act in the presence of an (endogenous)
CRH-stimulus. Under physiological circumstances, the endogenous release of CRH
varies considerably, depending on circadian influences and environmental stress
factors. Most experiments in healthy volunteers occur in the mid-morning, when
HPA-axis activation is significantly lower than during the early morning hours.
Under these circumstances, AVP-release by MCP is expected to yield only partial
ACTH-activation, leading to a relatively small neuro-endocrine response with a
high variability. Recent experiments with systemically administered doses of an
desmopressin (dDAVP), provided some indications that vasopressinergic
ACTH-release is limited, when endogenous HPA-axis-activity is low. Higher doses
of desmopressin were precluded by the well-known systemic cardiovascular and
coagulatory effects, so it is possible that higher pituitary AVP levels could
have led to larger ACTH/cortisol increases. At any rate, considerably higher
increases can be achieved with a recently developed 5HTP-challenge test. The
combination of endogenous AVP with the 5HTP-challenge is therefore expected to
cause a more sizeable and more reproducible increase in ACTH- and cortisol
release, than AVP alone.

Primary:
1. To establish the effect of MCP on the release of plasma AVP and subsequent
ACTH and cortisol secretion in the absence of a 5HTP-challenge.
2. To establish the effect of MCP on the release of plasma AVP and subsequent
ACTH and cortisol secretion in the presence of a 5HTP-challenge.
3. To establish whether the effect of MCP combined with the 5HTP-challenge is
larger than the combined effects of the separate 5-HTP and MCP challenges.

Secondary:
1. To establish the effect of MCP on the release of plasma prolactin in the
presence and absence of a 5HTP-challenge.
2. To establish whether the serotonergic 5-HTP-challenge could also cause
plasma AVP release.
3. To establish the effect of these challenges on the salivary cortisol release.
4. To establish the concentration-effect-relationships for the pharmacodynamic
(neuroendocrine) responses.

Double blind, randomized, placebo-controlled, four-way cross-over trial.

Risks:
5-HTP
Single-dose oral administration of 5-HTP can result in short-lasting nausea,
vomiting, palpitations and lightheadedness.

Carbidopa
There are no expected side effects of short-term use of carbidopa, although it
can intensify the side-effects of 5-HTP.

Granisetron
Granisetron can cause headache, constipation, diarrhoea and sedation.

MCP
Metoclopramide can cause drowsiness, acute extra-pyramidal side-effect (EPS),
anxiety and either accelerated absorption or decreased bioavailability for
concomitantly administered drugs due to its prokinetic effect. Long term use of
metoclopramide may lead to tardive dyskinesia, depression and erectile
dysfunction.

Drug-drug interaction effects:
MCP and granisetron may have a synergistic effect on sedation and depression of
the CNS. MCP may cause increased stomache transit time and decreased duodenal
transit time. No other pharmacokinetic or pharmacodynamic drug-drug interaction
effects for the combinations 5-HTP; CBD; MCP; granisetron are known.

Rare adverse events during the study
As with any medication, rare side effects cannot be excluded beforehand.
Occasional reports of the following adverse events have been made:
• 5-HTP may cause dullness and depressed mood.
• Granisetron may rarely cause allergic reactions (varying from rash to
anaphylactic reactions) or transient elevation of serum transaminases.
• Hypotension and depression may occur with i.v. use of metoclopramide.

Antidotes:
Adverse events will be treated symptomatically if necessary (paracetamol for
headaches, 2mg granisetron p.o. additionally for breakthrough nausea or
vomiting).

For 5-HTP and granisetron no specific antidotes exist. Metoclopramide-induced
acute EPS (eg. acute dystonia) can be treated with an anti-cholinergic agent
eg. biperiden hydrochloride administered either orally or intramuscularly,
depending on the severity of the EPS.

Burden:
1. no coffee/tea/chocolate on study days;
2. no smoking on study days;
3. no alcohol 24 hours preceding and during each study day;
4. no excessive physivcal activity (eg. sport) 48 hours preceding every study
day;
5. no brushing of teeth on the morning of each study day;
6. tryptophane deficient diet will be supplied. Fluid intake restricted to
water and no fruit allowed;
7. 4,5 hours semi-supine on bed to minimalize basal HPA-axis activity on each
study day.