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Of the biogenic amines, norepinephrine

and serotonin are the two
neurotransmitters most implicated
in the pathophysiology of mood

Placidity : a feeling
of calmness; a quiet
and undisturbed

obsessive or
abnormal reflection
upon an idea or
deliberation over a

Downregulation or decreased sensitivity

of -adrenergic receptors
Presynaptic 2-receptors
Activation NE released
Regulate the amount of serotonin released

The biogenic amine neurotransmitter

most commonly associated with
Depletion of serotonin may precipitate
Some pt with suicidal impulses have
low CSF concentration of serotonin
low CSF concentration of serotonin uptake
sites on platelets

Dopamine activity may be reduced in

depression and increased in mania
Two recent theories about dopamine and
depression :
Mesolimbic dopamine pathway may be
Dopamine D1 receptor may be hypoactive

Dopaminergic projections are

classically divided in nigrostriatal, mesolimbic and
mesocortical systems (Lindvall
and Bjrklund 1983)
The nigro-striatal system projects
from the substantia nigra (SN) to
the dorsal striatum, and has
been classically involved in
cognitive integration,
habituation, sensorimotor
coordination and initiation of
The mesolimbic system projects
from the ventral tegmental area
(VTA) to limbic structures such as
ventral striatum, hippocampus,
and amygdala.
The mesocortical system projects
from the VTA to cortical regions,
mostly orbitofrontal, medial
prefrontal and cingulate cortices,
but also to the dorso-lateral
prefrontal cortex (DLPFC),
temporal and parietal cortex.
The mesolimbic and mesocortical
systems are involved in
regulation of motivation,
attention and reward (Mogenson
et al. 1980).

The heterocyclic antidepressants are
postulated to work through their effects on
monoamine neurotransmitters, such as
serotonin, norepinephrine and dopamine.
These agents block the reuptake of these
neurotransmitters to varying degrees and also
interact with muscarinic, cholinergic, alpha-1adrenergic, and histaminic receptors, which
results in their characteristic side-effect profile.
Amitriptiline, Imipramine, Amoxapine

Serotonin-Specific Reuptake Inhibitors

SSRIs block serotonin reuptake into
presynaptic nerve terminals, leading to
enhanced serotonergic
Fluoxetine, Sertraline, Citalopram,

Monoamine oxidase inhibitors (MAOIs)

Monoamine oxidase inhibitors irreversibly
inhibit the enzyme, monoamine oxidase,
located in the central nervous system, gut
and platelets, leading to lack of degradation
of monoamines.
Two weeks are required after discontinuing
an MAOI to replenish the body with normal
amounts of the monoamine oxidase enzyme.
Phenelzine, Isocarboxazid

Serotonin-Norephinephrine Reuptake
Inhibitors (SNRIs): venlafaxine, duloxetine

Norephinephrine reuptake Inhibitors

(NRIs): reboxetine

Norephinephrine-dopamin reuptake
Inhibitors (NDRIs): Bupropoion

Activity of the gene coding for the neurokinin

brain-derived neurotrophic growth factor
(BDNF) is decreased after chronic stress, as
is the process of neurogenesis.
Protracted stress thus can induce changes in
the functional status of neurons and,
eventually, cell death.
Recent studies in depressed humans indicate
that a history of early trauma is associated
with increased HPA activity accompanied by
structural changes (i.e., atrophy or
decreased volume) in the cerebral cortex.

HPA activity in depression

Hallmark of mammalian stress responses
One of the clearest links between depression
& the biology of chronic stress
Apparent in 20-40 % of depressed outpatients
& 40-60 % of depressed inpatients
Hypercortisolema in depression suggests one
or more of the following central disturbances:

decreased inhibitory serotonin tone

increased drive from norepinephrine (NE), ACh,

or corticotropin releasing hormone (CRH)

decreased feedback inhibition from the

Thyroid axis activity

5-10 % of depressed patients have previously

undetected thyroid dysfunction
basal TSH level
TSH response to 500 mg infusion of TRH

Growth hormone

Secretion is inhibited by somatostatin, a

hypothalamic neuropeptide, and CRH
Depression CSF somatostatin level
Mania CSF somatostatin level

Prolactin ???

released from the pituitary by serotonin stimulation

and inhibited by DA.
Most studies have not found significant abnormalities
of basal or circadian prolactin secretion in
depression, although a blunted prolactin response to
various serotonin agonists has been described.
This response is uncommon among premenopausal
women, suggesting that estrogen has a moderating

In depression

Premature loss of deep (slow wave) sleep

nocturnal arousal

nocturnal awakenings
total sleep time
phasic REM sleep
core body temperature

The combination of increased REM drive and decreased slow

wave sleep results in a significant reduction in the first
period of non-REM (NREM) sleep, a phenomenon referred
to as reduced REM latency. Reduced REM latency
and deficits of slow wave sleep typically persist
after recovery of a depressive episode.
Abnormal sleep profile less responsive to psychotherapy,
greater risk of relapse/recurrence, benefit preferentially
from pharmacotherapy

Depressive disorder
lymphocyte proliferation in response to
These lymphocytes produce
neuromodulators, such as corticotropinreleasing factor (CRF), and cytokines,
peptides known as interleukins.
There appears to be an association with
clinical severity, hypercortisolism, and
immune dysfunction, and the cytokine
interleukin-1 may induce gene activity for
glucocorticoid synthesis.

Depressive disorders :
abnormal hyperintensities in subcortical
regions such as periventricular regions, the
basal ganglia and the thalamus (More
common in bipolar I disorder and among the
elderly, these hyperintensities appear to
reflect the deleterious neurodegenerative
effects of recurrent affective episodes.)
The most widely replicated positron
emission tomography (PET) finding in
depression is decreased anterior brain
metabolism, which is generally more
pronounced on the left side

depression may be associated with a

relative increase in nondominant
hemispheric activity.
In addition to a global reduction of anterior
cerebral metabolism, increased glucose
metabolism has been observed in several
limbic regions, particularly among patients
with relatively severe recurrent depression
and a family history of mood disorder.
During episodes of depression,
increased glucose metabolism is
correlated with intrusive ruminations.

Modern affective neuroscience focuses on

the importance of four brain regions in
the regulation of normal emotions:

prefrontal cortex (PFC)

anterior cingulate cortex (ACC)

left-sided activation of regions of the PFC

is more involved in goal-directed or
appetitive behaviors
regions of the right PFC are implicated in
avoidance behaviors and inhibition of
appetitive pursuits.
Subregions in the PFC appear to localize
representations of behaviors related to
reward and punishment.

an affective subdivision in the rostral and ventral

regions of the ACC - shares extensive connections
with other limbic regions (hippocampus,
amygdala, anterior thalamic nuclei, limbic cortex)
a cognitive subdivision involving the dorsal ACC
interacts more with the PFC and other cortical
It is proposed that activation of the ACC facilitates
control of emotional arousal, particularly when
goal attainment has been thwarted or when novel
problems have been encountered.

learning and memory, including fear

conditioning, as well as inhibitory
regulation of the HPA axis activity.