Posted by jrbecker on September 16, 2004, at 10:12:49
In reply to Re: Cymbalta honeymoon is over » Mistermindmasta, posted by alesta on September 15, 2004, at 23:16:34
for a good overview about each of the neurotransmitter pathways (including NE), see below. This was published in this months' Journal of Clinical Psychiatry....
MONOAMINES, NEUROPEPTIDES, AND NEUROTROPHINS
IN THE PATHOPHYSIOLOGY OF DEPRESSIONKerry J. Ressler, M.D., Ph.D., opened with the statement that the symptoms of major depressive disorder can be viewed as a result of brain circuit dysfunction. Three classes of molecules involved in depressive symptoms include the monoamines, which regulate broad functioning of neural circuits; neuropeptides, which mediate behavior-specific Components of neural circuits; and neurotrophins, which allow for plasticity of the brain and maintenance of neural circuits.
MONOAMINES
The neurotransmitters that have received the most attention in depression,
according to Dr. Ressler, are the biogenic monoamines norepinephrine,
serotonin, and dopamine. The role of dopamine in motivation and drive and
the role of norepinephrine in arousal and vigilance are well understood.
Other symptom pathways are more speculative, such as the role of serotonin
in impulsivity. Some symptoms require multiple neurotransmitter systems;
for example, norepinephrine and serotonin both play a role in anxiety
symptoms of depression.
Dr. Ressler explained that the neurotransmitter
system that produces the monoamines was originally called the
reticular activating system but is now called the ascending arousal system
of the midbrain. The raphe nucleus produces serotonin, the locus ceruleus
produces norepinephrine, and the tuberomammillary nucleus produces histamine. In addition, the ventral tegmental area produces dopamine while
areas such as the laterodorsal and pedunculopontine tegmental nuclei
produce acetylcholine.
All of these neurotransmitters project broadly through the brain and
are thought to regulate multiple behavioral circuits. Norepinephrine and serotonin
in particular have been shown to be involved in regulating the amygdala,
the bed nucleus of the stria terminalis, and the hippocampal systems. These
areas and systems contribute to the fear and stress response as well as anxiety
symptoms and emotional memory. Dopamine has been shown to be involved
regulation of the nucleus accumbens and its roles in reward, pleasure, drive,
and motivation.
Several other regions of the brain are regulated by monoamines as well.
The hypothalamus is regulated by all of the monoamine systems, and it plays a
critical role as the leader of the endocrine system in stress response and
sleep, wake, and appetite regulation. The thalamus is known to be involved
arousal and sleep, as well as sensorimotor gating. Finally, multiple cortical
areas, principally the prefrontal cortical areas, are known to be involved in
executive functioning, cognition, and working memory.
Dr. Ressler posed the question, what the evidence for these neurotransmitter
systems in depression? The serotonin system is well understood; evidence suggests decreased activity of the serotonin system in depression. The norepinephrine system appears more complicated, related Dr. Ressler, in that depression probably does not
involve grossly increased or decreased static levels of this neurotransmitter.
Rather, it probably involves dysregulation of dynamic levels of norepinephrine,
such as an overactivation of norepinephrine release or a hypersensitivity
of the norepinephrine receptor systems.
Understanding what norepinephrine and serotonin do in the awake,
normally behaving animal can illuminate the dysfunction of these neurotransmitters
in depression. Aston-Jones and colleagues1 have shown that norepinephrine plays a crucial role in organizing the behavioral state of an animal. Activity of the locus ceruleus
was measured in monkeys that were trained to respond in a specific way to
specific, randomly given cue. The authors found that immediately after this cue, there was a burst of firing of the locus ceruleus neurons, indicating that norepinephrine was being released by the axon terminals during the switch from a calm, wakeful state
to a state of vigilance and attention. When a different cue was given, one
that the animals were not trained to respond to, no extra activity was seen
in the locus ceruleus. These results suggest that the norepinephrine system
plays a critical role in the arousal, vigilance, and stress response system.
Serotonin, explained Dr. Ressler, seems to have an opposite response to
external cues. Fornal and coworkers2 have shown that, for the most part,
serotonin fires in a rhythmic and relatively slow way, a few times per second,
during quiet, internally directed activity. When an animal has a period
of vigilance and attention to outside stimuli, serotonin completely shuts
down for a second or two. The authors studied a cat in which raphe nucleus
activity was recorded. During quiet, normal activities, such as bathing and
grooming, serotonergic neurons were active. However, when an unexpected
event occurred, in this case, the door to the cat’s room was opened and
closed, serotonergic activity in the raphe nucleus shut down for 1 to 5
seconds.
Dr. Ressler then proposed an experiment in which the locus ceruleus
and the raphe nucleus would be monitored in the same animal. He hypothesized
that such an experiment might demonstrate different but complementary
responses from the norepinephrine and serotonin systems, such that
when the serotonin system shuts down in response to an external stimulus,
the norepinephrine system fires in a burst of activity.
Dr. Ressler went on to address how normal norepinephrine and serotonin
activity fits with what is understood about depression. While it is well established
that decreased levels of serotonin and its metabolites are present
in patients with depression and/or anxiety, only recently has robust evidence
of norepinephrine’s role in depression been provided by studies of tyrosine
hydroxylase.
Tyrosine hydroxylase is an enzyme required for the production of norepinephrine,
and levels of it have been shown to be increased in the locus ceruleus of patients with depression.
Zhu and others3 conducted a postmortem study of 13 patients with depression
and 13 control subjects. They used antibodies to measure the levels of tyrosine hydroxylase within the locus ceruleus of the deceased. They found higher levels of tyrosine hydroxylase
in the patients with major depression compared with control
subjects.
Dr. Ressler emphasized that recent theories point to the dynamic interplay
between these neurotransmitter systems as being critically important
in depression. Geracioti and colleagues4 found a negative linear relationship
between serotonin (the metabolite 5-hydroxyindoleacetic acid 5-HIAA]) and norepinephrine levels
in the cerebrospinal fluid (CSF) of healthy volunteers (Figure 1A). This
finding is consistent with the results of the electrophysiologic studies1,2 that
imply that serotonin activity is quiet when norepinephrine activity increases
and vice versa. In depressed participants, however, no relationship
between 5-HIAA and norepinephrine levels was found (Figure 1B). Patients
with major depression seem to experience a complete uncoupling of
this normally regulated system. Dr. Ressler concluded that it may not be
the static levels of neurotransmitters but the ways in which these different
systems interact that is at the crux of depression.
NEUROPEPTIDES
Dr. Ressler moved to a discussion
of neuropeptide systems, such as those
regulated by corticotropin-releasing
hormone (CRH). CRH is released from
the hypothalamus, which leads to increased
adrenocorticotropic hormone
ACTH, also known as corticotropin)
release from the pituitary gland, which
then leads to increased cortisol release
from the adrenal gland. Cortisol has
multiple stress effects on the brain via
the vagus nerve, including increasing
norepinephrine release from the locus
ceruleus. Dr. Ressler noted that CRH
also has a direct projection from the
amygdala, one of the principal sources
of CRH in the brain, to the locus ceruleus,
another way in which it may help
modulate norepinephrine and thereby
be indirectly involved in vigilance and
arousal.
Depressed patients, according to Dr.
Ressler, have increased levels of CSF
CRH compared with people who are
not depressed.5 Because CRH affects
so many parts of the brain that control
stress, arousal, and depression, the dysregulation
of CRH seen in depressed
patients may be part of the pathophysiology
of the disorder.
Dr. Ressler went on to discuss
another neuropeptide from the hypothalamus,
hypocretin. He noted that the
hypothalamus has an important role
in modulating sleep and arousal. The
neurotransmitter ã-aminobutyric acid
GABA) is released from the hypothalamus
and affects multiple monoamine
systems in the midbrain that
normally mediate arousal. Sleep is induced
in part via the shutting down
of these different areas by the hypothalamus.
Hypocretin, a recently discovered
neuropeptide, is also released
into these same areas; it appears to be
required for normal modulation of
sleep and wake cycles.
Preliminary evidence suggests that
hypocretin is involved in depression.
Salomon and colleagues6 measured
CSF hypocretin-1 levels in 14 control
subjects and 15 depressed subjects. Diurnal
hypocretin-1 levels varied during
the course of the day in control
subjects by 10%, whereas in depressed
patients, levels varied only 3% during
the day.NEUROPLASTICITY AND
NEUROTROPHIC FACTORS
Neurogenesis and neurotrophic factors
have also been studied in depression,
Dr. Ressler reported, especially
since it is now known that new neurons
are developed through adulthood.
One of the most repeated findings in
the depression literature is a decreased
hippocampal size in patients with depression
compared with control patients
(Figure 2).7–11 Dr. Ressler explained
that CRH and/or cortisol may
decrease hippocampal size by inducing
atrophy or cell death.
Alternatively, neurotrophic factors
such as brain-derived neurotrophic factor
(BDNF) are thought to be involved
in enhancing neuroplasticity and the
number of neurons that are born within
the hippocampus. Theoretically, argued
Dr. Ressler, if depression is associated
with a decrease in neuroplasticity
and with neural atrophy, then
increasing plasticity and growth may
be associated with alleviation of depression,
but much more research is
needed in this area.EFFECTS OF CHRONIC ANTIDEPRESSANT
TREATMENT ON PATHOPHYSIOLOGY
Dr. Ressler postulated that chronic
antidepressant treatment, if effective,
could begin to correct the pathophysiology
associated with depression
Table 1). To test this theory, Nestler
and colleagues12 studied the effects of
chronic antidepressant administration
on tyrosine hydroxylase levels in the
rat locus ceruleus. All major types of
antidepressant treatment were studied,
including electroconvulsive therapy,
tricyclic antidepressants, selective serotonin
reuptake inhibitors (SSRIs),
and bupropion. No matter what the
mechanism of treatment for depression
was, tyrosine hydroxylase levels were
decreased. Other psychotropic agents,
such as haloperidol, diazepam, cocaine,
and morphine, had no such effect.
If antidepressants down-regulate
the expression of tyrosine hydroxylase
in rat brains, they may have the same
effect in depressed patients whose levels
of tyrosine hydroxylase are increased.
Another study13 found that serotonin
was increased in the hypothalamus,
hippocampus, and frontal cortex
of guinea pig brains during chronic
SSRI treatment, again suggesting that
antidepressant treatment may counteract
the neurotransmitter dysfunction,
in this case serotonin decrease, in patients
with depression.A similar effect has been reported
in BDNF levels and neuroplasticity.
Chen and colleagues14 reported results
from a postmortem study that examined
BDNF activity in the brains
of those who had been treated with
antidepressants at the time of death
compared with those who had not. The
authors found increased BDNF expression
in those who had been treated with
antidepressants. This finding is consistent
with that reported by Duman15: in
animals with chronic stress, the total
number of neurons was decreased, as
was axon and dendrite morphology.
Chronic antidepressant treatment was
found to increase both the number of
cells in the hippocampus and other
brain areas and the amount of cell
growth.
Santarelli and colleagues16 found
that hippocampal neurogenesis was required
for antidepressants to be effective
in mice. Neurogenesis was reported
to be greater in animals who
received an antidepressant (fluoxetine
or imipramine) for 2 to 4 weeks versus
those who did not receive an antidepressant.
If the hippocampus is xrayed,
cell division is blocked; animals
who received x-rays showed no alteration
in grooming latency, whereas
animals who received no x-rays experienced
decreased grooming latency,
suggestive of an antidepressant effect.
Dr. Ressler suggested that hippocampal
neurogenesis may be required for
full antidepressant effect in humans as
well.SUMMARY
Dr. Ressler concluded by summarizing
the data on the pathophysiology
of depression and the different brain
regions involved in depression. In euthymia,
normal dynamic regulation by
the dorsal prefrontal cortex involved in
executive functioning seems to inhibit
the amygdala in a counterexcitatory
manner halfway from the ventral prefrontal
cortex. The ventral prefrontal
cortex is involved in exciting the
amygdala as a result of emotional
stimuli and is regulated by the hippocampus.
The normal role of the amygdala is
to compare external sensory events
with internal memory events. If something
causes fear or is traumatic, the
amygdala responds with stress and
fear. However, the amygdala is also
involved in learning tolerance to aversion.
Pathways in the amygdala are
modulated by serotonin from the raphe
nucleus, which tends to decrease the
amygdala’s response to stress, and
norepinephrine from the locus ceruleus,
which, during burst firing, seems
to increase the amygdala’s response to
stress.17 All of these systems are interactive,
explained Dr. Ressler, such that
the amygdala can increase CRH release
into the locus ceruleus, thereby
increasing norepinephrine levels, and
the locus ceruleus and raphe nucleus
counterinhibit each other.
In states of depression, the amygdala
appears to be hyperactive, with
decreased activation of the dorsal prefrontal
cortex, which normally inhibits
the amygdala, and perhaps increased
activation of the ventral prefrontal areas,
which normally excite the amygdala.
This dysregulation is consistent
with decreased activation of the raphe,
decreased serotonin release, and increased
release of norepinephrine and
CRH, all of which lead to a state in
which external sensory information is
encoded and responded to as being
more stressful than it would be in a
normal euthymic state, so the animal
responds with a stressful or fearful reaction
and is less likely to be tolerant
to aversion.
Treatments for depression affect
this pathophysiology in different ways.
For example, SSRIs affect the system
through the serotonin pathway, selective
norepinephrine reuptake inhibitors
through the norepinephrine pathway,
and electroconvulsive therapy potentially
through the interactions of the
cortical areas with these limbic areas.
It is also possible that psychotherapy
plays a role in enhancing dorsal
prefrontal cortex control over the
amygdala.
Dr. Ressler concluded with the
following hypothesis: remission from
major depression occurs when correction
of one disrupted circuit, such as
the serotonin system, with a specific
treatment, such as an SSRI, leads to
the correction of the dysregulation of
the neural circuits. Treatment resistance
and partial response occur when
one disrupted circuit is corrected, but
the other circuits fail to be normalized.
REFERENCES
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3. Zhu MY, Klimek V, Dilley GE, et al.
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6. Salomon RM, Ripley B, Kennedy JS, et al.
Diurnal variation of cerebrospinal fluid
hypocretin-1 (Orexin-A) levels in control
and depressed subjects. Biol Psychiatry
2003;54:96–104
7. Sheline YI, Wang PW, Gado MH, et al.
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8. Sheline YI, Shanghavi M, Mintun MA, et
al. Depression duration but not age predicts
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157:115–118
10. Steffens DC, Byrum CE, McQuoid DR,
et al. Hippocampal volume in geriatric depression.
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11. Vythilingam M, Heim C, Newport J, et al.
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12. Nestler EJ, McMahon A, Sabban EL, et al.
Chronic antidepressant administration decreases
the expression of tyrosine hydroxylase
in the rat locus coeruleus. Proc Natl
Acad Sci U S A 1990;87:7522–7526
13. Blier P, Bouchard C. Modulation of 5-HT
release in the guinea-pig brain following
long-term administration of antidepressant
drugs. Br J Pharmacol 1994;113:485–495
14. Chen B, Dowlatshahi D, MacQueen GM,
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in subjects treated with antidepressant
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2001;50:260–265
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(suppl 1):2–19© COPYRIGHT 2004 PHYSICIANS POSTGRADUATE
J Clin Psychiatry 65:9, September 2004
his ACADEMIC HIGHLIGHTS section of The
Journal of Clinical Psychiatry presents
the highlights of the teleconference
“Enhancing Treatment Response in
Depression” held May 18, 2004, and supported
by an unrestricted educational grant from
Cephalon, Inc.
This teleconference was chaired by
Philip T. Ninan, M.D., Mood and Anxiety
Disorders Program, Emory University School
of Medicine, Atlanta, Ga. The faculty were
Maurizio Fava, M.D., Depression Clinical
and Research Program, Massachusetts General
Hospital, Boston, and Kerry J. Ressler, M.D.,
Ph.D., Department of Psychiatry and Behavioral
Sciences, Emory University School of Medicine,
and the Yerkes Primate Research Center,
Atlanta, Ga.
Continuing Medical Education
Faculty Disclosure
In the spirit of full disclosure and in
compliance with all ACCME Essential Areas
and Policies, the faculty for this CME activity
were asked to complete a full disclosure
statement.
The information received is as follows:
Dr. Ninan is an employee of Emory University;
is a consultant for Cephalon, Eli Lilly, Forest,
Janssen, Solvay, Wyeth, and UCB Pharma; has
received research grant support from Cephalon,
Cyberonics, Eli Lilly, Forest, Janssen, and
Glaxo; and has received honoraria from and is
on the speakers or advisory board for Cephalon,
Forest, GlaxoSmithKline, Janssen, Pfizer, and
Wyeth. Dr. Ressler has received research grant
support from Pfizer and has received honoraria
from Cephalon. Dr. Fava has received research
support from Abbott, Lichtwer Pharma GmbH,
and Lorex; has received honoraria from Bayer
AG, Compellis, Janssen, Knoll Pharmaceutical,
Lundbeck, and Somerset; and has received both
research grant support and honoraria from
Aspect Medical Systems, AstraZeneca, Bristol-
Myers Squibb, Cephalon, Eli Lilly, Forest,
GlaxoSmithKline, Johnson & Johnson, Novartis,
Organon, Pharmavite, Pfizer, Roche, Sanofi-
Synthelabo, Solvay, and Wyeth.
The opinions expressed herein are those
of the authors and do not necessarily reflect the
views of the CME provider and publisher or the
commercial supporter.
poster:jrbecker
thread:390747
URL: http://www.dr-bob.org/babble/20040915/msgs/391473.html