World J Biol Psychiatry (2001) 2, 115 - 143
REVIEW/MINI-REVIEW b
Stress Hormone-Related Psychopathology:
Pathophysiological and Treatment Implications
Owen M. Wolkowitz, Elissa S. Epel, Victor 1. Reus
Department o f Psychiatry, University o f California, School o f Medicine, San Francisco, USA
Summary
Stress is commonly associated with a variety of
psychiatric conditions, iiicluding major depression,
anti with chronic medical conditions, including
diabetes and insulin resistance. Whether stress
causes these conditions is uncertain, but plausible
World J Biol Psychiatry Downloaded from informahealthcare.com by University of Colorado Libraries on 12/31/14
mechanisms exist by which such effects might occur.
To the extent stress-induced hormonal alterations
(eg., chronically elevated cortisol levels and lowered
dehydroepiandrosterone [DHEA] levels) contribute to
psychiatric and medical disease states, manipula-
tions that normalize these hormonal aberrations
should prove therapeutic. In this review, we discuss
mechanisms by which hormonal imbalance (dis-
cussed in the pameworks of "allostatic load" and
"aiiabolic balance'? might contribute to illness. W e
then review certain clinical manifestations of such
hormonal imbalances and discuss pharmacological
and behavioural treatment strategies aimed a t nor-
malizing hormonal output and lessening psychiatric
For personal use only.
and physical pathology.
Key Words: stress, allostasis, depression, memory,
hippocampus, Cushing's Syndrome,
dehydroepiandrosterone (DHEA), cortisol,
neurosteroids, BDNF, antiglucocorticoid, Metabolic
Syndrome, visceral obesity.
Correspondence:
Prof. Owen M. Wolkowitz
UCSF Medical Center
401 Parnassus Avenue, Box F
San Francisco, C A 94143-0984
USA
Tel: +I 41 5 476 7433
Fax: + I 41 5 502 2661
E-mail: owenw@itsa.ucsf.edu
115
Introduction
"We are on our guard against external intoxicants,
but hormones are parts of our bodies; it lakes more
wisdom to recognize and overcome the fi)e who fights
P o m within .... (But) what can we do abornt this? ...
W e do not yet know enough about their workings to
justify any attempt a t regulating our emctional key
b y taking hormones. " -
The Stress of Life (Selye 1956)
Forty-five years after Hans Selye, the "Father of
Stress Physiology," wrote these words, we are see-
mingly in a much stronger position to "regulate
our emotional key" by recognizing arid correc-
ting hormonal imbalances that are associated
with behavioural disturbances. In this review, we
attempt to summarize our current understan-
ding of the relationship of stress and stress hor-
mone dysregulation to psychiatric disorders and
to certain health outcomes, and we speculate on
the role of novel hormonal interventions in
treating such disorders. We specifically address
the following questions: (1) Do alterations in
stress hormones directly contribute to psycho-
pathology? (2) Do these changes in stress hor-
mones also contribute to the high c omorbidity
between depression and certain chronic dis-
eases? ( 3 ) If so, what are the mechanisms of these
effects? (4) How ,are these effects manifest in
clinical settings? (51) Can beneficial effects accrue
from treatment strategies primarily aimed at
normalizing stress hormone activity? (6) Which
specific treatment rtrategies hold promise in this
regard? Pharmacological treatment si rategies are
our primary focus here, but we also review evi-
dence suggesting that certain behavioural inter-
ventions have comparable effects, perhaps via
similar endocrinological mechanisms. While our
primary emphasis in this review is the relation-
ship of stress hormones to depression and cogni-
tion, we also consider alterations in energy me-
tabolism (e.g.l visceral obesity, eating and insulin
resistance) as a somatic example of a network of
regulatory systems that is directly affected by
stress and that commonly becomes disturbed in
psychiatric illness. Understanding common
causes for depression and metabolic dysregula-
tion could provide insight into effective treat-
ments for people with this comorbidity.
Stress responses, allostatic load and
anabolic balance
Acute stress
When stress is acute, adaptive biochemical res-
ponses include increased adrenocortical secre-
 RE VIE W/MINI-R E VIE W b
tion of stress hormones, prominently cortisol
and dehydroepiandrosterone (DHEA). Glucocor-
ticoid secretion (specifically, cortisol in humans,
corticosterone in many animal species) increases
appetite, antagonizes insulin's cellular actions
(thereby inhibiting further glucose storage),
stimulates glycogenolysis and gluconeogenesis,
breaks down protein stores and redistributes
fatty acids from fat stores into the circulation to
make energy more readily available to muscle
tissue; this facilitates muscles' ability to respond
robustly to imminent threat. Stress-induced cor-
tisol surges also focus attention, arousal and
alertness, increase vascular tone and blood
pressure, demarginate white blood cells from the
vascular linings into the circulation and tempo-
World J Biol Psychiatry Downloaded from informahealthcare.com by University of Colorado Libraries on 12/31/14
rarily suppress "unnecessary" bodily functions
such as digestion, bone growth, wound repair
and reproduction. The role of concomitant
DHEA secretion in the acute stress response is
less clear, but it has anabolic effects and may
serve to buffer the organism from excessive
cortisol activity due to DHEA's intrinsic "anti-
glucocorticoid" effects (Browne et a1 1992;
Hechter et a1 1997; Hu et a1 2000; Kalimi et a1
1994; Leblhuber et a1 1992; Patchev and Almeida
1997; Wolkowitz et a1 1992). Under chronic
stress, however, DHEA levels decline, and thus
the ability to counteract the catabolic effects of
For personal use only.
glucocorticoids becomes impaired.
Allostasis
The role of glucocorticoids in the adaptive acute
response to stress has been divided into separate
classes of action that have differing time do-
mains in response to the stressful stimulus (Sa-
polsky et a1 2000). Permissive actions are those
exerted by glucocorticoids prior to the onset of
stress and tonically involved in the mediation of
the initial response. Stimulatory and suppressive
actions induced by glucocorticoids either en-
hance or inhibit the effects of the initial phasic
change in stress responsive hormones, while pre-
parative actions alter the physiological responses
of the organism to the presentation of a subse-
quent stressor. In general, permissive actions are
regulated by the mineralocorticoid ("Type 1")
receptor (MR) at lower free cortisol or cortico-
sterone concentrations. Stress-induced increases
in cortisol or corticosterone output tend to result
in a shift to suppressive actions (e.g., glucocor-
ticoid negative feedback) mediated by the gluco-
corticoid ("Type 2") receptor (GR) (De Kloet et a1
1998; Plihal et a1 1996).
Acute adrenocortical responses are critical for
successful adaptation to stress, and, indeed, for
life itself. However, when these responses are
excessive or are extended for long periods of
time, as in tonic activation of the GR, detri-
mental effects on both emotional well-being and
physical health may ensue (McEwen 2000a;
McEwen and Stellar 1993; McEwen et a1 1992;
Raber 1998; Seeman et a1 1997; Sterling and Eyer
1988). Successful adaptation to stress has been
116
termed "allostasis" (as opposed to "homeostasis")
to reflect the fact that organisms must be facile
in meeting the energetic and other demands
of acutely stressful situations in a dynamic way
and must, likewise, be able to restrain stress
reactions when acute stressors subside (Sterling
and Eyer 1988).
Allostatic load and anabolic balance
The excessive "wear and tear" associated with
prolonged or inappropriate stress responses has
been termed "allostatic load" (McEwen and Stel-
lar 1993). Notably, under long-term stress, DHEA
secretion decreases to below baseline levels while
cortisol levels frequently remain elevated, ren-
dering the individual especially vulnerable to the
detrimental, unopposed effects of prolonged cor-
tisol exposure. Framed in complementary terms,
cortisol exerts prominent catabolic effects in the
body (i.e., breakdown of metabolic compounds
to produce energy); these can be adaptive acutely
but can destroy essential tissue and function if
left unchecked for long periods of time. DHEA
(and other hormones such as growth hormone,
testosterone and insulin-like growth factor [IGF-
11) have anabolic effects (i.e., promoting growth
and repair) thus repairing catabolic damage so
long as their levels remain sufficiently high in
the circulation (Sterling and Eyer 1988). This
understanding of the relationship between ana-
bolic hormones, such as DHEA, testosterone and
growth hormone, and catabolic hormones, such
as cortisol, has led to the recent introduction of
the term "anabolic balance" to highlight the
importance of the ratio of anabolic-to-catabolic
activity in determining health and well-being
(Wolkowitz, O., Epel, E., & Reus, V. (2001). Anti-
glucocorticoid strategies in treating major
depression and health outcome. In T. Jogin (Ed.),
The Physical Consequences of Depression (pp.
181-212). Petersfield, UK: Wrightson Biomedical
Publishing.). A low anabolic balance (e.g., low
DHEA and/or high cortisol) is thought to be a
primary response to chronic stress that leads to a
cascade of dysregulation across systems and
allostatic load (Barbieri et a1 2001; Christeff et a1
2000; Epel et a1 1998; Goodyer et a1 1996;
Hechter et a1 1997; Herbert 1997; Herbert 1998;
Matoulek et a1 2000; McEwen 1998; McEwen and
Seeman 1999; Wolkowitz and Reus 2000;
Seeman et a1 2001), contributing to depression
and certain chronic diseases. Relevant to the pri-
mary thesis of this review, failure to hormonally
"adapt" to repeated or persistent stressors with
normalization of adrenocortical output and of
anabo1ic:catabolic balance may be a heuristically
useful model of depression and other illnesses in
humans (c.f. (Kennett et a1 1985)). Catabolic vs.
anabolic effects on glucose disposition provide a
unifying theme for explaining the consequences
discussed here of chronic glucocorticoids on
both brain and body. In the brain, glucocorticoid
inhibition of hippocampal glucose transport
(which occurs at stress levels of glucocorticoids)
(de Leon et a1 1997) likely contributes to hippo-
 campal neuronal endangerment (Sapolsky et a1
2000; Sapolsky et a1 1990; Sapolsky 1993; Sapol-
sky 1994). In the periphery, chronic exposure to
elevated levels of glucocorticoids may result in
insulin resistance, hyperinsulinemia, hyper-
glycemia and visceral adiposity, which are major
components of the "Metabolic Syndrome X"
(Bjorntorp et a1 1999a; Matoulek et a1 2000;
Raber 1998). Additional components of this
syndrome include hyperlipidemia, hyperten-
sion, and other factors leading to disordered fat
metabolism (Reaven 1994). In turn, the Meta-
bolic Syndrome X is a risk factor for diabetes and
cardiovascular disease (Reaven 1994).
Allostatic load is also thought to precede the ex-
World J Biol Psychiatry Downloaded from informahealthcare.com by University of Colorado Libraries on 12/31/14
the neurotransmitter, neuropeptide, neuroste-
roid and neurotrophin actions described in this
section. Glucocorticoids may impact the brain
and behaviour by at least three mechanisms:
genomic, non-gemomic and neurotrophic or
neurotoxic. Glucocorticoids freely cross neuro-
nal cell membranes and, in neurons containing
specific cytoplasmic steroid receptors, translo-
cate as a steroid-receptor complex to the cell
nucleus (De Kloet et a1 1998; McEwen et a1
1979). Neurons arid astrocytes Containing corti-
costeroid-specific receptors are densely located
in the hippocam.pus, septum and amygdala
(McEwen et a1 1979), parts of the brain believed
to be intimately involved in behaviour, mood,
learning and memory (Xu et al 1998). The pre-

pression of certain diagnosable chronic diseases
(McEwen and Seeman 1999; Eriksen et a1 1999).
The concept of allostatic load has only been tes-
ted in preliminary ways so far. To date, allostatic
load markers have included a composite index of
markers reflecting regulation across multiple sys-
tems - high cortisol, catecholamines, cholesterol
and blood pressure, poor blood sugar control,
visceral fat deposition and low DHEA sulphate
(DHEA-S). In the MacArthur Successful Aging
Study, this index predicted declines in cognitive
function (memory, spatial ability, abstract rea-
soning) and physical ability, the development of
For personal use only.
frontal cortex is likely also a behaviourally-
relevant target of glucocorticoids (LUpien and
McEwen 1997; Raikowska 2000). In these brain
regions, steroids regulate transcription of genes,
such as those controlling neuropeptide, G-pro-
tein, neurotransmitter and neurotransmitter
receptor synthesis and metabolism (De Kloet et
a1 1998; McEwen et a1 1979; Mcl?wen 1987;
Biegon 1990; Chauloff 1993; Curzon 1994; Lesch
and Lerer 1991; Lopez et a1 1998; McEtven 1968;
McEwen et a1 197'3; Price et a1 1997; Schatzberg
et a1 1985; Slotkin et a1 1996; Wolkowitz 1994;
Wolkowitz et a1 1990b; Wolkowitz et a1 1987b).

hypertension, diabetes and cardiovascular dis- For example, glucocorticoids may decrease (or, in
ease (stroke and heart attacks) in 1189 elderly some cases, increase) norepinephrine (-YE) levels
people 2.5 years later (Seeman et a1 1997), and of (Wolkowitz et a1 1987a; McEwen et a1 1979;
mortality and cognitive decline seven years later McEwen 1987) and alter the synthesis of a, and
(Seeman et a1 2001). Most striking, what appear fl,-adrenergic receptors as well as the 5,ensitivity
to be subtle and subclinical signs of dysregu- of NE receptor-coupled adenylate cyclase (De
lation may be pathophysiological. For example, Kloet et a1 1998). Such actions i n the nor-
relatively higher levels of stress mediators, such as adrenergic system may counteract antidepres-
cortisol and catecholamines, rather than clini- sant drug effects on p-adrenergic receptor res-
cally abnormal levels, confer risk of disease ponsiveness (Holsboer and Barcleii 1996).
(McEwen 2000a; Seeman et a1 1997; Seeman et a1 Corticosteroids also increase brain regional
2001). Seeman and colleagues created a separate dopamine turnover. This effect may be especially
composite measure of stress mediators (high important in the pathophysiology of psychotic
levels of cortisol and catecholamines, and low depression, a condition associated with signifi-
levels of DHEA-S), which can be considered an cantly elevated cortisol levels (Schatzberg et a1
index of anabolic balance, and compared it to a 1985; Wolkowitz et a1 1986; Wolkowitz et a1
composite of more traditional risk factors for car- 1989; Wolkowitz et a1 1987a) and in the patho-
diovascular disease processes (visceral fat, blood physiology of stiinulant drug abuse (Goeders
pressure, hemoglobin glycosylation and blood 1997; Piazza and L,e Moal 1996).
lipids) (Seeman et a1 2001). The stress mediators
were equally predictive of mortality and declines In addition, glucocorticoids significantly alter
in physical functioning, supporting the impor- serotonin (5HT) activity and regulate the synthe-
tance of anabolic balance in contributing to phy- sis of SHT,,,receptors (Meijer et a1 1997; Lopez et
sical decline and disease processes, although the a1 1998). Glucocorticoid effects on 5141. function
stress mediators did not significantly predict are very complex but likely play a prominent
cognitive decline (Seeman et a1 2001). role in regulating (affectand vegetative function
(Biegon 1990; Chauloff 1993; Curzon 1994; Joels
Glucocorticoid hormone mechanisms of et a1 1997; Lopez et a1 1998; Maes and Meltzer
action 1995; Price et a1 11397; Slotkin et a1 1906; Meijer
et a1 1997; McEwen 1987). Kennett and col-
Central nervous system effects leagues (Kennett et a1 1985) noted that stressed
rats developed increased corticosterone secre-
Genomic effects: neurotransmitters tion, decreased hippocampal SHT,, receptor
and neuropeptides mRNA levels and increased "depressive" beha-
The central nervous system (CNS) effects of stress viours such as decreased locomotion, decreased
and glucocorticoids are ultimately mediated by open-field behaviour and anorexia. After 5-7
 RE VIE W/MINI-RE VIE W b
days of stress exposure, however, the rats showed
a normalization of corticosterone levels, 5HT,,
receptor activity and behaviour. These pre-
sumably "adaptive" responses in 5HT,, receptor
activity and behaviour were curtailed by re-
peated corticosterone injections but were facili-
tated by the corticosterone synthesis inhibitor,
metyrapone, suggesting that persistently ele-
vated glucocorticoid levels decrease adaptive res-
ponses in an animal model of depression. In the
same experimental paradigm, female rats show-
ed relatively increased corticosterone responses
to stress, relatively decreased 5HT,, receptor
function and relatively decreased behavioural
adaptation to chronic stress, compared to male
rats. However, when their heightened endo-
World J Biol Psychiatry Downloaded from informahealthcare.com by University of Colorado Libraries on 12/31/14
genous corticosterone response was inhibited
with the antiglucocorticoid drug metyrapone,
their serotonergic and behavioural responses
became similar to those of the males (Haleem et
a1 1988). This latter finding may help explain the
higher incidence of depression in females
(Haleem et a1 1988). Healy et a1 (Healy et a1 1999)
have also shown "antidepressant" effects of me-
tyrapone in animal models and have suggested
that such effects are related to treatment-
induced changes in SHT,, receptor function.
Consistent with the notion of "anabolic balance"
described above, Flugge et a1 (Flugge et a1 1998)
For personal use only.
found that administration of testosterone to
chronically stressed male tree shrews reversed
certain "depressive" behaviours and normalized
(i.e., increased) hippocampal SHT,, receptors,
despite cortisol levels remaining high, suggesting
t
5-albha-Dihydro- 2 i
Progesterone
progesterone
11-Deoxycorticosterone
I
Corticosterone
Tetrahydro-DOC
!
18-OH-Corticosterone
1
AJosterone
19-OH-Androstenedione
11-OH-Androstenedione
6-OH-Androstenedione
Figure 1
Schematic p a t h w a y of steroid a n d neurosteroid biosynthesis a n d metabolism. T h e neurosteroids discussed in this review article are
indicated in boxes.
that a balance between glucocorticoids and an-
drogens is important in maintaining normal
numbers of these monoamine receptors. Experi-
mental data on serotonergic mediation of anti-
glucocorticoid effects in humans are reviewed
below. Cumulatively, such findings are consis-
tent with the hypotheses of depressogenic effects
of chronic hypercortisolemia (or of catabo-
lidanabolic imbalance) and possible antidepres-
sant effects of antiglucocorticoid drugs.
Non-genomic effects: neurosteroids
In addition to genomically-mediated effects,
certain steroids (e.g., "neurosteroids") interact
directly (non-genomically) with neuronal cell
surface receptors (e.g., the GABA, and NMDA
receptors (Majewska 1987)). The steroid meta-
bolic pathway, highlighting known neurosteroid
hormones, is presented in Figure 1. The cell sur-
face receptor-related effects of neurosteroids are
bi-directional, with certain steroid metabolites
having excitatory, and others having inhibitory
effects (Majewska 1987; Starkman 1987; Zakon
1998). Although the vast majority of endocrino-
logical studies in depression have focused on
cortisol, changes in adrenal, gonadal or CNS
synthesis of other steroid hormones, such as the
neurosteroids, DHEA or DHEA sulphate (to-
gether abbreviated IIDHEA(S)'I), tetrahydrode-
oxycorticosterone (THDOC), androsterone, preg-
nenolone sulphate and allopregnanolone (all of
which possess agonist or antagonist activity at
brain GABA, and other receptors), may prove
equally if not more important for maintenance
Cholesterol
I 7-alpha-OH-Pregnenolone
17-OH-Progesterone -17-OH-Pregnenolone
I
+
1 1
11-Deoxycortisol
I
1
I Lipoidal DHEA
DHEA-S
Cortisol Androstenedione
Androstenediol (AED)
Androstenetriol (AET)
delta-4-3-0x0-DHEA
1I-OH-DHEA
16-OH-DHEA
7-beta-OH-DHEA
7-alpha-OH-DHEA
1
7-alpha-OH-DHEAS
Etiocholanolone
3-alpha- Androstanediol
Androstanedione
3-beta-Androstanediol
118
 of allostatic balance (Goodyer et a1 1998;
Goodyer et a1 1996; Herbert 1997; Herbert 1998;
Herbert et a1 1996; Raven et a1 1996; Uzunova et
a1 1998; Wolkowitz et a1 2000a; Romeo et a1
1998; Baulieu 1997; Rupprecht 1997; Rupprecht
et a1 1998; Rupprecht and Holsboer 1999a;
Rupprecht and Holsboer 1999b; Majewska 1987;
Starkman 1987).
Morphological effects: neurotoxicity,
neuroendangerment and neuroprotection
Finally, chronic exposure of animals to stress or
to high levels of glucocorticoids can induce mor-
phological changes, such as decreased dendritic
length and decreased apical dendritic branching,
and even contribute to cell death in certain
World J Biol Psychiatry Downloaded from informahealthcare.com by University of Colorado Libraries on 12/31/14
vulnerable neurons, e.g., hippocampal CA1 and
CA3 neurons (Sapolsky et a1 1986; Virgin Jr et a1
1991; Souza et a1 2000), although glucocorticoids
have trophic effects in certain hippocampal
subfields (McEwen et a1 1992). Sapolsky (Sapol-
sky 1996) and McEwen (McEwen 2000b) have
elaborated several mechanisms through which
glucocorticoids can directly damage hippo-
campal neurons or increase their vulnerability to
damage. By impairing hippocampal cell glucose
uptake, glucocorticoids may induce an energetic
crisis, setting into motion a cascade of excitatory
amino acid and calcium neurotoxicity as well as
For personal use only.
oxidative stress (Behl et a1 1997), thereby aug-
menting the effects of ongoing or coincident
metabolic or neurological insults ("neuroendan-
germent"), such as ischaemia, seizures, head
trauma and hypoglycemia (Sapolsky 2000b). In
the presence of excessive glucocorticoid levels,
glutamate release is increased (McEwen 2000b;
Venero and Borrell 1999) as is NMDA receptor
binding (Mangat et a1 1998). Additionally, the
calcium influx into hippocampal neurons is in-
creased (Nair et a1 1998), and calcium's destruc-
tive effects are amplified (Elliott et a1 1993).
Keuronal damage by these mechanisms is likely
further exacerbated by decreased astrocytic
survival, since astrocytes play an important role
in facilitating neuronal glucose uptake and in
removing damaging levels of glutamate from the
synapse (VirginJr et a1 1991). Cumulatively, such
events may prove directly neurotoxic even in the
absence of extraneous insults.
Recently, an additional possible mechanism of
neurotoxicity has been explored. Neurogenesis
(the birth of new neurons) continues into
adulthood in the dentate gyrus of the hippo-
campus (Gould and Tanapat 1999) as well as in
the neocortex (Gould et al 1999). Stress and
excessive glucocorticoid exposure decrease brain
expression of brain-derived neurotrophic factor
(RDNF); this process has been hypothesized to
contribute to hippocampal damage by inhibiting
cell proliferation in the dentate gyrus and to play
a causal role in the development of major de-
pression and cognitive dysfunction (Duman et al
1997; Gould and Tanapat 1999; Manji et a1 2000;
Jacobs et a1 2000). Strategies that directly lower
119
glucocorticoid levels, including adrenalectomy,
increase hippocampal expression of BDNF
mRNA (Grundy el, a1 2000), although they do
not fully abolish the ability of stress to decrease
BDNF levels (Smith et a1 1995). Stress-induced
neurotoxicity, therefore, seems multifactorial
and only partially due to increased gluco-
corticoid exposure (Souza et a1 2000; Oh1 et a1
2000). Reducing glucocorticoid levels facilitates
neurogenesis, even in aged animals, and results
in increased numbers of hippocam pal granule
cells (Cameron and McKay 1999). Glutamate
antagonists, such as MK-801, also enhance
neurogenesis, while glutamate analogs inhibit it
(Gould et a1 1994).
As mentioned above, DHEA physiologically
antagonizes certain of the deleterious effects
of chronic cortisol or corticosterone exposure
and, in addition, protects hippocampal tissue
(Bastianetto et a1 1999; Cardounel et a1 1999;
Kimonides et a1 19'38; Kimonides et al 1999; Mao
and Barger 1998) and enhances hippocampal
function (Murialdo et a1 2000). Indeed, in nor-
mal aging and in Alzheimer's disease, hippo-
campal perfusion (Murialdo et al 2000) and vo-
lume (Magri et a1 2000) are positively related to
serum DHLAS levels and to the DHI:AS/cortisol
ratio. Mechanisms proposed for DHEA, putative
neuroprotective effects include: interactions
with GABA,, NMDA and sigma receptors, chan-
ges in brain regional serotonin and dopamine
levels, increases in hippocampal primed burst
potentiation and cholinergic function, decreases
in hippocampal nuclear glucocorticoicl receptor
levels, decreases in the production and deposi-
tion of amyloid 13 protein, inhibition of the
production of pro-inflammatory cytokines (e.g.,
IL-l-alpha, IL-6, and TNF-alpha), scavenging of
free radicals, prevention of oxidative damage
and increases in bioavailable levels of IGF-I
(Bastianetto et a1 1999; Cardounel et a1 1999;
Kimonides et a1 1998; Kimonides et al 1999; Mao
and Barger 1998; Murialdo et a1 2000). These
mechanisms are reviewed elsewhere (V\iolkowitz
and Reus 2000; Wolkowitz et a1 200Oa; Wol-
kowitz et a1 2 0 0 0 ~ )Of
. particular interest, DHEA
protects hippocampal neurons from glutamate
toxicity, at least in part, by decreasing the
nuclear localization of glucocorticoid receptors
(GR) induced by glutamate treatment
(Cardounel et al 1999). Anabolic hormones
other than DHEA can also have actions opposite
to those seen with chronic glucocorticoid expo-
sure. IGF-1, for example, increases hrppocampal
glucose utilization in aged animals (Lynch et al
2001) and increases adult hippocampal neuro-
genesis (Aberg et a1 2000; Trejo et a1 2001). Tes-
tosterone also enhances survival of new neurons
in the adult canary brain; this is likely effected
by an increase in brain BDNF levels (Rasika et a1
1999).
Chronic antidepressant or mood stabilizer treat-
ment also opposes many of the adverse cellular
 RE VIE W/MINI-RE VIE W
events caused by stress or chronic glucocorticoid
exposure (Duman et a1 1997; Manji et a1 2000;
Jacobs et a1 2000). Antidepressant treatment, in
animals, has been found to increase neuro-
genesis in rat hippocampus (Malberg et a1 2000),
to increase hippocampal expression of BDNF and
to completely block the down-regulation of hip-
pocampal BDNF mRNA that occurs in response
to stress (Nibuya et a1 1995). Actions at the
5HT1,4receptor seem particularly important in
regulating hippocampal neurogenesis; none-
theless, both serotonergic and noradrenergic
antidepressants increase neurogenesis and BDNF
expression and prevent stress-induced down-
regulation of 5HT1, receptors Uacobs et a1 2000;
Jacobs et a1 1998; Lopez et a1 1998). Anti-
World J Biol Psychiatry Downloaded from informahealthcare.com by University of Colorado Libraries on 12/31/14
b
decreasing group I metabotropic glutamate
receptor responsiveness in the hippocampus
(Zahorodna and Bijak 1999). Cumulatively, such
data suggest that chronic antidepressant treat-
ment can exert neuroprotective effects in the
face of stress or major depression (Michael-Titus
et a1 2000). Such neuroprotective effects may
represent previously unrecognized mechanisms
of therapeutic action in treating depression and
anxiety disorders (Rosenberg et a1 2000;
Zahorodna and Bijak 1999; Jacobs et a1 2000). A
simplified, theoretical model of the relationship
between stress, major depression, antidepres-
sants, corticosteroid activity, neurotransmitter
activity, neurotrophin expression and hippo-
campal cell viability is presented in Figure 2.

depressant treatment also decreases intracellular

calcium concentrations via inhibition of voltage- Data suggesting neurotoxic or neuroendangering
gated calcium channels (Deak et a1 2000) and effects of glucocorticoids derive principally from
thus would be expected to interfere with the studies with rodents, and it is uncertain to which
glutamate-calcium neurotoxic cascade described extent they are applicable to humans and other
above (Takebayashi et a1 2000; Sapolsky 2000b). primates. In a prospective study in Macaques
Antidepressants may also dampen glutamatergic examining hippocampal cell number at autopsy,
neurotoxicity by decreasing glutamate concen- administration of 3-6 mg/kg/day of hydrocor-
trations in prefrontal cortex (Michael-Titus et a1 tisone for 12 months could not be distinguished
2000) and caudate (Rosenberg et a1 2000) and by from placebo (Leverenz et a1 1999). However,
chronically stressed vervet monkeys did show
loss of hippocampal neurons, probably secon-
dary to increased glucocorticoid exposure (Uno
For personal use only.

et a1 1989). These observations suggest that, at

Chronic Stress 1 least in non-human primates, chronically ele-
I I vated glucocorticoid concentrations are more
Potential Sites of
Intervention:
1. Antidepressants
I <3> <3>
likely to produce hippocampal neuronal damage
under stressful than under non-stressful condi-
2. CRH antagonists tions (Sapolsky 2000a; Souza et a1 2000), perhaps
3. Stress reduction;
behavioural therapies because chronic stress evokes other biochemical
4. Antiglucocorticoids; changes which have synergistic effects on neuro-
RU-486 toxicity and neuroendangerment (Herbert 1997;
5. Energy supplementation i I I
6. Glutamate antagonists; Herbert 1998; Souza et a1 2000). Data from a
lamotrigine, phenytoin number of human populations, including
7. Calcium channel
blockers patients with major depression, Alzheimer's
8. DHEA disease, post-traumatic stress disorder and
9. 3-alpha-HSDstimulation Cushing's syndrome, are consistent with the
10. Environmental Glucose Availability
enrichment; exercise possibility that prolonged exposure to elevated

13
11. Small molecule BDNF cortisol levels leads to decreased hippocampal
analog volume (Bremner 1999; Herbert 1998; McEwen
Glutamate 2000c; O'Brien et a1 1996; Sapolsky 2000a;
- 1 l<6> I Sapolsky 2000b; Sheline et a1 1999; Starkman et
1Calcium
i

<i,io,i;> ~JB~NF j a1 1992) and to impaired hippocampus-depen-

dent memory function (Lupien et a1 1999;
Starkman et a1 1992; Newcomer et a1 1999). The
diminished hippocampal volume observed in
Cushing's syndrome seems (at least partially)
,Neurotoxicity/Neuroendangerment
I
, reversible with normalization of glucocorticoid
status (Starkman et a1 1999), but in some cases,
+ areas of brain damage may be irreversible or only
[Cognitive Dysfunction and Depression) partially reversible (Trethowen and Cobb 1952).
Hippocampal volume loss seen in patients with
extensive past histories of major depression (pos-
Figure 2 sibly associated with hypercortisolemia) may
A simplified, theoretical m o d e l o f t h e relationship b e t w e e n stress, persist for years after the resolution of the
antidepressants, corticosteroid activity, neurotransmitter activity, depression and the presumed hypercortisolemic
n e u r o t r o p h i n expression a n d h i p p o c a m p a l cell viability. Potential state (Sheline et a1 1999); however, see Shah et a1
sites o f intervention are keyed to t h e bracketed n u m b e r s in t h e
figure. References to t h e specific pathways a n d potential sites of (1998), although the direction of any causality in
intervention are p r o v i d e d in t h e text. such studies remains questionable, as does the

120
 linkage with hypercortisolemia. Interestingly, Appetite and food consumption
even in the absence of gross morphological da- Eating behaviour iis an important link between
mage (e.g., major loss of pyramidal cell neurons), depression, stress and certain chronic diseases.
rare but convincing signs of apoptosis are seen in Both negative mood (Greeno and Wing 1994)
hippocampal tissue from patients with major and cortisol may stimulate appetite and eating
depression and from medically ill patients trea- (Sapolsky et al 2000). Glucocorticoids lead to
ted with glucocorticoid medication (Lucassen et hyperphagia and weight gain in rodents prone to
al 2001). obesity (Bray 1985). Relationships between
cortisol and eating behaviour have been studied
The question of reversibility of glucocorticoid- less frequently in humans, but several studies
induced hippocampal damage is immensely suggest that elevated cortisol stimulate:; appetite
important, both clinically and theoretically, and and food consumption. High cortisol reactivity
the best data addressing this question derive in response to a laboratory stressor predicted
from animal studies. Recent data in rats suggest greater caloric consumption, especially of sweet
reversibility of neuronal damage ("structural food, in the stress recovery period in healthy
reorganization") following recovery from chro- women (Epel et a1 2000b). Further, exogenously
World J Biol Psychiatry Downloaded from informahealthcare.com by University of Colorado Libraries on 12/31/14

nic stress or glucocorticoid administration, administered glucocorticoids signific.antly in-

possibly due to neurogenesis (Souza et al 2000). crease appetite and food intake (Tataranni et a1
However, tree shrews exposed to chronic stress 1996). Eating in turn, especially hig,h fat food,
or month-long cortisol administration showed stimulates the HI'A axis (Tannenbaum et al
residual "traces" of impairment even after seven 1997), possibly creating a positive feedback loop
weeks of recovery (Oh1 et al2000). Tree shrews in of subsequent eat:ing behaviour and increased
both the stressed and cortisol treatment groups, cortisol. Thus, elevated basal or reactive cortisol
studied longitudinally in a within subject design, may be implicated in overeating and obesity,
showed a tendency towards a reduction in MRI- and possibly in obesity-related metabolic
determined hippocampal volume (of about 5- diseases.
lV%, p< 0.16); this failed to normalize after the
seven weeks of recovery. Hippocampus-mediated Visceral fat
memory in the cortisol-treated group was Central or visceral obesity (as opposed to gene-
For personal use only.

impaired during cortisol treatment but showed ralized obesity) is an important risk factor for
recovery by seven weeks post-treatment. The chronic disease (Kissebah and Krakower 1994).
chronically stressed group, however, showed Depression or stress and stress-eating behaviour
memory impairments that developed only after may work synergistically to promote fat depo-
termination of the stress (Oh1 et a1 2000). sition, especially visceral fat. Raikkonen et al
found that anger and depression ratings predic-
Peripheral effects: metabolic syndrome ted increased visceral fat (Raikkonen et a1 1999),
as well as a cluster of factors related to the meta-
As in the brain, cortisol affects cellular targets bolic syndrome (Raikkonen et a1 2001), many
possessing cortisol receptors throughout the years later in post-menopausal women. Primate
periphery. Chronic exposure to elevated levels of and rodent studies, have also shown that expo-
cortisol without the protective effects of anabolic sure to chronic stress increases visceral fat pre-
hormones, such as IIHEA, can have extensive ferentially over peripheral fat Uayo et al 1993;
effects on physiological functioning, and, in Rebuffe-Scrive et a1 1992). Hypercortisolemia, or
particular, on aspects of metabolism (as can be limbic-hypothalamic-pituitary-adrenal (LHPA)
seen in chronic stress, depression and Cushing's axis dysregulation, is a likely mediator of these
syndrome) (McEwen 1998; McEwen and Stellar effects. In humam, visceral fat deposition is
1993; Seeman et al 1997). These effects on associated with Cushing's syndrome, lnypercor-
physiology may be important contributing tisolemic major depression (Thakore el al 1997)
factors to the high comorbidity of Metabolic and HPA axis dysregulation in a non-clinical
Syndrome X and other chronic diseases with sample (l'asquali et al 1996). High reactivity to
depression (Bjorntorp 2001). stress, even amidst normal basal cortisol levels, is
similarly associated with increased visceral fat. In
Cortisol is intimately involved in regulating a non-clinical healthy sample, women with
caloric consumption, insulin sensitivity and fat greater visceral fat had basal cortisol levels com-
deposition. Chronically elevated, unopposed parable to women with predominant peripheral
glucocorticoid activity is thus associated with fat but had greater life stress and exaggerated
indicators of metabolic dysregulation such as in- cortisol reactivity to psychological stress (Epel et
creased eating behaviour (Epel et a1 2001b), a1 2000a). Together, these studies provide an-
changes in body composition such as increased other example of associations between stress-in-
visceral (central) adiposity and fat-to-lean mass duced cortisol and a major indicator of metabo-
ratio, peripheral muscle wasting, and insulin lic dysregulation, with suggestion of a causal ef-
resistance (Bjorntorp 2001). Below we examine fect of glucocorticoids, based on animal studies.
evidence that cortisol may influence risk for
disease through inducing Metabolic Syndrome X Insulin resistance and diabetes
features. In rats, exposure tlo chronic stress increases hy-

121
 RE VIE W/MINI-RE VIE W b
perglycemia, insulin resistance and blood lipids
(Surwit and Williams 1996). Elevated levels of
glucocorticoids can also decrease insulin sen-
sitivity (Bjorntorp 1997; Rizza et a1 1982;
Sapolsky et a1 2000). Despite a wealth of circum-
stantial evidence (Bjorntorp 1997), no controlled
studies have demonstrated that a chronically
stressed or depressed human sample also has
actual insulin resistance (using the gold standard
clamp method, rather than proxy measures such
as fasting insulin levels), and whether this is
mediated by LHPA axis hyperactivity. On the
other hand, Bjorntorp and colleagues have
found that LHPA axis dysregulation, in the form
of a blunted cortisol rhythm and sluggish
response to stimuli, rather than cortisol hyper-
World J Biol Psychiatry Downloaded from informahealthcare.com by University of Colorado Libraries on 12/31/14
As in the CNS, DHEA has antiglucocorticoid ef-
fects in the periphery. In animals, DHEA may
antagonize some of the peripheral catabolic
effects of glucocorticoids by increasing sensiti-
vity to insulin, enhancing adipocyte glucose
uptake and diminishing hyperglycemia (Cole-
man et a1 1982) and reducing adiposity (Dong-
Ho et a1 1998), but similar effects have not been
uniformly found in humans (Wellman et a1
1999). However, in humans, other anabolic
hormones such as testosterone in men and IGF-
1 and growth hormone in both genders, espe-
cially for those who are growth hormone
deficient, can reverse metabolic defects such as
visceral and total adiposity (Marin 1995; Thomp-
son et a1 1998) and decrease insulin resistance

activity, is related to components of the meta- (Berneis and Keller 1996) and, in many cases,
bolic syndrome (Bjorntorp et a1 1999b). How- depressive symptoms (Thompson et a1 1998).
ever, it is unclear whether this particular profile
of LHPA axis dysregulation precedes or follows Exogenous corticosteroid effects
the other signs of metabolic dysregulation.
Steroid psychosis
Type I1 diabetes may develop from insulin Several clinical models highlight the ability of
resistance, and is highly comorbid with major glucocorticoids to regulate human behaviour,
depression (Geringer 1990). A prospective study and each poses important theoretical and
found that depression ratings in a community treatment issues. Among the earliest indications
population predicted onset of diabetes mellitus was the observation of behavioural changes,
eight years later (Kawakami et a1 1999). There occasionally profound (e.g., delirium, confusion,
are likely bi-directional relations between insomnia, emotional lability, depression, hypo-
For personal use only.

depression and diabetes, and a possible common mania, attentional impairments, sensory flood-
underlying diathesis is LHPA axis dysregulation. ing, psychosis and even suicidality) in medically
In fact, even in nondepressed diabetics, there ill patients prescribed cortisone, dexamethasone,
is higher DST non-suppression (43% non- prednisone and other synthetic glucocorticoids
supressors) compared to normal controls (Hall et a1 1979; Ling et al 1981; Naber et a1 1996;
(Hudson et a1 1984). Pies 1995; Wolkowitz et a1 1997a; Wolkowitz et
a1 1990b; Reus and Wolkowitz 1993; Boston
Patients with adrenal adenomas provide a clear Collaborative Drug Surveillance Program 1972).
example of the somatic effects of chronic expo- Such severe reactions, occurring even in patients
sure to excessively high endogenously produced with no prior psychiatric history, are frequently
cortisol levels and of the comorbidity between termed "steroid psychosis." Whereas synthetic
depression and allostatic load or frank disease. glucocorticoid medication-induced affective
Cushing's syndrome leads to central obesity, changes are often activational or manic-like
muscle wasting, high blood pressure, insulin initially, they typically become more depressive
resistance and osteoporosis (Newell-Price et a1 in nature with continued steroid treatment
1999). In patients without frank Cushing's syn- (Plihal et a1 1996). Recent studies have also
drome, adrenal masses ("incidentalomas") are a highlighted the deleterious effects of gluco-
relatively common type of tumour and are corticoid medication on memory in both
typically thought to be asymptomatic, though a patients and normal controls (Keenan et a1 1996;
recent clinical evaluation showed otherwise. Keenan et a1 1995; Kirschbaum et a1 1996;
Rossi and colleagues found that subtle hypercor- Lupien and McEwen 1997; Newcomer et a1 1999;
tisolemia due to such masses is frequent in a Varney et a1 1984; Wolkowitz et a1 1997a;
normal population, and health sequelae may be Wolkowitz et a1 1990a; Wolkowitz et a1 1 9 9 3 ~ ) .
as well (Rossi et a1 2000). In studies examining In light of the preceding discussion of the
symptoms of such adrenal masses, participants primary anatomic loci of glucocorticoid effects
who met criteria for subtle hypercortisolemia in the brain, it is notable that these studies have
showed signs of hypertension, impaired glucose generally reported specific disruption of
tolerance or diabetes, hyperlipidemia and obe- hippocampus- (and, in some cases, frontal
sity (Rossi et a1 2000; Reincke 2000). Compared cortex-) mediated memory functions (such as
to a control group, they had a lower anabolic disruption of explicit, episodic and declarative
balance and greater LHPA axis dysregulation memory, with sparing of non-hippocampus-
(higher cortisol, lower ACTH, less cortisol sup- mediated implicit, procedural and semantic
pression to dexamethasone, and lower DHEA-S memory). A number of biochemical and brain
and DHEA-S responsivity to ACTH). Surgical electrophysiological correlates of exogenous
removal of adrenal masses led to remission of glucocorticoid-induced behavioural and cogni-
these symptoms. tive changes have been elucidated (Wolkowitz et

122
 al 1986; Wolkowitz et al 1993a; Wolkowitz et al catabolic effects of long-term prednisone treat-
1990b; Wolkowitz et a1 1993c; Joels et a1 1997; ment have proven reversible by administration
Dubrovsky 1991). of other anabolic hormones, GH or IGF-1
(Moxley 1994).
Although infrequently described in the lite-
rature, a small percentage of glucocorticoid- While studies with exogenous glucocorticoids
treated patients (perhaps up to 7%) may expe- clearly demonstrate the potential of such hor-
rience a "steroid dementia syndrome," or long- mones to induce psychiatric symptoms, it is not
lasting memory impairment (again, hippo- possible to extrapolate directly from their effects
campal in nature) even after cessation of t o those of endogenous hypercortisolernia
glucocorticoid medication (Lewis and Smith (Plihal et a1 1996; Wolkowitz 1994; Wolkowitz et
1983; Reckart and Eisendrath 1990; Varney et a1 a1 1997a). Endogenous states of glucocorticoid
1984; Wolkowitz et al 1997a). As noted earlier, a excess are discussed in the following sections.
small proportion of steroid-treated patients
shows signs of hippocampal neuronal apoptosis, Endogenous glucocorticoid effects
as well as heat shock protein 70 staining (an
World J Biol Psychiatry Downloaded from informahealthcare.com by University of Colorado Libraries on 12/31/14

index of response to oxidative damage and Cushing's Syndrome

cellular stress), at autopsy (Lucassen et a1 2001).
Neuropsychiatric syndromes
Treatment Cushing's syndrorne is associated with a very
Surprisingly, few studies have addressed treat- high incidence of fatigue, decreased energy,
ment options for patients suffering from steroid irritability, decreased memory and concentra-
psychosis or for patients withdrawn from tion, depressed or labile mood, anxiety, de-
steroids who have persisting "steroid dementia." creased libido, insomnia and crying (Starkman et
Anecdotally, lithium, antipsychotic drugs and a1 1981; Trethowen and Cobb 1952; Whelan
anticonvulsants have been used with varying et a1 1980). These symptoms are reminiscent of
degrees of effect, either prophylactically or in those commonly seen in major depression
treating acute symptoms (reviewed in: Reus and (Haskett 1985j, although certain differences,
Wolkowitz 1993; Wolkowitz et al 1997a). Several such as a preponderance of "atypical" depressive
For personal use only.

novel experimental approaches have also been features in Cushing's syndrome patients, may
suggested for the treatment or prophylaxis of exist (Kling et al 1991; Loosen et a1 1992). Neuro-
steroid psychosis. McEwen and Magarinos psychiatric symptoms in Cushing's, syndrome
(McEwen and Magarinos 2001j, examining the patients are directly correlated with circulating
role increases in serotonin and excitatory amino cortisol levels (Cohen 1980; Starkman et a1
acid levels may play in steroid-associated hippo- 1981). As was the case with individuals adminis-
campal damage, suggest that tianeptine (a tered exogenous glucocorticoids, patients with
serotonin reuptake enhancer) and phenytoin Cushing's syndrome demonstrate a pattern of
(which blocks excitatory amino acid release and cognitive disturbance that is consistent with
actions) may lessen such deleterious effects. Also, hippocampal dysfunction (involving episodic
based on the suggestion that steroids potentiate but not semantic memory) (Martignoni et a1
metabolic insults to the hippocampus via im- 1992; Mauri et a1 1993). Cushing's syndrome
paired neuronal glucose uptake (reviewed patients also have diminished hippocampal
above), Sapolsky (Sapolsky 1994) suggests that formation volume (assessed radiographically)
glucose or mannose co-administration might (Starkman et a1 1.992) that has been directly
be protective, as might decreasing neuronal correlated with cognitive performance and
stimulation and energy demands. Lastly, co- inversely correlated with urinary free cortisol
administration of dehydroepiandrosterone output (Starkman et a1 1992).
(DHEA), along with the prescribed gluco-
corticoid medication, might allow the usage of Antiglucocorticoid treatment
lower glucocorticoid doses in some situations To the extent hypercortisolemia is directly res-
and might buffer certain deleterious neuro- ponsible for these neuropsychiatric symptoms,
psychiatric and somatic effects of the gluco- direct lowering of cortisol levels should amelio-
corticoid (Koo et a1 1987; Straub et a1 2000; rate them. Indeed, the depressive and cognitive
Van Vollenhoven et a1 1994; Dubrovsky 1997). symptoms seen in Cushing's syndrorne typically
DHEA co-administration makes particularly resolve with treatment of the hypercortisolemia
good sense from the vantage point of main- (Angeli and Frairia 1985; Arteaga et a1 1989;
taining an optimal "anabolic balance," since pro- Cohen 1980; Gifford and Gunderson 1970;
longed glucocorticoid treatment inhibits ACTH Hamm 1955; Jeffcoate et a1 1979; Kelly et a1
secretion, involutes the adrenal cortex and 1979; Kelly et a1 1980; Kelly et a1 1983; Kelly et
results in diminished endogenous DHEA al 1996; Kramlinger et al 1985; Li et a1 1996; Loli
secretion (Robinzon and Cutolo 1999). This stra- et a1 1986; Mauri et a1 1993; Nieman et a1 1985;
tegy, however, remains inadequately tested Ravaris et a1 1994; Ravaris et a1 1988; Regestein et
except in the treatment of systemic lupus ery- al 1972; Sonino et a1 1986; Sonino el: a1 1991;
thematosus (van Vollenhoven 1997; Van Vollen- Sonino et a1 1993; Starkman et a1 1986,:Taft et al
hoven et al 1994). Interestingly, some of the 1970; Trethowen and Cobb 1952; van der Lely et
- -
123
 RE VIE W/MINI-RE VIE W b
al 1991; Verhelst et a1 1991; Voigt et a1 1985;
Welbourn et a1 1971; Zeiger et a1 1993; Berwaerts
et a1 1998; Saad et a1 1984; Hirsch et a1 2000), in
direct proportion to the reductions in circulating
cortisol levels. At least 31 separate reports have
documented decreased depression, anxiety,
suicidality, irritability, psychosis and cognitive
impairment, and even complete psychiatric
remission, in Cushing's patients who received
either surgical or medical (e.g., ketoconazole,
metyrapone, aminoglutethimide, RU-486) treat-
ment aimed at lowering cortisol levels or cortisol
activity. The largest two case series documented
a response rate of 70-73% of treated patients
(Sonino et a1 1993; Verhelst et a1 1991),
although, in several cases, psychiatric im-
World J Biol Psychiatry Downloaded from informahealthcare.com by University of Colorado Libraries on 12/31/14
Major depression and other conditions
Neuropsychiatric syndromes
Hypercortisolemia and resistance of the LHPA
axis to suppression by dexamethasone ("DST
nonsuppression") are the most widely replicated
biological abnormalities in major depression,
affecting up to one half of depressed patients.
The degree of cortisol hypersecretion is directly
correlated with the extent of certain behavioural
alterations such as sleep disturbance, decreased
energy, decreased attention and cognitive perfor-
mance, psychosis, psychomotor disturbance and
anxiety (Reus 1982; Wolkowitz and Reus 1999;
Wolkowitz et a1 1994).

provement was erratic, delayed or incomplete As was the case with Cushing's syndrome pa-
(Haskett 1985; Hamm 1955; Ernest and Ekman tients, depressed patients may have hippo-
1972). In rare cases, psychiatric status apparently campal volume loss (Shah et a1 1998; Sheline et
fails to recover despite adequate treatment, a1 1999) along with deficits in hippocampally-
possibly in association with cerebral cortical mediated cognitive function (Shah et a1 1998;
atrophy (Mancini et a1 1999). Most of these Sheline et a1 1999; Wolkowitz et a1 1990a). In
antiglucocorticoid treatment trials have been one report, this hippocampal volume abnor-
reviewed in greater detail elsewhere (Wolkowitz mality persisted for years after clinical recovery
and Reus 1999). from depression and was directly correlated with
the number of lifetime days of depression
Levels of steroid hormones other than cortisol, (Sheline et af 1999), which may itself be a marker
which are also abnormal in Cushing's syndrome of lifetime exposure to stress levels of cortisol,
patients and which also have neuroactive although this remains to be further tested. In the
For personal use only.

properties, such as DHEA, have received virtually other study, however, hippocampal volume loss,
no attention to date (Dubrovsky 1991; Levine which was seen in chronically depressed
and Mitty 1988; Murphy 1991a). Indeed, the patients, was not seen in previously depressed
anabolic balance, e.g., the ratio of DHEA-to- patients who had been recovered for an average
cortisol, may be more important than cortisol of three months (Shah et a1 1998).
alone in determining severity of depression and
cognitive impairment in these patients (Du- Persistent cortisol hyperactivity (manifest as DST
brovsky 1991; Dubrovsky 1997). Further diffi- nonsuppression, high cortisol response to the
culty in interpreting the Cushing's syndrome combined dexamethasone-CRH test or elevated
literature is that patients with Addison's disease evening cortisol-to-DHEA ratios) following ap-
(adrenocortical insufficiency) also frequently parent clinical recovery is strongly associated
present with depression and cognitive impair- with early relapse and poor outcome on follow-
ment (Cleghorn 1951; Leigh and Kramer 1984); up (Goodyer et a1 1998; Greden et a1 1983;
in such patients, psychiatric disturbances are Ribeiro et a1 1993; Zobel et a1 1999), suggesting
negatively correlated with serum cortisol levels that LHPA axis normalization is a prerequisite for
(Lobo et a1 1988), and glucocorticoid (Riedel et a1 more abiding recovery. Traditional antidepres-
1993) and DHEA (Arlt et a1 1999; Arlt et a1 1998) sant medications increase brain levels of cor-
administration both relieve the psychiatric ticosteroid receptors, rendering individuals more
symptoms. The relationship between cortisol sensitive to glucocorticoid negative feedback. A
and neuropsychiatric function is undoubtedly recent body of literature, reviewed by Holsboer
complex and may even resemble an inverted U- and Barden (Holsboer and Barden 1996), sug-
shaped dose-response curve, with optimal func- gests that these effects are shared by most anti-
tioning at mid-range levels (Lupien and McEwen depressants, and that the time course of these
1997; McEwen 1987). changes parallels that of clinical antidepressant
responses. These authors hypothesized that a
In general, antiglucocorticoid strategies (as well primary and common mechanism of action of
as pituitary or adrenal surgery) are also effective antidepressants is the stimulation of cortico-
at reversing the physical complications of steroid receptor expression, leading to enhanced
Cushing's syndrome. In fact, they may be more negative feedback, lowered LHPA activity and
effective than traditional treatment targeted to lowered levels of CRH and cortisol. Secondary
individual somatic symptoms (Neto et a1 2000). effects of lowered cortisol levels would be a
Antiglucocorticoid medication normalizes blood lessening of expression of genes that are under
pressure, blood sugar control, hypokalemia, hir- glucocorticoid regulatory control (e.g., those
sutism and menstrual disturbances in the related to biogenic amine neurotransmission, as
majority of Cushing's syndrome patients reviewed above), and secondary effects of
(Sonino et a1 1991). lowered CRH levels would be a lessening of

124
 anxiety and certain depressive symptoms (as re- are 12 studies of antiglucocorticoids, (as solitary
viewed below). This re-conceptualization of anti- treatments) in treating depression; only four of
depressant action is directly relevant to the these were single- or double-blinded. These
primary thesis of this review, and it accords with studies are reviewed in greater detail elsewhere
the treatment data reviewed below. (Wolkowitz and Reus 1999). In interpreting these
studies, it is important to consider that, although
Substance abuse cortisol was the major endocrinological "target"
Another rapidly evolving area of study is the of the endocrinological interventions, the syn-
possible role of LHPA axis dysregulation in the thesis of other steroid hormones was invariably
relationship between stress and substance abuse. affected by these drugs (Figure 3). Figure 3 dis-
In fact, the high comorbidity between depres- plays the sites of enzymatic blockade of several
sion and substance abuse and dependence may steroid biosynthesis inhibitors. As is ebident, en-
depend in part on common alterations in gluco- zymatic blockade with these agents affects the
corticoid regulation. A variety of animal and synthesis of multiple steroid hormones, ren-
human studies have documented that gluco- dering the actual mechanism of any observed
corticoids alter the acute psychomotor and behavioural effects indeterminate.
World J Biol Psychiatry Downloaded from informahealthcare.com by University of Colorado Libraries on 12/31/14

reinforcing effects of psychostimulant and

sedative-hypnotic drugs, and modulate the phe- In each of the studies utilizing the ,mtigluco-
nomenon of stress-induced relapse (Deroche et corticoid approach (Amsterdam et a1 1994;
a1 1997; Goeders 1997; Heinz et a1 1999; Piazza Anand et a1 1995; Ghadirian et a1 1995; Iizuka et
and Le Moal 1996; Sinha et a1 1999; Sinha et a1 a1 1996; Malison et a1 1999; Murphy 1991a;
2000; Stewart 2000). Whether strategies directed Murphy 1991b; Murphy et a1 1991; Murphy et a1
at blocking the LHPA response to reinforcing 1993; Murphy et a1 1998; Murphy 199'; Murphy
drugs (such as the strategies outlined in the fol- and Wolkowitz 1993; O'Dwyer et a1 1995; Raven
lowing section) will lead to a decrease in sub- et a1 1996; Reus et a1 1997; Sovner and Fogelman
stance self-administration and, ultimately, to a 1996; Thakore and Dinan 1995; Wolkowitz et a1
practical therapeutic intervention, is presently 1999a; Wolkowitz et a1 1993b), antidepressant
unknown. effects were reported in at least some patients.
Across the 12 studies reviewed, an average of
For personal use only.

Antiglucocorticoid treatment 67.5% of the treated patients showed at least a

It is surprising that, until 1991, few studies had partial antidepressant response, and 55%
assessed the behavioural effects of direct phar- showed a "full" or clinically meaningful respon-
macological lowering of cortisol levels in pa- se. Of the studies that were single- or double-
tients with major depression. At present, there blinded, 50% of the treated patients :,bowed at

Cholesterol

21-OH 21-OH 17,20/yase 3 17,20/yase SST

11-deoxycorticosterone 11-deoxycortisol DHEA - DHEA-S

11-OH 33% 11-OH a@:% 3-II-HSD

5: 3 18-OH 18-OH-D 7 7-1j-HSD

Aldosterone Testosterone

Arornatase

Figure 3
Steroid metabolic pathway and sites of antiglucocorticoid enzymatic blockade.
SCC=side chain cleavage; OH=hydroxylase; HSD=hydroxysteroid dehydrogenase; SSTxteroid sulfotransferase. 'Z = site of blockade by
ketoconazole; Z = site of blockade b y metyrapone; '3= site of blockade b y aminoglutethimide.

125
 RE VIE W/MINI-R E VIE W b
least a partial antidepressant response, and Two other studies have attempted to clarify
46.2% showed a "full" or clinically meaningful the mechanisms by which antiglucocorticoids
response. These results must be interpreted very might alleviate depression. Thakore and Dinan
cautiously due to the small sample sizes in all of (Thakore and Dinan 1995) treated eight depres-
these studies. sed patients with ketoconazole for four weeks
and noted significant antidepressant effects
Endocrinological predictors and correlates of (average decrease in depression ratings = 60%)
antiglucocorticoid response remain uncertain. and significant decreases in serum cortisol levels.
While it is appealing to postulate that patients They had postulated that elevated cortisol
who are hypercortisolemic (or DST non-sup- activity might provoke or maintain depressive
pressing) at baseline are most likely to respond to symptoms via the induction of serotonin system
this approach, few studies have meaningfully sub-sensitivity (as reviewed above). They based
assessed this. In an early study by Murphy et a1 their hypothesis partially on observations that,
(Murphy 1991a), five of six antiglucocorticoid in depressed patients, baseline cortisol levels are
treatment responders who were DST non-sup- inversely related to the magnitude of serum
pressors before starting therapy had reverted to prolactin (PRL) responses to 5HT agonists such as
World J Biol Psychiatry Downloaded from informahealthcare.com by University of Colorado Libraries on 12/31/14

normal suppression when tested after comple- d-fenfluramine (a putative marker of serotonin
tion of therapy; the one patient who did not system sensitivity). To test this hypothesis, they
revert to normal suppression suffered an early administered the d-fenfluramine challenge to
relapse (Murphy and Wolkowitz 1993). Baseline their subjects at baseline and after four weeks of
8:OO a.m. serum cortisol levels, however, did not ketoconazole treatment. Ketoconazole norma-
predict treatment response, and treatment- lized the PRL response to d-fenfluramine (i.e.,
associated decreases in 8:OO a.m. serum cortisol increased the response relative to baseline), and
levels were inconsistent and not statistically the increases in PRL responses were significantly
significant. Other studies, however, have noted correlated with reductions in depression ratings.
significant correlations between antigluco- These findings are consistent with the notion
corticoid-associated antidepressant effects and that hypercortisolemia down-regulates 5HT
changes in cortisol levels. Anand et a1 (Anand et system sensitivity (as suggested by the animal
a1 1995), for example, in a double-blind case studies reviewed above), and that antigluco-
For personal use only.

report utilizing ketoconazole, noted clinically corticoid treatments may have antidepressant
significant improvements in depression and effects via a normalization (increase) of 5HT
memory in one treatment-resistant patient; sensitivity.
treatment-associated decreases in cortisol levels
were closely related to decreases in depression Lastly, O'Dwyer et a1 (O'Dwyer et a1 1995)
ratings. Wolkowitz et a1 (Wolkowitz et a1 1993b) treated eight depressed patients with metyra-
also reported that ketoconazole, administered to pone (plus replacement doses of hydrocortisone)
medication-free depressed patients in an open- vs. placebo in a single-blind manner in a two-
label manner for three to six weeks, significantly week-per-arm crossover design and noted signi-
improved depression ratings and significantly ficant decreases in depression ratings as well as
decreased 4:OO p.m. serum cortisol levels. in serum cortisol levels during metyrapone
Changes in Beck Depression Inventory ratings treatment. After discontinuation of metyrapone,
were directly correlated with changes in serum depression ratings remained low despite return
cortisol levels. These researchers subsequently of cortisol to baseline levels. Checkley et a1
reported on a sample of depressed patients (Checkley et a1 1994), commenting on the same
treated with ketoconazole in a double-blind, group of subjects as O'Dwyer et a1 (O'Dwyer et a1
placebo-controlled trial (Wolkowitz et a1 1999a). 1995), noted that, in addition to normalizing
Of 20 patients studied, eight were hyper- cortisol levels, metyrapone led to an increased
cortisolemic at baseline (4:OO pm serum cortisol urinary excretion of the neuroactive steroids,
>10 mg/dl) and 12 were eucortisolemic. Whereas tetrahydro- 11-deoxycortisol and tetrahydrode-
no significant main effect of ketoconazole vs. oxycorticosterone (THDOC). They suggested
placebo on depression ratings was observed, that either the decreases in cortisol levels or the
there was a significant interaction of drug increases in levels of these "neurosteroids" may
(ketoconazole vs. placebo) x baseline cortisol have been related to the antidepressant effects
status (eucortisolemic vs. hypercortisolemic). (Checkley et a1 1994; Raven et a1 1996). The
Specifically, ketoconazole was superior to latter possibility is important to entertain when
placebo in alleviating depressive symptoms in evaluating the literature on antiglucocorticoids
the hypercortisolemic but not in the eucorti- in depression, since several of the treatment
solemic patients. These findings are consistent studies reviewed above failed to demonstrate
with the hypothesized specificity of anti- decreases in serum cortisol levels despite demon-
glucocorticoid benefits in hypercortisolemic strating significant antidepressant effects, and
states and raise the possibility of biologically since neurosteroid hormones, such as pregneno-
distinct sub-groups of patients with major de- lone, DHEA and allopregnanolone, that are
pression. Such conclusions must remain ten- altered by stress and depression, are also affected
tative, however, due to the very small sample by antidepressant and antiglucocorticoid drugs
size of this and other studies. (Murphy 1991b; Griffin and Mellon 1999;

126
 Herbert 1998; Rupprecht and Holsboer 1999a; in some studies ((Klinget a1 1991; Wong et a1
Rupprecht and Holsboer 1999b; Uzunov et al ZOOO), including an especially comprehensive
1996; Uzunova et al 1998; Wolkowitz and Reus one (Geracioti et a1 19921, this finding was not
1999; Wolkowitz et a1 1999a; Romeo et a1 1998). replicated. It is possible that different subtypes of
major depression (e.g., "typical" vs. "atypical")
In addition to studies of antiglucocorticoids used differ in patterns of CRH secretion (Gold and
alone in depression, other studies have exa- Chrousos 1985; Gold and Chrousos 1999; Kling
mined their utility in treating other psychiatric et a1 1989; Kling et a1 1991). A compelling role
conditions or as augmentation agents in patients can be posited for the aetiological involvement
with treatment-resistant depression and other of CRH hypersecretion in symptoms such as
psychiatric illnesses. For example, refractory anxiety, fear, over-arousal, decreased slow wave
anxiety disorders associated with late-onset con- sleep, decreased eating and decreased libido
genital adrenal hyperplasia benefited from (Gold and Chrousos 1985; Gold and Chrousos
adrenal suppressive doses of ketoconazole 1999; Holsboer 1988; Holsboer 1999: Holsboer
(Jacobs et a1 1999). Beneficial effects of anti- 2000; Kling et a1 1991; O'Brien et a1 2001;
glucocorticoid adjunctive treatment have been Schulkin et a1 1994).
World J Biol Psychiatry Downloaded from informahealthcare.com by University of Colorado Libraries on 12/31/14

noted in some patients with refractory bipolar I

and I1 depression (Brown et a1 2001; Ravaris et al To the extent CRH hypersecretion plays a
1994), in severe refractory obsessive compulsive pathophysiological role in the development or
disorder patients (Chouinard et a1 1996), in de- maintenance of anxiety or major depression,
pressed schizophrenic and schizoaffective disor- CRH receptor antagonists should be therapeutic
der patients (Marco et a1 In Review), and in a (Holsboer 1999; O'Brien et a1 2001; Owens and
patient with treatment-resistant depression and Nemeroff 1999). Rats and non-hurrian primates
a coexisting "metabolic syndrome" comprised of administered the CRH-1 receptor a.ntagonist,
hypercortisolemia, hypertension and insulin R121919/ NBI 30775 ("antalarmin"), show di-
resistance (Bech et a1 1999). The latter example minished anxiety, fear and lowered ACTH and
represents the importance of treating the presu- corticosterone responses to novelty and intense
med neuroendocrine causes of comorbidity. social stress (Gutman et a1 2000; Habib et a1
2000). Early open-label human trials with CRH-1
For personal use only.

Alternate antiglucocorticoid and receptor antagonists have suggested significant

glucocorticoid treatments in depression antidepressant and anti-anxiety effects in de-
pressed patients (Holsboer 2000; Nemeroff 2000;
Steroid receptor antagonist: RU-486 Zobel et a1 2000). The development of safe and
RU-486 (Mifepristone) does not inhibit steroid effective CRH receptor blockers represents an
biosynthesis but blocks progesterone and, at important pharmaceutical goal (O'Brien et a1
higher doses, glucocorticoid (Type 11) receptors 2001) and will provide an important tool for
in the brain. Indeed, circulating cortisol levels further studying the role of CRH hypersecretion
may significantly increase secondary to RU-486's in psychiatric and other stress-related illnesses.
receptor blockade. In preclinical models, KU-486
has been found to significantly protect hippo- Dexamethasone, prednisone and
campal neurons from oxidative stress-induced hydrocortisone
damage (Behl et a1 1997). Early trials treating In what seems a diametrically opposite approach
depressed patients with RU-486 in Canada to altering steroidal activity in depressed pa-
showed promising results, but studies were tients, Arana and colleagues (Arana 1991; Arana
curtailed due to unavailability of the drug at that et a1 1995; Beale and Arana 1995) reported
time (Murphy et a1 1993). Ongoing studies at antidepressant effects of acute high dose dexa-
Stanford University, using four days of RU-486 methasone administration. In this paradigm,
treatment vs. placebo in the treatment of psy- dexamethasone was administered intravenously
chotic depression, have reportedly found some as a one-time bolus of 4-8 mg or orally as 4 mg
signs of efficacy in the small number of patients per day for four days. Results of the open-label
treated to-date, although psychotic and cogni- intravenous dexamethasone trial indicated an
tive symptoms seemed to respond better than average 56(% improvement within 10 days in
depressive ones (Belanoff and Schatzberg 2000). 75%) of depressed subjects, including five of
The use of RU-486 for other than subacute seven treatment-refractory ones who had failed
administration has been infrequently studied at least two prior antidepressant trials. In the
and has been associated with occasional rashes blinded oral dexamethasone trial, dexametha-
(Murphy et a1 1993). Other corticosteroid recep- sone was associated with only a ;!7.5(2/0 im-
tor blocking compounds, such as ORG-34116, provement in depression ratings compared with
arc in development (Karst et a1 1997). a 13.6% improvement with placebo. A signi-
ficantly greater number of dexarriethasone-
Corticotropin releasing hormone (CRH) treated subjects responded to treatrnent than
receptor antagonists placebo-treated subjects. The authors suggested
Elevated CSF CRH levels have been frequently that the beneficial effect of dexameth.asone was
described in depressed patients compared to con- secondary to regulation of CRH receptors,
trols (Nemeroff 1988; Nemeroff ZOOO), although increased serotonergic activity or other geno-

127
 RE VIE W/MINI-RE VIE W b
mically mediated changes in neurotransmission. hypercortisolemic at baseline, and long-term
Alternative explanations are offered below. antidepressant effects were not assessed.
DeBattista et a1 (DeBattista et a1 2000) acutely
Similar results were obtained by another group treated, in a double-blind manner, six depressed
using an open-label design. Dinan et a1 (Dinan et patients with hydrocortisone (15 mg i.v. over 2
a1 1997) studied 10 depressed patients who had hours), six patients with ovine CRH (1 mcg/kg
not responded to sertraline or fluoxetine, and i.v.) and 10 patients with placebo at 7:OO p.m.
added dexamethasone, 3 mg p.0. daily for four and assessed depression ratings the following
days, to the ongoing antidepressant regimen. By day at 4:00 p.m. Hydrocortisone-treated pa-
the following day (Day 5), three of the six sertra- tients, compared to both placebo and CRH-
line patients and three of the four fluoxetine treated ones, showed a significant acute anti-
patients demonstrated significant antidepressant depressant response. It was not reported whether
responses (50% reduction in depression ratings). the antidepressant responses were related to
Remarkably, this initial improvement was main- baseline cortisol levels, whether they were
tained through Day 21, the last assessed day. correlated with increases in circulating cortisol
Cortisol changes in response to dexamethasone levels, or whether the antidepressant responses
World J Biol Psychiatry Downloaded from informahealthcare.com by University of Colorado Libraries on 12/31/14

treatment were not reported, but baseline mor- persisted beyond one day.
ning serum cortisol levels were directly corre-
lated with antidepressant responses (viz., higher If acute dexamethasone treatment proves to
baseline cortisol was associated with better have antidepressant effects, how might this be
responses to dexamethasone). The dexametha- reconciled with antiglucocorticoids having
sone was relatively well tolerated, but several similar effects? Antiglucocorticoids and dexa-
patients reported sleep disruption, nausea and/or methasone administration could both have
anxiety during dexamethasone treatment. More antidepressant effects via: (1) their common
recently, Bodani et a1 (Bodani et a1 1999) effect of curtailing endogenous cortisol syn-
described two elderly patients with resistant thesis; (2) inducing up-regulation of brain gluco-
depression who appeared to benefit from dexa- corticoid receptors (with the effect of re-
methasone treatment, and Hardy et a1 (Hardy et establishing effective negative feedback) (Pepin
a1 2001) noted that terminally ill cancer patients et a1 1990); ( 3 ) altering levels of other adrenal or
For personal use only.

generally experienced mood improvement with neurosteroid hormones (e.g., shifting cholesterol
sub-chronic dexamethasone treatment. metabolism in the direction of increased syn-
thesis of certain GABA'ergic neurosteroids)
Finally, Wolkowitz et a1 (Wolkowitz et a1 1996) (Raven et a1 1996; Romeo et a1 1998); or (4)
reported negative results in a very small, double- increasing ACTH levels (with acute high dose
blind replication study. Five depressed patients dexamethasone treatment, this might occur after
received one-time intravenous infusions of dexamethasone's acute inhibitory effects are
either 6 mg dexamethasone or placebo and were terminated and the suppressed LHPA axis signals
evaluated 10 days later. The three subjects who increased ACTH output). Additionally, recent
received dexamethasone all fared more poorly evidence suggests that dexamethasone is actively
than the two who received placebo; two of the excluded from brain and does not replace
three dexamethasone-treated subjects actually endogenous glucocorticoids at hippocampal MR
worsened following treatment, and the trial was and GR sites (De Kloet et a1 1998). Its beha-
discontinued. The one dexamethasone-treated vioural effects, therefore, may result from
subject who showed any antidepressant effect indirect effects of dexamethasone-induced
had the lowest baseline serum cortisol concen- ACTH and cortisol suppression on the balance of
tration of the group. This observation is perhaps occupation of the two corticosteroid receptor
consistent with a case series of hypocortisolemic types in the hippocampus (De Kloet et a1 1998).
atypical depressed patients who responded Antiglucocorticoids and dexamethasone, then,
favourably to antidepressant augmentation with could share the net effect of increasing hippo-
prednisone (Bouwer et a1 2000). The authors of campal MR relative to GR occupation: antigluco-
the latter report theorized that either hyper- or corticoids by directly lowering cortisol levels to a
hypocortisolemia may be associated with de- degree insufficient to occupy brain GR, and
pressive symptoms (perhaps related to "typical" dexamethasone by binding to pituitary, but not
vs. "atypical" symptom profiles, respectively), hippocampal, GR, resulting in decreased cortisol
and that the hypocortisolemic subgroup might levels and lessened brain GR occupation (Plihal
respond preferentially to glucocorticoid aug- et a1 1996). Plihal et al, have suggested that MR
mentation therapy (Ibid.). activation, as opposed to GR activation, induces
positive mood states (Plihal et a1 1996).
In a related strategy, several investigators have
assessed the mood-altering effects of cortisol The beneficial effects of hydrocortisone, if
(hydrocortisone) (Cameron et a1 1985). In one confirmed, are more difficult to explain, unless
small-scale study, Goodwin et a1 (Goodwin et a1 the effects are transient (Plihal et a1 1996) and
1992) noted that an acute cortisol infusion secondary, perhaps, to increased dopamine le-
transiently improved self-rated mood in 12 vels (DeBattista et al 2000; Wolkowitz et al 1986).
depressed patients. These patients were not Alternatively, even in the face of persistent

128
 hypercortisolemia, phasic ("burst") increases in
cortisol levels may induce a rapid "re-setting'' of
LHPA axis negative feedback control (DeBattista
et al 2000; Murphy 1991a). Lastly, as suggested
above, it is possible that different subgroups of
depressed patients respond differentially to corti-
costeroid augmentation vs. suppression, perhaps
related to their baseline adrenocortical output
(Rouwer et a1 2000; DeBattista et a1 2000;
Wolkowitz et al 1996). Considerably more work
needs to be done to determine the predictors and
mediators of glucocorticoid-based treatments of
depression as well as their long-term effects.
Dehydroepiandrosterone (DHEA) and
neurosteroids
World J Biol Psychiatry Downloaded from informahealthcare.com by University of Colorado Libraries on 12/31/14
DHEA may have therapeutic effects and counter-
act certain deleterious effects of allostatic load.
DHEA treatment reportedly has antidepressant
effects in patients with major depression
(Wolkowitz et a1 1995; Wolkowitz et a1 1999b;
Wolkowitz et a1 1997b) and dysthyrnia (Bloch et
a1 1999), mildly and transiently improves cogni-
tive performance in patients with Alzheimer's
disease (Wolkowitz et a1 2000b) and enhances
well-being, energy and libido in hypo-adrenal
patients with Addison's disease (Arlt It' al 1999;
Arlt et a1 1998; Hunt et al 2000). However, as is
the case with most antidepressants, DHEA
treatment can result in overactivation, mania or
psychosis in some patients (Howard I11 1992;
Kline and Jaggers 1999; Markowitz et a1 1999).

We have discussed previously that DHEA may

serve as one of the body's endogenous "anti-
cortisol" hormones and that the ratio of DHEA-
to-cortisol (the "anabolic balance") may be more
informative regarding psychiatric and health
status than levels of either hormone alone
(Ferrari et a1 2001; Hechter et al 1997; Leblhuber
et al 1992; Wolkowitz et al 1992). Indeed,
multiple studies have verified DHEA's ability,
both in vitro and in vivo, to antagonize certain of
cortisol's physiological effects (Browne et al
1992; Hechter et a1 1997; Kalimi et a1 1994;
Patchev and Almeida 1997; Svec and Porter
For personal use only.
Beneficial mood and memory effect!, of DHEA
treatment in normal individuals ,md in very
mildly symptomatic populations have been
demonstrated less consistently (Barn hart et a1
1999; Diamond et al 1996; Hupperi and Van
Niekerk 2001; Morales et a1 1994; Wolf et a1
1997). Improvements in anthropomet ric indices
of allostatic load, such as muscle-to-fat ratio,
fasting glucose and insulin level5 and bone
mineral density, have been noted in healthy
volunteers in some, but not all studies (Baulieu
et a1 2000; Diamond et a1 1996; Labrie et a1 1997;

1998) and to prevent certain physiological Morales et al 1998; Nestler et a1 1988), although,
sequellae of stress (Hu et al 2000; Singh et al again, gender differences may have been appa-
1994). In particular, DHEA administration can rent (Baulieu et a1 2000; Morales et a1 1998).
reverse important detrimental effects of Despite the widespread use of DHEA in the
glucocorticoids in the CNS (Dubrovsky 1997; United States, more studies are needed before
Kimonides et a1 1999), can have neuroprotective any conclusions are reached regarding any
and cognition-enhancing effects and can beneficial effects (Katz and Morales 1998; van
counteract the development of "depression"-like Vollenhoven 1997; Wolkowitz et a1 2000a;
behaviours in animals [reviewed in (Kroboth et Wolkowitz and Reus 2000; Kroboth et a1 1999).
a1 1999; Svec and Porter 1998; Wolkowitz et al
2000a)l. Conversely, high levels of glucocor- To the extent DHEA treatment improves mood
ticoids or exposure to high levels of stress can and sense of well-being by improving "anabolic
block DHEA's beneficial neurosteroid actions balance" (as discussed in the introduction to this
(Diamond and Fleshner 2000). article), other anabolic hormones might have
similar effects. Indeed, recent epidemiological
and cross-sectional studies have demonstrated
Whereas multiple beneficial effects of DHEA positive correlations between serum levels of
have been observed in rodent models, rats and bioavailable testosterone and ratings of mood
mice produce little adrenally-derived DHEA and cognitive function in men (Barrett-Connor
naturally, so these findings may be of limited et al 1999; Morley et a1 1997). Testosterone repla-
generalizability to humans. Nonetheless, several cement therapy does improve mood in hypo-
studies reviewed in detail elsewhere raise the gonadal and elderly men and men with HIV
possibility that decreased DHEA(S) levels (or disease (Wang et a1 1996; Seidman and Walsh
decreased DHEA(S)-to-cortisolratios) contribute 1999; Kabkin et a1 2000), but effects in eugona-
to the development or progression of affective dal patients with major depression are less clear
disturbances, cognitive decline, fatigue and (Margolese 2000; Seidman and WaIsh 1999).
impaired physical and emotional well-being in Growth hormone treatment typically has posi-
humans (Wolkowitz et a1 2000a; Kroboth et a1 tive effects on mood and cognitive function in
1999; Svec and Porter 1998; Seeman et a1 2001), patients with growth hormone deficiency
although it is possible that differing patterns are (Nyberg 2000). XGF-1, another anabolic hor-
seen in men vs. women (Kroboth et a1 1999). mone, improves mood in obese (Thompson et a1
1998), but not non-obese (Friedlander et a1
Regardless of whether low endogenous levels of 2001), postmenopausal women.
DHEA are associated with depression, cognitive
impairment or physical disease risk factors in A rapidly evolving literature is highlighting the
humans, exogenous supplementation with importance of neurosteroids other than DHEA in

129
 RE VIE W/MINI-RE VIE W b
the pathophysiology and treatment of anxiety
and depression. For example, social isolation in
rats significantly decreases brain and plasma
levels of the GABA-A receptor agonist neuro-
steroids, allopregnanolone and THDOC, while
significantly increasing levels of corticosterone;
these changes are accompanied by increased
"anxiety"-like behaviours (Serra et a1 2000).
Decreasing concentrations of allopregnanolone
may be especially problematic in the face of
chronic stress, since allopregnanolone can re-
strain the glucocorticoid response to stress (Guo
et a1 1995), and since allopregnanolone can
protect against glutamate hippocampal neuro-
toxicity (Frank and Sagratella 2000). In humans,
levels of allopregnanolone are low in depressed
World J Biol Psychiatry Downloaded from informahealthcare.com by University of Colorado Libraries on 12/31/14
patients, and serotonin specific reuptake blocker
(SSRI) antidepressant treatment increases CSF
levels of this hormone, in direct proportion to
the antidepressant effect (Uzunov et a1 1996;
Uzunova et a1 1998). In addition to allo-
pregnanolone, pregnenolone, THDOC and an-
drosterone are promising neurosteroid targets for
novel antidepressant or neuroprotective agent
development (Barrot et a1 1999; Frank and
Sagratella 2000; George et a1 1994; Maurice et a1
1999; Meieran et a1 In Review; Patchev et a1
1997; Rupprecht and Holsboer 1999a; Urbanoski
et a1 2000).
For personal use only.
Behavioural treatment approaches to
depression and hormonal dysregulation
To the extent that altered stress hormone
secretion underlies or perpetuates depressive
symptoms and physical illness, behavioural as
well as pharmacological interventions that nor-
malize the hormonal milieu should prove
therapeutic (Cohen 2000; Drugan et a1 1994;
Sapolsky 1993). In fact, behavioural approaches
to decreasing stress and arousal (e.g., decreasing
"demand"while increasing predictability, control
and feedback) might prove superior in the long
run to the pharmacological approaches outlined
above, since pharmacological strategies tend to
"clamp"hormonal activity at either a low or high
state and thereby reduce responsiveness to
environmental demands (Sterling and Eyer
1988). Behavioral techniques, on the other
hand, have the potential to increase flexibility
and adaptability (Sterling and Eyer 1988). In the
following section, we explore evidence for the
hormonal mediation of some of the health
benefits of "stress-reduction" and other beha-
vioural treatment modalities. While most re-
search in this area has focused on cortisol and
DHEA, other stress-related neurosteroids may
also mediate certain benefits of behavioural
treatments, as discussed at the end of this
section.
Decreasing cortisol
Numerous studies have examined the effects of
relaxation and stress-reduction techniques on
cortisol and other stress-responsive hormones.
130
Controlled studies of short-term interventions
such as listening to music (Mockel et a1 1994),
biofeedback (McGrady et a1 1987) or massage
therapy (Field et a1 1992; Field et a1 1998) have
shown decreases in cortisol levels; these
reductions in cortisol levels were associated with
improvements in anxiety and depression in
some populations (Field et a1 1998). Also, relaxa-
tion training (Cruess et a1 2000) and cognitive-
behavioural stress management therapies (Perna
et a1 1998) significantly lower cortisol levels, in
direct proportion to decreases in negative affect
and fatigue. Participants randomized to an 18-
month comprehensive lifestyle intervention
programme, compared to controls, showed nor-
malization of initially elevated cortisol levels, in
association with decreased body mass index,
improvement in lipoprotein profiles and better
overall health (Nilsson et a1 2001). Experimental
groups that learned to regularly meditate sup-
pressed cortisol compared to controls (Gallois et
a1 1984; Jevning et a1 1978; Sudsuang et a1 1991);
however, see Michaels et a1 (1979). Long-term
meditators (average of 8.5 years) had 50% lower
urinary free cortisol levels than a control group
(Walton and Pugh 1995; Walton et a1 1995),
although these results are probably affected by
selection bias. In a prospective four-month
random-assignment study, meditators showed
lower basal cortisol levels and slightly increased
acute cortisol and growth hormone responses to
stress (Maclean et a1 1997). The biological
significance of increased acute cortisol and GH
responses to stress is unknown, but such rapid
stress responses may indicate a more "healthy"
allostasis. Finally, lending "controllability" to the
experience of stress demonstrably lowers cortisol
responses, even in healthy controls (Breier et a1
1988; Cohen 2000).
As noted earlier, one mechanism by which
cortisol over-exposure may lead to depression,
cognitive impairment and/or hippocampal pa-
thology is by decreasing hippocampal expression
of BDNF (Duman et a1 1997; Grundy et a1 2000).
It is unknown if stress reduction or behavioural
interventions that lower cortisol levels, such as
those discussed here, are capable of increasing
BDNF levels, but in animals, physical exercise
blocks stress-induced decreases in brain BDNF
mRNA levels (Russo-Neustadt et a1 2001) and
increases adult hippocampal neurogenesis (Trejo
et a1 2001). These latter effects may be mediated
via an increase in brain levels of the catabolic
hormone, IGF-1 (Trejo et a1 2001).
Increasing DHEA and neurosteroids
Behavioural treatment programmes also sig-
nificantly increase DHEA(S) levels. Cognitive-
behavioural treatment of depressed patients
increased urinary DHEA-S levels, in comparison
to imipramine, which lowered levels (Tollefson
et a1 1990). In a prospective study, Army officers
participating in a stress-reduction programme
showed significant increases in DHEA-S levels
 compared to non-participants (Littman et a1
1993).Similarly, Cruess and colleagues (Cruess et
a1 1999) reported that 10 weeks of "cognitive-
behavioural stress management" (comprised of
treatments such as identification of cognitive
distortions, assertiveness training, anger ma-
nagement, social support, group discussions, ex-
periential exercises, progressive muscle relaxa-
tion, autogenic training, meditation and guided
imagery), compared to a 10-week control "wait
list" condition, significantly increased plasma
DHEA-S levels and decreased cortisol-to-DHEA-S
ratios in HIV-seropositive men. Treated subjects,
compared to control subjects, also showed sig-
nificant improvements in mood disturbance and
perceived stress; these improvements were
World J Biol Psychiatry Downloaded from informahealthcare.com by University of Colorado Libraries on 12/31/14
directly correlated with the decreases in plasma
cortisol-to-DHEA ratios.
Consistent with these studies, Arnetz and
colleagues (Arnetz et a1 1983) assigned elderly
individuals from a senior citizen apartment
building to either a "social enrichment" program-
me (e.g., study groups in botany, history, music
and geography, as well as outings, picnics and
visits to the opera and theatre) or to a pro-
gramme of normal pre-existing activities for six
months. The experimental group, compared to
the control group, showed significant increases
For personal use only.
in DHEA, testosterone, oestradiol and GH levels,
as well as significantly attenuated decreases in
height (suggesting slowing of osteoporosis
progression). The authors speculated that social
isolation in the elderly decreases anabolic-to-
catabolic hormone ratios, leading to increased
susceptibility to illness (such as osteoporosis),
and that social enrichment counteracts this
process. Lokk (Lokk 1998) presented confir-
matory data in an uncontrolled study of 1 7 non-
demented geriatric day-care attendees who
participated in a new rehabilitation programme
designed to decrease the "stress of uncertainty
and passivity" by giving patients greater control
and responsibility over their own rehabilitation
programmes. Patients were assessed at entry into
the programme, after three months of treatment
and again three months after discharge. Pro-
lactin and cortisol levels significantly decreased
over the three months of treatment, while DHEA
and oestradiol levels significantly increased.
These changes coincided with improvements in
Activities of Daily Living ratings and with
increases in "optimism" ratings. By three months
after discharge from the programme, prolactin,
cortisol and oestradiol levels had returned to pre-
treatment levels, but DHEA levels remained
elevated. In another prospective study, but one
lacking a control group for the hormonal
determinations, healthy adult participants in an
"emotional self-management programme" expe-
rienced a 100% increase in salivary DHEA(S)
levels; these levels were significantly correlated
with the psychological variable "warmhearted-
ness" (McCraty et a1 1998). Experienced prac-
titioners of transcendental meditation (TM) were
131
also found to have elevated DHEA-S levels
(Glaser et al 1992; Walton et a1 1995), generally
comparable to the levels seen i.n non-prac-
titioners 5-10 years younger, increased urinary S-
HIAA (the major SHT metabolite') levels and
decreased urinary free cortisol levels compared
to non-TM practitioners. The authors of the
former report noted that extraneous factors,
such as diet, body mass index and exercise, did
not account for the difference in hormone levels
(Glaser et a1 1992), and the authors of the latter
report noted that DHEA-S levels in women
varied directly with the months of T-M practice
(Walton et a1 1995). Music therapy ,and group
drumming exercises were also found to increase
DHEA-to-cortisol ratios in normal volunteers
(Bittman et a1 2001). Lastly, as was the case with
exercise effects on IGF-1 and on BDNF (discussed
above), aerobic exercise training programmes
can significantly increase serum DHEA levels
(Boudou et a1 2000). In contrast to such chronic
or subchronic behavioural interventions, one
session of Qigong training (a "stre!;s coping"
method) did not alter DHEA(S) or cortisol levels
(Ryu et al 1996).
An important therapeutic goal of cognitive-
behavioural and other psychotherapies is
increased perception of control over, and
predictability of, life's aversive events (Sterling
and Eyer 1988). Animal studies suggest one
possible biochemical correlate of "control-
lability" that might bear upon its beneficial
effects. Rats exposed to escapable shock,
compared to non-shocked controls and to rats
exposed to inescapable shock, c8howed a
threefold increase in brain benzodia.iepine-like
substances (likely GABA-A agonist neurosteroids
such as allopregnanolone or THDOC) and a
marked protection against seizures induced by
picrotoxin, a GABA-A receptor antagonist
(Drugan et a1 1994). The authors concluded that
the active behavioural "coping" and "stress
control" these rats experienced led to the release
of endogenous benzodiazepine-like compounds
in brain which protected them from stress
pathology (Drugan et a1 1994). This animal study
raises the intriguing, but yet untested, possibility
that cognitive-behavioural and other psycho-
therapies that are designed to increase one's
sense of control and predictability might also
increase brain allopregnanolone (or other
GABA'ergic neurosteroids) levels in anxious or
depressed patients, in a manner similar to that
seen following serotonin antidepres8jant treat-
ment (Uzunov et a1 1996).
Clinical implications of behavioural
treatment approaches
Stress reduction interventions usually reduce
physiological arousal levels and lead to cognitive
changes, such as increased perceptions of
controllability and predictability. In. these ways,
they may have direct antidepressant effects as
well as indirect ones by restoring balance to the
 RE VIE W/MINI-RE VIE W b
endocrine milieu (e.g., decreasing cortisol and
increasing levels of DHEA or other anabolic
hormones). In a complementary way, restoring
cortisol and DHEA levels to normal may alter
cognitive function and social behaviour in a
direction less conducive to depression and to
experiencing disappointing life events (Goodyer
et a1 1998). Interestingly, experiencing control or
predictability over aversive events (Drugan et a1
1994; Weiss 1972), or experiencing "environ-
mental enrichment" (e.g., increased physical
activity, social stimulation and learning expe-
riences) (Meaney et al 1988; Mohammed et a1
1993; Kempermann et a1 1997), yields neuro-
chemical and behavioural benefits that are not
even seen in unstressed individuals. Indeed, in
World J Biol Psychiatry Downloaded from informahealthcare.com by University of Colorado Libraries on 12/31/14
and increased glycemic control at six months
follow-up, compared to a control group (Lust-
man et a1 1998). In preliminary data, reducing
depressive and anxiety symptoms in Type I1
diabetics via stress reduction techniques also
significantly reduces visceral fat up to six
months later, compared to a control group (Epel
et a1 2001). These examples demonstrate the
tight interplay between the LHPA axis, mood,
and physical health. Treatments that affect
common underlying causes of mood disturbance
and allostatic load, such as improved anabolic
balance, should theoretically be most effective.
Choice of antiglucocorticoid drug and
risk of side effects

animals, exposure to environmental enrichment

or to the mild stress of regular postnatal hand-
ling enhances cognition, attenuates age-associa-
ted hippocampal atrophy, induces nerve growth
factor gene expression and BDNF mRNA
expression in hippocampus, elevates expression
of hippocampal glucocorticoid (Type 11) recep-
tors, enhances negative feedback efficiency of
the LHPA axis and decreases glucocorticoid
output (Meaney et a1 1988; Mohammed et a1
1993; Falkenberg et a1 1992; Kempermann et a1
1997). These findings in animals suggest that
even relatively subtle, transient environmental
For personal use only.
Whereas the stress reduction and cognitive-
behavioural techniques outlined here are already
in routine clinical use, the pharmacological
antiglucocorticoid approaches reviewed in this
chapter remain largely experimental, and their
full risk/benefit ratios remain to be determined.
They are not yet recommended for routine clini-
cal use (other than antiglucocorticoids in the
treatment of Cushing's syndrome and DHEA in
the adjunctive treatment of Addison's disease). A
more detailed discussion of the clinical differen-
ces between existing antiglucocorticoid drugs

or behavioural changes can have long-lasting and the risk of side effects with each one is
impact on the brain and LHPA axis (Sapolsky presented elsewhere (Wolkowitz and Reus 1999).
1993; Sterling and Eyer 1988; Jacobs et a1 2000).
Summary
It remains unclear whether patients with initial-
ly disturbed LHPA activity are more or less likely The data reviewed here raise the possibility that
to respond to behavioural interventions. How- antiglucocorticoid drug treatments or treatments
ever, behavioural treatments alone may be less that improve anabolic balance ameliorate de-
appropriate for patients with clinically signifi- pressive symptoms in some patients with major
cant LHPA axis dysregulation. Thase and col- depression or other psychiatric disorders, and,
leagues, for example, found that depressed inpa- additionally, can reduce certain physical signs of
tients with elevated urinary free cortisol levels allostatic load. Such beneficial effects would be
showed poorer responses to cognitive-beha- consistent with those observed in Cushing's
vioural therapy (CBT) than did those with syndrome patients treated with the same drugs.
normal urinary free cortisol levels (Thase et a1 The majority of the reviewed treatment trials,
1993; Thase 1994). however, were non-blinded or small-scale.
Therefore, any conclusions at this point must be
There is some evidence that stress reduction considered tentative. Behavioural techniques,
interventions like those described above also which also normalize elevated cortisol levels
have direct impact on reducing physical disease and/or increase DHEA levels, have proven
or risk for disease (Castillo-Richmond et a1 2000; clinical efficacy, but whether their efficacy is
Fahrion et a1 1987; Whitehouse et a1 1996). mediated by their hormonal effects is unknown.
Diabetic control, for example, may be an
important target of behavioural "antigluco- If this endocrinological model of depression and
corticoid" strategies. Diabetic glycemic control is allostatic load is correct, it provides several novel
often upset by stressful events, and decreases in sites for therapeutic intervention (Figure 3).
cortisol levels may improve glycemic control by "Biopsychosocial" interventions could be under-
attenuating cortisol-induced insulin resistance. stood as having actions in common leading to
Biofeedback practiced over three months re- normalization of stress hormone secretion, with
duced blood sugar in adults with insulin-depen- attendant downstream normalization of neuro-
dent diabetes, but the patients who were also transmitter, neuropeptide and neurotrophin
depressed showed no benefit (McGrady and levels and restoration of the balance between
Horner 1999). However, in another recent study, catabolic and anabolic processes.
a 12-week cognitive behavioural intervention for
depression among patients with non-insulin The studies reviewed here cumulatively suggest
dependent diabetes mellitus reduced depression the dual importance of further studying anti-

132
 glucocorticoid strategies in major depression and
in other conditions characterized by allostatic
load:
1. On a practical clinical level, it may lead to the
development of novel pharmacotherapeutic
approaches for certain psychiatric patients. In
many of the reviewed studies, good responses
to antiglucocorticoid agents were seen in pa-
tients refractory to traditional antidepres-
sants. Improvements often occurred rapidly
(as early as one to three weeks), and remission
occasionally persisted for long periods of time
(in some cases even after antiglucocorticoid
treatment was stopped). Since a substantial
proportion of depressed patients is resistant to
or intolerant of traditional antidepressants,
World J Biol Psychiatry Downloaded from informahealthcare.com by University of Colorado Libraries on 12/31/14
the availability of a new class of anti-
depressant medication would be significant.
2. On a theoretical level, it may lead to a better
understanding of the role of dysregulation of
the LHPA axis in major depression and other
psychiatric disorders. This issue has been dis-
cussed and considered for over 45 years
(Quarton et a1 1955), but until the availability
and use of relatively safe antiglucocorticoid
drugs, no suitable paradigm has existed to test
it. It may also help clarify whether neuro-
transmitter, neuropeptide and neurotrophin
dysregulation and insensitivity to glucocor-
For personal use only.
ticoid negative feedback are primary or
secondary pathological events in the develop-
ment of depression. The well-replicated
finding that persistent DST nonsuppression
after antidepressant treatment portends
poorly for long-term outcome (Ribeiro et a1
1993) suggests that re-establishment of LHPA
axis negative feedback may itself be an
important therapeutic goal.
Further studies will be needed to determine the
appropriate clinical role of antiglucocorticoids in
psychiatric treatment and their role (as well as
the role of certain behavioural interventions) in
reducing the "allostatic load" sequellae of depres-
sion and other stressful conditions. Confirma-
tion of antidepressant and health-promoting
effects of the antiglucocorticoid drugs reviewed
here would undoubtedly spur the development
of safer compounds and would refine our
notions of appropriate targets of pharmaco-
therapy. Elucidation of the relationship of hor-
monal normalization to clinical improvement
might also lead to a laboratory "yardstick" by
which to measure (and perhaps predict) inci-
pient clinical response to drug or psychothera-
peutic interventions. The exciting recent deve-
lopments in biological psychiatry and molecular
biology that were reviewed in this article are
undoubtedly harbingers of new treatments for
depression, cognitive impairment and perhaps
"brain aging" that lie on the horizon.
Acknowledgements
The authors gratefully acknowledge support
from the National Institute on Aging (Grant R41-
133
AG13334-01), the National Alliance for Research
in Schizophrenia and Affective Disorders
(NARSAD), the Stanley Foundation of the
National Alliance for the Mentally I11 (NAMI),
the Scottish Rite Foundation and the UCSF
Research Evaluation and Allocation Committee
(REAC). We also gratefully acknowledge helpful
discussions about antiglucocorticoid and DHEA
treatments with Eugene Roberts, 1'h.D. and
Bruce McEwen, r'h.D., but the views presented
here are not necessarily reflective of their own.
Portions of this article are based on the chapter:
"Antiglucocorticoid strategies in treal ing major
depression and 'allostatic load','' by OM Wolko-
witz, ES Epel and VI Reus, which appeared in: JH
Thakore (ed) Physical Consequences of Depres-
sion. Wrightson Biomedical l'ubl. Lid., Peters-
field, UK, 2001.
References
Aberg MA, Aberg ND, Hedbacker H, Oscarsson 1, Eriksson PS
(2000) Peripheral infusion of ICF-1 selectively induces neurogenesis
in the adult rat hippocampus. I Neurosci 20: 2896.2903.
Amsterdam I, Mosley PD, Rosenzweig M (1994) Assessment of
adrenocortical activity in refractory depression: steroid suppression
with ketoconazole. In: Nolan W, Zohar J, Roose 5, Amsterdam ]
(eds) Refractory Depression. John Wiley, Chichester, pp 199-210.
Anand A, Malison R, McDougle C], Price 1.H (1995) Anti-
glucocorticoid treatment of refractory depresion with keto-
conazole: a case report. Biol Psychiatry 37: 338-340.
Angeli A, Frairia R (1 985) Ketoconazole therapy in Cushing's
disease [letter]. Lancet 1 : 821.
Arana CW (1 991) Intravenous dexamethasone for symptoms of
major depressive disorder [letter]. Am ] Psychiatry 148: 1401-1 402.
Arana CW, Santos AB, Laraia MT, McLeod-Bryant S, Beale MD,
Rames L], Roberts JM, Dias JK, Molloy M (1 995) Dexamethasone
for the treatment of depression: a randomized, placebo-controlled,
double-blind trial. Am J Psychiatry 152: 265-267.
Ark W, Just1HC, Callies I', Reincke M, Hubler D, Oettel M, Ernst M,
Schulte HM, Allolio B (1 998) Oral dehydroepiandrosterone for
adrenal androgen replacement: pharmacokinetics and peripheral
conversion to androgens and estrogens in young healthy females
after dexamethasone suppression. ] Clin Endocrinol Metab 83:
1928-1934.
Ark W, Callies F, van Vlijmen JC, Koehler I, Reincke M, Bidlingmaier
M, Huebler D, Oettel M, Ernst M, Schulte HM, Allolio B (1999)
Dehydroepiandrosterone replacement in women with adrenal
insufficiency. N Engl J Med 341 : 101 3-1020.
Arnetz BB, Theorell T, Levi L, Kallner A, Eneroth P (1983) An
experimental study of social isolation of elderly people: psycho-
endocrine and metabolic effects. Psychosomatic Med 45: 395-406.
Arteaga E, Mahana D, Conzalez R, Martinez P (1989) [Cushing
syndrome caused by rnacronodular adrenal hyperplasia, inde-
pendent of ACTH: report of a case]. Rev Med Chi1 117: 1398-1402.
Barbieri M, Rosaria Rizzo M, Manzella D, Paolisso G (2001) Age-
related insulin resistance: is it an obligatory finding? The lesson
from healthy centenarians. Diabetes Metab Res Rev 17: 19-26.
Barnhart KT, Freeman E, Crisso ]A, Rader D], Sammel M, Kapoor 5,
Nestler J E (1 999) The effect of dehydroepiandrtxterone sup-
plementation to symptomatic perimenopausal wornen on serum
endocrine profiles, lipid parameters and health-related quality of
 R F VIF W/MINI-R E VIE W b
life. J Clin Endocrinol Metab 84: 3896-3902.
Barrett-Connor E, Von Huhlen DC, Kritz-Silverstein D (1 999)
Bioavailable testosterone and depressed mood in older men: the
Rancho Bernard0 study. J Clin Endocrinol Metab 84: 573-577.
Barrot M, Vallee M, Cingras MA, Le Moal M, Mayo W, Piazza PV
(1 999) The neurosteroid pregnenolone sulfate increases dopamine
release and the dopaminergic response t o morphine in the rat
nucleus accumbens. Eur J Neuroscience 11 : 3757-3760.
Bastianetto 5, Ramassamy C, Poirier J,Quirion R (1 999) Dehydro-
epiandrosterone (DHEA) protects hippocampal cells from oxidative
stress-induced damage. Brain Res Mol Brain Res 66: 35-41.
Baulieu EE (1997) Neurosteroids: of the nervous system, by the
nervous system, for the nervous system. Recent Prog Horm Res 52:
1-32.
World J Biol Psychiatry Downloaded from informahealthcare.com by University of Colorado Libraries on 12/31/14
Baulieu E, Thomas C, Legrain S, Lahlou N, Roger M, Debuire B,
Faucounau V, Cirard L, Hervy MP, Latour F, Leaud MC, Mokrane A,
Pitti-Ferrandi H, Trivalle C, de Lacharriere 0, Nouveau S, Rakoto-
Arison B, Souberbielle JC, Raison J, Le BOUCY, Raynaud A, Cirerd X,
Forette F (2000) Dehydroepiandrosterone (DHEA), DHEA sulfate,
and aging: Contribution of the DHEAge Study to a sociobiomedical
issue. Proc Natl Acad Sci USA 97: 4279-4284.
Beale MD, Arana CW (1995) Dexamethasone for treatment of
major depression in patients with bipolar disorder [letter]. Am J
Psychiatry 152: 959-960.
Bech P, Raabaek Olsen L, Jarlov N, Hammer M, Schutze T, Breum L
(1 999) A case of sequential anti-stress medication in a patient with
major depression resistant to amine-reuptake inhibitors. Acta
Psychiatrica Scand 100: 76-78.
Behl C, Lezoualc'h F, Trapp T, Widmann M, Skutella T, Holsboer F
For personal use only.
(1 997) Clucocorticoids enhance oxidative stress-induced cell death
in hippocampal neurons in vitro. Endocrinology 138: 101.1 06.
Belanoff 1, Schatzberg AF (2000) Clucocorticoid antagonists.
Neuropsychopharmacology 23: 556.
Berneis K, Keller U (1 996) Metabolic actions of growth hormone:
direct and indirect. Ballieres Clinical Endocrinology and
Metabolism 10: 337-353.
Berwaerts JJ, Verhelst ]A, Verhaert CC, Verhaegen AA, Abs RE (1 998)
Corticotropin-dependent Cushing's syndrome in older people:
presentation of five cases and therapeutical use of ketoconazole. J
Am Geriatr Soc 46: 880-884.
Biegon A (1 990) Effects of steroid hormones on the serotonergic
system. Ann N Y Acad Sci 600: 427-432.
Bittman BE, Berk LS, Felten DL, Westengard 1, Simonton OC,
Pappas J, Ninehouser M (2001) Composite effects of group drum-
ming therapy on modulation of neuroendocrine-immune para-
meters in normal subjects. Altern Ther Health Med 7: 38-47.
Bjorntorp P (1 997) Body fat distribution, insulin resistance, and
metabolic diseases. Nutrition 9: 795-803.
Bjorntorp P (In Press) Hypothalamic Origin of Prevalent Human
Disease: In: Pfaff D, Arnold A, Etgen A, Fahrbach S, Rubin R,:
Hormones, Brain and Behavior. San Diego: Academic Press.
Bjorntorp P, Holm C, Rosmond R (1999a) Hypothalamic arousal,
insulin resistance and type 2 diabetes mellitus. Diabet Med 16:
373-383.
Bjorntorp P, Holm C, Rosmond R (1999b) Hypothalamic arousal,
insulin resistance, and Type 2 diabetes mellitus. Diabetic Medicine
16: 373-383.
Bloch M, Schmidt PJ, Danaceau MA, Adams LF, Rubinow DR (1999)
Dehydroepiandrosterone treatment of mid-life dysthymia. Biol
Psychiat 45: 1533-1541.
Bodani M, Sheehan 6, Philpot M (1 999) The use of dexamethasone
in elderly patients with antidepressant-resistant depressive illness. J
Psychopharmacol 13: 196-197.
134
Boston Collaborative Drug Surveillance Program (1 972) Acute
adverse reactions to prednisone in relation t o dosage. Clin
Pharmacol Ther 13: 694-698.
Boudou P, De Kerviler E, Vxiau P, Fiet J, Cathelineau C, Cautier J
(2000) Effects of a single bout of exercise and exercise training on
steroid levels in middle-aged type 2 diabetic men: relationship to
abdominal adipose tissue distribution and metabolic status.
Diabetes Metab 26: 450-457.
Bouwer C, Claassen J, Dinan TC, Nemeroff CB (2000) Prednisone
augmentation in treatment-resistant depression with fatigue and
hypocortisolemia: a case series. Depress Anxiety 12: 44-50.
Bray C (1 985) Autonomic and endocrine factors in the regulation
of food intake. Brain Research Bulletin 14: 505-510.
Breier A, Albus M, Pickar D, Zahn TP, Wolkowitz OM, Paul SM
(1 988) Controllable and uncontrollable stress in humans:
Alterations in mood and neuroendocrine and psychophysiological
function. Am J Psychiatry 144: 1419-1 425.
Bremner JD (1 999) Does stress damage the brain? Biol Psychiatry
45: 797-805.
Brown ES, Bobadilla L, Rush AJ (2001) Ketoconazole in bipolar
patients with depressive symptoms: a case series and literature
review. Bipolar Disord 3: 23-29.
Browne ES, Wright BE, Porter JR, Svec F (1992) Dehydro-
epiandrosterone: antiglucocorticoid action in mice. Am J Med Sci
303: 366-371.
Cameron HA, McKay RD (1999) Restoring production of
hippocampal neurons in old age. Nat Neurosci 2: 894-897.
Cameron OC, Addy RO, Malitz D (1985) Effects of ACTH and
prednisone on mood: incidence and time of onset. Int J Psychiatry
Med 15: 21 3-223.
Cardounel A, Regelson W, Kalimi M (1999) Dehydroepian-
drosterone protects hippocampal neurons against neurotoxin-
induced cell death: mechanism of action. Proc Soc Exp Biol Med
222: 145-149.
Castillo-Richmond A, Schneider R, Alexander C, Cook R, Myers H,
Nidich S, Haney C, Rainforth M, Salerno J (2000) Effects of stress
reduction on carotid atherosclerosis in hypertensive African
Americans. Stroke 31 : 568-573.
Chauloff F (1993) Physiopharmacological interactions between
stress hormones and central serotonergic systems. Brain Research
Reviews 18: 1-32.
Checkley AS, O'Dwyer AM, Raven P, Taylor N, Lightman S (1 994)
Antidepressant effects of treatments with metyrapone and hydro-
cortisone. Biol Psychiatry 35: 71 1.
Chouinard C, Belanger MC, Beauclair L, Sultan 5, Murphy BE
(1 996) Potentiation of fluoxetine by aminoglutethimide, an
adrenal steroid suppressant, in obsessive-compulsive disorder resis-
tant t o SSRls: a case report. Prog Neuropsychopharmacol Biol
Psychiatry 20: 1067-1079.
Christeff N, Nunez EA, Cougeon ML (2000) Changes in
cortisol/DHEA ratio in HIV-infected men are related to immuno-
logical and metabolic perturbations leading to malnutrition and
lipodystrophy. Ann NY Acad Sci 91 7: 962-970.
Cleghorn RA (1 951) Adrenal cortical insufficiency: psychological
and neurologic observations. Canada MAJ 65: 449-454.
Cohen SI (1980) Cushing's syndrome: a psychiatric study of 29
patients. Br J Psychiatry 136: 120-124.
Cohen JI (2000) Stress and mental health. Issues Mental Health
Nursing 21: 185-202.
Coleman D, Leiter E, Schwizer R (1982) Therapeutic effects of
dehydroepiandrosterone in diabetic mice. Diabetes 31 : 830-833.
Cruess DG, Antoni MH, Kumar M, Ironson C, McCabe P, Fernandez
 JB, Fletcher MA, Schneiderman N (1 999) Cognitive-behavioral
stress management buffers decreases in dehydroepiandrosterone
sulfate (DHEA-S) and increases in the cortisol/DHEA-S ration and
reduces mood disturbance and perceived stress among HIV-
seropositive men. Psychoneuroendocrinology 24: 537-549.
Cruess DC, Antoni MH, Kumar M, Schneiderman N (2000) Reduc-
tions in salivary cortisol are associated with mood improvement
during relaxation training among HIV-seropositive men. j Behav
Med 23: 107-122.
Curzon C (1994) Effects of stress on 5-HT function. Neuro-
psychopharmacology 10: 9285.
De Kloet ER, Vreugdenhil E, Oitz MS, Joels M (1998) Brain corti-
costeroid receptor balance in health and disease. Endocr Rev 19:
269-301.
de Leon MJ, McRae T, Rusinek H, Convit A, De Santi 5, Tarshish C,
Colomb 1, Volkow N, Daisley K, Orentreich N, McEwen B (1997)
World J Biol Psychiatry Downloaded from informahealthcare.com by University of Colorado Libraries on 12/31/14
Cortisol reduces hippocampal glucose metabolism in normal
elderly, but not in Alzheimer's disease. J Clin Endocrinol Metab 82:
3251-3259.
Deak F, Lasztoczi B, Pacher P, Petheo CL, Valeria K, Spat A (2000)
Inhibition of voltage-gated calcium channels by fluoxetine in rat
hippocampal pyramidal cells. Neuropharmacology 39: 1029-1036.
DeBattista C, Posener ]A, Kalehzan BM, Schatzberg AF (2000)
Acute antidepressant effects of intravenous hydrocortisone and
CRH in depressed patients: A double-blind, placebo-controlled
study. Am J Psychiatry 157: 1334-1337.
Deroche V, Marinelli M, Le Moal M, Piazza PV (1997)
Clucocorticoids and behavioral effects of psychostimulants. II:
Cocaine intravenous self-administration and reinstatement depend
on glucocorticoid levels. J Pharrnacol Exp Ther 281: 1401-1407.
For personal use only.
Diamond DM, Fleshner M (2000) Constraints on the DHEAS-
induced enhancement of hippocampal function: non-linear dose-
response functions and DHEAS-stress interactions. In: Kalimi M,
Regelson W (eds) Dehydroepiandrosterone (DHEA): Biochemical,
Physiological and Clinical Aspects. Walter de Cuyter, Berlin, pp
261 -270.
Diamond P, Cusan L, Comez JL, Belanger A, Labrie F (1996)
Metabolic effects of 12-month percutaneous dehydroepian-
drosterone replacement therapy in postmenopausal women. J
Endocrinol 150 Suppl: 543-50.
Dinan TC, Lavelle E, Cooney J,Burnett F, Scott L, Dash A, Thakore
J, Berti C (1 997) Dexamethasone augmentation in treatment-
resistant depression. Acta Psychiatr Scand 95: 58-61.
Dong-Ho H, Hansen P, Chen M, Holloszy J (1998) DHEA treatment
reduces f a t accumulation and protects against insulin resistance in
male rats. Journal of Gerontology 53: B19-B24.
Drugan RC, B a d e AS, Ha JH, Ferland RJ (1994) The protective
effects of stress control may be mediated by increased brain levels
of benzodiazepine receptor agonists. Brain Res 661 : 127-1 36.
Dubrovsky B (1 991) Adrenal steroids and the physiopathology of a
subset of depressive disorders. Med Hypotheses 36: 300-305.
Dubrovsky B (I 997) Natural steroids counteracting some actions of
putative depressogenic steroids on the central nervous system:
potential therapeutic benefits. Med Hypotheses 49: 51 - 5 5 .
Duman RS, Heninger CR, Nestler EJ (1 997) A molecular and cellular
theory of depression. Arch Cen Psychiatry 54: 597-606.
Elliott EM, Mattson MP, Vanderklish P, Lynch C, Chang I, Sapolsky
RM (1 993) Corticosterone exacerbates kainate-induced alterations
in hippocampal tau immunoreactivity and spectrin proteolysis in
vivo. J Neurochem 61: 57-67.
Epel E, McEwen B, lckovics J (1998) Embodying psychological
thriving: Physical thriving in response to stress. Journal of Social
Issues 54: 301-322.
Epel E, McEwen B, Seeman T, Matthews K, Castellazzo C, Brownell
135
K, Bell J, lckovics J (2000a) Stress and body shape. Consistently
greater stress-induced cortisol reactivity among women with
abdominal fat. Psychosomatic Medicine 62: 623-1532,
Epel E, Kiratli J, Young B, Chapman J, Hegde 5, Standard 5,
Osterberg L (2001) Stress reduction for Type II Diabetics reduces
visceral adiposity. Manuscript in progress .
Epel E, Lapidus R, Brownell K, McEwen B (2000b) Stress may add
bite to appetite in women: A laboratory study of stress-induced
cortisol and eating behavior. Psychoneuroendocrinology 26: 37-
49.
Eriksen HR, Olff M, Murison R, Ursin H (1 999) The time dimension
in stress responses: Relevance for survival and health. Psychiatry res
85: 39-50.
Ernest I, Ekman H (1 972) Adrenalectomy in Cushiiig's disease. Acta
Endocrinol 160: 4-41.
Fahrion 5, Norris P, Ci-een E, Green A, Schnar It (1987) Bio-
behavioral treatment of essential hypertension. Biofeedback and
Self-Regulation 11: 257-278.
Falkenberg T, Mohammed AK, Henriksson B, Persson H, Winblad B,
Lindefors N (1 992) Increased expression of brain-derived neuro-
trophic factor mRNA in rat hippocampus is associated with
improved spatial memory and enriched environment. Neurosci
Lett 138: 153-156.
Ferrari E, Cravello L, Muzzoni B, Casarotti D, Paltro M, Solerte SB,
Fioravanti M, Cuzzoni C, Pontiggia B, Magri F (2001) Age-related
changes of the hypothalamic-pituitary-adrenal axis: patho-
physiological correlates. Eur J Endocrinol 144: 319-329.
Field T, Morrow C, Valdeon C, Larson S, Kuhn C, Schanberg S
(1 992) Massage reduces anxiety in child and adolescent psyschia-
tric patients. Child Adolescence 31 : 125-131.
Field T, Schanberg 5, Kuhn C, Field T, Fierro K, Henteleff T, Mueller
C, Yando R, Shaw 5, Burman I (1 998) Bulimic adolescents benefit
from massage therapy. Adolescence 33: 555-563.
Flugge G, Kramer M, Rensing 5, Fuchs E (1 998) 5HT1A-receptors
and behavior under chronic stress: selective counteraction by
testosterone. Eur J Neurosci 10: 2685-2693.
Frank C, Sagratella S (2000) Neuroprotective effects of allo-
pregnanolone on hippocampal irreversible neurotoxicity in vitro.
Prog Neuropsychopharniacol Biol Psychiatry 24: I 1 1 7-1 126.
Friedlander AL, Butterfield CE, Moynihan 5, Crillo J, Pollack M,
Holloway L, Friedman L, Yesavage 1, Matthias D, Lee 5, Marcus R,
Hoffman AR (2001) One year of insulin-like growth factor I treat-
ment does not affect bone density, body composition, or psycho-
logical measures in postmenopausal women. J C in Endocrinol
Metab 86: 1496-1503.
Callois P, Forzy C, Dhont J (1984) [Hormonal changes during
relaxation]. L'encephale 10: 79-82.
George MS, Cuidotti A, Rubinow D, Pan P, Mikalausltas K, Post RM
(1 994) CSF neuroactive steroids in affective disorders:
pregnenolone, progesterone and DBI. Biol Psychiaty 35: 775-780.
Ceracioti TD, jr., Orth DN, Ekhator NN, Blumenkop: B, Loosen PT
(1 992) Serial cerebrospinal fluid corticotropin-releasing hormone
concentrations in healthy and depressed humans. J C:lin Endocrinol
Metab 74: 1325-1 330.
Ceringer E (1 990) Affective Disorders and Diabetes Mellitus. In:
Holmes C (ed), Neuropsychological and Behavioral Aspects of
Diabetes. Springer-Verlag, New York, p p 239-272.
Chadirian AM, Englesmann F, Dhar V, Filipini D, K d e r R, Chouinard
G, Murphy BEP (1995) The psychotropic effect:i of inhibitors of
steroid biosynthesis in depressed patients refractory to treatment.
Biol Psychiatry 37: 369-375.
Cifford S, Cunderson JC i(1970) Cushing's Disease ,as a psychosoma-
tic disorder: a selective review of the clinical and experimental lite-
rature and a report of ten cases. Perspectives Biol Med 13: 169-221.
 R F VIF W/MINI-R E VIE W b
Claser JL, Brind JL, Vogelman JH, Eisner MJ, Dillbeck MC, Wallace
RK, Chopra D, Orentreich N (1 992) Elevated serum dehydroepian-
drosterone sulfate levels in practitioners of the Transcendental Me-
ditation (TM) and TM-Sidhi programs. J Behav Med 15: 327-341.
Coeders NE (1997) A neuroendocrine role in cocaine rein-
forcement. Psychoneuroendocrinology22: 237-259.
Cold PW, Chrousos CP (1 985) Clinical studies with corticotropin
releasing factor: implications for the diagnosis and patho-
physiology of depression, Cushing's disease, and adrenal in-
sufficiency. Psychoneuroendocrinol 10: 401 -41 9.
Cold PW, Chrousos CP (1 999) The endocrinology of melancholic
and atypical depression: relation t o neurocircuitry and somatic
consequences. Proc Assoc Am Physicians 1 1 1: 22-34.
Coodwin CM, Muir WJ, Seckl JR, Bennie J, Carroll 5, Dick H, Fink G
(1992) The effects of cortisol infusion upon hormone secretion
World J Biol Psychiatry Downloaded from informahealthcare.com by University of Colorado Libraries on 12/31/14
from the anterior pituitary and subjective mood in depressive
illness and in controls. J Affect Disord 26: 73-83.
Coodyer IM, Herbert 1, Altham PM, Pearson j, Secher SM, Shiers
HM (1 996) Adrenal secretion during major depression in 8- t o 16-
year-olds, I. Altered diurnal rhythms in salivary cortisol and dehy-
droepiandrosterone (DHEA) at presentation. Psychol Med 26: 245-
256.
Coodyer IM, Herbert 1, Altham PM (1 998) Adrenal steroid secretion
and major depression in 8- to 16-year-olds, 111. Influence of
cortisol/DHEA ratio at presentation on subsequent rates of dis-
appointing life events and persistent major depression. Psychol
Med 28: 265-273.
Could E, Tanapat P (1999) Stress and hippocampal neurogenesis.
Biol Psychiatry 46: 1472-1479.
For personal use only.
Could E, Cameron HA, McEwen BS (1994) Blockade of NMDA
receptors increases cell death and birth in the developing dentate
gyrus. J Comp Neurol 340: 551 -565.
Could E, Reeves A], Craziano MSA, Cross CC (1999) Neurogenesis
in the neocortex of adult primates. Science 286: 548-552.
Creden JF, Cardner R, King D, Crunhaus L, Carroll BJ, Kronfol 2
(1 983) Dexamethasone suppression tests in antidepressant treat-
ment of melancholia. The process of normalization and test-retest
reproducibility. Arch Cen Psychiatry 40: 493-500.
Creeno C, Wing R (1 994) Stress-induced eating. Psychological
Bulletin 1 1 5: 444-464.
Griffin LD, Mellon SH (1999) Selective serotonin reuptake inhibitors
directly alter activity of neurosteroidogenic enzymes. Proc Natl
Acad Sci 96: 13512-13517.
Crundy PL, Patel N, Harbuz MS, Lightman SL, Sharples PM (2000)
Clucocorticoids modulate BDNF mRNA expression in the rat hip-
pocampus after traumatic brain injury. Neuroreport 11: 3381 -
3384.
Cuo AL, Petraglia F, Criscuolo M, Ficarra C, Nappi RE, Palumbo MA,
Trentini CP, Purdy RH, Cenazzani AR (1 995) Evidence for a role of
neurosteroids in odulation of diurnal changes and acute stress-
induced corticosterone secretion in rats. Cyn Endocrinol 9: 1-7.
Cutman DA, Owens MJ, Skelton KH, Knight DL, Thrivirkraman KV,
Plotsky PM, Nemeroff CB (2000) Behavioral, neuroendocrine, and
pharmacokinetic observations on CRF-1-selective antagonist,
R121919 in the rat. Neuropsychopharmacology 23: S119.
Habib KE, Weld KP, Rice KC, Pushkas J, Champoux M, Listwak 5,
Webster EL, Atkinson A], Schulkin J, Contoreggi C, Chrousos CP,
McCann SM, Suomi SJ, Higley ID, Gold PW (2000) Oral admini-
stration of a corticotropin-releasing hormone receptor antagonist
significantly attenuates behavioral, neuroendocrine, and auto-
nomic responses to stress in primates. Proc Natl Acad Sci USA 97:
6079-6084.
Haleem DJ, Kennett G, Curzon C (1 988) Adaptation of female rats
to stress: Shift t o male pattern by inhibition of corticosterone
synthesis. Brain Res 458: 339-347.
136
Hall RC, Popkin MK, Stickney SK, Cardner ER (1 979) Presentation
of the steroid psychoses. J Nerv Ment Dis 167: 229-236.
Hamm FC (1955) Adrenal surgery for psychosis associated with
Cushing's syndrome. Arch Surg 71: 61 7-61 9.
Hardy JR, Rees E, Ling J, Burman R, Feuer D, Broadley K, Stone P
(2001) A prospective study of the use of dexamethasone on a
palliative care unit. Palliat Med 15: 3-8.
Haskett RF (1 985) Diagnostic categorization of psychiatric distur-
bance in Cushing's syndrome. Am J Psychiatry 142: 91 1-916.
Healy DC, Harkin A, Cryan JF, Kelly JP, Leonard BE (1999) Metyra-
pone displays antidpressant-like effects in preclinical paradigms.
Psychopharmacology (Berl) 145: 303-308.
Hechter 0, Crossman A, Chatterton Jr, RT (1 997) Relationship of
dehydroepiandrosterone and cortisol in disease. Med Hypotheses
49: 85-91.
Heinz A, Weingartner H, George D, Hommer D, Wolkowitz OM,
Linnoila M (1999) Severity of depression in abstinent alcoholics is
associated with monoamine metabolites and dehydroepiandroste-
rone-sulfate concentrations. Psychiatry Res 89: 97-1 06.
Herbert J (1 997) Fortnightly review. Stress, the brain, and mental
illness. BMJ 31 5: 530-535.
Herbert J (1 998) Neurosteroids, brain damage, and mental illness.
Exp Gerontol 33: 71 3-727.
Herbert J, Coodyer IM, Altharn PME, Pearson J, Secher SM, Shiers
HM (1996) Adrenal secretion and major depression in 8- to 16-
year-olds, II. Influence of co-morbidity at presentation. Psychol
Med 26: 257-263.
Hirsch D, Orr C, Kantarovich V, Herrnesh H, Stern E, Blum I(2000)
Cushing's syndrome presenting as a schizophrenia-like psychotic
state. Isr J Psychiatry Relat Sci 37: 46-50.
Holsboer F (1988) Implications of altered limbic-hypothalamic-
pituitary-adrenocortical (LHPA)-function for neurobiology of de-
pression. Acta Psychiatr Scand Suppl 341 : 72-1 l l .
Holsboer F (1 999) The rationale for corticotropin-releasing hor-
mone receptor (CRH-R) antagonists to treat depression and
anxiety. J Psychiatr Res 33: 181-214.
Holsboer F (2000) Molecular approaches and the CRH hypothesis
of mood and anxiety disorders, CRF Antagonists. Held during the
2nd International Congress on Hormones, Brain and Neuropsycho-
pharmacology, Rhodes, Greece.
Holsboer F, Barden N (1 996) Antidepressants and hypothalamic-
pituitary-adrenocortical regulation. Endocr Rev 1 7: 187-205.
Howard 111 JS (1 992) Severe psychosis and the adrenal androgens.
lntegr Physiol Behav Sci 27: 209-215.
Hu Y, Cardounel A, Cursoy E, Anderson P, Kalimi M (2000) Anti-
stress effects of dehydroepiandrosterone: protection of rats against
repeated immobilixation stress-induced weight loss, glucocorticoid
receptor production, and lipid peroxidation. Biochem Pharmacol
59: 753-762.
Hudson 1, Hudson M, Rothschild A, Vignati L, Schatzburg A, Melby
J (1 984) Abnormal results of dexamethasone suppression tests in
nondepressed pteints with diabetes mellitus. Archives of General
Psychiatry 41 : 1086-1089.
Hunt PJ, Curnell EM, Huppert FA, Richards C, Prevost AT, Wass JA,
Herbert J, Chatterjee VK (2000) Improvement in mood and fatigue
after dehydroepiandrosterone replacement in Addison's disease in
a randomized, double blind trial. J Clin Endocrinol Metab 85:
4650-4656.
Huppert FA, Van Niekerk JK (2001) Dehydroepiandrosterone
(DHEA) supplementation for cognitive function (Cochrane
Review), Cochrane Database Syst Rev, 2.
lizuka H, Kishimotor A, Nakamura J, Mizukawa R (1996) Clinical
 effects of cortisol synthesis inhibition on treatment-resistant de-
pression. Nihon Shinkei Seishin Yakurigaku Zasshi 16: 33-36.
Jacobs BL, Tanapat P, Reeves A], Could E (1 998) Serotonin stimu-
lates the production of new hippocampal granule cells via the 5HT-
1A receptor in the adult rat. SOC Neurosci Abstr 24: 1992.
JacobsAR, Edelheit PB, Coleman AE, Herzog AC (1999) Late-onset
congenital adrenal hyperplasia: a treatable cause of anxiety. Biol
Psychiatry 46: 856-859.
Jacobs BL, van Praag H, Caqe FH (2000) Adult brain neuroqenesis
and psychiatry: a novel theory of depression. Mol Psychiatry 5:
262-269.
Jayo JM, Shively CA, Kaplan JR, Manuck SB (1993) Effects of
exercise and stress on body fat distribution in male cynomolgus
monkeys. International Journal of Obesity and Related Metabolic
Disorders 17: 597-604.
World J Biol Psychiatry Downloaded from informahealthcare.com by University of Colorado Libraries on 12/31/14
Jeffcoate WJ, Silverstone IT, Edwards CR, Besser C M (1979)
Psychiatric manifestations of Cushing's syndrome: response to
lowering of plasma cortisol. Q J Med 48: 465-472.
Jevning R, Wilson A, Davidson J (1 978) Adrenocortical activity
during meditation. Hormones and Behavior 10: 54-60.
Joels M, Karten Y, Hesen W, de Kloet ER (1997) Corticosteroid
effects on electrical properties of brain cells: temporal aspects and
role of antiglucocorticoids. Psychoneuroendocrinology 22: 581-86.
Kagan B, Leskin C, Haas 8, Wilkins J,Foy D (1999) Elevated lipid
levels in Vietnam Veterans with Chronic Posttraumatic Stress
Disorder. Biological Psychiatry 45: 374-377.
Kalimi M, Shafagoj Y, Loria R, Padgett D, Regelson W (1 994) Anti-
glucocorticoid effects of dehydroepiandrosterone (DHEA). Mol Cell
For personal use only.
Biochem 131 : 99-104.
Karst H, de Kloet ER, Joels M (1 997) Effect of ORC 341 16, a
corticosteroid receptor antagonist, on hippocampal Ca2+ currents.
Eur J Pharmacol 339: 17-26
Katz 5, Morales A] (1 998) Dehydroepiandrosterone (DHEA) and
DHEA-sulfate (DS) as therapeutic options in menopause. Semin
Reprod Endocrinol 16: 161-1 70.
Kawakami N, Shimizu H, Takatsuka N, lshibashi H (1999) Depres-
sive symptoms and occurrence of type 2 diabetes among Japanese
men. Diabetes Care 22: 1071-1 076.
Keenan PA, Jacobson MW, Soleymani RM, Newcomer JW (1995)
Commonly used therapeutic doses of glucocorticoids impair
explicit memory. Ann N Y Acad Sci 761 : 400-402.
Keenan PA, Jacobson MW, Soleymani RM, Mayes MD, Stress ME,
Yaldoo DT (1996) The effect on memory of chronic prednisone
treatment in patients with systemic disease. Neurology 47: 1396-
1402.
Kelly WF, Barnes A], Cassar J, White M, Mashiter K, Loizou S ,
Welbourn RB, Joplin CF (1979) Cushing's syndrome due to
adrenocortical carcinoma- a comprehensive clinical and biochemi-
cal study of patients treated by surgery and chemotherapy. Acta
Endocrinolologica 91 : 303-318.
Kelly WF, Checkley SA, Bender DA (1980) Cushing's syndrome,
tryptophan and depression. Br J Psychiatry 136: 125-132.
Kelly WF, Checkley SA, Bender DA, Mashiter K (1983) Cushing's
syndrome and depression--a prospective study of 26 patients. Br J
Psychiatry 142: 16-19.
Kelly WF, Kelly MI, Faragher B (1996) A prospective study of
psychiatric and psychological aspects of Cushing's syndrome. Clin
Endocrinol 45: 71 5-772.
Kempermann C, Kuhn HC, Cage FH (1997) More hippocampal
neurons in adult mice living in a n enriched environment. Nature
386: 493-495.
Kennett CA, Dickinson SL, Curzon C (1 985) Central serotonergic
137
responses and behavioural adaptation to repeated immobilisa-
tion: the effect of the corticosterone synthesis inhibitor metyra-
pone. Eur J Pharmacol 1 19: 143-152.
Kimonides VG, Khatibi NH, Svendsen CN, Sofroniew MV, Herbert
J (1 998) Dehydroepiandrosterone (DHEA) and DHEA-sulfate
(DHEAS) protect hippocampal neurons against exci.tatory amino
acid-induced neurotoxicity. Proc Natl Acad Sci USA.95:1852-1857.
Kimonides VC, Spillantini MC, Sofroniew MV, Fawcett JW, Herbert
1 (1 999) Dehydroepiandrosterone antagonizes the neurotoxic
effects of corticosterone and translocation of stress-activated
protein kinase 3 in hippocampal primary cultures. Neuroscience
89: 429-436.
Kirschbaum C, Wolf OT, May M (1996) Stress arld treatment
induced elevations of cortisol levles associated with impaired de-
clarative memory in healthy adults. Life Sciences .58: 1475-1483.
Kissebah AH, Krakower C (1 994) Regional adiposity and
morbidity. Physiol Rev 74: 761-81 1.
Kline MD, Jaggers ED (1999) Mania onset while using dehydro-
epiandrosterone. Am 1 Psychiatry 156: 971.
Kling MA, Perini GI, Demitrack MA, Ceracioti 1-D, Linnoila M,
Chrousos CP, Cold PW (1 989) Stress-responsive neurohormonal
systems and the symptom complex of affective illness. Psycho-
pharmacol Bull 25: 31 2-31 8.
Kling MA, Roy A, Doran AR, Calabrese JR, Rubinow IIR, Whitfield
HI Jr, May C, Post RM, Chrousos CP, Cold PVV (1991) Cere-
brospinal fluid immunoreactive corticotropin-releasing hormone
and adrenocorticotropin secretion in Cushing's di:iease and major
depression: potential clinical implications. J Clin Endccrinol Metab
72: 260-271.
Koo E, Katalin FC, Tibor F, Cyorgy EF (1987) Experiences with
dehydroepiandrosterone therapy in steroid-dependent intrinsic
bronchial asthma. Orvosi-Hetilap 38: 1995-1997.
Kramlinger KC, Peterson CC, Watson PK, Leonard LL (1985)
Metyrapone for depression and delirium secondary to Cushing's
syndrome. Psychosomatics 26: 67, 71.
Kroboth PD, Salek FS, Pittenger AL, Fabian TJ, Frye RF (1999)
DHEA and DHEA-S: a review. J Clin Pharmacol 39: 3.27-348.
Labrie F, Diamond P, Cusan L, Comer JL, Belanger A, Candas B
(1 997) Effect of 12-month dehydroepiandrosterone replacement
therapy on bone, vagina, and endometrium in postmenopausal
women. J Clin Endocrinol Metab 82: 3498-3505.
Leblhuber F, Windhager E, Neubauer C, Weber J, Reisecker F,
Dienstl E (1 992) Antiglucocorticoid effects of DHEA-S in Alzhei-
mer's disease [letter] [published erratum appears in Am J Psychia-
try 1992 Nov;149(11):1622]. Am J Psychiatry 149: 1125.1126.
Leigh H, Kramer SI (1 984) The psychiatric manifestations of endo-
crine disease. Adv Intern Med 29: 41 3-445.
Lesch KP, Lerer B (1 991) The 5-HT receptor--C-protein--effector
system complex in depression. I. Effect of gliJcocorticoids. J
Neural Transm Cen Sect 84: 3-18.
Leverenz JB, Wilkinson CW, Wamble M, Corbin 5, Grabber JE,
Raskind MA, Peskind EK (1999) Effect of high-clos? exogenous
cortisol on hippocampal neuronal number in aged nonhuman
primates. J Neurosci 19: 2356.2361,
Levine A, Mitty H (1988) Steroid content of the peripheral and
adrenal vein in Cushing's syndrome due to adrenocortical
adenoma and carcinoma. Journal of Urology 140: 1 1-15.
Lewis DA, Smith RE (1983) Steroid induced psychiatric syn
dromes. J Affective Disord 5: 319-332.
Li KL, Tung SC, Wang PW (1996) The effect of ketoconazole in
pre-operative treatment in Cushing's syndrome: three cases
report. Chang Keng I Hsueh 19: 358-363.
Ling MH, Perry PJ, Tsuang MT (1 981) Side effects (of corticosteroid
 R F VIF W/MINI-R E VIE W b
therapy. Psychiatric aspects. Arch Cen Psychiatry 38: 471 -477.
Littman AB, Fava M, Halperin P, Lamon-Fava 5, Drews FR,
Oleshansky MA, Bielenda CC, MacLaughlin RA (1 993) Physiologic
benefits of a stress reduction program for healthy middle-aged
Army officers. J Psychosom Res 37: 345-354.
Lob0 A, Perez-Echeverria MI, Jimenez-Aznarez A, Sancho MA
(1 988) Emotional disturbances in endocrine patients. Validity of
the scaled version of the General Health Questionnaire (CHQ-28).
Br J Psychiatry 152: 807-81 2.
Lokk J (1 998) Psychoendocrine concomitants in patients following
a new design of a geriatric day-care unit. Psychother Psychosom
67: 323-327.
Loli P, Berselli ME, Tagliaferri M (1 986) Use of ketoconazole in the
treatment of Cushing's syndrome. J Clin Endocrinol Metab 63:
1365-1371.
World J Biol Psychiatry Downloaded from informahealthcare.com by University of Colorado Libraries on 12/31/14
Loosen PT, Chambliss 6, DeBold CR, Shelton R, Orth D N (1992)
Psychiatric phenomenology in Cushing's disease. Pharmaco-
psychiatry 25: 192-198.
Lopez IF, Chalmers DT, Little KY, Watson SJ (1998) Regulation of
serotonin1A, glucocorticoid, and mineralocorticoid receptor in rat
and human hippocampus: implications for the neurobiology of
depression. Biol Psychiatry 43: 547-573.
Lucassen PI, Muller MB, Holsboer F, Bauer J, Holtrop A, Wouda J,
Hoogendijk WJ, De Kloet ER, Swaab DF (2001) Hippocampal
apoptosis in major depression is a minor event and absent from
subareas at risk for glucocorticoid overexposure. Am J Pathol 158:
453-468.
Lupien SJ, McEwen BS (1 997) The acute effects of corticosteroids
on cognition: integration of animal and human studies. Brain Res
For personal use only.
Rev 24: 1-27.
Lupien Sj, Nair NP, Briere S, Maheu F, Tu MT, Lemay M, McEwen
BS, Meaney M J (1999) Increased cortisol levels and impaired
cognition in human aging: implications for depression and
dementia in later life. Rev Neurosci 10: 117-1 39.
Lustman P, Criffith L, Freedland K, Kissel 5, Clouse R (1998) Cog-
nitive behavior therapy for depression in type 2 diabetes: A rando-
mized controlled trial. Annals of Internal Medicine 129: 61 3-621.
Lynch CD, Lyons D, Khan A, Bennett SA, Sonntag WE (2001)
Insulin-like growth factor-1 selectively increases glucose utilization
in brains of aged animals. Endocrinology 142: 506-509.
Maclean C, Walton K, Wenneberg 5, Levitsky D, Mandarin0 1,
Waziri R, Hillis S, Schneider R (1997) Effects of the Transcendental
Meditation program on adaptive mechanisms: Changes in
hormone levels and respones t o stress after 4 months of practice.
Psychoneuroendocrinology 22: 277-295.
Maes M, Meltzer HY (1995) The serotonin hypothesis of major
depression. In: Bloom FE, Kupfer DJ (eds) Psychopharmacology:
The Fourth Generation of Progress. Raven Press Ltd, New York, p p
933-944.
Magri F, Terenzi F, Ricciardi T, Fioravanti M, Solerte SB, Stabile M,
Balza C, Candini C, Villa M, Ferrari E (2000) Association between
changes in adrenal secretion and cerebral morphometric correlates
in normal aging and senile dementia. Dement Ceriatr Cogn Disord
1 1: 90-99.
Majewska MD (1 987) Steroids and brain activity. Essential dialogue
between body and mind. Biochem Pharmacol 36: 3781-3788.
Malberg JE, Eisch AJ, Nestler EJ, Duman RS (2000) Chronic
antidepressant treatment increases neurogenesis in adult rat
hippocampus. J Neurosci 20: 91 04-91 10.
Malison RT, Anand A, Pelton CH, Kirwin P, Carpenter L, McDougle
CJ, Heninger CR, Price LH (1 999) Limited efficacy of ketoconazole
in treatment-refractory major depression. J Clin Psychopharmaco-
logy 19: 466-470.
Mancini A, Bianchi A, Milardi D, Centilella R, Ciampietro A, Veuosi
138
C, Perrelli M, De Marinis L (1 999) Cushing's syndrome: psychiatric
involvement as important aspect of the clinical picture in old age.
] Endocrinol Invest 22: 83-84.
Mangat HS, Islam A, Heigenskold C, Mustafa A, Winblad B, Adem
A (1 998) Long-term adrenalectomy decreases NMDA receptors in
rat hippocampus. Neuroreport 9: 201 1-2014.
Manji HK, Moore GI, Rajkowska C, Chen C (2000) Neuroplasticity
and cellular resilience in mood disorders. Mol Psychiatry 5: 578-
593.
Mao X, Barger SW (1 998) Neuroprotection by dehydroepiandros-
terone-sulfate: role of an NFkappaB-like factor. Neuroreport 9: 759-
763.
Marco E, Wolkowitz OM, Vinogradov SP, I.,Lichtmacher J, Reus VI
(In Review) Double-blind anti-glucocorticoid treatment of schizo-
phrenia and schizoaffective disorder.
Margolese HC (2000) The male menopause and mood: testos-
terone decline and depression in the aging male-is there a link? 1
Ceriatr Psychiatry Neurol 13: 93-101.
Marin P (1 995) Testosterone and regional fat distribution. Obesity
Research 3: 609s-612s.
Markowitz IS, Carson WH, Jackson CW (1999) Possible dehydro-
epiandrosterone-induced mania. Biol Psychiat 45: 241-242.
Martignoni E, Costa A, Sinforiani E, Luiui P, Chiodini M, Mauri M,
Bono C, Nappi C (1992) The brain as a target for adrenocortical
steroids: Cognitive implications. Psychoneuroendocrinology 1 7:
343-354.
Matoulek M, Hampl R, Svacina S, Sulcova J,Haas T (2000) [No title
available]. Cas Lek Cesk 139: 772-775.
Mauri M, Sinforiani E, Bono C, Vignati F, Berselli ME, Attanasio R,
Nappi C (1993) Memory impairment in Cushing's disease. Acta
Neurol Scand 87: 52-55.
Maurice T, Phan VL, Urani A, Karnei H, Noda Y, Nabeshima T
(1 999) Neuroactive neurosteroids as endogenous effectors for the
sigma1 receptor: pharmacological evidence and therapeutic
opportunities. Jpn j Pharmacol 81: 125-155.
McCraty R, Barrios-Choplin B, Rozman D, Atkinson M, Watkins AD
(1 998) The impact of a new emotional self-management program
on stress, emotions, heart rate variability, DHEA and cortisol. lntegr
Physiol Behav Sci 33: 151-1 70.
McEwen B (1 968) Clucocoricoid-biogenic amine interactions in
relation to mood and behavior. Biochemical Pharmacology 36:
1755-1763.
McEwen BS (1 987) Clucocorticoid-biogenic amine interactions in
relation to mood and behavior. Biochem Pharmacol 36: 1755-1763.
McEwen B (1998) Protective and damaging effects of stress
mediators. New England Journal of Medicine 338: 171-1 79.
McEwen B (2000a) Allostasis and allostatic load: Implications for
neuropsychopharmacology. Neuropsychopharmacology 22:108-
124.
McEwen BS (2000b) Effects of adverse experiences for brain struc-
ture and function. Biol Psychiatry 48: 721 -731.
McEwen BS ( 2 0 0 0 ~The
) neurobiology of stress: from serendipity
to clinical relevance. Brain Res 886: 172-189.
McEwen BS, Magarinos AM (2001) Stress and hippocampal
plasticity: implications for the pathophysiology of affective dis-
orders. Human Psychopharmacol Clin Exp 16: 57-51 9.
McEwen B, Seeman T (1999) Protective and damaging effects of
mediators of stress: Elaborating and testing the concepts of allos-
tasis and allostatic load. Annals of the New York Academy of
Sciences 896: 30-47.
McEwen B, Stellar E (1 993) Stress and the individual: Mechanisms
 leading to disease. Archives of Internal Medicine 153: 2093-21 91.
McEwen BS, Davis PC, Parsons B, Pfaff DW (1979) The brain as
target for steroid hormone action. Annual Review of Neuroscience
2: 65-1 12.
McEwen BS, Angulo 1, Cameron H, Chao HM, Daniels D, Cannon
MN, Could E, Mendelson 5, Sakai R, Spencer R (1 992) Paradoxical
effects of adrenal steroids on the brain: protection versus dege-
neration. Biol Psychiatry 31: 177-199.
McCrady A, Horner J (1 999) Role of mood in outcome of biofeed-
back assisted relaxation therapy in insulin dependent diabetes
mellitus. Applied Psychophysiology 24: 79-88.
McCrady A, Woerner M, Cuillermo A, Bernal A, Higgins J (1987)
Effect of biofeedback-assisted relaxation on blood pressure and
cortisol levels in normotensives and hypertensives. Journal of
Behavioral Medicine 10: 301-310.
World J Biol Psychiatry Downloaded from informahealthcare.com by University of Colorado Libraries on 12/31/14
Meaney M, Aitken D, Bhatnagar S, Van Berkel C, Sapolsky R (1 988)
Postnatal handling attenuates neuroendocrine, anatomical, and
cognitive impairments related to the aged hippocampus. Science
238: 766-768.
Meieran 5, Wolkowitz OM, Webster R, Shafton R, Reus VI (In
Review) The effect of pregnenolone on mood, memory and arousal
in normal and benzodiazepine-treated volunteers.
Meijer OC, Van Oosten RV, DeKloet ER (1997) Elevated basal
trough levels of corticosterone suppress hippocampal 5-hydroxy-
tryptamine-1 A receptor expression in adrenally intact rats:
implication for the pathogenesis of depression. Neuroscience 80:
41 9-426.
Michael-Titus AT, Bains S, Jeetle 1, Whelpton R (2000) lmipramine
and phenelzine decrease glutamate overflow in the prefrontal
For personal use only.
cortex-. a possible mechanism of neuroprotection in major depres-
sion? Neuroscience 100: 681 -684.
Michaels R, Parra J, McCann D, Vander J (1 979) Renin, cortisol, and
aldosterone during transcendental meditation. Psychosomatic
Medicine 41: 50-54.
Mockel M, Rocker L, Stork T, Vollert J, Danne 0, Eichstadt H,Muller
R, Hochrein H (1 994) Immediate physiological responses of healthy
volunteers to different types of music: cardiovascular, hormonal
and mental changes [published erratum appears in Eur J Appl
Physiol 1994;69(3):274]. Eur J Appl Physiol 68 :451-459.
Mohammed AH, Henriksson BC, Soderstrom S, Ebendal T, Olsson
T, Seckl JR (1 993) Environmental influences on the central nervous
system and their implications for the aging rat. Behav Brain Res 57:
183-191.
Morales AJ, Nolan JJ, Nelson JC, Yen SS (1994) Effects of replace-
ment dose of dehydroepiandrosterone in men and women of ad-
vancing age [published erratum appears in J Clin Endocrinol Metab
1995 Sep;80(9):2799]. J Clin Endocrinol Metab 78: 1360-1367.
Morales A, Haubricht R, Hwang J, Asakura H, Yen S (1998) The
effect of six months treatment with a 100 m g daily dose of de-
hydroepiandrosterone on circulating sex steroids, body compo-
sition and muscle strength in age advanced men and women.
Clinical Endocrinology 49: 421-432.
Morley JE, Kaiser F, Raum WJ, Perry HM 3rd, Flood JF, JensenJ, Silver
AJ, Roberts E (I 997) Potentially predictive and manipulable blood
serum correlates of aging in the healthy human male: progressive
decreases in bioavailable testosterone, dehydroepiandrosterone
sulfate, and the ratio of insulin-like growth factor 1 to growth
hormone. Proc Natl Acad Sci USA 94: 7537-7542.
Moxley RT, 3rd (1994) Potential for growth factor treatment of
muscle disease. Curr Opin Neurol 7: 427-434.
Murialdo C, Nobili F, Roller0 A, Cianelli MV, Copello F, Rodriguez
C, Polleri A (2000) Hippocampal perfusion and pituitary-adrenal
axis in Alzheimer's disease. Neuropsychobiology 42: 51 -57.
Murphy BE (1 991 a) Steroids and depression. J Steroid Biochem
Mol Biol 38: 537-559.
139
Murphy BE (1 991 b) Treatment of major depres:jion with steroid
suppressive drugs. J Steroid Biochem Mol Biol 39: 239-244.
Murphy BEP (1 997) Antiglucocorticoid therapies in major depres-
sion: A review. Psychoneuroendocrinology 22: 521 5-5132.
Murphy BEP, Wolkowitz O M (1 993) The pathophysiologic signifi-
cance of hypercorticism: antiglucocorticoid strategies. Psychiat
Ann 23: 682-690.
Murphy BE, Dhar V, Ghadirian AM, Chouinard C, Keller R (1991)
Response to steroid suppression in major depre:jsicrn resistant to
antidepressant therapy. J Clin Psychopharmacol 11: 121-1 26.
Murphy BE, Filipini D, Chadirian AM (1993) Possible use of gluco-
corticoid receptor antagonists in the treatment of major depres-
sion: preliminary results using RU 486. J Psychiatry Neurosci 18:
209-21 3.
Murphy BE, Chadirian AM, Dhar V (1998) Neuroendocrine res-
ponses t o inhibitors of steroid biosynthesis in patierits with major
depression resistant to antidepressant therapy. Canadian Journal of
Psychiatry 43: 279-286.
Naber D, Sand P, Heigl B (1996) Psychopathological and neuro-
psychological effects of 8-days' corticosteroid treatment. A pros-
pective study. Psychoneuroendocrinology 21 : 25-31.
N a i r SM, Werkman TR, Craig J, Finnell R, Joels M , Eberwine JH
(1 998) Corticosteroid regulation of ion channel c'mductances and
mRNA levels in individual hippocampal CA1 neurons. J Neurosci
18: 2685-2696.
Nemeroff CB (1 988) The role of corticotropin-relezisirg factor in the
pathogenesis of major depression. Pharmacopsychial 21 : 76-82.
Nemeroff CB (2000) Clinical studies on the role of CRF in mood
and anxiety disorders, CRF Antagonists, Held duriiig the 2nd Inter-
national Congress on Hormones, Brain and Neuropsycho-
pharmacology, Rhodes, Greece.
Nestler JE, Barlascini CO, Clore IN, Blackard WC (1 988) Dehydro-
epiandrosterone reduces serum low density lipoprolein levels and
body fat but does not alter insulin sensitivity in normal men. J Clin
Endocrinol Metab 66: 57-61.
Net0 L, Fihlo A, Bustotf-Silva J, Koler H, Epelman S, Marini 5, Junior
C (2000) Pre-operative control of arterial hypertension using
ketoconazole in pediatric patients with adrenocortical tumors.
Journal of Pediatric Endocrinology and Metabolisrn 13: 201 -204.
Newcomer JW, Selke C, Melson AK, Hershey T, Craft 5, Richards K,
Aiderson AL (1 999) Decreased memory performance in healthy
humans induced by stress-level cortisol treatment. Arch Cen
Psychiatry 56: 527-533.
Newell-Price 1, Jorgensen JO, Crossman A (1 999) The diagnosis and
differential diagnosis of Cushing's syndrome. Horm Res 51 : 81 -94.
Nibuya M, Morinobu S, Duman RS (1 995) Regulation of BDNF and
trkB mRNA in rat brain by chronic electroconvulsive seizure and
antidepressant drug treatments. J Neurosci 15: 7535-7547.
Nieman LK, Chrousos CP, Kellner C, Spitz IM, Niswla '3C, Cutler CB,
Merriam CR, Bardin CW, Loriaux DL (1 985) Successful treatment of
Cushing's syndrome with the glucocorticoid antagonist RU 486. 1
Clin Endocrinol Metab 61: 536-540.
Nilsson PM, Klasson EB, Nyberg P (2001) Life-stylie intervention at
the worksite-. reduction of cardiovascular risk factors in a
randomized study. Scand J Work Environ Health 27: 57-62.
Nyberg F (2000) Growth hormone in the brain: characteristics of
specific brain targets for the hormone and their functional
significance. Front Neuroendocrinol 21 : 330-348.
O'Brien JT, Ames D, Schweitzer I, Colman P, Desmond P, Tress B
(1 996) Clinical and magnetic resonance imaging correlates of
hypothalamic-pituitary-adrenal axis function in depression and
Alzheimer's disease. Br J Psychiatry 168:679-87.
O'Brien D, Skelton KH, Owens MJ, Nemeroff CB (iOO1) Are CRF
 RE VlF W/MINI-RE VIE W 1
recptor antagonists potential antidepressants? Hum Psychophar-
macol Clin Exp 16: 81-87.
O'Dwyer AM, Lightman SL, Marks MN, Checkley SA (1 995) Treat-
ment of major depression with metyrapone and hydrocortisone.
Journal of Affective Disorders 33: 123-128.
Oh1 F, Michaels T, Vollmann-Honsdorf CK, Kirschbaum C, Fuchs E
(2000) Effect of chronic psychosocial stress and long-term cortisol
treatment on hippocampus-mediated memory and hippocampal
volume: a pilot study in tree shrews. Psychoneuroendocrinology
25: 357-363.
Owens MI, Nemeroff CB (1 999) Corticotropin-releasing factor
antagonists in affective disorders. Expert Opin Invest Drugs 8:
1849-1858.
Pasquali R, Anconetani 6, Chattat R, Biscotti M, Spinucci C,
Casimirri F, Vicennati V, Carcello A, Labate A (1 996) Hypothalamic-
World J Biol Psychiatry Downloaded from informahealthcare.com by University of Colorado Libraries on 12/31/14
pituitary-adrenal axis activity and i t s relationship to the autonomic
nervous system in women with visceral and subcutaneous obesity:
Effects of the Corticotropin Releasing Factor/Arginine-Vasopressin
test and of stress. Metabolism 45: 351 -356.
Patchev VK, Almeida OFX (1 997) Daily DHEA or melatonin treat-
ment prevents glucocorticoid-induced dysregulation of the hypo-
thalamic-pituitary-adrenal axis, 2nd International Conference on
Cortisol and Anti-cortisols, p p 46.
Patchev VK, Montkowski A, Rouskova D, Koranyi L, Hlsboer F,
Almeida OFX (1997) Neonatal treatment of rats with the neuro-
active steroid tetrahydrodeoxycorticosterone (THDOC) abolishes
the behavioral and neuroendocrine consequences of adverse early
life events. J Clin Invest 99: 962-966.
Pepin MC, Beaulieu 5, Barden N (1990) Differential regulation by
dexamethasone of glucocorticoid receptor messenger RNA con-
For personal use only.
centrations in neuronal cultures derived from fetal rat hypo-
thalamus and cerebral cortex. Cell Mol Neurobiol 10: 227-235.
Perna FM, Antoni MH, Kumar M, Cruess DC, Schneiderman N
(1 998) Cognitive-behavioral intervention effects on mood and
cortisol during exercise training. Ann Behav Med 20: 92-98.
Piazza PV, Le Moal ML (1996) Pathophysiological basis of vul-
nerability to drug abuse: role of an interaction between stress,
glucocorticoids, and dopaminergic neurons. Annu Rev Pharmacol
Toxic01 36: 359-378.
Pies R (1 995) Differential diagnosis and treatment of steroid-
induced affective syndromes. Cen Hosp Psychiatry 17: 353-361.
Plihal W, Krug R, Pietrowsky R, Fehm HL, Born J (1996) Corti-
costeroid receptor mediated effects on mood in humans. Psycho-
neuroendocrinology 21 : 51 5-523.
Price LH, Cappiello A, Malison RT, McDougle CJ, Pelton CH,
Schollnhammer C, Heninger CR (1997) Effects of antigluco-
corticoid treatment on 5-HT1A function in depressed patients and
healthy subjects. Neuropsycopharmacology 1 7: 246-257.
Quarton CC, Clark LD, Cobb S, Bauer W (1955) Mental distur-
bances associated with ACTH and cortisone: A review of
explanatory hypotheses. Medicine 34: 13-50.
Raber J (1 998) Detrimental effects of chronic hypothalamic-
pituitary-adrenal activation: From obesity t o memory deficits. Mol
Neurobiol 18: 1-22.
Rabkin JC, Wagner CJ, Rabkin R (2000) A double-blind, placebo-
controlled trial of testosterone therapy for HIV-positive men with
hypogonadal symptoms. Arch Gen Psychiatry 57: 141-147.
Raikkonen K, Matthews K, Kuller L (2001). Psychosocial risk and the
metabolic syndrome: prospective evidence from the healthy
women study - submitted.
Raikkonen K, Matthews K, Kuller L, Reiber C, Bunker C (1999).
Anger, hostility, and visceral adipose tissue in healthy
postmenopausal women. Metabolism, 48, 1146-1 151.
Rajkowska C (2000) Postmortem studies in mood disorders
140
indicate altered numbers of neurons and glial cells. Biol Psychiatry
48: 766-777.
Rasika 5, Alvarez-Buylla A, Nottebohm F (1 999) BDNF mediates the
effects of testosterone on the survival of new neurons in an adult
brain. Neuron 22: 53-62.
Ravaris CL, Sateia MI, Beroza KW, Noordsy DL, Brinck-johnsen T
(1 988) Effect of ketoconazole on a hypophysectomized, hyper-
cortisolemic, psychotically depressed woman [letter]. Arch Cen
Psychiatry 45: 966-967.
Ravaris CL, Brinck-Johnsen T, Elliott B (1 994) Clinical use of keto-
conazole in hypercortisoluric depressives. Biol Psychiatry 35: 679.
Raven PW, O'Dwyer AM, Taylor NF, Checkley SA (1996) The
relationship between the effects of metyrapone treatment on
depressed mood and urinary steroid profiles. Psychoneuro-
endocrinol 21 : 277-286.
Rebuffe-Scrive M, Walsh U, McEwen 6, Rodin J (1992) Effect of
chronic stress and exogenous glucocorticoids on regional fat dis-
tribution and metabolism. Physiology and Behavior 52: 583-590.
Reckart MD, Eisendrath SJ (1 990) Exogenous corticosteroid effects
on mood and cognition. Int J Psychosom 37: 57-61.
Regestein QR, Rose LI, Williams CH (1972) Psychopathology in
Cushing's sundrome. Arch Intern Med 130: 114-117.
Reincke M (2000) Subclinical Cushing's syndrome. Endocrinol
Metab Clin North Am 29: 43-56.
Reus VI (1 982) Pituitary-adrenal disinhibition as the independent
variable in the assessment of behavioral symptoms. Biological
Psychiatry 17: 31 7-325.
Reus VI, Wolkowitz OM (1993) Behavioral side effects of corti-
costeroid therapy. Psychiatric Annals 23: 703-708
Reus VI, Wolkowitz OM, Frederick S (1 997) Antiglucocorticoid
treatments in psychiatry. Psychoneuroendocrinology 22: S121-
51 24.
Ribeiro SC, Tandon R, Crunhaus L, Creden JF (1 993) The DST as a
predictor of outcome in depression: a meta-analysis. Am J
Psychiatry 150: 1618-1 629.
Riedel M, Wiese A, Schurmeyer TH, Brabant C (1 993) Qulaity of life
in patients with Addison's disease: effects of different cortisol
replacement modes. Exp Clin Endocrinol 101 : 106-1 11.
Rizza R, Mandarin0 L, Cerich J (1 982) Cortisol-induced insulin
resistance in man: impaired suppression of glucose production and
stimulation of glucose utilization due to a postreceptor defect of
insulin action. Journal of Clinical Endocrinology and Metabolism
54: 131-1 38.
Robinzon 6, Cutolo M (1 999) Should dehydroepiandrosterone
replacement therapy be provided with glucocorticoids? Rheuma-
tology 38: 488-495.
Romeo E, Strohle A, Spalletta C, di Michele F, Hermann 6, Holsboer
F, Pasini A, Rupprecht R (1998) Effects of antidepressant treatment
on neuroactive steroids in major depression. Am J Psychiatry 155:
910-91 3.
Rosenberg DR, MacMaster FP, Keshavan MS, Fitzgerald KD, Stewart
CM, Moore CJ (2000) Decrease in caudate glutamatergic concen-
trations in pediatric obsessive-compulsive disorder patients taking
paroxetine. J Am Acad Child Adolesc Psychiatry 39: 1096-1103.
Rossi R, Tauchmanova L, Lucian0 A, Di Martino M, Battista C, Del
Viscovo L, Nuzzo V, Lombardi C (2000) Subclinical Cushing's
syndrome in patients with adrenal incidentaloma: clinical and
biochemical features. Journal of Clinical Endocrinology and
Metabolism 85: 1440-1448.
Rupprecht R (1 997) The neuropsychopharmacologicalpotential of
neuroactive steroids. J Psychiatr Res 31: 297-314.
Rupprecht R, Holsboer F (1 999a) Neuroactive steroids: Mecha-
 nisms of action and neuropsychopharmacological perspectives.
Trends Neurosci 22: 41 0-416.
Rupprecht R, Holsboer F (1 999b) Neuropsychopharmacological
properties of neuroactive steroids. Steroids 64: 83-91.
Rupprecht R, Strohle A, Hermann B, di Michele F, Spalletta G, Pasini
A, Holsboer F, Romeo E (1 998) Neuroactive steroid concentrations
following metyrapone administration in depressed patients and
healthy volunters. Biol Psychiatry 44: 91 2-91 4.
Russo-Neustadt A, Ha T, Ramirez R, Kesslak JP (2001) Physical
activity-antidepressant treatment combination: impact on brain-
derived neurotrophic factor and behavior in an animal model.
Behav Brain Res 120: 87-95.
Ryu H, Lee HS, Shin YS, Chung SM, Lee MS, Kim HM, Chung HT
(1 996) Acute effect of qigong training on stress hormonal levels in
man. Am J Chin Med 24: 193-198.
World J Biol Psychiatry Downloaded from informahealthcare.com by University of Colorado Libraries on 12/31/14
Saad MF, Adams F, Mackay B, Ordonez NG, Leavens ME, Samaan
NA (1 984) Occult Cushing's diseasepresenting with acute psy-
chosis. Am J Med 76: 759-766.
Sapolsky R, Romero M, Munck A (2000) How do glucocorticoids
influence stress responses? Integrating permissive, suppressive,
stimulatory, and preparative actions. Endocrine Reviews 21 : 55-89.
Sapolsky RM (1 993) Potential behavioral modification of glucocor-
ticoid damage to the hippocampus. Behav Brain Res 57: 175-182.
Sapolsky RM (1 994) The physiological relevance of glucocorticoid
endangerment of the hippocampus. Ann NY Acad Sci 746: 294-
307.
Sapolsky RM (1996) Stress, glucocorticoids, and damage to the
nervous system: the current state of confusion. Stress 1: 1-1 9.
For personal use only.
Sapolsky RM (2000a) Glucocorticoids and hippocampal atrophy in
neuropsychiatric disorders. Arch Cen Psychiatry 57: 925-935.
Sapolsky RM (2000b) The possibility of neurotoxicity in the hippo-
campus in maior depression: a primer on neuron death. Biol
Psychiatry 48: 755-765.
Sapolsky RM, Krey LC, McEwen BS (1 986) The neuroendocrinology
of stress and aging: the glucocorticoid cascade hypothesis. Endocr
Rev 7: 284-301.
Sapolsky R, Uno H, Rebert C, Finch C (1990) Hippocampal Damage
Asociated with Prolonged Cluccocorticoid Exposure in Primates.
The Journal of Neuroscience 10: 2897-2902.
Schatzberg AF, Rothschild Al, Langlais PJ, Bird ED, Cole I0 (1 985)
A corticosteroididopamine hypothesis for psychotic depression
and related states. J Psychiatr Res 19: 57-64.
Schulkin J, McEwen BS, Cold PW (1 994) Allostasis, amygdala, and
anticipatory angst. Neurosci Biobehav Rev 18: 385-396.
Seeman T, Singer B, Rowe J, Horwitr R, McEwen B (1 997) Price of
adaptation--Allostatic load and i t s health consequences. Archives of
Internal Medicine 157: 2259-2268.
Seeman TE, McEwen BS, Rowe JW, Singer BH (2001) Allostatic load
as a marker of cumulative biological risk: MacArthur studies of
successful aging. Proc Natl Acad Sci USA 98: 4770-4775.
Seidman SN, Walsh BT (1999) Testosterone and depression in
aging men. Am J Ceriatr Psychiatry 7: 18-33.
Selye H (1 956) The Stress of Life. McCraw-Hill, New York, NY.
Serra M, Pisu MC, Littera M, Papi C, Sanna E, Tuveri F, Usala L,
Purdy RH, Biggio G (2000) Social isolation-induced decreases in
both the abundance of neuroactive steroids and CABA(A) receptor
function in rat brain. J Neurochem 75: 732-740.
Shah PI, Ebmeier KP, Clabus MF, Coodwin C M (1998) Cortical grey
matter reductions associated with treatment-resistant chronic
unipolar depression. Controlled magnetic resonance imaging
study. Br J Psychiatry 172: 527-532.
141
Sheline YI, Sanghavi M, Mintun MA, Cado MH (1 999) Depression
duration but not age predicts hippocampal vdume loss in
medically healthy women with recurrent major depression. J
Neurosci 19: 5034-5043.
Singh VB, Kalimi M, Phan TH, Boadle-Biber MC (1 994) lntracranial
dehydroepiandrosterone blocks the activation cf tryptophan
hydroxylase in response to acute sound stress. Mol Cell Neurosci 5:
176-181.
Sinha R, Catapano D, O'Malley S (1 999) Stress--inducedcraving
and stress response in cocaine dependent individuals. Psycho-
pharmacology (Berl) 142: 343-351.
Sinha R, Fuse T, Aubin LR, O'Malley SS (2000) Psychological stress,
drug-related cues and cocaine craving. Psychopharrracology (Berl)
152: 140-148.
Slotkin TA, McCook EC,. Ritchie JC, Seidler FJ (1996) Do gluco-
corticoids contribute to the abnormalities in serotoriin transporter
expression and function seen in depression? An animal model. 6101
Psychiatry 40: 576-584.
Smith MA, Makino 5, Kvetnansky R, Post RM (195'5) Stress and
glucocorticoids affect the expression of brain-derived neurotrophic
factor and neurotrophin-3 mRNAs in hippocampus. J Neurosci 15:
1768-1777.
Sonino N, Boscaro M, Ambroso C, Merola G, Mantero C (1986)
Prolonged treatment of Cushing's disease with metyrapone and
aminoglutethimide. IRCS Medical Science 14: 485-486.
Sonino N, Boscaro M, Paoletta A, Mantero F, Ziliotto D (1991)
Ketoconazole treatment in Cushing's syndrome: 'experience in 34
patients. Clin Endocrinol ( 0 x 0 35: 347-352.
Sonino N, Fava CA, Belluardo P, Cirelli ME, Boscaro M (1993)
Course of depression in Cushing's syndrome: response to treat-
ment and comparison with Graves' disease. Horm Re!, 39: 202-206.
Souza N, Lukoyanov NV, Madeira MD, Almeida OFX, Paula-Barbosa
M M (2000) Reorganization of the morphology of hippocampal
neurites and synapses after stress-induced damage correlates with
behavioral improvement. Neuroscience 97: 253.266.
Sovner R, Fogelman S (1996) Ketoconazole therapy for atypical
depression. J Clin Psychiatry 57: 227-228.
Starkman M N (1987) Commentary on Majewsk.a IM: Actions of
steroids on neurons: role in personality, mood, stress and disease.
Integrative Psychiatry 5: 258-273.
Starkman MN, Schteingart DE, Schork MA (1981) Depressed mood
and other psychiatric manifestations of Cushing's syndrome:
relationship to hormone levels. Psychosom Med 43: 3-18.
Starkman MN, Schteingart DE, Schork MA (.I986) Cushing's
syndrome after treatment: changes in cortisol and ACTH levels,
and amelioration of the depressive syndrome. P,yciiatry Res 19:
177-188.
Starkman M, Cebarski 5 , Berent S, Schteingart [I (1992) Hippo-
campal formation volume, memory dysfunction, and cortisol levels
in patients with Cushing's syndrome. Biological Psychiatry 32: 756-
765.
Starkman MN, Giordani B, Gebarski SS, Berent 5 . Schork MA,
Schteingart DE (1 999) Decrease in cortisol reverses human
hippocampal atrophy following treatment of CiJsl-ling's disease.
Biol Psychiatry 46: 1595-1602.
Sterling P, Eyer J (1988) Allostasis: A new paradigm to explain
arousal pathology. In: Fisher S , Reason J (eds) Handbook of Life
Stress: Cognition and Health. John Wiley & Sons Ltd, Chichester,
p p 629-652.
Stewart J (2000) Pathways to relapse: the neurobiology of drug-
and stress-induced relapse to drug-taking. J Psychidtry Neurosci 25:
125-1 36.
Straub RH, Scholmerich J, Zietz B (2000) Replacement therapy with
DHEA plus corticosteroids in patients with chronic inflammatory
 R F VIF W/MINI-R E VIE W b
diseases-. substitutes of adrenal and sex hormones. Z Rheumatol
59: 11/108-118.
Sudsuang R, Chentazez V, Veluvan K (1991) Effect of Buddhist
meditation on serum cortisol and total protein levels, blood
pressure, pulse rate, lung volume and reaction time. Physiology
and Behavior 50: 543-548.
Surwit R, Williams P (1996) Animal models provide insight into
psychosomatic factors in diabetes. Psychosomatic Medicine 58:
582-589.
Svec F, Porter JR (1998) The actions of exogenous dehydro-
epiandrosterone in experimental animals and humans. P.S.E.B.M.
21 8: 174-191.
Taft P, Martin FIR, Melick R (1 970) Cushing's syndrome- a review of
the response to treatment of 42 patients. Australian Ann Med 4:
295-303.
World J Biol Psychiatry Downloaded from informahealthcare.com by University of Colorado Libraries on 12/31/14
Takebayashi M, Kagaya A, lnagaki M, Kozuru T, JitsuikiH, Kurata K,
Okamoto Y, Yamawaki S (2000) Effects of antidepressants on
gamma-aminobutyric acid- and N-methyl-D-aspartate-induced
intracellular Ca(2+) concentration increases in primary cultured rat
cortical neurons. Neuropsychobiology 42: 120-126.
Tannenbaum B, Brindley D, Tannenbaum C, Dallman J, McArthur
D, Meaney M (1 997) High-fat feeding alters both basal and stress-
induced hypothalamic-pituitary-adrenal activity in the rat.
American Journal of Physiology 273: E l 168-1 177.
Tataranni PA, Larson D, Snitker 5, Young J, Flatt 1, Ravussin E (1 996)
Effects of glucocorticoid on energy metabolism and food intake in
humans. American Journal of Physiology 271 : €317-325.
Thakore JH, Dinan T (1995) Cortisol synthesis inhibition: A new
treatment strategy for the clinical and endocrine manifestations of
For personal use only.
depression. Biol Psychiatry 37: 364-368.
Thakore 1, Richards P, Reznek R, Martin A, Dinana T (1997). .
Increased intraabdominal fat in major depression. Biol Psychiatry
41: 1140-1142.
Thase ME (1 994) Cognitive-behavioral therapy of severe unipolar
depression. In Nolen WA, Zohar 1, Roose SP, Amsterdam JD (eds),
Refractory Depression: Current Strategies and Future Directions.
john Wiley & Sons, Chichester, p p 269-296.
Thase M, Simons A, Reynolds C (1 993) Psychobiological correlates
of poor response t o cognitive behavior therapy: potential
indications for antidepressant pharmacotherapy. Psychopharma-
cology Bulletin 29: 293-301.
Thompson JL, Butterfield CE, Cylfadottir UK, Yesavage J, Marcus R,
Hintz RL, Pearman A, Hoffman AR (1998) Effects of human growth
hormone, insulin-like growth factor I, and diet and exercise on
body composition of obese postmenopausal women. J Clin
Endocrinol Metab 83: 1477-1484.
Tollefson CD, Haus E, Carvey MI, Evans M, Tuason V8 (1990) 24
hour urinary dehydroepiandrosterone sulfate in unipolar depres-
sion treated with cognitive and/or pharmacotherapy. Ann Clin
Psychiatry 2: 39-45.
Trejo JL, Carro E, Torres-Aleman I (2001) Circulating insulin-like
growth factor I mediates exercise-induced increases in the number
of new neurons in the adult hippocampus. J Neurosci 21: 1628-
1634.
Trethowen WH, Cobb W (1 952) Neuropsychiatric aspects of
Cushing's syndrome. Arch Neurol Psychiat 67: 283-309.
Uno H, Tarara R, Else 1, Suleman M, Sapolsky R (1989) Hippo-
campal damage associated with prolonged and fatal stress in
primates. J Neurosci 9: 1705-1 71 1.
Urbanoski K, Harris J, Cijsbers K, Dubrovsky B (2000) Androsterone
sulfate increases dentate gyrus population spike amplitude
following tetanic stimulation. Physiol Behav 71 : 435-440.
Uzunov DP, Cooper TB, Costa E, Cuidotti A (1996) Fluoxetine-
elicited changes in brain neurosteroid content measured by
negative ion mass fragmentography. Proc Natl Acad Sci USA 93:
142
12599-1 2604.
Uzunova V, Sheline Y, Davis JM, Rasmusson A, Uzunov DP, Costa E,
Cuidotti A (1 998) Increase in the cerebrospinal fluid content of
neurosteroids in patients with unipolar major depression who are
receiving fluoxetine or fluvoxamine. Proc Natl Acad Sci USA 95:
3239-3244.
van der Lely A], Foeken K, van der Mast RC, Lamberts SW (1991)
Rapid reversal of acute psychosis in the Cushing syndrome with the
cortisol-receptor antagonist mifepristone (RU 486). Ann Intern
Med 114: 143-144.
van Vollenhoven RF (1997) Dehydroepiandrosterone: Uses and
abuses. In: Kelley WN, Harris Jr ED, Ruddy 5, Sledge CB (eds)
Textbook of Rheumatology, Vol Update Series #25. W.B. Saunders
Co., Philadelphia, PA, p p 1-25.
Van Vollenhoven RF, Engleman EC, McCuire JL (1994) An open
study of dehydroepiandrosterone in systemic lupus erythematosus.
Arthritis & Rheumatism 37: 1 305-1 310.
Varney NR, Alexander B, Maclndoe JH (1984) Reversible steroid
dementia in patients without steroid psychosis. Am. J Psychiatry
141: 369-372.
Venero C, Borrell J (1999) Rapid glucocorticoid effects on
excitatory amino acid levels in the hippocampus: a microdialysis
study in freely moving rats. Eur J Neurosci 11: 2465-2473.
Verhelst ]A, Trainer PJ, Howlett TA, Perry L, Rees LH, Crossman AB,
Wass JA, Besser C M (1991) Short and long-term responses to
metyrapone in the medical management of 91 patients with
Cushing's syndrome. Clin Endocrinol ( 0 x 0 35: 169-178.
Virgin Jr CE, Ha TP, Packan DR, Tombaugh CC, Yang SH, Horner
HC, Sapolsky RM (1 991) Clucocorticoids inhibit glucose transport
and glutamate uptake in hippocampal astrocytes: implications for
glucocorticoid neurotoxicity. J Neurochem 57: 1422-1428.
Voigt KH, Bossert 5, Bretschneider S, Bliestle A, Fehm HL (1985)
Disturbed cortisol secretion in man: contrasting Cushing's syn-
drome and endogenous depression. Psychiatry Res 15: 341-350.
Walton C, Pugh N (1995) Stress, steroids, and "ojas": Neuro-
endocrine mechanisms and current promise of ancient approaches
to disease prevention. Indian Journal of Physiology and Pharma-
cology 39: 3-34.
Walton KG, Pugh ND, Celderloos P, Macrae P (1995) Stress
reduction and preventing hypertension: preliminary support for a
psychoneuroendocrine mechanism. J Altern Complement Med 1 :
263-283.
Wang C, Alexander C, Berman N, Salehian B, Davidson T,
McDonald V, Steiner B, Hull L, Callegari C, Swerdloff RS (1996)
Testosterone replacement therapy improves mood in hypogonadal
men- a clinical research center study. J Clin Endocrinol Metab 81:
3578-3583.
Weiss J M (1972) Psychological factors in stress and disease.
Scientific American 226: 104-1 13.
Welbourn RB, Montgomery DAD, Kennedy TL (1971) The natural
history of treated Cushing's syndrome. Br J Surgery 58: 1-16.
Wellman M, Shane-McWhorter L, Orlando X, Jennings JP (1999)
The role of dehysroepiandrosterone in dibetes rnellitus.
Pharmacotherapy 19: 582-591.
Whelan TB, Schteingart DE, Starkman MN, Smith A (1980)
Neuropsychological deficits in Cushing's syndrome. I Nerv Ment
Dis 168: 753-757.
Whitehouse W, Dinges D, Orne E, Keller 5, Bates B, Bauer N,
Morahan P, Haupt B, Carlin M, Bloom P, Zaugg L, Orne M (1996)
Psychosocial and immune effects of self-hypnosis training for stress
management throughout the first semester of medical school.
Psychosomatic Medicine 58: 249-263.
Wolf OT, Neumann 0, Hellhammer DH, Ceiben AC, Strasburger C],
Dressendorfer RA, Pirke KM, Kirschbaum C (1 997) Effects of a two-
week physiological dehydroepiandrosterone substitution on cog-
 nitive performance and well-being in healthy elderly women and
men. Journal of Clinical Endocrinology and Metabolism 82: 2363-
2367.
Wolkowitz OM (1 994) Prospective controlled studies of the
behavioral and biological effects of exogenous corticosteroids.
Psychoneuroendocrinology 19: 233-255.
Wolkowitz OM, Reus VI (1999) Treatment of depression with
antiglucocorticoid drugs. Psychosomatic Medicine 61 : 698-71 1.
Wolkowitz OM, Reus VI (2000) Neuropsychiatric effects of
Dehydroepiandrosterone (DHEA). In Kalimi M, Regelson W (eds)
Dehydroepiandrosterone (DHEA): biochemical, physiological and
clinical aspects. Walter de Cruyter, Berlin, pp 271 -298.
Wolkowitz 0, Sutton M, Koulu M (1986) Chronic corticosterone
administration in rats: behavioral and biochemical evidence of
increases in central dopaminergic activity. European Journal of
Pharmacology 122: 329-338.
World J Biol Psychiatry Downloaded from informahealthcare.com by University of Colorado Libraries on 12/31/14
Wolkowitz OM, Doran AR, Breier A, Roy A, Jimerson DC, Sutton
ME, Golden RN, Paul SM, Pickar D (1987a) The effects of
dexamethasone on plasma homovanillic acid and 3-methoxy-4-
hydroxyphenylglycol. Evidence for abnormal corticosteroid-
catecholamine interactions in major depression. Arch Cen
Psychiatry 44: 782-789.
Wolkowitz OM, Rubinow DR, Breier A, Doran AR, Davis C, Pickar D
(1 987b) Prednisone decreases CSF somatostatin in healthy
humans: implications for neuropsychiatric illness. Life Sci 41 : 1929-
1933.
Wolkowitz OM, Doran A, Breier A, Roy A, Pickar D (1989) Speci-
ficity of plasma HVA response to dexamethasone in psychotic
depression. Psychiatry Res 29:l 77-86.
For personal use only.
Wolkowitz OM, Reus VI, Weingartner H, Thompson K, Breier A,
Doran A, Rubinow D, Pickar D (1 990a) Cognitive effects of corti-
costeroids. Am j Psychiatry 147: 1297-1 303.
Wolkowitz OM, Rubinow D, Doran AR, Breier A, Berrettini WH,
Kling MA, Pickar D (1 990b) Prednisone effects on neurochemistry
and behavior. Preliminary findings. Arch Len Psychiatry 47: 963-
968.
Wolkowitz OM, Reus VI, Manfredi F, Roberts E (1992) Antigluco-
corticoid effects of DHEA-S in Alzheimer's Disease (Reply). Am J
Psychiatry 149: 1126.
Wolkowitz OM, Coppola R, Breier A, Doran AR, Rubinow DR,
Berrettini WH, Kling MA, Pickar D (1 993a) Quantitative electro-
encephalographic correlates of steroid administration in man.
Neuropsychobiology 27: 224-230.
Wolkowitz OM, Reus VI, Manfredi F, lngbar J, Brizendine L, Wein-
gartner H (1 993b) Ketoconazole treatment of hypercortisolemic
depression. Am J Psychiatry 150: 81 0-812.
Wolkowitz OM, Weingartner H, Rubinow DR, Jimerson D, Kling M,
Berretini W, Thompson K, Breier A, Doran A, Reus VI, et al (1 993c)
Steroid modulation of human memory: biochemical correlates. Biol
Psychiatry 33: 744-746.
Wolkowitz OM, Reus VI, Manfred IF, Chan T, Canick J, Ormiston 5,
lngbar J, Brizendine L (1 994) Antiglucocorticoid medication effects
on specific depressive symptoms. Biol Psychiatry 35: 678.
Wolkowitz 0, Reus V, Robers E, Manfredi F, Chan T (1 995) Antide-
pressant and cognition-enhancing effects of DHEA in major depres-
sion. Annals of the New York Academy of Science 774: 337-339.
Wolkowitz OM, Reus VI, Manfredi F, Chan T, Ormiston 5, Johnson
R ( 1 996) Dexamethasone for depression [letter]. Am j Psychiatry
153: 1112.
Wolkowitz OM, Reus VI, Canick J, Levin B, Lupien S (1 997a) Cluco-
corticoid medication, memory and steroid psychosis in medical
illness. Ann N Y Acad Sci 823: 81-96.
Wolkowitz OM, Reus VI, Roberts E, Manfredi F, Chan T, Raum WJ,
Ormiston 5, johnson R, Canick J, Brizendine L, Weingartner H
143
(1 997b) Dehydroepiandrosterone (DHEA) treatment of depression.
Biol Psychiatry 41 : 31 1-318.
Wolkowitz OM, Reus VI, Chan T, Manfredi F, Raum W, Johnson R,
Canick J (1 999a) Antiglucocorticoid treatment (if depression:
Double-blind ketoconazole. Biol Psychiat 45: 1070-1074.
Wolkowitr OM, Reus VI, Keebler A, Nelson N, Friedland M ,
Brizendine L, Roberts E (1 999b) Double-blind tresatrnent of major
depression with dehydroepiandrosterone (DHEA). Am j Psychiatry
156: 646-649.
Wolkowitz OM, Brizendine L, Reus VI (2000a) The Role of Dehydro-
epiandrosterone (DHEA) in Psychiatry. Psychiatric Annals 30: 123-
128.
Wolkowitz OM, Kramer J, Reus VI, Costa M, Yaffe K, Walton P,
Raskind M, Peskind E, Newhouse P, Sack D, De Souza E, Sadowsky
C, et al (2000b) DHEA treatment of Alzheimer's Disease: a ran-
domized, double-blind, placebo-controlled study, The 2nd Interna-
tional Congress on Hormones, Brain and Neuropsychopharma-
cology, Rhodes, Greece.
Wolkowitz OM, Kroboth P, Reus VI, Fabian TI ( 2 0 0 0 ~ )DHEA
in Aging and Mental Health. In: Morrison M (ed) Hormones,
Aging and Mental Disorders. Cambridge Univ Pres.5, Cambridge,
pp 144-167
Wong ML, Kling MA, Munson PI, Listwak S, Licinio J, Prolo P, Karp
B, McCutcheon IE, Ceracioti TD jr. DeBellis MD, Rice KC, Coldstein
DS, Veldhuis ID, Chrousos CP, Oldfield EH, McCann SM, Gold PW
(2000) Pronounced and sustained central hypernoradrenergic
function in major depression with melancholic featur-es: relation to
hypercortisolism and corticotropin-releasing hormone. Proc Natl
Acad Sci USA 97: 325-330.
Xu L, Holscher C, Anwyl R, Rowan M j (1 998) Glucocorticoid recep-
tor and proteiniRNA synthesis-dependent mecharisms underlie
the control of synaptic plasticity by stress. Proc Natl Acad Sci USA
95: 3204-3208.
Lahorodna A, Bijak M (1 999) An antidepressant-induced decrease
in the responsiveness of hippocampal neurons to group I mata-
botropic glutamate receptor activation. Eur J Pharmacol 386: 173-
179.
Zakon HH (1998) The effects of steroid hormoner, on electrical
activity of excitable cells, Trends Neurosci 21 : 2021-207.
Zeiger MA, Fraker DL, Pass HI, Nieman LK, Cutlei CB jr, Chrousos
CP, Norton ]A (1993) Effective reversibility of the signs and
symptoms of hypercortisolism by bilateral adrenalectomy. Surgery
114: 1138-1143.
Zobel AW, Yassouridid A, Frieboes RM, Holsboer F ( 1 999) Predic-
tion of medium-term outcome by cortisol response to the com-
bined dexamethasone-CRH test in patients with remitted depres-
sion. Am J Psychiatry 156: 949-951.
Zobel AW, Nickel T, Kunzel HE, et al (2000) Effect, of the high-
affinity corticotropin-releasing hormone receptor 1 antagonist
R121919 in major depression: the first 20 patients treated. J
Psychiatr Res 34: 171-1 81.