vasopressin and depression


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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.
Neuropsychopharmacology 2003 Jan;28(1):140-7
"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]

van 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
"BACKGROUND: 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." [Abstract]

van 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.
Neuropsychopharmacology 1997 Oct;17(4):284-92
"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]

Syvalahti E.
Dexamethasone suppression test and the levels of serum growth hormone, plasma vasopressin and plasma homovanillic acid in depressed in- and outpatients.
Acta Psychiatr Scand 1985 Feb;71(2):105-10
"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]

Gjerris A, Hammer M, Vendsborg P, Christensen NJ, Rafaelsen OJ.
Cerebrospinal fluid vasopressin--changes in depression.
Br J Psychiatry 1985 Dec;147:696-701
"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]

Timothy G. Dinan, Ena Lavelle, Lucinda V. Scott, John Newell-Price, Sami Medbak, and Ashley B. Grossman
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." [Full Text]

Meller WH, Kathol RC, Jaeckle RS, Lopez JF.
Stimulation of the pituitary-adrenal axis with arginine vasopressin in patients with depression.
J 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.
Psychiatry 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]

Gispen-de Wied CC, Westenberg HG, Koppeschaar HP, Thijssen JH, van Ree JM.
Stimulation of the pituitary-adrenal axis with a low dose [Arg8]-vasopressin in depressed patients and healthy subjects.
Eur Neuropsychopharmacol 1992 Dec;2(4):411-9
"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]

van Londen L, Goekoop JG, Kerkhof GA, Zwinderman KH, Wiegant VM, De Wied D.
Weak 24-h periodicity of body temperature and increased plasma vasopressin in melancholic depression.
Eur Neuropsychopharmacol 2001 Feb;11(1):7-14
"Earlier 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." [Abstract]

Marianne B. Müller, Rainer Landgraf, Jens Preil, Inge Sillaber, Adelheid E. Kresse, Martin E. Keck, Stephan Zimmermann, Florian Holsboer, and Wolfgang Wurst
Selective Activation of the Hypothalamic Vasopressinergic System in Mice Deficient for the Corticotropin-Releasing Hormone Receptor 1 Is Dependent on Glucocorticoids
Endocrinology 141: 4262-4269
"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 Text]

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.
Life Sci 1998;63(1):23-31
"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]

Raadsheer FC, Hoogendijk WJ, Stam FC, Tilders FJ, Swaab DF.
Increased numbers of corticotropin-releasing hormone expressing neurons in the hypothalamic paraventricular nucleus of depressed patients.
Neuroendocrinology 1994 Oct;60(4):436-44
"The 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.
Increased number of vasopressin- and oxytocin-expressing neurons in the paraventricular nucleus of the hypothalamus in depression.
Arch Gen Psychiatry 1996 Feb;53(2):137-43
"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.
Biol Psychiatry 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 levels." [Abstract]

Kathol RG, Jaeckle RS, Lopez JF, Meller WH.
Consistent reduction of ACTH responses to stimulation with CRH, vasopressin and hypoglycaemia in patients with major depression.
Br J Psychiatry 1989 Oct;155:468-78
"Eleven 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]

Van Londen L, Goekoop JG, Zwinderman AH, Lanser JB, Wiegant VM, De Wied D.
Neuropsychological performance and plasma cortisol, arginine vasopressin and oxytocin in patients with major depression.

Psychol Med 1998 Mar;28(2):275-84
"BACKGROUND: 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 RK.
Hypothalamo-pituitary-adrenal cortical responses to low-dose physostigmine and arginine vasopressin administration: sex differences between major depressives and matched control subjects.
Psychiatry 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.
Mol 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]

Scott LV, Dinan TG.
Vasopressin and the regulation of hypothalamic-pituitary-adrenal axis function: implications for the pathophysiology of depression.
Life Sci 1998;62(22):1985-98
"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]

Griebel G, Simiand J, Stemmelin J, Gal CS, Steinberg R.
The vasopressin V1b receptor as a therapeutic target in stress-related disorders.
Curr Drug Target CNS Neurol Disord. 2003 Jun;2(3):191-200.
"The complexity 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]

Guy Griebel, Jacques Simiand, Claudine Serradeil-Le Gal, Jean Wagnon, Marc Pascal, Bernard Scatton, Jean-Pierre Maffrand, and Philippe Soubrié
Anxiolytic- and antidepressant-like effects of the non-peptide vasopressin V1b receptor antagonist, SSR149415, suggest an innovative approach for the treatment of stress-related disorders
PNAS 99: 6370-6375; published online before print as 10.1073/pnas.092012099
"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." [Full Text]

Scott LV, Dinan TG.
Vasopressin as a target for antidepressant development: an assessment of the available evidence.
J Affect Disord 2002 Nov;72(2):113-24
"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]

Serradeil-Le Gal C, Wagnon J, Valette G, Garcia G, Pascal M, Maffrand JP, Le Fur G.
Nonpeptide vasopressin receptor antagonists: development of selective and orally active V1a, V2 and V1b receptor ligands.
Prog Brain Res 2002;139:197-210
"Finally, 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 drugs." [Abstract]

Serradeil-Le 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.
Characterization of (2S,4R)-1-[5-chloro-1-[(2,4-
1H-indol-3-yl]-4-hydroxy-N,N-dimethyl-2-pyrrolidine carboxamide (SSR149415), a selective and orally active vasopressin V1b receptor antagonist.

J Pharmacol Exp Ther 2002 Mar;300(3):1122-30
dihydro-1H-indol-3-yl]-4-hydroxy-N,N-dimethyl-2-pyrrolidine 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." [Abstract]

De Bellis MD, Gold PW, Geracioti TD Jr, Listwak SJ, Kling MA.
Association of fluoxetine treatment with reductions in CSF concentrations of corticotropin-releasing hormone and arginine vasopressin in patients with major depression.
Am 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]

David Michelson, Elise Galliven, Lauren Hill, Mark Demitrack, George Chrousos, and Philip Gold
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 Text]

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]

Liu 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]

Muller MB, Landgraf R, Keck ME.
Vasopressin, major depression, and hypothalamic-pituitary-adrenocortical desensitization.
Biol Psychiatry 2000 Aug 15;48(4):330-3
"BACKGROUND: 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]

Keck ME, Wigger A, Welt T, Muller MB, Gesing A, Reul JM, Holsboer F, Landgraf R, Neumann ID.
Vasopressin mediates the response of the combined dexamethasone/CRH test in hyper-anxious rats: implications for pathogenesis of affective disorders.
Neuropsychopharmacology 2002 Jan;26(1):94-105
"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]

Landgraf 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
"In 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]


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Recent Vasopressin and Depression Research

1) Meyer I, Frank D, Janssens U
[A case of venlafaxine-induced syndrome of inappropriate ADH secretion (SIADH) - treatment with tolvaptan].
Dtsch Med Wochenschr. 2012 May;137(21):1096-9.
[PubMed Citation] [Order full text from Infotrieve]

2) Kokras N, Sotiropoulos I, Pitychoutis PM, Almeida OF, Papadopoulou-Daifoti Z
Citalopram-mediated anxiolysis and differing neurobiological responses in both sexes of a genetic model of depression.
Neuroscience. 2011 Oct 27;194:62-71.
Disorders such as depression and anxiety exhibit strong sex differences in their prevalence and incidence, with women also differing from men in their response to antidepressants. Furthermore, receptors for corticotrophin releasing hormone (CRHR1) and arginine vasopressin receptor subtype 1b (AVPR1b) are known to contribute to the regulation of mood and anxiety. In the present study, we compared the anxiety profile and CRHR1 and AVPR1b expression levels in control Sprague-Dawley (SD) rats and rats of the SD-derived Flinders Sensitive Line (FSL), a genetic model of depression. Additionally, given the apparent sex differences in the therapeutic efficacy of antidepressants and because antidepressants are commonly used to treat comorbid anxiety and depressive symptoms, we assessed whether the anxiolytic effects of an antidepressant occur in a sex-dependent manner. Male and female FSL rats were treated with citalopram 10 mg/kg once daily for 14 days and were then tested in the open field and the elevated plus maze paradigms. Upon completion of the behavioural analysis, AVPR1b and CRHR1 expression levels were monitored in the hypothalamus and the prefrontal cortex (PFC) using Western blotting. According to our results, male FSL rats were more anxious than control SD rats, a difference abolished by citalopram treatment. Baseline anxiety levels were similar in female FSL and SD rats, and citalopram further reduced anxiety in female FSL rats. Importantly, whereas citalopram altered AVPR1b expression in the hypothalamus of male FSL rats, its actions on this parameter were restricted to the PFC in female FSL rats. In both sexes of FSL rats, citalopram did not alter CRHR1 expression in either the hypothalamus or PFC. Our results demonstrate that antidepressant treatment reduces anxiety levels in FSL rats of both sexes: the magnitude of treatment effect was related to the starting baseline level of anxiety and the antidepressant elicited sexually differentiated neurobiological responses in specific brain regions. [PubMed Citation] [Order full text from Infotrieve]

3) Touma C
Stress and affective disorders: animal models elucidating the molecular basis of neuroendocrine-behavior interactions.
Pharmacopsychiatry. 2011 May;44 Suppl 1:S15-26.
Profound dysfunctions in several neuroendocrine systems have been described in patients suffering from affective disorders such as major depression. In order to elucidate the mechanisms underlying these functional alterations, animal models including mice genetically modified by either direct gene-targeting or by selective breeding approaches have been used exceedingly, revealing valuable insights into neuroendocrine pathways conserved between rodents and men. This review focuses on altered function and regulation of the hypothalamic-pituitary-adrenocortical axis, including its involvement in emotionality and stress responsiveness. In this context, the corticotropin-releasing hormone system and disturbances in glucocorticoid receptor signaling seem to be of central importance. However, changes in the expression and release patterns of vasopressin, dopamine and serotonin have also been shown to contribute to variation in emotionality, stress coping, cognitive functions and social behaviors. Affective disorders show a high degree of complexity, involving a multitude of molecular, neuroendocrine, and behavioral alterations as well as an intense gene-environment interaction, making it difficult to dissociate the primary causes from secondary consequences of the disease. Thus, interdisciplinary research, as applied in the emerging field of systems biology, involving adequate animal models and combined methodologies can significantly contribute to our understanding regarding the transmission of genetic predispositions into clinically relevant endophenotypes. It is only with deep insight into the mechanisms by which the stress hormone systems are regulated that novel treatment strategies and promising targets for therapeutic interventions can be developed in the future. Such in-depth understanding is ultimately essential to realizing our goal of predictive, preventive, and personalized medicine. [PubMed Citation] [Order full text from Infotrieve]

4) Szczepanska-Sadowska E, Cudnoch-Jedrzejewska A, Ufnal M, Zera T
Brain and cardiovascular diseases: common neurogenic background of cardiovascular, metabolic and inflammatory diseases.
J Physiol Pharmacol. 2010 Oct;61(5):509-21.
In spite of significant progress in pharmacotherapy the incidence of newly diagnosed cases of cardiovascular diseases and cardiovascular morbidity is alarmingly high. Treatment of hypertension or heart failure still remains a serious challenge. Continuous attempts are made to identify the mechanisms that decide about susceptibility to pathogenic factors, and to determine effectiveness of a specific therapeutic approach. Coincidence of cardiovascular diseases with metabolic disorders and obesity has initiated intensive research for their common background. In the recent years increasing attention has been drawn to disproportionately greater number of depressive disorders and susceptibility to stress in patients with coronary artery disease. An opposite relationship, i.e. a greater number of sudden cardiovascular complications in patients with depression, has been also postulated. Progress in functional neuroanatomy and neurochemistry provided new information about the neural network responsible for regulation of cardiovascular functions, metabolism and emotionality in health and under pathological conditions. In this review we will focus on the role of neuromodulators and neurotransmitters engaged in regulation of the cardiovascular system, neuroendocrine and metabolic functions in health and in pathogenesis of cardiovascular diseases and obesity. Among them are classical neurotransmitters (epinephrine and norepinephrine, serotonin, GABA), classical (CRH, vasopressin, neuropeptide Y) and newly discovered (orexins, apelin, leptin IL-1beta, TNF-alpha, ghrelin) neuropeptides, gasotransmitters, eicozanoids, endocannabinoids, and some other compounds involved in regulation of neuroendocrine, sympatho-adrenal and parasympathetic nervous systems. Special attention is drawn to those factors which play a role in immunology and inflammatory processes. Interaction between various neurotransmitter/neuromodulatory systems which may be involved in integration of metabolic and cardiovascular functions is analyzed. The survey gives evidence for significant disturbances in release or action of the same mediators in hypertension heart failure, obesity, diabetes mellitus, metabolic syndrome, starvation, chronic stress, depression and other psychiatric disorders. With regard to the pathogenic background of the cardiovascular diseases especially valuable are the studies showing inappropriate function of angiotensin peptides, vasopressin, CRH, apelin, cytokines and orexins in chronic stress, cardiovascular and metabolic diseases. The studies surveyed in this review suggest that multiple brain mechanisms interact together sharing the same neural circuits responsible for adjustment of function of the cardiovascular system and metabolism to current needs. [PubMed Citation] [Order full text from Infotrieve]

5) Garcia FD, Coquerel Q, Kiive E, Déchelotte P, Harro J, Fetissov SO
Autoantibodies reacting with vasopressin and oxytocin in relation to cortisol secretion in mild and moderate depression.
Prog Neuropsychopharmacol Biol Psychiatry. 2011 Jan 15;35(1):118-25.
[PubMed Citation] [Order full text from Infotrieve]

6) Letourneau JJ, Riviello CM, Li H, Cole AG, Ho KK, Zanetakos HA, Desai H, Zhao J, Auld DS, Napier SE, Thomson FJ, Goan KA, Morphy JR, Ohlmeyer MH, Webb ML
Identification and optimization of novel 2-(4-oxo-2-aryl-quinazolin-3(4H)-yl)acetamide vasopressin V3 (V1b) receptor antagonists.
Bioorg Med Chem Lett. 2010 Sep 15;20(18):5394-7.
The discovery, synthesis, and preliminary structure-activity relationship (SAR) of a novel class of vasopressin V3 (V1b) receptor antagonists is described. Compound 1, identified by high throughput screening of a diverse, three million-member compound collection, prepared using ECLiPS technology, had good activity in a V3 binding assay (IC50=0.20 microM), but less than desirable physicochemical properties. Optimization of compound 1 yielded potent analogs 19 (IC50=0.31 microM) and 24 (IC50=0.12 microM) with improved drug-like characteristics. [PubMed Citation] [Order full text from Infotrieve]

7) Goekoop J, de Winter R, Wolterbeek R, Wiegant V
Support for two increased vasopressinergic activities in depression at large and the differential effect of antidepressant treatment.
J Psychopharmacol. 2011 Oct;25(10):1304-12.
Animal models of depression support a pathogenetic role for vasopressinergic activation involving increased arginine vasopressin (AVP) release and AVP receptor (V1b) synthesis. Evidence of this has been found particularly in patients with highly anxious-retarded (HAR) and above-normal AVP (ANA) depression. A general pathogenetic theory however predicts vasopressinergic activities to play a role in at least all major depressive disorders, and antidepressant (AD) treatment to be mediated by vasopressinergic reduction. We tested these hypotheses by re-analysing the data of 66 depressed patients; 27 with and 39 without AD treatment. The plasma AVP concentration and the AVP-cortisol correlation were used as presumed parameters of AVP release and pituitary V1b receptor function. A high AVP-cortisol correlation (r?=?0.72; p?[PubMed Citation] [Order full text from Infotrieve]

8) Serby MJ, Lantz M, Chabus BI, Bernay LJ
Takotsubo cardiomyopathy and electroconvulsive treatments: a case study and review.
Int J Psychiatry Med. 2010;40(1):93-6.
A 90-year-old woman who had received more than 100 electroconvulsive treatments (ECT) over many years requested another course for depression. After the third ECT, an electrocardiogram showed new T-wave inversion (V2-V6) and ST elevation (V2). Catheterization revealed severe left ventricular dysfunction but no coronary obstruction, leading to a diagnosis of Takotsubo cardiomyopathy (stress-related). The patient's recovery was uneventful. Recent literature cites three other cases post-ECT. It appears that elderly women are at greatest risk, repeated stress is generally required, and recovery is achieved quickly. Elevated levels of catecholamines and of vasopressin may be implicated. [PubMed Citation] [Order full text from Infotrieve]

9) Karaiskos D, Mavragani CP, Sinno MH, Déchelotte P, Zintzaras E, Skopouli FN, Fetissov SO, Moutsopoulos HM
Psychopathological and personality features in primary Sjogren's syndrome--associations with autoantibodies to neuropeptides.
Rheumatology (Oxford). 2010 Sep;49(9):1762-9.
[PubMed Citation] [Order full text from Infotrieve]

10) Parker KJ, Kenna HA, Zeitzer JM, Keller J, Blasey CM, Amico JA, Schatzberg AF
Preliminary evidence that plasma oxytocin levels are elevated in major depression.
Psychiatry Res. 2010 Jul 30;178(2):359-62.
It is well established that the neuropeptide oxytocin (OT) is involved in regulating social behavior, anxiety, and hypothalamic-pituitary-adrenal (HPA) axis physiology in mammals. Because individuals with major depression often exhibit functional irregularities in these measures, we test in this pilot study whether depressed subjects (n=11) exhibit dysregulated OT biology compared to healthy control subjects (n=19). Subjects were hospitalized overnight and blood samples were collected hourly between 1800 and 0900h. Plasma levels of OT, the closely related neuropeptide argine-vasopressin (AVP), and cortisol were quantified. Results indicated that depressed subjects exhibit increased OT levels compared to healthy control subjects, and this difference is most apparent during the nocturnal peak. No depression-related differences in AVP or cortisol levels were discerned. This depression-related elevation in plasma OT levels is consistent with reports of increased hypothalamic OT-expressing neurons and OT mRNA in depressed patients. This present finding is likewise consistent with the hypothesis that dysregulated OT biology may be a biomarker of the emotional distress and impaired social relationships which characterize major depression. Additional research is required to elucidate the role of OT in the pathophysiology of this psychiatric disorder. [PubMed Citation] [Order full text from Infotrieve]

11) Bao AM, Swaab DF
Corticotropin-releasing hormone and arginine vasopressin in depression focus on the human postmortem hypothalamus.
Vitam Horm. 2010;82:339-65.
The neuropeptides corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP) are crucially involved in the pathogenesis of depression. The close correlation between the etiology of depression and dysregulation of the stress responses is based upon a hyperactivity of the hypothalamo-pituitary-adrenal (HPA) axis. CRH neurons in the paraventricular nucleus are the motor of the HPA-axis. Centrally released CRH, AVP, and increased levels of cortisol all contribute to the signs and symptoms of depression. Single-nucleotide polymorphisms in the CRH and AVP receptor genes are associated with the risk for depression. Activation of the HPA-axis is generally regarded to be the final common pathway of the pathogenesis of depression. Sex hormones are crucially involved in the regulation of CRH gene expression. The decreased activity of the biological clock, the suprachiasmatic nucleus, as indicated by its lower AVP expression, is the basis for the disturbed rhythms in depression. Both similarities and differences are found in the activity changes in the CRH and AVP systems in depressive disorders and depression in Alzheimer's disease. [PubMed Citation] [Order full text from Infotrieve]

12) Binder EB, Owens MJ, Liu W, Deveau TC, Rush AJ, Trivedi MH, Fava M, Bradley B, Ressler KJ, Nemeroff CB
Association of polymorphisms in genes regulating the corticotropin-releasing factor system with antidepressant treatment response.
Arch Gen Psychiatry. 2010 Apr;67(4):369-79.
[PubMed Citation] [Order full text from Infotrieve]

13) Schmidt MV, Scharf SH, Liebl C, Harbich D, Mayer B, Holsboer F, Müller MB
A novel chronic social stress paradigm in female mice.
Horm Behav. 2010 Apr;57(4-5):415-20.
Major depression is one of the most prevalent stress-related psychiatric diseases. Next to environmental influences such as chronic social stress, gender is among the strongest risk factors for major depression, with women having a twice as high risk to develop the disease compared to men. While there is abundant literature on the effects of chronic social stress in male rodents, there is a serious lack of information on gender-specific effects. Especially in mice, which due to the wide availability of transgenic lines offer a unique opportunity to study gene x environment interactions, there is no existing model of chronic social stress that is applicable to both sexes. We here describe the effects of chronic social stress based on the disruption of the social network in a group-housed situation in female mice, a model that was recently described and validated for male mice. In this model, the group composition of the mice is changed twice per week for a period of 7 weeks, covering the adolescent and early adulthood period. We observed that housing in an unpredictable social environment resulted in chronic stress in female mice. The observed effects, which included increased adrenal weight, decreased thymus weight, increased corticosterone levels, and increased anxiety-like behavior, were very similar to the described effects of this paradigm in male mice. In addition, we observed a distinct expression of stress system-related genes in female mice following chronic stress exposure. Our results validate this model as a suitable approach to study chronic social stress in female mice and open up the opportunity to use this model with transgenic or knockout mouse lines. [PubMed Citation] [Order full text from Infotrieve]

14) Goekoop JG, de Winter RF, Wolterbeek R, van Kempen GM, Wiegant VM
Evidence of vasopressinergic-noradrenergic mechanisms in depression with above-normal plasma vasopressin concentration with and without psychotic features.
J Psychopharmacol. 2011 Mar;25(3):345-52.
Previous studies in the field of melancholic or endogenous depression have resulted in support for a subcategory of depression with above-normal plasma vasopressin (AVP) concentration (ANA). Since an analogous animal model with increased release of above-normal plasma vasopressin exhibits reduced Sympathetic-Nervous-System activity, the present study investigated the plasma norepinephrine concentration and the correlation between plasma norepinephrine and AVP in this ANA depression. As psychotic-melancholic patients may have increased plasma norepinephrine concentration, and noradrenergic activation may stimulate AVP release, potentially confounding effects of psychotic features were also investigated. The data set of the same depressed patient sample that was used before, but limited to those with complete hormonal data (n = 75), was re-analysed. ANA depression (n = 14) had negatively correlating AVP and norepinephrine concentrations. A very small subcategory of ANA depression with psychotic features (n = 3) had high plasma norepinephrine concentration, suggesting that this could be an independent subcategory. This was supported by the combination of relatively low above-normal plasma AVP concentrations with the highest severity scores for depression in this subcategory, which does not correspond with the positive correlation between AVP concentration and severity in non-psychotic ANA depression. The results further support the validity of ANA depression and the analogy with the High Anxiety Behaviour animal model of depression. Further investigations are needed to replicate these findings and to search for genetic and traumatic factors involved. [PubMed Citation] [Order full text from Infotrieve]

15) Madaan V, Wilson DR
Neuropeptides: relevance in treatment of depression and anxiety disorders.
Drug News Perspect. 2009 Jul-Aug;22(6):319-24.
The etiology and pathophysiology of both depression and anxiety remain unclear, but involve dysfunctional monoaminergic neurotransmission and function. The currently available antidepressant medications that work through optimizing the monoaminergic system are often limited by their lack of efficacy or their adverse effects. There is increasing evidence that some neuropeptides, including substance P, corticotropin-releasing factor, neuropeptide Y, vasopressin and galanin, may have relevance in both depression and anxiety. Integration of anatomical, physiological and clinical evidence suggests that modulation of monoaminergic transmission is the most likely mechanism by which neuropeptides may work in these disorders. These neuropeptides and their receptors may serve not only as potential therapeutic targets for treatment of depression and anxiety, but may also help enhance our understanding of the psychopathology of these two major psychiatric disorders. [PubMed Citation] [Order full text from Infotrieve]

16) Paschos KA, Veletza S, Chatzaki E
Neuropeptide and sigma receptors as novel therapeutic targets for the pharmacotherapy of depression.
CNS Drugs. 2009 Sep;23(9):755-72.
Among the most prevalent of mental illnesses, depression is increasing in incidence in the Western world. It presents with a wide variety of symptoms that involve both the CNS and the periphery. Multiple pharmacological observations led to the development of the monoamine theory as a biological basis for depression, according to which diminished neurotransmission within the CNS, including that of the dopamine, noradrenaline (norepinephrine) and serotonin systems, is the leading cause of the disorder. Current conventional pharmacological antidepressant therapies, using selective monoamine reuptake inhibitors, tricyclic antidepressants and monoamine oxidase inhibitors, aim to enhance monoaminergic neurotransmission. However, the use of these agents presents severe disadvantages, including a delay in the alleviation of depressive symptoms, significant adverse effects and high frequencies of non-responding patients. Neuroendocrinological data of recent decades reveal that depression and anxiety disorders may occur simultaneously due to hypothalamus-pituitary-adrenal (HPA) axis hyperactivity. As a result, the stress-diathesis model was developed, which attempts to associate genetic and environmental influences in the aetiology of depression. The amygdala and the hippocampus control the activity of the HPA axis in a counter-balancing way, and a plethora of regulatory neuropeptide signalling pathways are involved. Intervention at these molecular targets may lead to alternative antidepressant therapeutic solutions that are expected to overcome the limitations of existing antidepressants. This prospect is based on preclinical evidence from pharmacological and genetic modifications of the action of neuropeptides such as corticotropin-releasing factor, substance P, galanin, vasopressin and neuropeptide Y. The recent synthesis of orally potent non-peptide micromolecules that can selectively bind to various neuropeptide receptors permits the onset of clinical trials to evaluate their efficacy against depression. [PubMed Citation] [Order full text from Infotrieve]

17) Nicolai NJ
[Chronic stress, sex and gender].
Tijdschr Psychiatr. 2009;51(8):569-77.
Many psychiatric disorders are a result of a disturbance in or exhaustion of the human stress response system. It is striking that many of these disorders such as depression, anxiety disorders and post-traumatic stress and somatoform and dissociative disorders are more prevalent in women. There are various explanations for this differing prevalence: it can be attributed to molecular, genetic, neurophysiological, relational and neurohormonal differences. Among the topics discussed are differences in exposure to chronic and traumatic stressors, the role of vasopressin and oxytocin in recovery and neurophysiological differences, the differentiating effect of hormones and neuropeptides such as oxytocin and vasopressin, the tend and befriend response and factors such as abuse and attachment disruption in early childhood. [PubMed Citation] [Order full text from Infotrieve]

18) Meynen G, Unmehopa UA, Hofman MA, Swaab DF, Hoogendijk WJ
Hypothalamic vasopressin and oxytocin mRNA expression in relation to depressive state in Alzheimer's disease: a difference with major depressive disorder.
J Neuroendocrinol. 2009 Aug;21(8):722-9.
Arginine vasopressin (AVP) and oxytocin (OXT), produced in the hypothalamic paraventricular (PVN) and supraoptic nucleus (SON), are considered to be involved in the pathophysiology of major depressive disorder (MDD). The objective of this study was to determine, for the first time, the relationship between AVP and OXT gene expression and depressive state in Alzheimer's disease (AD). Post-mortem brain tissue was obtained from six control subjects, and from a prospectively studied cohort of 23 AD patients, using the DSM-IIIR and the Cornell Scale for Depression in Dementia to determine depression diagnosis and severity. The amount of AVP and OXT mRNA was determined by in situ hybridisation. AD patients did not differ from controls with respect to the amount of AVP or OXT mRNA in the PVN or SON. Also, no differences were found between depressed and nondepressed AD patients and no relationship was found between the depression severity and AVP or OXT mRNA expression. The results indicate that AVP and OXT gene expression in the PVN and SON is unchanged in depressed AD patients compared to nondepressed AD patients. This is in contrast with the enhanced AVP gene expression in MDD, suggesting a difference in pathophysiology between MDD and depression in AD. [PubMed Citation] [Order full text from Infotrieve]

19) Kulkarni SK, Dhir A
Current investigational drugs for major depression.
Expert Opin Investig Drugs. 2009 Jun;18(6):767-88.
[PubMed Citation] [Order full text from Infotrieve]

20) Scantamburlo G, Pitchot W, Ansseau M, Legros JJ
[Neurohypophyseal neuropeptides and unipolar depression: which future?].
Rev Med Liege. 2008 May-Jun;63(5-6):385-90.
Vasopressin (AVP) and oxytocin (OT) are two chemically similar neurohypophyseal neuropeptides which could be involved in mood disorders. Those two sister neuropeptides might be considered as ago-antagonist hormones. They act as neuromodulators of the stress response. AVP is known as an ACTH stimulating factor synergistic to CRH while OT could act as an antagonist of AVP on ACTH secretion. AVP seems to play an important role in the pathophysiology of major depression. Evidence suggests a role for OT as an endogenous antidepressant/anxiolytic hormone. OT release is also an important aspect of the pharmacological action of SSRIs. In addition, their receptors are of growing interest for psychiatric research. A selective AVP V1b receptor, SSR1419415, has been characterized and is endowed with anxiolytic- an and antidepressant-like properties. This paper proposes an overview of neurohypophyseal hormones in major depression. [PubMed Citation] [Order full text from Infotrieve]