de Winter RF, van Hemert AM, DeRijk RH, Zwinderman KH, Frankhuijzen-Sierevogel
AC, Wiegant VM, Goekoop JG.
Anxious-retarded depression: relation
with plasma vasopressin and cortisol.
"Dysregulation of the hypothalamus-pituitary-adrenal
(HPA) axis is related to melancholic or endogenous depression; however, the strength
of this relationship depends on the definition of the specific depression subcategory.
A two-dimensionally defined subcategory, anxious-retarded depression, is related
to melancholic depression. Since arginine vasopressin (AVP) activates the HPA
axis, and both major depression and the melancholic subcategory are associated
with elevated plasma AVP levels, we investigated whether the plasma AVP level
is also elevated in anxious-retarded depression, melancholic depression and anxious-retarded
melancholic depression, and whether plasma AVP and cortisol levels are correlated
in these subcategories. A total of 66 patients with major depression not using
oral contraception were investigated. Patients with anxious-retarded depression
had a highly significant AVP-cortisol correlation, while no such correlation was
found in patients with nonanxious-retarded depression. Log-transformed mean plasma
AVP values were higher in patients with anxious-retarded depression than in patients
with nonanxious-retarded depression. Patients with anxious-retarded melancholic
depression also had a significantly elevated level of plasma AVP and a highly
significant correlation between plasma AVP and cortisol levels. The correlation
was low in patients with melancholic depression. Anxious-retarded depression may
be a useful refinement of the melancholic subcategory with regard to dysregulation
of the HPA axis and plasma AVP release." [Abstract]
Londen L, Kerkhof GA, van den Berg F, Goekoop JG, Zwinderman KH, Frankhuijzen-Sierevogel
AC, Wiegant VM, de Wied D.
Plasma arginine vasopressin and motor
activity in major depression.
Biol Psychiatry 1998 Feb 1;43(3):196-204
Previously, we found that mean plasma concentrations of arginine vasopressin (AVP),
but not of oxytocin (OT), were higher in depressed patients than in healthy controls.
Plasma AVP concentrations were positively correlated to clinically rated psychomotor
retardation. To further explore this previously reported relation we studied psychomotor
retardation by means of an activity monitor, which is a more fine-focused and
more objective instrument to analyze motor retardation than a clinical rating
scale. METHODS: Plasma AVP and OT concentrations, and day- and nighttime wrist
activity were measured in 48 in- and outpatients with major depression and 30
healthy controls during a period of 5 consecutive days and nights. RESULTS: Principal
components analysis revealed three components of motor activity: motor activity
during wakefulness, motor activity during sleep, and the awake/sleep time ratio.
In patients and controls an inverse relationship between plasma AVP concentrations
and motor activity during wakefulness was found. Patients with elevated AVP plasma
levels showed increased motor activity during sleep. CONCLUSIONS: These results
suggest that high plasma AVP levels are related to the clinical picture of daytime
psychomotor retardation and nighttime motor activity in major depression. Mean
plasma OT concentrations were not related to measures of motor activity."
Londen L, Goekoop JG, van Kempen GM, Frankhuijzen-Sierevogel AC, Wiegant VM, van
der Velde EA, De Wied D.
Plasma levels of arginine vasopressin elevated
in patients with major depression.
"Mentally healthy subjects show increased plasma
concentrations of the neuropeptides, arginine vasopressin (AVP) and oxytocin (OT),
under conditions of stress, but data are lacking about plasma concentrations of
AVP and OT in patients with major depression. We thus assessed plasma concentrations
of AVP and OT in patients with major depression (n = 52) and healthy controls
(n = 37). Mean plasma AVP concentrations were higher in the group of depressed
patients than in controls. A subgroup of 16 patients showed very high levels of
plasma AVP, but no other feature differentiating this subgroup from the other
patients was found. In-patients showed higher plasma AVP levels than out-patients,
and melancholic patients had higher plasma AVP levels than did nonmelancholic
patients. Plasma AVP levels were slightly related to psychomotor retardation and
significantly inversely to neuroticism. Patients' plasma OT concentrations had
a wider range than in controls. AVP and AVP-mediated functions may be a factor
in the clinical picture of depression, possibly by influencing the activity of
the hypothalamic-pituitary-adrenal axis." [Abstract]
test and the levels of serum growth hormone, plasma vasopressin and plasma homovanillic
acid in depressed in- and outpatients.
Acta Psychiatr Scand
"A total of 206 depressive patients (176 outpatients
and 30 inpatients) underwent a dexamethasone suppression test (DST). Resting levels
of serum growth hormone (GH), plasma vasopressin (AVP) and plasma homovanillic
acid (HVA) were also measured in a proportion of the patients. Fifty-seven per
cent of the endogenous patients showed nonsuppression of cortisol in the DST,
while 92% in the nonendogenous group showed normal suppression. The diagnostic
confidence of a positive test was 83%. The sensitivity and specificity of the
test was slightly higher among inpatients than out-patients, and serum cortisol
value at 4 p.m. was more useful than the morning value. No significant correlation
was found between severity of the depression as measured by the Hamilton Rating
Scale for Depression and serum cortisol. In single subjects there was, however,
an obvious correlation. The levels of serum GH, plasma AVP and plasma HVA did
not differ in the endogenous and nonendogenous groups, and there was no correlation
between serum cortisol in the DST and the concentrations of the other hormones
or HVA in plasma." [Abstract]
A, Hammer M, Vendsborg P, Christensen NJ, Rafaelsen OJ.
fluid vasopressin--changes in depression.
Br J Psychiatry
"Cerebrospinal fluid (CSF), thyrotropin releasing
hormone (TRH), CSF-vasopressin (AVP), plasma-AVP, CSF-osmolality, plasma-osmolality,
CSF-adrenaline (A) and -noradrenaline (NA) were measured in psychiatric patients
and controls. Psychiatric patients were classified according to ICD-9 and grouped
into endogenous depression, non-endogenous depression, mania and schizophrenia.
The depressive groups were classified according to the Newcastle Rating Scale
for Depression 1965. Severity of disease was quantified by BRMES, BRMS and BPRS.
No difference in CSF-TRH levels was seen among the different diagnostic groups
and controls. A positive correlation between CSF-TRH and CSF-A was demonstrated.
CSF-AVP concentrations were significantly lowered in both endogenous and non-endogenous
depression; no correlation with CSF-A or -NA was seen. Neither did any difference
between plasma levels of AVP, plasma-osmolality or CSF-osmolality appear among
the groups investigated." [Abstract]
G. Dinan, Ena Lavelle, Lucinda V. Scott, John Newell-Price, Sami Medbak, and Ashley
Desmopressin Normalizes the Blunted Adrenocorticotropin
Response to Corticotropin-Releasing Hormone in Melancholic Depression: Evidence
of Enhanced Vasopressinergic Responsivity
J. Clin. Endocrinol.
Metab. 84: 2238-2240
"Major depression is associated with significant
disturbance in hypothalamic-pituitary-adrenal axis functioning, including blunted
release of ACTH in response to CRH infusion. Eight melancholic depressives and
eight matched healthy comparison subjects underwent, in random order, the following
challenges: placebo, CRH, CRH+DDAVP. Blood for ACTH and cortisol estimation was
drawn at -15, 0, 15, 30, 45, 60, 90, and 120 min. A blunted release of ACTH, in
response to CRH challenge, was observed in depression (P < 0.01), whereas maximal
cortisol responses in both groups were similar, despite elevated baseline levels
in depression (P < 0.05). The combined CRH/DDAVP infusion produced similar
ACTH and cortisol release in both groups. These results suggest that melancholic
depression is associated with enhanced pituitary vasopressinergic responsivity."
Meller WH, Kathol RC, Jaeckle RS, Lopez JF.
of the pituitary-adrenal axis with arginine vasopressin in patients with depression.
Psychiatr Res 1987;21(3):269-77
"The ACTH response to arginine vasopressin
was the same in patients with depression while cortisol response was significantly
greater in patients with depression when compared to the control population. These
findings are consistent with the hypothesis that vasopressin corticotroph receptors
are not downregulated in depression and that there is increased adrenal responsiveness
in patients with depression to endogenous ACTH." [Abstract]
Carroll BT, Meller WH, Kathol RG, Gehris TL, Carter
JL, Samuelson SD, Pitts AF.
Pituitary-adrenal axis response to arginine
vasopressin in patients with major depression.
Res 1993 Feb;46(2):119-26
"Arginine vasopressin (AVP) was administered
to 21 patients with major depression and 20 normal control subjects. Thirty-two
subjects also underwent an overnight dexamethasone suppression test. The patient
group did not differ significantly from the control group in adrenocorticotropic
hormone (ACTH) or cortisol response. Dexamethasone suppression status did not
affect ACTH or cortisol response. This study supports the hypothesis that unlike
the response to corticotropin releasing hormone, the ACTH response to AVP is not
attenuated in depression." [Abstract]
Wied CC, Westenberg HG, Koppeschaar HP, Thijssen JH, van Ree JM.
of the pituitary-adrenal axis with a low dose [Arg8]-vasopressin in depressed
patients and healthy subjects.
"Graded doses arginine-vasopressin (AVP) were administered
to depressed patients and control subjects to compare the sensitivity of the pituitary-adrenal
system of these subjects for this compound. The plasma levels of cortisol, adrenocorticotropic
hormone (ACTH) and beta-endorphin were measured before and after intravenous AVP
injection. The hormonal output was taken as a measure of pituitary-adrenal function.
In control subjects 3 doses AVP and placebo were used, whereas in patients two
doses AVP, a low and a high dose, and placebo were tested. All tests were carried
out in the afternoon when the pituitary-adrenal system is stable and more susceptible
for stimulation. Patients were subdivided into dexamethasone suppressors and nonsuppressors
based on their DST status before testing to look for differences among these groups.
Control subjects showed no response of the hormones to the lowest dose AVP and
a moderate response to the higher doses. Interestingly, depressed patients as
compared to controls responded more to the lowest dose AVP in particular with
respect to ACTH. DST status did not influence the results. These findings suggest
an enhanced sensitivity of the pituitary to low doses AVP in depressed patients.
Thus, AVP might play a role in HPA dysfunction in depression." [Abstract]
Londen L, Goekoop JG, Kerkhof GA, Zwinderman KH, Wiegant VM, De Wied D.
24-h periodicity of body temperature and increased plasma vasopressin in melancholic
Eur Neuropsychopharmacol 2001 Feb;11(1):7-14
work has shown that plasma vasopressin levels of depressed patients were higher
than those of healthy controls. The aim of the present study was to determine
whether plasma vasopressin levels were correlated to parameters of the circadian
rhythm. Forty-one patients with major depression and twenty-five controls participated
in a case-control design under natural circumstances in a field study to investigate
plasma vasopressin levels three times daily, circadian motor activity, and the
24-h periodicity of body temperature for five consecutive 24-h periods. Temperature
measurements consisted of at least five, but mostly six or more measurements every
24 h. Twenty-two percent of the patients, but none of the controls lacked 24-h
periodicity of body temperature. In melancholic patients increased vasopressin
levels in plasma correlated with a weak 24-h periodicity of body temperature.
The role of vasopressin is discussed in the light of the present findings."
B. Müller, Rainer Landgraf, Jens Preil, Inge Sillaber, Adelheid E. Kresse,
Martin E. Keck, Stephan Zimmermann, Florian Holsboer, and Wolfgang Wurst
Activation of the Hypothalamic Vasopressinergic System in Mice Deficient for the
Corticotropin-Releasing Hormone Receptor 1 Is Dependent on Glucocorticoids
"Deficiency of CRH receptor 1 (CRHR1) severely impairs
the stress response of the hypothalamic-pituitary-adrenocortical (HPA) system
and reduces anxiety-related behavior in mice. Intriguingly, in mice deficient
for the CRHR1 (Crhr1-/-), basal plasma levels of ACTH are normal, suggesting the
presence of compensatory mechanisms for pituitary ACTH secretion. We therefore
studied the impact of the hypothalamic neuropeptides arginine vasopressin (AVP)
and oxytocin (OXT) on HPA system regulation in homozygous and heterozygous Crhr1
mutants under basal and different stress conditions. Basal plasma AVP concentrations
were significantly elevated in Crhr1-/- mice. AVP messenger RNA expression was
increased in the paraventricular nucleus of Crhr1-/- mutants together with a marked
increase in AVP-like immunoreactivity in the median eminence. Administration of
an AVP V1-receptor antagonist significantly decreased basal plasma ACTH levels
in mutant mice. After continuous treatment with corticosterone, plasma AVP levels
in homozygous Crhr1-/- mice were indistinguishable from those in wild-type littermates,
thus providing evidence that glucocorticoid deficiency is the major driving force
behind compensatory activation of the vasopressinergic system in Crhr1-/- mice.
Neither plasma OXT levels under several different conditions nor OXT messenger
RNA expression in the paraventricular nucleus were different between the genotypes.
Taken together, our data reveal a selective compensatory activation of the hypothalamic
vasopressinergic, but not the oxytocinergic system, to maintain basal ACTH secretion
and HPA system activity in Crhr1-/- mutants." [Full
Nakase S, Kitayama I, Soya H, Hamanaka
K, Nomura J.
Increased expression of magnocellular arginine vasopressin
mRNA in paraventricular nucleus of stress-induced depression-model rats.
"Exposure of rats to long-term intermittent walking
stress results in a persistent inactive behavior in the subsequent two weeks in
about 50% of rats (depression-model rats) while the activity returns gradually
toward baseline in other rats (spontaneous recovery rats). To explore the role
of hypothalamic-pituitary-adrenal (HPA) axis in these depression-model rats, we
examined changes in the gene expression of corticotropin-releasing factor (CRF)
and arginine vasopressin (AVP) in the paraventricular nucleus (PVN) of the hypothalamus
using in situ hybridization histochemistry. We imposed the intermittent walking
stress for two weeks in male Wistar rats, then compared the response of the depression-model
rats and spontaneous recovery rats. The expression of CRF mRNA in PVN increased
significantly by 60% and 80% compared to controls, in the model and the recovery
rats, respectively. The magnocellular AVP mRNA in PVN increased significantly
in the model rats by 60% compared to controls. The concentration of plasma ACTH
increased in the model rats, but no significant change in plasma corticosterone
or AVP level was noted in all three groups. Our results suggest that increased
magnocellular AVP in PVN plays an important role in the regulation of HPA axis
of the depression-model rats induced by long-term walking stress." [Abstract]
FC, Hoogendijk WJ, Stam FC, Tilders FJ, Swaab DF.
of corticotropin-releasing hormone expressing neurons in the hypothalamic paraventricular
nucleus of depressed patients.
Neuroendocrinology 1994 Oct;60(4):436-44
hypothalamo-pituitary-adrenal (HPA) axis is known to be activated in depressed
patients. Although direct evidence is lacking, this activation is hypothesized
to be due to hyperactivity of corticotropin-releasing hormone (CRH) neurons of
the hypothalamic paraventricular nucleus (PVN). Recent immunocytochemical studies
in experimental animals and in humans showed that the number of CRH-expressing
neurons correlated with the activity of these neurons. In addition, colocalization
of AVP in CRH neurons has been shown to be an index for the secretory activity.
Therefore, we estimated the total number of CRH-immunoreactive neurons and their
fraction showing colocalization with AVP in the PVN of 10 control subjects and
of 6 depressed patients who were diagnosed to be suffering from a major depression
or a bipolar disorder. The mean total number of CRH-expressing neurons of the
6 depressed patients was four times higher, and the number of CRH neurons co-expressing
AVP was almost three times higher than those in the control group. We also determined
the two activity parameters of CRH neurons in the PVN of 2 subjects with a depressive
organic mood syndrome or a depressive disorder not otherwise specified. In these
two 'non-major depressed' subjects, the activity parameters of CRH neurons were
comparable to those of control subjects. Our observations strongly support the
hypothesis that CRH neurons in the PVN are hyperactivated in major depressed patients.
This hyperactivity might be causally related to at least part of the symptomatology
of depression." [Abstract]
Purba JS, Hoogendijk WJ, Hofman MA, Swaab DF.
number of vasopressin- and oxytocin-expressing neurons in the paraventricular
nucleus of the hypothalamus in depression.
Arch Gen Psychiatry
"BACKGROUND: Cerebrospinal fluid levels of arginine
vasopressin (AVP) and oxytocin (OXT) have been found to change in mood disorders.
In the present study, the numbers of AVP-immunoreactive (IR) and OXT-IR neurons
were determined in the paraventricular nucleus (PVN) of the human hypothalamus.
METHODS: Postmortem brain tissue was fixed in formalin, embedded in paraffin,
and stained for AVP and OXT using immunocytochemical techniques. The number of
IR neurons in the PVN was estimated by morphometry in eight depressed patients
ranging in age from 21 to 85 years and eight age-matched controls ranging in age
from 23 to 88 years. RESULTS: The numbers of AVP-IR and OXT-IR neurons in the
PVN of patients with mood disorder were increased by 56% and 23%, respectively.
No differences were found in AVP-IR or OXT-IR cell numbers between three patients
with major depression and three patients with bipolar depression. The numbers
of AVP-IR and OXT-IR neurons in two patients with depression not otherwise specified
were within the same range as in the six other patients with a mood disorder.
CONCLUSIONS: The AVP and OXT neurons were activated in the PVN in patients with
major depression or bipolar disorder. This activation may be associated with activation
of the hypothalamic-pituitary-adrenal axis in these patients, since both AVP and
OXT are known to potentiate the effects of corticotropin-releasing hormone. Because
of their central effects, activation of AVP and OXT neurons may also be related
to symptoms of major depression or bipolar disorder." [Abstract]
Lenzinger E, Meszaros K, Hornik K, Parzer P, Hollerer
E, Langer G, Resch F, Legros JJ.
Correlation between vasopressin
baseline and TSH-blunting in depressives.
1996 Mar 1;39(5):341-5
"A blunted thyrotropin (TSH) response is a predictor
of a good response to antidepressant drug treatment in depressives and neuroleptic
treatment in paraphrenic patients (Larger et al 1986). The aim of the following
study was to elucidate possible relationships between different endocrine systems
and to shed light on the pathogenetic hypotheses of TSH-blunting. In order to
evaluate especially hypothalamic activity in severe depression we were interested
in the vasopressin system as another hormonal system underlying hypothalamic control.
Thirty-four patients who met the criteria for major depression according to DSM-III-R
were subjected to the thyrotropin-releasing hormone (TRH) test. We also took baseline
readings of the cortisol, neurophysinI (hNpI, reflecting vasopressin plasma levels),
and neurophysinII (hNpII, reflecting oxytocin plasma levels) levels. Likelihood
ratio tests were done with logistic regression models to analyze the phenomenon
of TSH-blunting. We observed that the likelihood of a blunted TSH response increases
with higher levels of hNpI and low levels of cortisol, but is unrelated to hNpII
RG, Jaeckle RS, Lopez JF, Meller WH.
Consistent reduction of ACTH
responses to stimulation with CRH, vasopressin and hypoglycaemia in patients with
Br J Psychiatry 1989 Oct;155:468-78
patients with major depression and 12 control subjects were administered corticotropin-releasing
hormone (CRH), aqueous arginine vasopressin (AVP), and insulin hypoglycaemia (IH)
to test for differences in hypothalamic-pituitary-adrenal (HPA) axis function.
Patients with major depression demonstrated lower ACTH responses to CRH when compared
with controls, and a trend toward such after administration of AVP. Despite lower
ACTH responses in patients with depression, there were no differences in cortisol
responses to these stimuli. In the CRH and AVP tests, there was no correlation
between the basal cortisol and ACTH responses in either controls or patients,
but in the IH test there was a negative correlation between these responses for
both groups. The ACTH responses to CRH and AVP were positively correlated in controls
and patients. Cortisol responses to all three provocative stimuli were positively
correlated in both subject groups. These findings are consistent with the hypothesis
that hypothalamic or supra-hypothalamic overactivity may be involved in the development
of HPA-axis abnormalities in patients with depression." [Abstract]
Londen L, Goekoop JG, Zwinderman AH, Lanser JB, Wiegant VM, De Wied D.
performance and plasma cortisol, arginine vasopressin and oxytocin in patients
with major depression.
Psychol Med 1998 Mar;28(2):275-84
The aim of the study was to search for the existence of, and define, a possible
relationship between performance in neuropsychological tests and baseline concentrations
of plasma cortisol, vasopressin and oxytocin in medication-free patients with
a major depressive episode. METHODS: Measures of depression and anxiety were obtained
and a neuropsychological battery was presented. Blood for neuropeptide analysis
was drawn by venepuncture at 8.00, 16.00 and 23.00 h. RESULTS: The melancholic
patients performed less well on the neuropsychological battery than did the non-melancholic
patients, but these differences could be accounted for by the severity of the
illness. Global intellectual functioning was negatively correlated with mean baseline
plasma concentrations of cortisol. Patients with high mean plasma vasopressin
concentrations remembered more auditory presented words in the delayed recall
test and produced more intrusions in the visual word learning list than did patients
with low or normal mean plasma vasopressin concentrations. No association was
found between neuropsychological performance and plasma concentrations of oxytocin.
CONCLUSIONS: Our findings support the hypothesis that elevated baseline plasma
cortisol concentrations are related to cognitive impairment in depressed patients
and the hypothesis that the neuropeptide vasopressin independently enhances memory,
directly or indirectly through increasing arousal and attention." [Abstract]
Rubin RT, O'Toole SM, Rhodes ME, Sekula LK, Czambel
Hypothalamo-pituitary-adrenal cortical responses to low-dose
physostigmine and arginine vasopressin administration: sex differences between
major depressives and matched control subjects.
Res 1999 Dec 13;89(1):1-20
"Of heuristic value in understanding the neurochemistry
of major depression is whether the hypothalamo-pituitary-adrenocortical (HPA)
axis hyperactivity that occurs in this illness can be related to putative neurotransmitter
dysfunction(s). Cholinergic neurotransmission stimulates hypothalamic corticotropin
releasing hormone (CRH) and arginine vasopressin (AVP) secretion, both of which
stimulate pituitary corticotropin (ACTH) secretion, but whether the HPA axis in
humans is activated only by doses of cholinergic agonists that produce noxious
side effects remains controversial. To test the hypothesis of increased cholinergic
sensitivity in major depression, physostigmine (PHYSO), a reversible cholinesterase
inhibitor, was administered to patients and control subjects at a dose that elevated
plasma ACTH, cortisol, and AVP concentrations but produced few or no side effects.
Exogenous AVP also was administered to determine if it would augment the effect
of low-dose PHYSO on the HPA axis. Twelve premenopausal or estrogen-replaced female
major depressives, 12 individually matched female control subjects, eight male
major depressives, and eight matched male control subjects underwent four test
sessions 5-7 days apart: PHYSO (8 microg/kg IV), AVP (0.08 U/kg IM), PHYSO + AVP,
and saline control. Serial blood samples were taken before and after pharmacologic
challenge and analyzed for ACTH1-39, cortisol, and AVP. Estradiol and testosterone
were also measured at each test session. PHYSO (8 microg/kg) significantly increased
plasma ACTH, cortisol, and AVP, while producing no side effects in approximately
half the subjects and predominantly mild side effects in the other half. These
hormone increases following PHYSO occurred primarily in the female depressives
and the male control subjects and were not significantly related to the presence
or absence of side effects. The greater the ACTH and AVP responses to PHYSO, the
stronger their correlation, suggesting that AVP may have been acting as a secretagogue
for ACTH. Administered AVP significantly increased the secretion of ACTH in the
patients and control subjects to a similar degree, and AVP given after PHYSO did
not augment the HPA axis response to a greater degree in the depressives than
in the control subjects. Plasma estradiol and testosterone were within the normal
range for all four groups of subjects and were not significantly related to their
HPA axis hormone responses. The study results support the hypothesis of heightened
cholinergic sensitivity in premenopausal female, but not in male, patients with
major depression. The low dose of PHYSO used may represent a useful paradigm for
central cholinergic stimulation of the HPA axis." [Abstract]
van West D, Del-Favero J, Aulchenko Y, Oswald P,
Souery D, Forsgren T, Sluijs S, Bel-Kacem S, Adolfsson R, Mendlewicz J, Van Duijn
C, Deboutte D, Van Broeckhoven C, Claes S.
A major SNP haplotype
of the arginine vasopressin 1B receptor protects against recurrent major depression.
Psychiatry. 2004 Mar;9(3):287-92.
"Increasing amounts of data suggest
that affective disorders might be related to dysregulation of the hypothalamic-pituitary-adrenal
(HPA) axis, one of the stress-response systems. Arginine vasopressin (AVP) influences
several symptoms, relevant to affective disorders, notable memory processes, pain
sensitivity, synchronization of biological rhythms and the timing and quality
of REM sleep. We examined whether genetic variations in the AVP receptor 1b gene
(AVPR1b) could be associated with increased susceptibility to affective disorders
using a gene-based association analysis of single-nucleotide polymorphisms (SNPs).
Five SNPs were identified in AVPR1b and genotyped in two well-diagnosed samples
of patients with recurrent major depression and matched controls. In the Swedish
sample, we observed significant allele (P=0.02) and genotype (P=0.01) association
with SNP AVPR1b-s3, and in the Belgian sample, a borderline significant association
with SNP AVPR1b-s5 (P=0.04). In both patient-control samples, the haplotype defined
by alleles A-T-C-A-G for the AVPR1b-s SNPs s1-s2-s3-s4-s5 was significantly over-represented
in controls compared to patients. Our data support a protective effect of this
major haplotype for recurrent major depression." [Abstract]
LV, Dinan TG.
Vasopressin and the regulation of hypothalamic-pituitary-adrenal
axis function: implications for the pathophysiology of depression.
"The role of arginine vasopressin (AVPNP) in the
control of adrenocorticotropic hormone (ACTH) secretion is explored, and in particular,
its involvement in various stress response paradigms which may be of relevance
in our understanding of the pathophysiology of depression. VP is released from
two sites in the hypothalamus; the parvicellular division of the paraventricular
nucleus (PVN), where corticotropin releasing hormone (CRH) is also formed, and
from the magnocellular neurons of the supraoptic nucleus (SON) and the PVN. The
intricate interaction with CRH, the other main ACTH secretagogue, and with glucocorticoids,
the inhibitory feedback component of hypothalamic-pituitary-adrenal-axis (HPA)
activity, is outlined. That VP plays an important role in the stress response
is now beyond doubt. Examination of the impact of psychological stressors on the
differential expression of VP and CRH at a hypothalamic and pituitary level has
been facilitated by advances in molecular biological techniques. Of importance
has been the cloning of the V1b receptor gene, the receptor at which AVP is active
in the anterior pituitary. Chronic stress paradigms, associated with HPA hyperresponsiveness,
and ACTH release following a novel superimposed stress, have been found with relative
consistency to show a shift in the CRH:AVP ratio. This may relate to differing
feedback sensitivity of AVP to glucocorticoid feedback restraint and the greater
responsivity of AVP over CRH to chronic stimulatory stress input. Evidence for
functionally distinct pools of ACTH releasing corticotropes, and the finding that
AVP levels more closely correlate with ACTH levels than do CRH levels, suggest
a more dynamic role for AVP in activity of the stress axis, and a primarily permissive
function for CRH. The renewed interest in the role of VP in HPA axis activity
may have important implications for furthering our understanding of psychiatric
conditions such as depression, where significant dysregulation of this axis is
seen. Elevated baseline cortisol, dexamethasone non-suppression and blunted CRH/ACTH
release have been consistently documented. The possible contribution of VP to
this hyperactivity, despite its known synergy with CRH, has been largely neglected.
In animal models there is clear evidence that chronic psychological stressors
increase the ratio of AVP to CRH production. Psychosocial stressors are intrinsically
linked with depressive illness. The finding of elevated levels of AVP in postmortem
studies of depressives and the lowering of CSF AVP levels by antidepressants,
raises the question of the precise role of AVP in the overactivity of the HPA
in depression, a finding that is currently attributed to overdrive of its HPA
regulatory companion, CRH." [Abstract]
G, Simiand J, Stemmelin J, Gal CS, Steinberg R.
The vasopressin V1b
receptor as a therapeutic target in stress-related disorders.
Drug Target CNS Neurol Disord. 2003 Jun;2(3):191-200.
of the stress response would appear to provide multiple opportunities for intervention,
but treatment strategies are often centered on the improvement of symptoms rather
than attempting to "treat" the stress response. However, recent efforts
have begun to focus on the development of pharmacological agents that can attenuate
the stress response itself, rather than the symptoms associated with stress. Although
CRF, which is the main regulator of the stress system, is the focus of current
interest, there is an accumulating body of evidence suggesting that the vasopressinergic
system may play an equal role in the regulation of the stress response, and that
V(1b) receptor antagonists may be of potential therapeutic benefit. The availability
of SSR149415, the first selective antagonist for the V(1b) receptor has allowed
us to evaluate this hypothesis. SSR149415 is able to attenuate some but not all
stress-related behaviors in rodents. While the antidepressant-like activity of
the compound was comparable to that of reference antidepressants, the overall
profile displayed in anxiety tests was different from that of classical anxiolytics,
such as benzodiazepines. The latter were active in a wide range of anxiety models,
whereas the V(1b) receptor antagonist showed clear-cut effects only in particularly
stressful situations. It is important to note that SSR149415 is devoid of central
depressant effects, even at high doses, and does not affect cognitive processes,
suggesting a large therapeutic window. Altogether, these findings suggest that
V(1b) receptor antagonists might be useful as a treatment for major depression
and stress disorders that result from traumatic events." [Abstract]
Griebel, Jacques Simiand, Claudine Serradeil-Le Gal, Jean Wagnon, Marc Pascal,
Bernard Scatton, Jean-Pierre Maffrand, and Philippe Soubrié
and antidepressant-like effects of the non-peptide vasopressin V1b receptor antagonist,
SSR149415, suggest an innovative approach for the treatment of stress-related
PNAS 99: 6370-6375; published online before print
"The limbic localization of the arginine vasopressin
V(1b) receptor has prompted speculation as to a potential role of this receptor
in the control of emotional processes. To investigate this possibility, we have
studied the behavioral effects of SSR149415, the first selective and orally active
non-peptide antagonist of vasopressin V(1b) receptors, in a variety of classical
(punished drinking, elevated plus-maze, and light/dark tests) and atypical (fear/anxiety
defense test battery and social defeat-induced anxiety) rodent models of anxiety,
and in two models of depression [forced swimming and chronic mild stress (CMS)].
When tested in classical tests of anxiety, SSR149415 produced anxiolytic-like
activity at doses that ranged from 1 to 30 mg/kg (i.p. or p.o.), but the magnitude
of these effects was overall less than that of the benzodiazepine anxiolytic diazepam,
which was used as a positive control. In contrast, SSR149415 produced clear-cut
anxiolytic-like activity in models involving traumatic stress exposure, such as
the social defeat paradigm and the defense test battery (1-30 mg/kg, p.o.). In
the forced swimming test, SSR149415 (10-30 mg/kg, p.o.) produced antidepressant-like
effects in both normal and hypophysectomized rats. Moreover, in the CMS model
in mice, repeated administration of SSR149415 (10 and 30 mg/kg, i.p.) for 39 days
improved the degradation of the physical state, anxiety, despair, and the loss
of coping behavior produced by stress. These findings point to a role for vasopressin
in the modulation of emotional processes via the V(1b) receptor, and suggest that
its blockade may represent a novel avenue for the treatment of affective disorders."
LV, Dinan TG.
Vasopressin as a target for antidepressant development:
an assessment of the available evidence.
J Affect Disord
"Hyperactivity of the hypothalamic-pituitary-adrenal
(HPA) axis is one of the key biological abnormalities described in major depressive
disorder, occurring in 30-50% of depressed subjects. Corticotropin-releasing hormone
(CRH) and vasopressin (AVP) are the main regulators of this stress system, with
the two neuropeptides acting synergistically in bringing about adrenocorticotropin
(ACTH) release from the anterior pituitary and cortisol from the adrenal gland.
Based on the demonstration of elevated cerebrospinal fluid levels of CRH in depressives,
and other evidence, it has been postulated that excess CRH and the resultant increased
HPA forward drive form the basis of neuroendocrine dysregulation in depression.
However, there is an accumulating body of evidence to support a significant role
for AVP in the regulation of pituitary-adrenal activity in health and also in
depressive disorder. This review, based on a Medline search from 1980 to 2001,
focuses on the functional neuroanatomy, receptor pharmacology, VP synergism with
CRH, and the data from clinical and pre-clinical studies that support an important
role for AVP in the pathophysiology of major depression. We suggest that future
antidepressants may target the vasopressinergic system." [Abstract]
Gal C, Wagnon J, Valette G, Garcia G, Pascal M, Maffrand JP, Le Fur G.
vasopressin receptor antagonists: development of selective and orally active V1a,
V2 and V1b receptor ligands.
Prog Brain Res 2002;139:197-210
further chemical developments in the oxindole family have led to the first specific
and orally active V1b receptor antagonists (with SSR149415 as a representative),
an awaited class of drugs with expected therapeutic interest mainly in ACTH-secreting
tumors and various emotional diseases such as stress-related disorders, anxiety
and depression. However, from the recently described tissue localization for this
receptor, we could also speculate on other unexpected uses. In conclusion, the
development of AVP receptor antagonists is a field of intensive pharmacological
and clinical investigation. Selective and orally active compounds are now available
to give new insight into the pathophysiological role of AVP and to provide promising
Gal C, Wagnon J, Simiand J, Griebel G, Lacour C, Guillon G, Barberis C, Brossard
G, Soubrie P, Nisato D, Pascal M, Pruss R, Scatton B, Maffrand JP, Le Fur G.
carboxamide (SSR149415), a selective and orally active vasopressin V1b receptor
J Pharmacol Exp Ther 2002 Mar;300(3):1122-30
carboxamide (SSR149415), the first selective, nonpeptide vasopressin V1b receptor
antagonist yet described, has been characterized in vitro and in vivo. SSR149415
showed competitive nanomolar affinity for animal and human V1b receptors and exhibited
much lower affinity for rat and human V1a, V2, and oxytocin receptors. Moreover,
this compound did not interact with a large number of other receptors, enzymes,
or ion channels. In vitro, SSR149415 behaved as a full antagonist and potently
inhibited arginine vasopressin (AVP)-induced Ca2+ increase in Chinese hamster
ovary cells expressing rat or human V1b receptors. The in vivo activity of SSR149415
has been studied in several models of elevated corticotropin secretion in conscious
rats. SSR149415 inhibited exogenous AVP-induced increase in plasma corticotropin,
from 3 mg/kg i.p. and 10 mg/kg p.o. upwards. Similarly, this compound antagonized
AVP-potentiated corticotropin release provoked by exogenous corticoliberin at
3 mg/kg p.o. The effect lasted for more than 4 h at 10 mg/kg p.o. showing a long-lasting
oral effect. SSR149415 (10 mg/kg p.o.) also blocked corticotropin secretion induced
by endogenous AVP increase subsequent to body water loss. Moreover, 10 mg/kg i.p
SSR149415 inhibited plasma corticotropin elevation after restraint-stress in rats
by 50%. In the four-plate test, a mouse model of anxiety, SSR149415 (3 mg/kg p.o.
upwards) displayed anxiolytic-like activity after acute and 7-day repeated administrations.
Thus, SSR149415 is a potent, selective, and orally active V1b receptor antagonist.
It represents a unique tool for exploring the functional role of V1b receptors
and deserves to be clinically investigated in the field of stress and anxiety."
Bellis MD, Gold PW, Geracioti TD Jr, Listwak SJ, Kling MA.
of fluoxetine treatment with reductions in CSF concentrations of corticotropin-releasing
hormone and arginine vasopressin in patients with major depression.
J Psychiatry 1993 Apr;150(4):656-7
"The authors measured CSF concentrations
of corticotropin-releasing hormone (CRH) and arginine vasopressin in nine depressed
patients before and after fluoxetine treatment. They found significant decreases
in CSF CRH, CSF arginine vasopressin, and Hamilton depression ratings. Thus, the
therapeutic effect of this serotonin-uptake inhibitor may be related to diminution
of these arousal-promoting neuropeptides." [Abstract]
Michelson, Elise Galliven, Lauren Hill, Mark Demitrack, George Chrousos, and Philip
Chronic Imipramine Is Associated with Diminished Hypothalamic-Pituitary-Adrenal
Axis Responsivity in Healthy Humans
J. Clin. Endocrinol.
Metab. 82: 2601-2606
"The hypercortisolism of melancholic depression is
thought to reflect hypothalamic hypersecretion of CRH and may be related to the
hyperarousal associated with this syndrome. Although chronic administration of
imipramine to experimental animals significantly decreases CRH messenger RNA levels
in the paraventricular nucleus, it is generally thought that resolution of hypercortisolism
following recovery from depression is related to the improvement in mood and decrease
in anxiety that accompanies recovery rather than an intrinsic effect of imipramine.
The present study was designed to explore whether chronic imipramine administration
to healthy, nondepressed volunteers is associated with effects on hypothalamic-pituitary-adrenal
(HPA) axis function. We studied basal and provocative measures of HPA axis function
in 14 healthy volunteers before and after 6 weeks of imipramine treatment at therapeutic
doses. Imipramine was associated with decreased responses in peak ACTH and cortisol
to ovine CRH and in peak ACTH to arginine vasopressin (P = 0.02, P = 0.003, and
P = 0.02, respectively) without changes in indices of basal HPA axis function.
These data are consistent with preclinical findings and support the hypothesis
that imipramine has an intrinsic effect on central components of HPA axis function,
potentially related to its therapeutic effects." [Full
Tilders FJ, Berkenbosch F, Vermes I, Linton
EA, Smelik PG.
Role of epinephrine and vasopressin in the control
of the pituitary-adrenal response to stress.
Fed Proc 1985
Jan;44(1 Pt 2):155-60
"In addition to corticotropin-releasing factor
(CRF) and structurally related peptides, arginine vasopressin (AVP), oxytocin,
angiotensin II, vasoactive intestinal polypeptide, peptide histidine isoleucinamide,
epinephrine (E), and norepinephrine induce secretion of adrenocorticotropin (ACTH)
from corticotropic cells in vitro. The apparent affinity and intrinsic ACTH-releasing
activity of these substances are lower than those of CRF. These substances can
also act synergistically with CRF. In this paper the role of catecholamines and
AVP in the control of ACTH release is discussed. Infusion i.v. of E increases
plasma ACTH and corticosterone to levels that are normally found during stress.
E-induced stimulation of pituitary-adrenal activity is mediated by beta adrenoceptors
and involves release of CRF, because it can be prevented by beta-adrenoceptor
blockers and by destruction of CRF neurons (hypothalamic lesions), blockade of
CRF release (chlorpromazine, morphine, and Nembutal), or administration of CRF
antiserum. Although stress can cause a vast increase in plasma E, circulating
E is not essential for the acute stress-induced release of ACTH because blockade
of beta (or alpha) adrenoceptors, administration of chlorisondamine, or extirpation
of the adrenal medulla and sympathectomy do not prevent the pituitary-adrenal
response to stress. In contrast, circulating E plays a major role in the release
of intermediate-lobe peptides during emotional stress. Studies of the role of
AVP in pituitary-adrenal control by the use of pressor receptor (V1) antagonists
are not valuable because of the ineffectiveness of such antagonists in blocking
AVP-induced release of ACTH from corticotropic cells in vitro. Treatment of rats
with an antiserum to AVP reduces the ACTH response to stress. We conclude that
AVP has an important role in stress-induced activation of the pituitary-adrenal
system, possibly by potentiating the effects of CRF." [Abstract]
JP, Clarke IJ, Funder JW, Engler D.
Studies of the secretion of corticotropin-releasing
factor and arginine vasopressin into the hypophysial-portal circulation of the
conscious sheep. II. The central noradrenergic and neuropeptide Y pathways cause
immediate and prolonged hypothalamic-pituitary-adrenal activation. Potential involvement
in the pseudo-Cushing's syndrome of endogenous depression and anorexia nervosa.
J Clin Invest 1994 Apr;93(4):1439-50
"Studies were performed to determine
the effects of intracerebroventricular norepinephrine (NE) or neuropeptide Y (NPY)
on the ovine hypothalamic-pituitary-adrenal (HPA) axis. NE (50 micrograms) increased
mean hypophysial-portal corticotropin-releasing factor (CRF) and arginine vasopressin
(AVP) levels (1 h, 1.3- and 2.9-fold; 4 h, 2.2- and 5.7-fold) and caused acute
and sustained increases in mean plasma ACTH and cortisol. NPY (50 microgram) also
increased mean CRF and AVP levels (1 h, 1.4- and 4.2-fold; 4 h, 1.1- and 1.9-fold),
increased pituitary-adrenal activity at 1 h, and caused ACTH hypersecretion at
4 h. When added to cultured ovine anterior pituitary cells, NPY neither increased
basal ACTH release nor augmented CRF- or AVP-induced ACTH release. We conclude
that: (a) activation of either the central noradrenergic or NPY pathways causes
an acute and sustained stimulation of the ovine HPA axis; (b) such activation
increases the AVP/CRF ratio, suggesting a dominant role for AVP in the ovine stress
response; and (c) the central noradrenergic or NPY systems may cause sustained
HPA activation by attenuating or disrupting the glucocorticoid negative feedback
on those brain areas concerned with regulation of the HPA axis. The possible roles
of the central noradrenergic and NPY systems in the etiology of the hypercortisolemia
of endogenous depression and anorexia nervosa are discussed." [Abstract]
MB, Landgraf R, Keck ME.
Vasopressin, major depression, and hypothalamic-pituitary-adrenocortical
Biol Psychiatry 2000 Aug 15;48(4):330-3
The hypothalamic neuropeptide arginine vasopressin is thought to play an important
role in the pathophysiology of affective disorders and the hyperactivity of the
hypothalamic-pituitary-adrenocortical system that frequently accompanies them.
Postmortem studies as well as clinical investigations have described elevated
levels of vasopressin in the brain and plasma of depressed patients, and this
finding has been suggested to contribute to depressive symptomatology. METHODS:
The case of a 47-year-old patient displaying chronically elevated plasma vasopressin
levels due to paraneoplastic vasopressin secretion by an olfactory neuroblastoma
and the first episode of major depression is presented. RESULTS: Depressive symptoms
improved markedly after surgical resection of the tumor and subsequent normalization
of plasma vasopressin levels. Unexpectedly, neither corticotropin nor cortisol
secretion could be stimulated by an intravenous corticotropin-releasing hormone
challenge under the condition of chronically elevated plasma vasopressin levels
in this patient. CONCLUSIONS: Chronically elevated plasma vasopressin levels may
induce depressive symptomatology, and-in contrast to the potent corticotropin
secretagogue effects of acute vasopressin administration-lead to a marked desensitization
of the hypothalamic-pituitary-adrenocortical system." [Abstract]
ME, Wigger A, Welt T, Muller MB, Gesing A, Reul JM, Holsboer F, Landgraf R, Neumann
Vasopressin mediates the response of the combined dexamethasone/CRH
test in hyper-anxious rats: implications for pathogenesis of affective disorders.
"To investigate the neuroendocrine alterations linked
to inborn emotionality in two Wistar rat lines selectively bred for either high
(HAB) or low (LAB) anxiety-related behavior, we administered the combined dexamethasone
(DEX)/corticotropin-releasing hormone (CRH) test. DEX (12:00 M. (noon); 30 microg/kg)
resulted in a significantly less efficient suppression of the diurnal increase
in the circulating corticotropin (ACTH) levels in the male HAB rats than in the
male LAB rats. In addition, plasma ACTH and corticosterone responses to subsequent
CRH (7:30 P.M.; 50 ng/kg) were significantly higher in male HAB rats. The rise
in ACTH after CRH in the DEX-pretreated male HAB rats points toward an enhanced
activity and involvement of endogenous vasopressin synthesized in the hypothalamic
paraventricular nucleus (PVN) and acting at pituitary corticotrope cells. We tested
this hypothesis by in situ hybridization and in vivo microdialysis, and found
an increase in both basal synthesis and release of vasopressin within the PVN
of the male HAB rats. As expected, pretreatment with a selective vasopressin type
1 receptor antagonist abolished the CRH-stimulated increase in ACTH secretion
in the DEX-pretreated male HAB rats. The results indicate that vasopressin-mediated
effects are critically involved in the profound disturbance of the hypothalamic-pituitary-adrenocortical
system in male HAB rats, thus revealing striking parallels to the neuroendocrine
situation in human depression." [Abstract]
R, Wigger A.
High vs low anxiety-related behavior rats: an animal
model of extremes in trait anxiety.
Behav Genet 2002 Sep;32(5):301-14
addition to their robust difference in trait anxiety, as illustrated by a variety
of behavioral tests, HAB and LAB rats differ in their stress coping strategies,
the former being more susceptible and vulnerable to stressor exposure and preferring
more passive strategies. HAB rats of either gender show signs of a hyper-reactive
hypothalamic-pituitary-adrenocortical (HPA) axis, thus resembling psychiatric
patients. As shown by in situ hybridization and microdialysis in freely behaving
animals, both the expression and release of vasopressin in the hypothalamic paraventricular
nucleus are higher in HAB than in LAB rats, thus contributing to the HPA axis
hyperdrive. Accordingly, in HAB animals, administration of a V1 receptor antagonist
normalized the pathological outcome of the dexamethasone/corticotropin-releasing
hormone test and triggered behavioral changes toward reduced anxiety and active
stress coping. Pharmacological validation has revealed signs of depressive-like
behavior, as HAB but not LAB rats have shown more active stress coping behavior
and a normalized HPA axis after treatment with paroxetine. Of interest, this antidepressant
reduced the hypothalamic overexpression of vasopressin; this novel mechanism of
action is likely to contribute to paroxetine effects on both behavioral and neuroendocrine
parameters. Cross-mating and cross-fostering paradigms showed that the divergent
emotionality in HAB vs. LAB rats is determined genetically, rather than postnatally
through maternal behavior. As the behavioral and neuroendocrine phenotyping pointed
to the vasopressin gene as a candidate gene critically involved in anxiety, preliminary
genetic approaches have been focused on this gene, revealing single nucleotide
polymorphisms (SNPs) in the promotor area of the vasopressin gene in HAB, but
not LAB rats. HAB/LAB rats are thus proving to be a unique animal model to identify
and characterize neurobiological, neuroendocrine, and genetic correlates of trait
anxiety, and perhaps depression, in humans." [Abstract]