- Email: [email protected]
Increased Arginine Vasopressin mRNA Expression in the Human Hypothalamus in Depression: A Preliminary Report
Increased Arginine Vasopressin mRNA Expression in the Human Hypothalamus in Depression: A Preliminary Report Gerben Meynen, Unga A. Unmehopa, Joop J. van Heerikhuize, Michel A. Hofman, Dick F. Swaab, and Witte J.G. Hoogendijk Background: Elevated arginine vasopressin (AVP) plasma levels have been observed in major depression, particularly in relation to the melancholic subtype. Two hypothalamic structures produce plasma vasopressin: the supraoptic nucleus (SON) and the paraventricular nucleus (PVN). The aim of this study was to establish which structure is responsible for the increased vasopressin plasma levels in depression. Methods: Using in situ hybridization, we determined the amount of vasopressin messenger ribonucleic acid (mRNA) in the PVN and SON in postmortem brain tissue of nine depressed subjects (six with the melancholic subtype) and eight control subjects. Results: In the SON, a 60% increase of vasopressin mRNA expression was found in depressed compared with control subjects. In the melancholic subgroup, AVP mRNA expression was significantly increased in both the SON and the PVN compared with control subjects. Conclusions: We found increased AVP gene expression in the SON in depressed subjects. This might partly explain the observed increased vasopressin levels in depression. Key Words: Depression, melancholic type, vasopressin, hypothalamus, postmortem, hypothalamic–pituitary–adrenal axis
N
eurons located in the paraventricular (PVN) and supraoptic (SON) nucleus of the hypothalamus that release vasopressin to the pituitary are considered to be involved in the signs and symptoms of depression (Swaab et al 2000). The vasopressinergic neurons of the PVN consist of two overlapping populations. First, the PVN contains parvocellular neurons that secrete arginine vasopressin (AVP) together with corticotropinreleasing hormone (CRH) from axon terminals into the pituitary portal circulation. This AVP potentiates the release of adrenocorticotropic hormone (ACTH) by CRH in the anterior pituitary (Antoni 1993). Second, magnocellular neurons in the PVN, together with magnocellular neurons from the SON, project to the posterior pituitary, where they release AVP directly into the blood, for instance in response to osmotic stimuli (Swaab 2003). Using postmortem tissue, we previously showed that in major depression (MD) the number of AVP-immunoreactive neurons in the PVN (Purba et al 1996), and in particular those colocalizing CRH (Raadsheer et al 1994), is increased. In support of the idea that hypothalamic AVP might be involved in the pathogenesis of depression, Nakase et al (1998) found that in a rat model for depression the expression of AVP messenger ribonucleic acid (mRNA) in the magnocellular neurons of the PVN was increased. Moreover, Keck et al (2003) showed in an animal model of depression that a reduction of the hypothalamic vasopressinergic hyperdrive after paroxetine treatment contributes to clinically relevant behavioral and neuroendocrine effects. Interestingly,
whereas in acute stress CRH is the main cause of increased ACTH release, animal models show that in chronic stress there is a switch from CRH to AVP stimulation of ACTH release (Scott and Dinan 2002). Because depression is a state that lasts for weeks at a minimum, these findings are in line with the hypothesis that the nonsuppression in the combined dexamethasone/CRH test in depressed subjects is due to increased hypothalamic AVP release (Holsboer 2001). In accordance with these findings, several studies found that depressed subjects have elevated AVP plasma levels (De Winter et al 2003; Inder et al 1997; Van Londen et al 1997), which normalize as patients improve (Van Londen 2003). Importantly, De Winter et al (2003) observed that patients with an anxious– retarded or “melancholic” type of depression had elevated AVP plasma levels. This observation is in line with that of Van Londen et al (1997), who found increased AVP plasma levels in melancholic depressed patients. There are also indications that elevated AVP plasma levels are related to risk-related symptoms of depression, such as psychomotor agitation (Van Londen et al 1997) and suicidal behavior (Inder et al 1997). To determine 1) whether the observed increase in AVP mRNA in an animal model of depression could also be found in depressed humans; and 2) which hypothalamic structure, PVN or SON, might be responsible for the increased plasma AVP levels in depression, we performed in situ hybridization on AVP mRNA in the PVN and SON of depressed and nondepressed subjects. Because of the indications that AVP release might especially be altered in the melancholic type of depression, we also analyzed our data for the melancholic subgroup of depressed patients.
Methods and Materials From the Netherlands Institute for Brain Research (GM, UAU, JvH, MAH, DFS) and Department of Psychiatry (GM, WJGH), Vrije Universiteit Medical Center and Geestelijke Gezondheidszorg Buitenamstel, Amsterdam, The Netherlands. Address reprint requests to Gerben Meynen, M.D., VU University Medical Center, Department of Psychiatry, GGZ Buitenamstel, Valeriusplein 9, Amsterdam 1075 BG. E-mail: [email protected]. Received June 2, 2005; revised November 20, 2005; accepted December 5, 2005.
0006-3223/06/$32.00 doi:10.1016/j.biopsych.2005.12.010
Subjects Hypothalami of nine depressed subjects and eight control subjects matched for age and gender (Table 1) were obtained from the Netherlands Brain Bank, in accordance with the formal protocols for use of human brain material and clinical information for research purposes. The MD patients were diagnosed during their lifetime, and the diagnosis was confirmed by a board-certified psychiatrist (WJGH) retrospectively using the BIOL PSYCHIATRY 2006;60:892– 895 © 2006 Society of Biological Psychiatry
G. Meynen et al
Table 1. Clinico-pathological Data of the Subjects NBB No.
Age (years)
PMD (hours)
Psychiatric Diagnosis
History of Depression/ Suicide Attempts
Cause of Death, Clinical Diagnosis
Medication
92003
F
55
7
94112
M
61
⬍61
MD (Me)
Depression lasted year before death. Yes 12 years before death MD, delusions, mood congruent. No Several PH admissions due to therapy resistant MD. Yes Two PH admissions due to MD in years before death. No Last 20 years recurrent MD, PH admissions. No Admission PH, MD with psychotic features just before suicide. Depression since death of his wife. Multiple suicide attempts. Last year before death MD. No From 1975 several PH admissions due to MD. No
Cardiac failure, urosepsis, DM II, suspicion of Parkinson Pneumonia, infarction of the right hemisphere, DM II
Dexetimide, bromocriptine, AB Biperiden 2 mg/day, glibenclamide
Fluoxetine, imipramine
94032
M
71
16
MD (Me)
Cerebral ischemia after suicide attempt by strangulation
Amiodarone, digoxin, phenprocoumon, D
None
94094
M
71
14
MD (Me)
Acute respiratory distress syndrome
AB
Bronchopneumonia, metastasized mesothelioma Suicide by strangulation. Chronic lymphatic leukemia
Prednisone, metoprolol, D
Lithium, nitrazepam, parnate, levomepromazine Maprotiline, mogadon, diazepam Zuclopentixol, paroxetine, nitrazepam
94017
F
72
⬍22
MD (Me)
95036
M
74
63
MD (Me)
93115
M
79
21
DDNOS
Suicide (jumped)
Digoxin, D
Fluvoxamine, diazepam
90122
F
85
71
MD (Me)
Sudden death while in PH, DM II Heart failure, septic shock, pyelonephritis
Insulin
Trazolan
94055
F
72
28
MD
Insulin
Brotizolam
99033
F
61
18
Control
MI, gastrointestinal tract bleeding Esophagus carcinoma Aneurysma aorta, MI Pneumonia, renal failure Lung carcinoma Heart failure, lung embolism, prostate carcinoma Aorta dissection, cardiac tamponade Pneumonia
Unknown
92042 95106 93061 93139 95093
M M M F M
61 74 70 78 78
14 8 9 6 7
Control Control Control Control Control
97130
M
58
17
Control
94074
F
85
5
Control
MD
None
Unknown Sympathicomimetics Unknown Ranitidine, AB, D Estramustine 560 mg/day
Psychiatric Medication, Last Month
Trifluoperazine
Temazepam
Unknown Prednisone, zantac
NBB, Netherlands Brain Bank; PMD, postmortem delay; F, female; M, male; MD, major depression; Me, melancholic type (retrospectively); DM, diabetes mellitus; PH, psychiatric hospital; D, diuretics; AB, antibiotics; DDNOS, depressive disorder not otherwise specified; MI, myocardial infarction.
BIOL PSYCHIATRY 2006;60:892– 895 893
www.sobp.org/journal
Gender
894 BIOL PSYCHIATRY 2006;60:892– 895
G. Meynen et al was not significant (Z ⫽ ⫺1.3, p ⫽ .21; Figure 2). Leaving out two patients who suffered from a cerebrovascular accident, leaving out the patient and control subject who used prednisone, and leaving out the DDNOS patient had no effect on the outcome. We did not find a significant difference in the amount of AVP mRNA in the SON or PVN between those patients who did or did not use antidepressants. Postmortem delay (PMD) in patients was longer than in control subjects, but correcting for PMD only increased the significance of the difference we found. In melancholic patients in both SON (Z ⫽ ⫺2.6, p ⫽ .01) and PVN (Z ⫽ ⫺2.2, p ⫽ .028), the AVP mRNA signal was significantly increased compared with control subjects.
Discussion
Figure 1. Amount of vasopressin (AVP) messenger ribonucleic acid (mRNA) signal (in arbitrary units [a.u.]) in the supraoptic nucleus and paraventricular nucleus in depressed subjects (Depr; n ⫽ 9) and control subjects (Ctr; n ⫽ 8). *Statistically significant difference (p ⬍ .05). Bars show means, error bars indicate the SEM.
medical record, according to DSM-IV criteria, paying special attention to the presence of melancholic features, also according to DSM-IV criteria. One patient, who used an antidepressant and eventually committed suicide, was diagnosed as having depressive disorder not otherwise specified (DDNOS), because his medical record did not yield sufficient information to diagnose MD. Six of the patients fulfilled the criteria for melancholic-type depression. The matched group of control subjects did not suffer from a primary neurological or psychiatric disease. Exclusion criteria were alcohol abuse (because of the reported loss of AVP neurons in the PVN and SON [Harding et al 1996]) and the use of corticosteroids (Erkut et al 1998; Kim et al 2001), except for one patient who used prednisone and was matched with one control subject who also used prednisone. Measurement of AVP mRNA in PVN and SON The method of Liu et al (2000) was used for in situ hybridization histochemistry. For quantitative analysis of AVP mRNA, within the Image Pro Plus version 4.5 image analysis package (Media Cybernetics Inc., Silverspring, Maryland), macros were developed for densitometric analysis of film autoradiographs. The procedures have been described previously (Lucassen et al 1995). Statistical Analysis Differences among groups were evaluated by the nonparametric Mann-Whitney U test. Analysis of covariance was used to correct for possible confounding factors.
Results The arginine vasopressin mRNA signal in the SON of depressed subjects was 60% higher than in control subjects (Z ⫽ ⫺2.3, p ⫽ .021; Figure 1). In the PVN, the signal in the depressed group was 15% higher than in control subjects, but this difference www.sobp.org/journal
This is the first report in which AVP mRNA has been quantified in the SON and the PVN in depressed and control subjects. We found a significant (60%) increase in the amount of AVP mRNA signal in the SON of depressed subjects (Figure 1). We also expected to find an increase in AVP expression in the PVN, which would have been in line with our earlier finding of an increased number of AVP-immunoreactive neurons in the PVN in depression (Purba et al 1996), but the rise we observed in the PVN was not significant, probably owing to the small sample. In the melancholic subgroup, however, we did find a significant difference in both the SON and the PVN. This indicates that the increase in AVP mRNA might be even more pronounced in melancholic-type depression, as was found in earlier studies (De Winter et al 2003; Van Londen et al 1997). An important question raised by our finding is whether increased AVP expression in the SON could also, at least partly, be responsible for the hypothalamic–pituitary–adrenal (HPA) axis hyperdrive in depression. Two points should be considered in this respect. First, animal studies show that the release of magnocellular AVP, originating in the PVN or SON, might take place in the median eminence and thus in the portal system, where it might potentiate ACTH release (Antoni 1993; Wotjak et al 1996). Second, it is possible that an increased AVP release from the SON into the systemic circulation contributes to the increased ACTH release from the pituitary. A clear indication that such a mechanism might exist is provided by Gispen-De Wied et al (1992), who found that intravenous administration of AVP results in increased levels of both ACTH and cortisol in both control and depressed subjects. Another indication is the finding that plasma AVP levels are positively correlated with cortisol levels in depression (Brunner et al 2002; De Winter et al 2003; Inder et al 1997). In addition, there might be a feedback mechanism between the HPA axis and the SON and PVN: glucocorticoid receptors are present in both the PVN and SON in rats (Morimoto et al 1996), as well as in rhesus monkeys (Sanchez et al 2000), and in our group Erkut et al (1998) found that in humans not only AVP in the PVN but also in the SON responds to glucocorticoid plasma levels. In some cases, antidepressants can cause the syndrome of inappropriate antidiuretic hormone secretion (SIADH), suggesting that they influence hypothalamic AVP release (Spigset and Hedenmalm 1995). We do not consider our results to be due to the use of antidepressants, on the basis of three findings. First, van Londen et al (1997) found elevated vasopressin levels in depressed subjects who did not use antidepressant medication at all. Second, in our group no significant difference was found in the amount of AVP mRNA in PVN or SON between patients who used antidepressants and those who did not. Third, in an
G. Meynen et al
Figure 2. Signal on film of the supraoptic nucleus (SON) and paraventricular nucleus (PVN) of a representative patient. Note the intense signal in both nuclei (III, third ventricle).
experiment especially designed to determine the influence of antidepressants on the occurrence of SIADH, no increase in either plasma AVP levels or AVP mRNA levels in PVN and SON was found (Marar and Amico 1998). In conclusion, our results point to the SON being the main source of the observed elevated AVP plasma levels in depression. This finding indicates that beside the PVN, the SON is a factor in HPA axis hyperdrive. Funded by Internationale Stichting Alzheimer Onderzoek, project 99512, Zorgonderzoek Nederland Medische Wetenschappen 907-00-012, and the Netherlands Organisation for Scientific Research (NWO), project 940-37-021. We thank Mr. B. Fisser and Mrs. A. Alkemade for technical assistance and the Netherlands Brain Bank for providing us with brain material. Antoni FA (1993): Vasopressinergic control of pituitary adrenocorticotropin secretion comes of age. Front Neuroendocrinol 14:76 –122. Brunner J, Keck ME, Landgraf R, Uhr M, Namendorf C, Bronisch T (2002): Vasopressin in CSF and plasma in depressed suicide attempters: Preliminary results. Eur Neuropsychopharmacol 12:489 – 494. De Winter RF, van Hemert AM, DeRijk RH, Zwinderman KH, FrankhuijzenSierevogel AC, Wiegant VM, et al (2003): Anxious-retarded depression: Relation with plasma vasopressin and cortisol. Neuropsychopharmacology 28:140 –147. Erkut ZA, Pool C, Swaab DF (1998): Glucocorticoids suppress corticotropinreleasing hormone and vasopressin expression in human hypothalamic neurons. J Clin Endocrinol Metab 83:2066 –2073. Gispen-de Wied CC, Westenberg HG, Koppeschaar HP, Thijssen JH, van Ree JM (1992): Stimulation of the pituitary-adrenal axis with a low dose [Arg8]-vasopressin in depressed patients and healthy subjects. Eur Neuropsychopharmacol 2:411– 419. Harding AJ, Halliday GM, Ng JL, Harper CG, Kril JJ (1996): Loss of vasopressinimmunoreactive neurons in alcoholics is dose-related and time-dependent. Neuroscience 72:699 –708.
BIOL PSYCHIATRY 2006;60:892– 895 895 Holsboer F (2001): Stress, hypercortisolism and corticosteroid receptors in depression: Implications for therapy. J Affect Disord 62:77–91. Inder WJ, Donald RA, Prickett TC, Frampton CM, Sullivan PF, Mulder RT, et al (1997): Arginine vasopressin is associated with hypercortisolemia and suicide attempts in depression. Biol Psychiatry 42:744 –747. Keck ME, Welt T, Muller MB, Uhr M, Ohl F, Wigger A, et al (2003): Reduction of hypothalamic vasopressinergic hyperdrive contributes to clinically relevant behavioral and neuroendocrine effects of chronic paroxetine treatment in a psychopathological rat model. Neuropsychopharmacology 28: 235–243. Kim JK, Summer SN, Wood WM, Schrier RW (2001): Role of glucocorticoid hormones in arginine vasopressin gene regulation. Biochem Biophys Res Commun 289:1252–1256. Liu RY, Zhou JN, Hoogendijk WJ, van Heerikhuize J, Kamphorst W, Unmehopa UA, et al (2000): Decreased vasopressin gene expression in the biological clock of Alzheimer disease patients with and without depression. J Neuropathol Exp Neurol 59:314 –322. Lucassen PJ, Goudsmit E, Pool CW, Mengod G, Palacios JM, Raadsheer FC, et al (1995): In situ hybridization for vasopressin mRNA in the human supraoptic and paraventricular nucleus: Quantitative aspects of formalinfixed paraffin-embedded tissue sections as compared to cryostat sections. J Neurosci Methods 57:221–230. Marar IE, Amico JA (1998): Vasopressin, oxytocin, corticotrophin-releasing factor, and sodium responses during fluoxetine administration in the rat. Endocrine 8:13–18. Morimoto M, Morita N, Ozawa H, Yokoyama K, Kawata M (1996): Distribution of glucocorticoid receptor immunoreactivity and mRNA in the rat brain: An immunohistochemical and in situ hybridization study. Neurosci Res 26:235–269. Nakase S, Kitayama I, Soya H, Hamanaka K, Nomura J (1998): Increased expression of magnocellular arginine vasopressin mRNA in paraventricular nucleus of stress-induced depression-model rats. Life Sci 63:23– 31. Purba JS, Hoogendijk WJ, Hofman MA, Swaab DF (1996): Increased number of vasopressin- and oxytocin-expressing neurons in the paraventricular nucleus of the hypothalamus in depression. Arch Gen Psychiatry 53:137– 143. Raadsheer FC, Hoogendijk WJ, Stam FC, Tilders FJ, Swaab DF (1994): Increased numbers of corticotropin-releasing hormone expressing neurons in the hypothalamic paraventricular nucleus of depressed patients. Neuroendocrinology 60:436 – 444. Sanchez MM, Young LJ, Plotsky PM, Insel TR (2000): Distribution of corticosteroid receptors in the rhesus brain: Relative absence of glucocorticoid receptors in the hippocampal formation. J Neurosci 20:4657– 4668. Scott LV, Dinan TG (2002): Vasopressin as a target for antidepressant development: An assessment of the available evidence. J Affect Disord 72:113– 124. Spigset O, Hedenmalm K (1995): Hyponatraemia and the syndrome of inappropriate antidiuretic hormone secretion (SIADH) induced by psychotropic drugs. Drug Saf 12:209 –225. Swaab DF (2003): The Human Hypothalamus. Basic and Clinical Aspects. Part I: Nuclei of the Hypothalamus. Handbook of Clinical Neurology. Amsterdam: Elsevier. Swaab DF, Fliers E, Hoogendijk WJ, Veltman DJ, Zhou JN (2000): Interaction of prefrontal cortical and hypothalamic systems in the pathogenesis of depression. Prog Brain Res 126:369 –396. Van Londen L (2003): Vasopressin in Major Depression. Leiden: Universitair Facilitair Bedrijf, Grafische Dienstverlening. Van Londen L, Goekoop JG, van Kempen GM, Frankhuijzen-Sierevogel AC, Wiegant VM, van der Velde EA, et al (1997): Plasma levels of arginine vasopressin elevated in patients with major depression. Neuropsychopharmacology. 17:284 –292. Wotjak CT, Kubota M, Kohl G, Landgraf R (1996): Release of vasopressin from supraoptic neurons within the median eminence in vivo. A combined microdialysis and push-pull perfusion study in the rat. Brain Res 726:237– 241.
www.sobp.org/journal
N
eurons located in the paraventricular (PVN) and supraoptic (SON) nucleus of the hypothalamus that release vasopressin to the pituitary are considered to be involved in the signs and symptoms of depression (Swaab et al 2000). The vasopressinergic neurons of the PVN consist of two overlapping populations. First, the PVN contains parvocellular neurons that secrete arginine vasopressin (AVP) together with corticotropinreleasing hormone (CRH) from axon terminals into the pituitary portal circulation. This AVP potentiates the release of adrenocorticotropic hormone (ACTH) by CRH in the anterior pituitary (Antoni 1993). Second, magnocellular neurons in the PVN, together with magnocellular neurons from the SON, project to the posterior pituitary, where they release AVP directly into the blood, for instance in response to osmotic stimuli (Swaab 2003). Using postmortem tissue, we previously showed that in major depression (MD) the number of AVP-immunoreactive neurons in the PVN (Purba et al 1996), and in particular those colocalizing CRH (Raadsheer et al 1994), is increased. In support of the idea that hypothalamic AVP might be involved in the pathogenesis of depression, Nakase et al (1998) found that in a rat model for depression the expression of AVP messenger ribonucleic acid (mRNA) in the magnocellular neurons of the PVN was increased. Moreover, Keck et al (2003) showed in an animal model of depression that a reduction of the hypothalamic vasopressinergic hyperdrive after paroxetine treatment contributes to clinically relevant behavioral and neuroendocrine effects. Interestingly,
whereas in acute stress CRH is the main cause of increased ACTH release, animal models show that in chronic stress there is a switch from CRH to AVP stimulation of ACTH release (Scott and Dinan 2002). Because depression is a state that lasts for weeks at a minimum, these findings are in line with the hypothesis that the nonsuppression in the combined dexamethasone/CRH test in depressed subjects is due to increased hypothalamic AVP release (Holsboer 2001). In accordance with these findings, several studies found that depressed subjects have elevated AVP plasma levels (De Winter et al 2003; Inder et al 1997; Van Londen et al 1997), which normalize as patients improve (Van Londen 2003). Importantly, De Winter et al (2003) observed that patients with an anxious– retarded or “melancholic” type of depression had elevated AVP plasma levels. This observation is in line with that of Van Londen et al (1997), who found increased AVP plasma levels in melancholic depressed patients. There are also indications that elevated AVP plasma levels are related to risk-related symptoms of depression, such as psychomotor agitation (Van Londen et al 1997) and suicidal behavior (Inder et al 1997). To determine 1) whether the observed increase in AVP mRNA in an animal model of depression could also be found in depressed humans; and 2) which hypothalamic structure, PVN or SON, might be responsible for the increased plasma AVP levels in depression, we performed in situ hybridization on AVP mRNA in the PVN and SON of depressed and nondepressed subjects. Because of the indications that AVP release might especially be altered in the melancholic type of depression, we also analyzed our data for the melancholic subgroup of depressed patients.
Methods and Materials From the Netherlands Institute for Brain Research (GM, UAU, JvH, MAH, DFS) and Department of Psychiatry (GM, WJGH), Vrije Universiteit Medical Center and Geestelijke Gezondheidszorg Buitenamstel, Amsterdam, The Netherlands. Address reprint requests to Gerben Meynen, M.D., VU University Medical Center, Department of Psychiatry, GGZ Buitenamstel, Valeriusplein 9, Amsterdam 1075 BG. E-mail: [email protected]. Received June 2, 2005; revised November 20, 2005; accepted December 5, 2005.
0006-3223/06/$32.00 doi:10.1016/j.biopsych.2005.12.010
Subjects Hypothalami of nine depressed subjects and eight control subjects matched for age and gender (Table 1) were obtained from the Netherlands Brain Bank, in accordance with the formal protocols for use of human brain material and clinical information for research purposes. The MD patients were diagnosed during their lifetime, and the diagnosis was confirmed by a board-certified psychiatrist (WJGH) retrospectively using the BIOL PSYCHIATRY 2006;60:892– 895 © 2006 Society of Biological Psychiatry
G. Meynen et al
Table 1. Clinico-pathological Data of the Subjects NBB No.
Age (years)
PMD (hours)
Psychiatric Diagnosis
History of Depression/ Suicide Attempts
Cause of Death, Clinical Diagnosis
Medication
92003
F
55
7
94112
M
61
⬍61
MD (Me)
Depression lasted year before death. Yes 12 years before death MD, delusions, mood congruent. No Several PH admissions due to therapy resistant MD. Yes Two PH admissions due to MD in years before death. No Last 20 years recurrent MD, PH admissions. No Admission PH, MD with psychotic features just before suicide. Depression since death of his wife. Multiple suicide attempts. Last year before death MD. No From 1975 several PH admissions due to MD. No
Cardiac failure, urosepsis, DM II, suspicion of Parkinson Pneumonia, infarction of the right hemisphere, DM II
Dexetimide, bromocriptine, AB Biperiden 2 mg/day, glibenclamide
Fluoxetine, imipramine
94032
M
71
16
MD (Me)
Cerebral ischemia after suicide attempt by strangulation
Amiodarone, digoxin, phenprocoumon, D
None
94094
M
71
14
MD (Me)
Acute respiratory distress syndrome
AB
Bronchopneumonia, metastasized mesothelioma Suicide by strangulation. Chronic lymphatic leukemia
Prednisone, metoprolol, D
Lithium, nitrazepam, parnate, levomepromazine Maprotiline, mogadon, diazepam Zuclopentixol, paroxetine, nitrazepam
94017
F
72
⬍22
MD (Me)
95036
M
74
63
MD (Me)
93115
M
79
21
DDNOS
Suicide (jumped)
Digoxin, D
Fluvoxamine, diazepam
90122
F
85
71
MD (Me)
Sudden death while in PH, DM II Heart failure, septic shock, pyelonephritis
Insulin
Trazolan
94055
F
72
28
MD
Insulin
Brotizolam
99033
F
61
18
Control
MI, gastrointestinal tract bleeding Esophagus carcinoma Aneurysma aorta, MI Pneumonia, renal failure Lung carcinoma Heart failure, lung embolism, prostate carcinoma Aorta dissection, cardiac tamponade Pneumonia
Unknown
92042 95106 93061 93139 95093
M M M F M
61 74 70 78 78
14 8 9 6 7
Control Control Control Control Control
97130
M
58
17
Control
94074
F
85
5
Control
MD
None
Unknown Sympathicomimetics Unknown Ranitidine, AB, D Estramustine 560 mg/day
Psychiatric Medication, Last Month
Trifluoperazine
Temazepam
Unknown Prednisone, zantac
NBB, Netherlands Brain Bank; PMD, postmortem delay; F, female; M, male; MD, major depression; Me, melancholic type (retrospectively); DM, diabetes mellitus; PH, psychiatric hospital; D, diuretics; AB, antibiotics; DDNOS, depressive disorder not otherwise specified; MI, myocardial infarction.
BIOL PSYCHIATRY 2006;60:892– 895 893
www.sobp.org/journal
Gender
894 BIOL PSYCHIATRY 2006;60:892– 895
G. Meynen et al was not significant (Z ⫽ ⫺1.3, p ⫽ .21; Figure 2). Leaving out two patients who suffered from a cerebrovascular accident, leaving out the patient and control subject who used prednisone, and leaving out the DDNOS patient had no effect on the outcome. We did not find a significant difference in the amount of AVP mRNA in the SON or PVN between those patients who did or did not use antidepressants. Postmortem delay (PMD) in patients was longer than in control subjects, but correcting for PMD only increased the significance of the difference we found. In melancholic patients in both SON (Z ⫽ ⫺2.6, p ⫽ .01) and PVN (Z ⫽ ⫺2.2, p ⫽ .028), the AVP mRNA signal was significantly increased compared with control subjects.
Discussion
Figure 1. Amount of vasopressin (AVP) messenger ribonucleic acid (mRNA) signal (in arbitrary units [a.u.]) in the supraoptic nucleus and paraventricular nucleus in depressed subjects (Depr; n ⫽ 9) and control subjects (Ctr; n ⫽ 8). *Statistically significant difference (p ⬍ .05). Bars show means, error bars indicate the SEM.
medical record, according to DSM-IV criteria, paying special attention to the presence of melancholic features, also according to DSM-IV criteria. One patient, who used an antidepressant and eventually committed suicide, was diagnosed as having depressive disorder not otherwise specified (DDNOS), because his medical record did not yield sufficient information to diagnose MD. Six of the patients fulfilled the criteria for melancholic-type depression. The matched group of control subjects did not suffer from a primary neurological or psychiatric disease. Exclusion criteria were alcohol abuse (because of the reported loss of AVP neurons in the PVN and SON [Harding et al 1996]) and the use of corticosteroids (Erkut et al 1998; Kim et al 2001), except for one patient who used prednisone and was matched with one control subject who also used prednisone. Measurement of AVP mRNA in PVN and SON The method of Liu et al (2000) was used for in situ hybridization histochemistry. For quantitative analysis of AVP mRNA, within the Image Pro Plus version 4.5 image analysis package (Media Cybernetics Inc., Silverspring, Maryland), macros were developed for densitometric analysis of film autoradiographs. The procedures have been described previously (Lucassen et al 1995). Statistical Analysis Differences among groups were evaluated by the nonparametric Mann-Whitney U test. Analysis of covariance was used to correct for possible confounding factors.
Results The arginine vasopressin mRNA signal in the SON of depressed subjects was 60% higher than in control subjects (Z ⫽ ⫺2.3, p ⫽ .021; Figure 1). In the PVN, the signal in the depressed group was 15% higher than in control subjects, but this difference www.sobp.org/journal
This is the first report in which AVP mRNA has been quantified in the SON and the PVN in depressed and control subjects. We found a significant (60%) increase in the amount of AVP mRNA signal in the SON of depressed subjects (Figure 1). We also expected to find an increase in AVP expression in the PVN, which would have been in line with our earlier finding of an increased number of AVP-immunoreactive neurons in the PVN in depression (Purba et al 1996), but the rise we observed in the PVN was not significant, probably owing to the small sample. In the melancholic subgroup, however, we did find a significant difference in both the SON and the PVN. This indicates that the increase in AVP mRNA might be even more pronounced in melancholic-type depression, as was found in earlier studies (De Winter et al 2003; Van Londen et al 1997). An important question raised by our finding is whether increased AVP expression in the SON could also, at least partly, be responsible for the hypothalamic–pituitary–adrenal (HPA) axis hyperdrive in depression. Two points should be considered in this respect. First, animal studies show that the release of magnocellular AVP, originating in the PVN or SON, might take place in the median eminence and thus in the portal system, where it might potentiate ACTH release (Antoni 1993; Wotjak et al 1996). Second, it is possible that an increased AVP release from the SON into the systemic circulation contributes to the increased ACTH release from the pituitary. A clear indication that such a mechanism might exist is provided by Gispen-De Wied et al (1992), who found that intravenous administration of AVP results in increased levels of both ACTH and cortisol in both control and depressed subjects. Another indication is the finding that plasma AVP levels are positively correlated with cortisol levels in depression (Brunner et al 2002; De Winter et al 2003; Inder et al 1997). In addition, there might be a feedback mechanism between the HPA axis and the SON and PVN: glucocorticoid receptors are present in both the PVN and SON in rats (Morimoto et al 1996), as well as in rhesus monkeys (Sanchez et al 2000), and in our group Erkut et al (1998) found that in humans not only AVP in the PVN but also in the SON responds to glucocorticoid plasma levels. In some cases, antidepressants can cause the syndrome of inappropriate antidiuretic hormone secretion (SIADH), suggesting that they influence hypothalamic AVP release (Spigset and Hedenmalm 1995). We do not consider our results to be due to the use of antidepressants, on the basis of three findings. First, van Londen et al (1997) found elevated vasopressin levels in depressed subjects who did not use antidepressant medication at all. Second, in our group no significant difference was found in the amount of AVP mRNA in PVN or SON between patients who used antidepressants and those who did not. Third, in an
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Figure 2. Signal on film of the supraoptic nucleus (SON) and paraventricular nucleus (PVN) of a representative patient. Note the intense signal in both nuclei (III, third ventricle).
experiment especially designed to determine the influence of antidepressants on the occurrence of SIADH, no increase in either plasma AVP levels or AVP mRNA levels in PVN and SON was found (Marar and Amico 1998). In conclusion, our results point to the SON being the main source of the observed elevated AVP plasma levels in depression. This finding indicates that beside the PVN, the SON is a factor in HPA axis hyperdrive. Funded by Internationale Stichting Alzheimer Onderzoek, project 99512, Zorgonderzoek Nederland Medische Wetenschappen 907-00-012, and the Netherlands Organisation for Scientific Research (NWO), project 940-37-021. We thank Mr. B. Fisser and Mrs. A. Alkemade for technical assistance and the Netherlands Brain Bank for providing us with brain material. Antoni FA (1993): Vasopressinergic control of pituitary adrenocorticotropin secretion comes of age. Front Neuroendocrinol 14:76 –122. Brunner J, Keck ME, Landgraf R, Uhr M, Namendorf C, Bronisch T (2002): Vasopressin in CSF and plasma in depressed suicide attempters: Preliminary results. Eur Neuropsychopharmacol 12:489 – 494. De Winter RF, van Hemert AM, DeRijk RH, Zwinderman KH, FrankhuijzenSierevogel AC, Wiegant VM, et al (2003): Anxious-retarded depression: Relation with plasma vasopressin and cortisol. Neuropsychopharmacology 28:140 –147. Erkut ZA, Pool C, Swaab DF (1998): Glucocorticoids suppress corticotropinreleasing hormone and vasopressin expression in human hypothalamic neurons. J Clin Endocrinol Metab 83:2066 –2073. Gispen-de Wied CC, Westenberg HG, Koppeschaar HP, Thijssen JH, van Ree JM (1992): Stimulation of the pituitary-adrenal axis with a low dose [Arg8]-vasopressin in depressed patients and healthy subjects. Eur Neuropsychopharmacol 2:411– 419. Harding AJ, Halliday GM, Ng JL, Harper CG, Kril JJ (1996): Loss of vasopressinimmunoreactive neurons in alcoholics is dose-related and time-dependent. Neuroscience 72:699 –708.
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