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ــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــ * Correspondence Author ([email protected])
203
The Egyptian Journal of Biochemistry & Molecular Biology VOL 30 (N.2)203- 216 Dec. 2012
A STUDY ON ANGIOTENSIN CONVERTING ENZYME GENE
INSERTION/DELETION POLYMORPHISM AND SERUM
CORTISOL AMONG A SAMPLE OF EGYPTIAN PATIENTS
WITH MAJOR DEPRESSION DISORDER
Mohga S. Abdullah1, Adel G. El-Missiry
2, Hayat M. Sharada
1,
Ahmad A.El-Missiry3, Fatma A. Abu Zahra
4*
1Department of Chemistry, Faculty of Science,
Helwan University, Cairo, Egypt 2Department of Parasitology, Faculty of Medicine,
Ain Shams University 3Department of Psychiatry, Faculty of Medicine,
Ain Shams University 4Medical Research Center, Faculty of Medicine,
Ain Shams University
Received 4/7/2012– Accepted 3/9/2012
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ABSTRACT
Angiotensin-converting enzyme (ACE) is assumed to influence
the activity of the hypothalamic-pituitary-adrenocortical (HPA)
system, which shows hyperactivity in the majority of patients with
major depression. The ACE gene, known to be associated with
cardiovascular disorders, which in turn are accompanied with an
increased susceptibility for depression, is therefore a promising
candidate gene for effective disorders. However, the results are
conflicting, with no reported studies on Egyptian depressed patients.
This study aimed to assess ACE insertion / deletion (I/D) gene
polymorphism among Egyptian depressed patients in order to clarify
HPA system dysregulation, and to determine its possible association
with severity of depression. This case/control study was conducted on
42 adult depressed patients, and 37 healthy controls were screened to
detect genetic associations with unipolar major depression.
Determination of ACE genotypes was performed for all subjects by
real time PCR. Total serum cortisol levels were measured by ELISA.
The frequencies of the DD, ID and II genotypes were 26.2%, 45.2%,
Mohga S. Abdullah et all
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204
and 28.2%, respectively among the cases, and 17.49%, 25.2%, and
56.41%, respectively among the controls. Significant differences in
ACE genotype distribution were observed between cases and controls
(p = 0.0384). Serum cortisol in patients show the highest value in the
ID polymorphism while II polymorphism shows the lowest value of
a.m. cortisol. Data illustrated a significant association of ID
polymorphism with the more severity of illness. Our findings support
that ACE gene I/D polymorphism and high D allele frequency are
associated with depression, also hypercortisolimia is significantly
higher in individuals with major depression compared to control
among Egyptian adults. ACE gene polymorphism might provide a
common link between developing depressive episode and
dysfunctional HPA-axis.
Keywords: ACE gene –insertion\deletion polymorphism –cortisol –
depression
INTRODUCTION
Depression is undoubtedly a common disabling disorder (Alonso et
al., 2004). The economic burden on society arises not only from the
direct health and social care costs, but also from the indirect costs, due
to the reduced work productivity of patients and premature death due
to suicide (Baghai et al., 2012). Experimental studies have
investigated many different types of stress, and their effects on the
hypothalamic-pituitary- adrenocortical (HPA) axis in many different
circumstances (Sower et al., 2009). Cortisol is released in response to
stress and a low level of blood glucocorticoids acting to restore
homeostasis (Holsboer, 2000). Changes in the activity of the renin-
angiontensin-aldosterone system (RAAS) in depression have recently
been reported (Murck et al., 2006). Angiotensin I is converted to
angiotensin II by angiotensin-converting enzyme (ACE) (Paul et al.,
2006). ACE is assumed to influence the activity of the HPA system,
which shows hyperactivity in the majority of patients with major
depression. The ACE gene, known to be associated with
cardiovascular disorders, which in turn are accompanied with an
increased susceptibility for depression, is therefore a promising
candidate gene for affective disorders (Baghai et al., 2006).
Given the abundance of the renin–angiotensin system (RAS)
components in the brain, their importance in behavior and cognition,
A STUDY ON ANGIOTENSIN CONVERTING ENZYME GENE ……..
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and the data that implicates them in the etiology and treatment of
depression, it is possible that those RAS gene polymorphisms
associated with increased RAS activity may also be associated with
depression (Saab et al., 2007).
This study aimed to examine the ACE/ID polymorphism and
estimation of serum cortisol level as a sign of the extent of HPA-axis
system dysregulation in relation to this polymorphism in a sample of
Egyptian patients with depression.
MATERIALS AND METHODS
1-Study population
The 42 cases of major depression disorder (MDD) patients were
selected from the Institute of Psychiatry, Ain Shams University
Hospitals. The control group consisted of 39 subjects of apparently
healthy recruited from the visitors of Ain Shams University Hospitals
and were selected to match the study group as much as possible.
The Structured Clinical Interview for DSM-IV Axis I Disorders
(SCID-I) has done by a clinician, semistructured interview with
psychiatric patients or with non-patient community subjects who are
undergoing evaluation for psychopathology for diagnosis of MDD.
Both groups have permanently resided in the same region, with sex
and age matched. The local committee for ethics of medical
experiments on human subjects approved the study, and all
participants gave their written informed consent. The Beck Depression
Inventory (BDI) (Beck et al., 1961) was used to measure the
behavioral manifestations of depression. On the other hand, Hamilton
Rating Scale for Depression (Ham-D) (Appendix-VI) was designed to
measure the severity of depressive symptoms in patients with primary
depressive illness (Hamilton, 1960).
The reliability of the scale varies with conditions but is generally
accepted, with internal consistency tends to be 0.92. It tends to be
higher with the structured than unstructured interview (Potts et al.,
1990). The inter rater reliability reached up to 0.9 (Rehm and
O’Hara, 1985).
2-Estimation of serum cortisol (a.m.): Samples of patients and
control had been estimated for the results of serum cortisol for in vitro
diagnostic use with the IMMULITE 1000 Analysis –for quantitative
measurement of cortisol (Siemens Healthcare, Diagnostics Products
Mohga S. Abdullah et all
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Ltd Llaberis, GwyneddLL55 4EL, United kingdom).
The candidate gene selected in this study was Angiotensin
converting enzyme gene (ACE gene).
3-Genotyping
Gene typing of genomic DNA samples obtained from 42 unrelated
patients with MDD (20 women and 22 men, aged 34.79±9.1 years)
and 39 unrelated healthy controls (20 women and 19 men, aged
35.56±10.8 years) was performed.
The molecular part of this work was carried out at the Medical
Research Center (MRC) Faculty of Medicine, Ain Shams University.
Genomic DNA was isolated from whole blood using the Qiagen-
Kit. PCR (polymerase chain reaction) amplification of the of ACE I/D
polymorphism was carried out using the
primers sequence:
Forward : 5’-GAT GTG GCC ATC ACA TTG GTC AGA T -3’.
Reverse : 5’-CTG GAG ACC ACT CCC ATC ATT TCT -3’.
The insertion (I-allele) resulted in a product of 478 bp, deletion (D-
allele) in 191 bp. We report here the development of a single-tube
real-time PCR assay to determine the ACE gene I/D polymorphism.
This method takes advantages of the SYBR Green I fluorescent dye
for real-time 45 ng of DNA is sufficient to use as a template for PCR.
Amplification with 45 cycles only was optimal for ligation
efficiencies. A mixture containing Taq polymerase and a proofreading
polymerase, Taq must be in excess of a 10:1 ratio to ensure the
presence of 3’A-overhangs on the PCR product.
The PCR in a 20 µl volume containing:
DNA Template 45 ng
10X PCR Buffer 2 µl
50 mM dNTPs 0.5 µl
Primers 1 µM each
Sterile water to a total volume of 19 µl
Taq Polymerase 1 unit
Total Volume 20 µl
Special care to avoid sources of nuclease contamination and long
exposure to UV light to prevent degradation of the single A-
overhangs.
Real-time PCR
Light cycler-based real-time PCR (LC-PCR) assay was used. Real-
time PCR were performed with a Light Cycler 1.5 instrument (Roche
A STUDY ON ANGIOTENSIN CONVERTING ENZYME GENE ……..
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207
Molecular Diagnostics, Penzberg, Germany) by using a total
reaction volume of 20µl in PCR capillaries. Optimization reactions
were first performed until the best primer concentrations.
Melting curve analysis reveals only one peak at the characteristic
melting temperature, when PCR results only in the specific amplicon
as in insertion (490 bp) or Deletion (190 bp). Two peak at the
characteristic melting temperature, when PCR results only in the two
specific amplicon (as in heterozygot insertion and Deletion case 490
bp and 190 bp). Primer dimers and other nonspecific products
would cause additional peaks.
According to the presence or absence of the insertion allele, the
genotype of the subjects could be classified as II (homozygote for the
insertion allele), DD (homozygote for the deletion allel), or ID
(heterozygote).
The PCR products were separated on a 2% agarose gel and visualized
by ethidium bromide staining under UV light. The insertion (I-allele)
resulted in a product of 490 bp, the deletion (D-allele) in 191 bp
(Bocchetta et al., 1999).
Statistical analyses: In some occasions Fisher-Exact probability was
used if less than 5 observations are expected in a cell. Student-t- test
was used to detect difference between 2 groups' means and ANOVA if
more than 2 groups. All statistical manipulation and data analyses
were performed using the 16th
version of SPSS (Statistical Package for
Social Sciences).
Mohga S. Abdullah et all
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RESULTS
Table (1) shows Socio-demographic characteristics of cases compared
to controls which show no significant differences between the two
groups.
Table (1): Socio-demographic characteristics of cases compared to
controls
Cases
n=
Controls
n=
Test of
Significance
df P
value
Education
years
Mean ±
SD
Mean ±
SD t= 1.89
◊ 79
0.062
(NS) Mean (SD) 6.4±5.3 8.8±6.1
Min – Max 0 – 16 0 – 17
Occupation N (%) N (%)
X2=6.80 5 0.236
(NS)
Jobless 4 (9.5) 3 (7.7)
House Wife 14 (33.3) 6 (15.4)
Non-skilled -- 2 (5.1)
Semi-skilled 6 (14.3) 5 (12.8)
Semi-
Professional
12 (28.6) 12 (30.8)
Professional 6 (14.3) 11 (28.2)
Social class N (%) N (%)
X2= 5.95 3 0.114
(NS)
High-Mid -- 5 (12.8)
Low Mid 20 (47.6) 18 (46.2)
Low 18 (42.9) 13 (33.3)
Very Low 4 (9.5) 3 (7.7)
Marital Status N (%) N (%)
X2= 1.161 3 0.762
(NS)
Single 10 (23.8) 7 (17.9)
Married 28 (66.7) 26 (66.7)
Divorced 2 (4.8) 4 (10.3)
Widow 2 (4.8) 2 (5.1)
In this study, II polymorphism was encountered more
frequently in the control group compared to only 28.6% in the cases.
ID polymorphism and DD polymorphism were significantly and
frequently found in the cases group than the controls (45.2% and
26.2% versus 25.6% and 17.94% respectively) (Figure 1).
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209
Figure (1): ACE Genotype among the studied depression patients
compared to controls
Table (2) shows significant difference between Insertion I and
deletion D alleles frequencies among the studied patients with
depression compared with matched controls by using the Fisher Exact
Probability. Data revealed that the D allele was significantly
prominent in the depressed group compared to controls (48.8% and
30.77% respectively).
Table (2): ACE Allele frequencies among the depression patients vs.
controls
Cases Controls χ2 P value
• I 43(51.19%) 54
(69.23%) 4.754 0.029
• D 41
(48.81%)
24
(30.77%) ¤Fisher Exact probability has been used
Table (3) illustrates a high significant level of serum cortisol in cases
as compared to controls.
0
10
20
30
40
50
60
II DD ID
CasesControls
Mohga S. Abdullah et all
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Table (3): Serum cortisol level in cases compared with control group
Cases Controls
Mean ±SD Mean ±SD
Plasma
Cortisol
Mean (SD)
Min – Max
17.33±5.2
15.7 – 18.9
10.68±5.3
8.9 – 12.4
t-value 5.69
P value <0.001*
Table (4) shows the distribution of different allele among depressed
patients illustrating higher percentage of ID allele in comparison to II
and DD alleles. We performed genotyping of the I/D polymorphism
using polymerase chain reactions (PCR) amplification of the ACE I/D
polymorphism in cases who were diagnosed according to DSM-VI
criteria to have major depression compared to matched healthy
controls.
Table (4): ACE polymorphism among the studied depression patients
RAS
Polymorphism N (%) 95% CI
• II 12 (28.6) 16.2 – 44.8
• DD 11 (26.2) 14.4 – 42.3
• ID 19 (45.2) 30.2 – 61.2
Table (5): Serum cortisol levels among the studied depression patients
in relation to ACE genotypes
II���� DD���� ID���� f value���� P value
Serum
Cortisol
Mean
(SD)
95% CI
14.9
(2.1)
13.9 –
15.9
17.5
(6.6)
13.1 –
22.0
� 21.0
(5.3)
17.6 –
24.4
6.438 0.004*
�F value (ANOVA test), df= 2 Between groups and within groups 39.
A STUDY ON ANGIOTENSIN CONVERTING ENZYME GENE ……..
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Figure (2): represents agarose gel electrophoresis illustrating 100 base
pair (bp) loading marker in first and last lanes. In lanes 1 and 6 show
homozygote insertion ACE gene polymorphism at 490 bp, in lanes 2
and 5, heterozygote insertion/deletion ACE gene polymorphism at 490
bp and 190 bp while lanes 3 and 4 represent homozygote deletion
ACE gene polymorphism at 190 bp, and lane 7 represents control
sample (no polymorphism).
DISCUSSION
Depression is a prevalent disorder and one of the leading disease
causing disability and economic burden according to the World Bank
reports (Kato and Serretti, 2010). Since epidemiological data denotes
that depression may affect 10% of population, we except that we have
about 8 million people with depression in Egypt (Ghanem et al.,
2009). That is why this study was designed to be the first step to find one
important parameter for a biological marker which helps for the early
detection of depression and reconfirmation of the diagnosis. This also
may lead to early intervention hoping for recovery from this
devastating disorder.
To fulfill our aim we investigated 42 patients suffering from major
depression according to the DSM IV criteria for diagnosis of
depression and we compared them with 39 matched healthy controls.
Recent studies have shown that genetics variants of angiotensin
converting enzyme (ACE) can contribute to disease susceptibility and
Mohga S. Abdullah et all
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inter-individual differences in antidepressants response (Yanfeng et
al., 2011). A genetic polymorphism is characterized by an insertion (I)
or deletion (D). Both alleles have concomitant effects on the level of
ACE. Thus individuals who are Homozygous for the I allele has the
lowest level of the enzyme, while those who are homozygous for the
D allele have the highest; while, heterozygous subjects have an
intermediate level (Zintzaras et al., 2008).
The renin-angiotensim-aldosterone system (RAAS) has been
implicated in mood disorders (Hallberg et al., 2011; Nasr et al.,
2011). The contribution of the RAAS in controlling mood has been
attributed to the angiotensin II that interacts with dopamine (DA) in
specific brain regions and the ACE has an important role in the
modulation of DA turnover. ACE is part of the renin-angiotensin
system (RAS) and is involved in the conversion of angiotensin I to
angiotensin II (Kobori et al., 2007), which is a peptide hormone acts
as a stimulator of proinflammatory cytokines and interferes with
hypothalamic pituitary adrenal (HPA) axis activation in response to
stress (Ising and Jolsboer, 2006; Yanfeng et al., 2011).
There has been a growing interest in the study of ACE/ID
polymorphism as a potential factor for developing depression (Baghai
et al., 2006). However, despite the large number of studies with
different designed, the role of the ACE gene I/D polymorphism on
depression is still controversial. Previous association studies for ACE
and depression conducted by genotyping ACE-I/D polymorphism
have yielded inconsistent results (Heck et al., 2009). On the other
hand, previous data pointed to the possibility that ACE/ID
polymorphism could be a finger point or a biological marker of major
depression and response to treatment (Baghai et al., 2003 and 2006;
Murck et al., 2006).
Wu et al. (2012) provided a strong evidence of a positive association
of the ACE/ID polymorphism as risk factor for depression in
Caucasians but not in Asians. On the other hand, they failed to detect
significant differences between cases and control groups as regards
ACE/ID polymorphism in Chinese population.
In a similar culture to ours, Saab et al. (2007) in Lebanese
population proved that the angiotensin receptor type I was
significantly associated with depression, however he could not prove
that the type of the ACE/ID polymorphism is associated with unipolar
depression.
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It seems that variation of results across ethnic groups could account
for the differences in race specific genetics effects, sample selection
diagnostic criteria, different methodology and different patient
recruitment methods for patients and controls.
The dysregulation of the activity of the hypothalamic-pituitary-
adrenocorticaI (HPA) system is one of the major neuroendocrine
abnormalities in major depressive disorder. These include elevated
circulating plasma levels of both corticotropin (adrenocorticotropic
hormone, ACTH) and cortisol (Holsboer, 2000). RAAS is closely
related to HPA-axis as ACTH is a common stimulus for both cortisol
and aldosterone, moreover, cortisol release is suppressed by
mineralocorticoide receptor agonists and finaly angiotensim II
releases corticotropin-releasing hormone (CRH) and vasopression
from the hypothalamus (Murck et al., 2003).
In this study, serum cortisol in patients show the highest value in the
ID polymorphism while II polymorphism shows the lowest value of
a.m. cortisol and DD polymorphism shows the intermediate value
(Table 5). The HPA-axis is suggested to be hyperactive in major
depressive disorder (MDD) (Bao et al., 2008) and chronic depression
is proved to be associated with increased level of cortisol (Lindquist
et al., 2008). Not only hypercortisolism but also reduced feedback
inhibition of the hypothalamus-pituitary adrenocortical (HPA) system
has been reported in patients with depression (van den Bos et al.,
2006).
The current research data are in agreement with previous reports
which found that serum cortisol is significantly higher in patients with
depression compared to controls (Murck et al., 2005; Baghi et al.,
2006; Häfner et al., 2012). In conclusion, our findings support that ACE gene I/D polymorphism
and high D allele frequency are associated with depression, also
hypercortisolimia is significantly higher in individuals with major
depression compared to control. ACE gene polymorphism might
provide a common link between developing depressive episode and
dysfunctional HPA-axis.
REFERENCES
Alonso, J.; Angermeyer, M.C.; Bernert, S.; Bruffaerts, R.; Brugha, T.S.; et al. (2004). 12-Month comorbidity patterns and associated
factors in Europe: results from the European Study of the
Mohga S. Abdullah et all
ــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــ
ـــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــ
214
Epidemiology of Mental Disorders (ESEMeD) project. Acta
Psychiatr. Scana. Suppl.; 420:28-37.
Baghai, T.C.; Binder, E.B.; Schule, C.; Salyakina, D.; Eser, D.; Lucae, S.; et al. (2006): Polymorphisms in the angiotensin-converting
enzyme gene are associated with unipolar depression, ACE activity
and hypercortisolism. Mol. Psych.; 11(11):1003-15.
Baghai, T.C.; Blier, P.; Baldwin, D.S.; Bauer, M.; Goodwin, G.M.;
Fountoulakis, K.N.; Kasper, S.; Leonard, B.E.; Malt, U.F.; Stein, D.J.; Versiani, M. and Möller, H.J. (2012). Executive summary of
the report by the WPA section on pharmacopsychiatry on general and
comparative efficacy and effectiveness of antidepressants in the acute
treatment of depressive disorders. Eur. Arch. Psychiatry Clin.
Neurosci.; 262(1):13-22.
Baghai, T.C.; Schule, C.; Zwanzger, P.; Zill, P.; Ella, R.; Eser, D.; Deiml, T.; Minov, C.; Rupprecht, R. and Bondy, B. (2003). Influence
of a functional polymorphism within the angiotensin I converting
enzyme gene on partial sleep deprivation in patients with major
depression. Neurosci. Lett.; 339 (3): 223-6.
Bao, A.M.; Meynen, G.; Swaab, D.F. (2008). The stress system in
depression and neurodegeneration: Focus on the human
hypothalamus. Brain Res. Rev.; 57: 531-53.
Beck, A.T.; Ward, C. H.; Mendelson, M.; Mock, J. and Erbaugh, J. (1961). An inventory for measuring depression. Arch. Gen. Psych.; 4:
561-71.
Bocchetta, A.; Piccardi, M. P.; Martinelli, V.; Quesada, G. and
Del Zompo, M. (1999). Maternal inheritance of manic depression in
hemizygotes for the G6PD-Mediterranean mutation. Indirect evidence
for Xq28 transmission in Sardinia. Psychiatr. Genet.; 9, 63-8 .
Ghanem, K.G.; Moore, R.D.; Rompalo, A.M.; Erbelding, E.J.; Zenilman, J.M. and Gebo, K.A. (2009). Lumbar puncture in HIV-
infected patients with syphilis and no neurologic symptoms. Clin.
Infect. Dis.; 15, 48(6): 816-21.
Häfner, S.; Baumert, J.; Emeny, R.T.; Lacruz, M.E.; Bidlingmaier,
M.; Reincke, M.; Kuenzel, H.; Holle, R.; Rupprecht, R.; Ladwig, K.H.; monica/kora Study Investigators (2012). To live alone and to
be depressed, an alarming combination for the renin-angiotensin-
aldosterone-system (RAAS). Psychoneuroendocrinol.; 37(2): 230-7.
Hallberg, L.; Westrin, A.; Isaksson, A. and Janelidze, S. (2011). Decreased aldosterone in the plasma of suicide attempters with
A STUDY ON ANGIOTENSIN CONVERTING ENZYME GENE ……..
ــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــ
ــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــ
215
major depressive disorder. Psych. Res.; 187: 135-9.
Hamilton, M. (1960). A rating scale for depression. J. Neuor.
Neurosurg. Psych.; 23: 56-62.
Heck, A.; Lieb, R.; Ellgas, A.; Pfister, H.; Lucae. S.; Erhardt. A.;
Himmerich, H.; Horstmann. S.; Kloiber, S.; Ripke, S.; Müller-
Myhsok, B.; Bettecken, T.; Uhr, M.; Holsboer, F. and Ising, M. (2009). Polymorphisms in the angiotensin-converting enzyme gene
region predict coping styles in healthy adults and depressed patients.
Am. J. Med. Genet.; Part B Neuropsych. Genet.; 150B (1):104-14.
Holsboer, F. (2000). The corticosteroid receptor hypothesis of
depression. Neuropsychopharmacology; 23: 477–501.
Ising, M. and Holsboer, F. (2006). Genetics of stress response and
stress related disorder. Dialog. Clin. Neurosc.; 8: 433-44.
Kato, M. and Serretti, A. (2010). Review and meta-analysis of
antidepressant pharmacogenetic findings in major depressive disorder.
Mol. Psych.; 15(5):473-500.
Kobori, H.; Nangaku, M.; Navar, L.G. and Nishyama, A. (2007). The interarenal Rennin-angiotensin system: from physiology to the
pathobiology of hypertension and kidney disease. Pharmacol. Rev.;
59: 251-87.
Lindquist, D.; Traskiman-Benz, L. and Vang, F. (2008). Suicidal
intent and the HPA –axis characteristics of suicide with major
depression disorder and adjustment disorder. Arch. Suicide Res.; 12:
197-207.
Murck, H.; Fava, M.; Alpert, J.; Nierenberg, A.A.; Mischoulon, D. and Otto, M.W. (2005). Hypericum extract in patients with
MDD and reversed vegetative signs: re-analysis from data of a
double-blind, randomized trial of Hypericum extract, fluoxetine,
and placebo. International Journal of Neuropsychopharmacol.; 8:
215–21.
Murck, H.; Held, K.; Ziegenbein, M.; Kunzel, H.; Koch, K. and Steiger, A. (2003). The renin—angiotensin—aldosterone system in
patients with depression compared to controls–—a sleep endocrine
study. BMC Psychiatry; 3, 15.
Murck, H.; Uhr, M.; Ziegenbein, M.; Künzel, H.; Held, K.; Antonijevic, I.A.; Schüssler, P. and Steiger, A. (2006). Renin-
angiotensin-aldosterone system, HPA-axis and sleep-EEG changes in
unmedicated patients with depression after total sleep deprivation.
Pharmacopsychiatry; 39(1):23-9.
Mohga S. Abdullah et all
ــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــ
ـــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــ
216
Nasr, S.J.; Crayton, J.W.; Agarwal, B.; Wendt, B. and Kora, R. (2011). Lower frequency of antidepressant use in patients on renin-
angiotensin –aldosterone system modifying medications. Cell Mol.
Neurobiol.; 31: 615-8.
Paul, S.L.; Dewey, H.M.; Sturm, J.W.; Macdonell, R.A. and Thrift, A.G. (2006). Prevalence of depression and use of antidepressant
medication at 5-years poststroke in the North East Melbourne Stroke
Incidence Study. Stroke; 37(11):2854-5.
Potts, M.K.; Daniels, M.; Brunam, M.A. and Wells, K.B. (1990). A
structured interview version of the Hamilton Depression Rating Scale:
evidence of reliability and versatility of administration. J. Psych. Res.;
24: 335–50.
Rehm, L.P. and O'Hara, M.W. (1985). Item characteristics of the
Hamilton Rating Scale for Depression. J. Psych. Res.; 19: 31-41.
Saab, Y.B.; Gard, P.R.; Yeoman, M.S.; Mfarrej, B.; El-Moalem, H. and Ingram, M.J. (2007). Renin–angiotensin-system gene
polymorphisms and depression. Progress in Neuro-
Psychopharmacology and Biological Psychiatry; 31(5): 1113-8.
Sower, S.A.; Freamat, M. and Kavanaugh, S.I. (2009). The origins
of the vertebrate hypothalamic-pituitary-gonadal (HPG) and
hypothalamic-pituitary-thyroid (HPT) endocrine systems: new
insights from lampreys. Gen. Comp. Endocrinol. 161 (1): 20–9.
van den Bos, K.; van Ameijde, J. and Hein van Gorp, H. (2006). On
the psychology of religion: The role of personal uncertainty in
religious worldview defense. Basic Appl. Soc. Psych.; 28(4):333-41
Wu, Y.; Wang, X.; Shen, X.; Tan, Z. and Yuan, Y. (2012). The I/D
polymorphism of angiotensin–converting enzyme gene in major
depressive disorder and therapeutic outcome: A case control study and
meta- analysis. J. Affect. Disord.; 136 (3): 971-8.
Yanfeng, W.A.; Berhane, H.; Mola, M.; Singh, J.; Jenny, A. and Mlodzik, M. (2011). Functional dissection of phosphorylation of
Disheveled in Drosophila. Dev. Biol.; 360(1): 132-42.
Zintzaras, E.; Raman, G. and Lau, J. (2008). Angiotensin converting
enzyme insertion/deletion gene polymorphic variants as a maker of
coronary artery disease: a meta-analysis. Arch. Int. Med.; 168, 1077-
89.