Both an excess of cortisol and DST nonsuppression have been reported for many years in patients with

mood disorders

During a physical or emotional stressor, the HPA axis is activated. The hypothalamus secretes 2
hormones—corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP)—that act on the
pituitary to increase adrenocorticotropin hormone (ACTH) release. CRH, also called corticotropin-
releasing factor (CRF), is a 41–amino acid peptide distributed in various parts of the central nervous
system and is the primary regulator of the mammalian stress response.4 CRH interacts with receptors on
the pituitary that secrete ACTH (Figure 1). ACTH is carried in the blood to the adrenal cortex and
interacts with receptors on adrenocortical cells that stimulate the production and release of cortisol.
Cortisol is the adrenal glucocorticoid stress hormone secreted in humans and other primates. Some other
animals, such as rats, produce a similar hormone called corticosterone. Most cortisol that circulates in the
body is protein bound to corticosteroid-binding globulin. Only the unbound or “free” cortisol binds to
receptors.
Cortisol binds to at least 2 types of receptors, both of which are located intracellularly. The first, called
type I or mineralocorticoid receptors, has the highest affinity for cortisol and generally is almost
completely bound by cortisol before the second, type II or glucocorticoid receptors, binds
cortisol.5,6 These binding properties of cortisol differ from those of some synthetic corticosteroids, such as
prednisone and dexamethasone (DEX), which bind fairly selectively to the type II receptor.
The loop is completed with the negative feedback of cortisol to the pituitary and hypothalamus. At least 2
forms of negative feedback to the HPA axis have been identified. The first is negative feedback of cortisol
to the pituitary that is dependent on the concentration of cortisol. A second process termed fast
feedback is dependent not on the absolute concentration of cortisol, but on the rate of change in
concentration and involves interactions with receptors in the hypothalamus and hippocampus.7–10
HPA axis functioning is frequently examined using neuroendocrine challenge tests that attenuate or
enhance cortisol, ACTH, or CRH release. The best known such test is the dexamethasone suppression test
(DST), in which a dose of the synthetic corticosteroid DEX is given in the evening and cortisol samples
are obtained the next day. The normal response is inhibition of cortisol release due to negative feedback
by the DEX. If cortisol does not decrease below a certain level, then the patient is said to have “DST
nonsuppression,” a finding that is frequently, but not always, associated with elevated cortisol levels. The
DST is easily administered in outpatient settings both in depressed patients and in the diagnosis of
Cushing's disease. A newer test that is increasingly used in research is the combined DEX/CRH challenge
test in which the HPA axis is both stimulated by the administration of CRH and inhibited with DEX

PROLACTIN

Prolactin alters neural circuits to help the individual to cope with stress. Reduced activation of neural
inputs, activation of ionic channels, or the modulation of several signaling pathways are some of the
putative mechanisms of action underlying the effects of PRL on brain circuits. It is unknown how PRL
regulates the HPA axis function during the stress response. PRL could affect hypothalamic and/or
hippocampal activity to regulate emotionality. The contribution of PRL to the onset of postpartum
depression is still unknown. Low PRL levels in nursing women have been associated with postpartum
depression. Inhibition of PRL reduces neurogenesis in the olfactory bulb, but the mechanisms that result
in a postpartum depressive state are unknown. Besides the pathways affected by PRL to regulate anxiety
are not yet known, and whether the PRL effects on hippocampal neurogenesis contribute to modulate
anxiety is still uncertain. Administration of PRL in the early postnatal stages reduces neurogenesis in the
hippocampus and the olfactory bulb and promotes a depressive-like state in adulthood. This suggests that
PRL affects a critical window during brain development and that PRL actions are dependent on the age
during which it is administrated. Further studies are needed to understand the mechanisms of action of
PRL in the brain, and how this hormone modulates emotionality and anxiety at different developmental
stages.

Stress is a critical factor that may lead to depressive disorders. Stress exposure activates the HPA axis,
triggering the release of corticotrophin releasing hormone (CRH) in the PVN, which promotes the
secretion of adrenocorticotrophin (ACTH) from the pituitary. In turn, ACTH triggers the release of
glucocorticoids from the adrenal glands. PRL is also secreted from the pituitary in response to a number
of stressors. Initial studies suggested that PRL may counteract glucocorticoid actions on the immune
system during the stress response (15). However, more recent studies showed that preventing PRL-R
expression in the brain via an antisense probe strongly increases the stress-induced ACTH secretion in
virgin and lactating rats, suggesting that PRL plays an inhibitory role on HPA axis reactivity (16, 17). It
has been hypothesized that PRL modulates the activity of the HPA axis through a reduction of neural
inputs to the PVN. Both acute and chronic PRL intracerebroventricular administrations in virgin female
rats reduce neuronal activation in the amygdala and CRH hypothalamic expression in response to stress
(18). Additionally, PRL is locally released from the PVN and MPOA in response to physiological stimuli,
including stress (4).
Prolactin has been recently associated with resilience in a model of chronic mild stress (CMS). Adult rats,
previously subjected to CMS, were selected as responders and non-responders, according to their reaction
to stress. The resilient animals (i.e., non-responders) presented higher plasma levels of PRL, and higher
PRL-R mRNA in the choroid plexus than their vulnerable (i.e., responders) counterpart (19).
Accordingly, a microarray study performed on heterozygous 5-Htt-deficient offspring subjected to
prenatal stress showed that PRL, growth hormone, and galanin receptor 3 were differentially expressed in
the hippocampus of resilient mice when compared to controls (7). These results suggest a role for PRL in
stress regulation at hippocampal level.

It is considered an adaptive hormone due to the key roles it plays in the modulation of
the stress response and during pregnancy and lactation. Within the brain, PRL acts as a
neuropeptide to promote physiological responses related to reproduction, stress adaptation,
neurogenesis, and neuroprotection

SLEEP
Sleep disturbances in depression are up to 70%. Patients frequently have difficulty in falling
asleep, frequent awakenings during the night and non-restorative sleep. Sleep abnormalities in
depression are mainly characterized by increased rapid eye movement (REM) sleep and
reduced slow wave sleep. Among the mechanisms of sleep disturbances in depression
are hyperactivation of the hypothalamic-pituitary-adrenal axis, CLOCK gene polymorphism and
primary sleep disorders. The habenula is a structure regulating the activities of monoaminergic
neurons in the brain. The hyperactivation of the habenula has also been implicated, together
with sleep disturbances, in depression. The presence of depression in primary sleep disorders is
common. Sleep disturbances treatment include pharmacotherapy or Cognitive Behavioral
Therapy.

11 yo
A number of studies have been conducted in recent years (e.g., Anthony, 5 Bluebond-
Langer, 23 Gibney, 58 Kane, 79 Koocher, 84 MenigPeterson and McCabe, 99 Piaget, 107 Pitcher and
Prelinger, 108 Spinetta, 132 Tallmer et al. 135 ) to determine how children at various ages comprehend death.
A fairly standard view was put forth by Nagy 104 in 1948. Analyzing the words and drawings of a
relatively large sample (378) of Hungarian children who had been exposed to considerable trauma and
death in the preceding few years, she conceptualized a three-stage model of awareness and linked the
stages to approximate chronological ages.
Prior to about three years of age, children's cognitive and language development is too immature for them
to have any concept of death. According to Nagy's stage 1 (roughly ages 3-5), death is seen as reversible;
the dead are simply considered "less alive," in a state analogous to sleep. Young children functioning at
what Piaget 107 termed the "preoperational" level of development will not generally recognize the
irreversibility of death. 84,86,95 In stage 2 (ages 5-9), children begin to comprehend the finality of death, but
believe that it happens only to other people. In the third stage (after age 10), the causes of death can be
understood, and death is perceived as final, inevitable, and associated with the cessation of bodily
activities. As is true in all child development, there is considerable age variation in attainment of the
different stages and children may regress when emotionally threatened
Sleep Stages
There are two basic types of sleep: rapid eye movement (REM) sleep and non-REM sleep (which has
three different stages). Each is linked to specific brain waves and neuronal activity. You cycle through
all stages of non-REM and REM sleep several times during a typical night, with increasingly longer,
deeper REM periods occurring toward morning.
Stage 1 non-REM sleep is the changeover from wakefulness to sleep. During this short period (lasting
several minutes) of relatively light sleep, your heartbeat, breathing, and eye movements slow, and
your muscles relax with occasional twitches. Your brain waves begin to slow from their daytime
wakefulness patterns.

Stage 2 non-REM sleep is a period of light sleep before you enter deeper sleep. Your heartbeat and
breathing slow, and muscles relax even further. Your body temperature drops and eye movements
stop. Brain wave activity slows but is marked by brief bursts of electrical activity. You spend more of
your repeated sleep cycles in stage 2 sleep than in other sleep stages.

Stage 3 non-REM sleep is the period of deep sleep that you need to feel refreshed in the morning. It
occurs in longer periods during the first half of the night. Your heartbeat and breathing slow to their
lowest levels during sleep. Your muscles are relaxed and it may be difficult to awaken you. Brain
waves become even slower.

REM sleep first occurs about 90 minutes after falling asleep. Your eyes move rapidly from side to side
behind closed eyelids. Mixed frequency brain wave activity becomes closer to that seen in
wakefulness. Your breathing becomes faster and irregular, and your heart rate and blood pressure
increase to near waking levels. Most of your dreaming occurs during REM sleep, although some can
also occur in non-REM sleep. Your arm and leg muscles become temporarily paralyzed, which
prevents you from acting out your dreams. As you age, you sleep less of your time in REM
sleep. Memory consolidation most likely requires both non-REM and REM sleep.