![[dr. bob]](/dr-bob-sm.gif)
Dr. Bob is Robert Hsiung, MD,
bob@dr-bob.orgShown: posts 1 to 25 of 26. This is the beginning of the thread.
Posted by steve12 on September 14, 2004, at 16:44:12
I'm on my 5th week of Cymbatla (60 mgs). Initially, Cymbalta had few side effects and controlled my anxiety. But within the past 10 days, the side effects have really picked up (sexual, sweating [a lot!]) and I feel anxious. In some ways I'm not suprised -- each new AD comes along with a lot of promises that generally don't pan out. I'm meeting with my doc next week and I'm considering 3 different routes:
1. Reduce Cymbalta to 40 mgs;
2. Return to Effexor
3. Go to Prozac -- which worked great for me in the past but I had a lot of side-effects (but I was on a high dose then, I wouldn't need that now)What do people think?
Posted by SLS on September 14, 2004, at 17:23:26
In reply to Cymbalta honeymoon is over, posted by steve12 on September 14, 2004, at 16:44:12
Hi Steve.
I'm sorry to hear that you are experiencing some disappointing side effects. Is the drug helping at all?
- Scott
Posted by steve12 on September 14, 2004, at 19:06:51
In reply to Re: Cymbalta honeymoon is over, posted by SLS on September 14, 2004, at 17:23:26
Hi Scott,
Yes, my mood is good and I'm less anxious in the evening (maybe bid dosing is better?). Also, to be perfectly frank, the sexual side effects are not as bad as other agents (but still there). For me, the sweating is really unbearable (probably the NE reuptake -- but I had it with prozac too, so maybe not). Since I'm a professional, I cannot tolerate having my shirts and suit drenched in sweat. I'm suprised that there isn't more literature on this with AD.
I may try the 40 mg dose -- it's just such a gamble: go another 10 weeks into the unknown or return to a drug that I know works, but has side effects.
Steve
> Hi Steve.
>
> I'm sorry to hear that you are experiencing some disappointing side effects. Is the drug helping at all?
>
>
> - Scott
Posted by alesta on September 15, 2004, at 3:25:33
In reply to Cymbalta honeymoon is over, posted by steve12 on September 14, 2004, at 16:44:12
hi,steve,:)
if it hasn't worked by now, it's not going to..it doesn't have a long half-life like the SSRIs..it's supposed to take only 2 to 3 weeks to work..i would start tapering slowly down now, b/c you might be in for a bumpy ride due to discontinuation syndrome..
and i would pick a med that includes enhancement of dopamine or gaba or both..i don't believe serotonin or norepinephrine alone tend to be very helpful for anxiety..
an added note: i believe many depressives might need dopaminergic meds as well (as well as norepinephrene enhancement for energy)..but that is speculation on my part...i think serotonin may not play a very important role in mood, but more, perception..but that is just a theory..
amy:)
Posted by yznhymer on September 15, 2004, at 4:35:11
In reply to Re: Cymbalta honeymoon is over, posted by steve12 on September 14, 2004, at 19:06:51
> Hi Scott,
>
> Yes, my mood is good and I'm less anxious in the evening (maybe bid dosing is better?). Also, to be perfectly frank, the sexual side effects are not as bad as other agents (but still there). For me, the sweating is really unbearable (probably the NE reuptake -- but I had it with prozac too, so maybe not). Since I'm a professional, I cannot tolerate having my shirts and suit drenched in sweat. I'm suprised that there isn't more literature on this with AD.
>
> I may try the 40 mg dose -- it's just such a gamble: go another 10 weeks into the unknown or return to a drug that I know works, but has side effects.
>
> Steve
>
>
>
> > Hi Steve.
> >
> > I'm sorry to hear that you are experiencing some disappointing side effects. Is the drug helping at all?
> >
> >
> > - Scott
>
>Steve...
Sorry about your dilemma. It is all too familiar. Hear what your doc has to say. I think I would be inclined to play around with the dosage before switching to another drug at this point, especially since the options you mention also pack similar side effects to the ones dogging you now. What would be the advantage of switching? Prozac yielded sweats and sexual dysfunction for you as well. I don't think you should have to commit to another 10 weeks of misery, though. There should be a way to consult with your pdoc by phone before your next office visit to switch gears if the lower dose of cymbalta doesn't do the trick.
Good luck,
Mark
Posted by Mistermindmasta on September 15, 2004, at 21:38:23
In reply to Re: Cymbalta honeymoon is over » steve12, posted by alesta on September 15, 2004, at 3:25:33
> hi,steve,:)
>
> if it hasn't worked by now, it's not going to..it doesn't have a long half-life like the SSRIs..it's supposed to take only 2 to 3 weeks to work..i would start tapering slowly down now, b/c you might be in for a bumpy ride due to discontinuation syndrome..
>
> and i would pick a med that includes enhancement of dopamine or gaba or both..i don't believe serotonin or norepinephrine alone tend to be very helpful for anxiety..
>
> an added note: i believe many depressives might need dopaminergic meds as well (as well as norepinephrene enhancement for energy)..but that is speculation on my part...i think serotonin may not play a very important role in mood, but more, perception..but that is just a theory..
>
> amy:)
>Actually, if you look at anxiety as being a "brain circuit" based problem as opposed to a "neurotransmitter" based problem, you see that serotonin and norepinephrine play a role. Anxiety is thought to mostly stem from increased activation of the amygdala. Increased GABA transmission slows firing in the amygdala. On the other hand, increasing firing of the serotonin 1a receptor also increases GABA activity in the amygdala, thus indirectly lowering anxiety (after a few weeks). How norepinephrine reuptake inhibitors lower anxiety is beyond me. I suspect that it might have to do with the prefrontal cortex... increasing NE there will lower activity in the amygdala. I might be wrong on that one, though.
Posted by alesta on September 15, 2004, at 23:16:34
In reply to Re: Cymbalta honeymoon is over, posted by Mistermindmasta on September 15, 2004, at 21:38:23
hi, mmm,:)
i knew i'd take some hits for my post on this topic.:) well, being as researchers themselves haven't figured out the exact cause of anxiety disorders, either, it makes sense for us to be having this discussion. through my research, i have seen dopamine, serotonin, and gaba, mentioned repeatedly as being possibly implicated in anxiety disorders. i have especially seen dopamine come up repeatedly, and gaba's impact on anxiety is obvious. i personally think serotonin plays a minor role, if at all, as i have taken an SSRI myself and received little or no alleviation of my anxiety. i think for the people SSRIs are effective for for anxiety (and i don't think there are that many), i believe it works *through abnormal means*--numbing of emotions. this to me is not a valid way of decreasing anxiety. these are just my opinions..i could definitely be wrong, too.:)
amy:)
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
1. Aston-Jones G, Chiang C, Alexinsky T.
Discharge of noradrenergic locus coeruleus
neurons in behaving rats and monkeys suggests
a role in vigilance. Prog Brain Res
1991;88:501–520
2. Fornal CA, Metzler CW, Marrosu F, et al.
A subgroup of dorsal raphe serotonergic
neurons in the cat is strongly activated during
oral-buccal movements. Brain Res
1996;716:123–133
3. Zhu MY, Klimek V, Dilley GE, et al.
Elevated levels of tyrosine hydroxylase
in the locus coeruleus in major depression.
Biol Psychiatry 1999;46:1275–1286
4. Geracioti TD Jr, Loosen PT, Ekhator NN,
et al. Uncoupling of serotonergic and
noradrenergic systems in depression:
preliminary evidence from continuous
cerebrospinal fluid sampling. Depress
Anxiety 1997;6:89–94
5. Raadsheer FC, Hoogendijk WJ, Stam FC,
et al. Increased numbers of corticotrophinreleasing
hormone expressing neurons in
the hypothalamic paraventricular nucleus
of depressed patients. Neuroendocrinology
1994;60:436–444
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.
Hippocampal atrophy in recurrent major
depression. Proc Natl Acad Sci U S A
1996;93:3908–3913
8. Sheline YI, Shanghavi M, Mintun MA, et
al. Depression duration but not age predicts
hippocampal volume loss in medically
healthy women with recurrent major depression.
J Neurosci 1999;19:5034–5043
9. Bremner JD, Narayan M, Anderson ER,
et al. Hippocampal volume reduction in
major depression. Am J Psychiatry 2000;
157:115–118
10. Steffens DC, Byrum CE, McQuoid DR,
et al. Hippocampal volume in geriatric depression.
Biol Psychiatry 2000;48:301–309
11. Vythilingam M, Heim C, Newport J, et al.
Childhood trauma associated with smaller
hippocampal volume in women with major
depression. Am J Psychiatry 2002;159:
2072–2080
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,
et al. Increased hippocampal BDNF immunoreactivity
in subjects treated with antidepressant
medication. Biol Psychiatry
2001;50:260–265
15. Duman RS. Synaptic plasticity and mood
disorders. Mol Psychiatry 2002;7(suppl 1):
S29–S34
16. Santarelli L, Saxe M, Gross C, et al. Requirement
of hippocampal neurogenesis for
the behavioral effects of antidepressants.
Science 2003;301:805–809
17. Ressler KJ, Nemeroff CB. Role of serotonergic
and noradrenergic systems in the
pathophysiology of depression and anxiety
disorders. Depress Anxiety 2000;12
(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.
Posted by steve12 on September 16, 2004, at 11:35:36
In reply to Re: Cymbalta honeymoon is over » Mistermindmasta, posted by alesta on September 15, 2004, at 23:16:34
I think 5HT is involved in anxiety -- certainly for most people, paxil, prozac, etc relieve anxiety. I would agree that dopamine stimulation is underused in depression -- but for a different reason. Thers is emerging evidence that chronic administration of SSRI's may downregulate DA receptors, which may account for the cognitive fuzzieness that many depressives report. Often, doc's will augment SSRI's with Wellbutrin for this -- but Wellbutrin really acts on NE not DA. Really, only stimuants will do the trick.
I think that NE (and cymbalta's re-uptake of it) is repsonsible for the anxiety that many experience. But that's just my 2 cents :)
Posted by alesta on September 16, 2004, at 12:03:28
In reply to Re: neurotransmitter systems in MDD, posted by jrbecker on September 16, 2004, at 10:12:49
Posted by alesta on September 16, 2004, at 12:14:42
In reply to Re: Cymbalta honeymoon is over, posted by steve12 on September 16, 2004, at 11:35:36
> I think 5HT is involved in anxiety -- certainly for most people, paxil, prozac, etc relieve anxiety.
well, i have already explained why i think SSRIs are mostly helpful for some for anxiety. emotional numbness..don't feel pleasure, pain, anxiety, etc.
<I would agree that dopamine stimulation is underused in depression -- but for a different reason. Thers is emerging evidence that chronic administration of SSRI's may downregulate DA receptors, which may account for the cognitive fuzzieness that many depressives report.
>
> I think that NE (and cymbalta's re-uptake of it) is repsonsible for the anxiety that many experience. But that's just my 2 cents :)so you're saying that the main neurotransmitters involved with anxiety are serotonin and norepinephrine? you are discounting lots of current research on the importance of dopamine and gaba.
and concerning norepinephrine's role in anxiety, i have compared the success rate of effexor and the success rate of prozac (an SSRI) for anxiety, and it was *exactly that same*. if norepinephrine played a significant role then you would expect the success rate to increase with effexor. but i admittedly am still unsure about norepinephrine...
amy
Posted by alesta on September 16, 2004, at 12:59:06
In reply to Cymbalta honeymoon is over, posted by steve12 on September 14, 2004, at 16:44:12
steve,
please just go with what you think is best. we're all just speculating here, and i was just trying to help (and hoped my response would be appreciated).amy
Posted by alesta on September 16, 2004, at 17:44:05
In reply to Cymbalta honeymoon is over, posted by steve12 on September 14, 2004, at 16:44:12
> I'm on my 5th week of Cymbatla (60 mgs). Initially, Cymbalta had few side effects and controlled my anxiety. But within the past 10 days, the side effects have really picked up (sexual, sweating [a lot!]) and I feel anxious. In some ways I'm not suprised -- each new AD comes along with a lot of promises that generally don't pan out. I'm meeting with my doc next week and I'm considering 3 different routes:
>
> 1. Reduce Cymbalta to 40 mgs;
> 2. Return to Effexor
> 3. Go to Prozac -- which worked great for me in the past but I had a lot of side-effects (but I was on a high dose then, I wouldn't need that now)
>
> What do people think?hi, steve,
i just reread your original post again. i am very fuzzy here lately due to food-deprivation (over the last 48 hours), so sorry about that. for that reason i think i'm gonna take a break from posting, lol. most of my views on the neurotransmitters still stand, but, anyway, looking at your personal situation, you had indicated that you had done well on an SSRI and cymbalta previously, so..to reanswer your question according to the options you listed, i would reduce to 40 mg first. i doubt you're still interested in my opinion at this point, but i just wanted to share that anyway. i was wrong not to take your personal response to these drugs into account. i should probably say more, but i honestly can't think at this point..amy:)
Posted by alesta on September 28, 2004, at 12:04:34
In reply to Cymbalta honeymoon is over, posted by steve12 on September 14, 2004, at 16:44:12
I now see that I made a mistake concerning serotonin’s role in anxiety, as I now think that it can definitely play an important role in anxiety. I didn’t see its importance, in part, due to my research concerning 5-htp’s not having much effect on anxiety for many people. However, I recently researched l-tryptophan, and see how, in contrast, it can work pretty well for anxiety. Here is some information that will shed some light as to why l-tryptophan is more effective for serotonin enhancement than 5-htp:
"L-Tryptophan and 5-HTP - How to decide which is right for you. Some people are helped by 5-HTP, others are not. There are several reasons for these differences that can help in deciding which is right for you.
1. The body remains in control with L-Tryptophan, but does not with 5HTP. The creation of neurotransmitter serotonin begins with L-Tryptophan which converts to 5HTP, which converts to serotonin. The rate-limiting step (the step the body uses to regulate serotonin production) is between L-Tryptophan and 5HTP. If you take 5HTP your body looses control of the serotonin pathway.
2. 5HTP converts to serotonin outside the brain. Since the conversion of 5HTP to serotonin is not regulated some of the 5HTP converts to serotonin in the gut, causing upset and nausea. Since serotonin does not cross the blood-brain barrier, serotonin produced outside the brain is not available to the brain. In Europe, 5HTP is combined with carbidopa, a pharmaceutical drug that reduces conversion of 5HTP to serotonin outside the brain. This is rarely done in the U.S.
3. Disease impairs 5HTP transport across the blood-brain barrier. In people with certain diseases, including severe depression, there is blockage of the transmission of 5HTP across the blood-brain barrier. In these patients supplementation with L-Tryptophan, which does cross the blood-brain barrier, can provide increased brain serotonin levels.
4. Unlike 5HTP L-Tryptophan has many other uses in the body. It can be converted to niacin. It is a required precursor to the kynurenines, a family of biochemicals that help regulate the immune system. As an essential amino acid, L-Tryptophan is required for your body to work properly.
Even though L-Tryptophan and 5HTP are metabolized to serotonin along the same biochemical pathway, individual differences in metabolism can cause significant differences in effectiveness.L-Tryptophan 5HTP
Body regulates conversion to serotonin Conversion is unregulated
Body controls WHERE conversion occurs Partially converts to serotonin in the gut and blood, not the brain
Cross the blood-brain barrier in sickness and health Disease blocks the absorption process
L-Tryptophan is an essential amino acid 5HTP is not essential
Utilized in many body functions Can convert to serotonin only"(I am not suggesting that serotonin alone can fully treat many anxiety disorders, but merely that it can play a role in anxiety. For instance, I don’t think SSRIs are sufficient to treat many anxiety disorders (although they help some people), and therefore other options are often necessary e.g. benzos, MAOIs, etc. (I also personally don’t prefer the SSRIs due to emotional numbness, anhedonia, akathesia, sexual side effects, etc., although some people find them tolerable.) )
Note: to anyone considering trying l-tryptophan, I think it might tend to poop out after a month or so. So it might be best used periodically, perhaps...
Another interesting note: I don’t know if this is true or not, but “For about 11 years now, Dr. Ann Blake Tracy (Prozac: Panacea or Pandora?), persistently warns the public against raising serotonin levels. Doctor Tracy has taught us that an increase in serotonin produces rushes of insulin dropping sugar levels and chemically inducing hypoglycemia (low blood sugar) in this way. Furthermore it has been established that too much serotonin damages blood vessels, particularly in the lungs, and may also harm heart valves. This would be due to the fact that serotonin is a powerful vasoconstrictor.” So, if this is true, perhaps it is unhealthy to vastly raise serotonin solely instead of raising it in moderation with several other neurotransmitters.
Amy
Posted by steve12 on September 28, 2004, at 14:59:47
In reply to serotonin's role in anxiety, posted by alesta on September 28, 2004, at 12:04:34
Very intresting! My observations on 5HT and anxiety is due to the fact that most people do report reduced anxiety on SSRI's. I think you were correct that glutamate and, perhaps DA, may also play a role -- but frankly that body of research is not compelling at this point. In addition, administration of stimulants in healthy people has long been know to induce panic. However, what is very interesting in my judgment is the emerging understanding of how, for instance, use of SSRI's can downregulate DA receptors in the forebrain; suggesting that when we tinker with neurotransmitters we often have no idea of the entire impact on the brain. Another intresting area is the understanding of ratio's of neurotransmitters -- for instance, Effexor and Cymbalta both work on 5HT/NE but in different ratios and their effects are quite different.
As for Dr. Tracy's statements -- has this been supported in peer reviewed journals? There are a lot of anti-pharm books out there that, in my opinion, are simply trying to make a $. Are we really to believe that use of SSRI's is strongly associated with hypoglycemia and... then diabetes? I'm not aware of a single study that has shown this to be true.
One interesting note: I am now at Cymbalta 40 and Concerta 18 and I'm really enjoying life! No anxiety and few sexual side effects -- so perhaps DA does lower anxiety?
Steve
> I now see that I made a mistake concerning serotonin’s role in anxiety, as I now think that it can definitely play an important role in anxiety. I didn’t see its importance, in part, due to my research concerning 5-htp’s not having much effect on anxiety for many people. However, I recently researched l-tryptophan, and see how, in contrast, it can work pretty well for anxiety. Here is some information that will shed some light as to why l-tryptophan is more effective for serotonin enhancement than 5-htp:
>
> "L-Tryptophan and 5-HTP - How to decide which is right for you. Some people are helped by 5-HTP, others are not. There are several reasons for these differences that can help in deciding which is right for you.
> 1. The body remains in control with L-Tryptophan, but does not with 5HTP. The creation of neurotransmitter serotonin begins with L-Tryptophan which converts to 5HTP, which converts to serotonin. The rate-limiting step (the step the body uses to regulate serotonin production) is between L-Tryptophan and 5HTP. If you take 5HTP your body looses control of the serotonin pathway.
> 2. 5HTP converts to serotonin outside the brain. Since the conversion of 5HTP to serotonin is not regulated some of the 5HTP converts to serotonin in the gut, causing upset and nausea. Since serotonin does not cross the blood-brain barrier, serotonin produced outside the brain is not available to the brain. In Europe, 5HTP is combined with carbidopa, a pharmaceutical drug that reduces conversion of 5HTP to serotonin outside the brain. This is rarely done in the U.S.
> 3. Disease impairs 5HTP transport across the blood-brain barrier. In people with certain diseases, including severe depression, there is blockage of the transmission of 5HTP across the blood-brain barrier. In these patients supplementation with L-Tryptophan, which does cross the blood-brain barrier, can provide increased brain serotonin levels.
> 4. Unlike 5HTP L-Tryptophan has many other uses in the body. It can be converted to niacin. It is a required precursor to the kynurenines, a family of biochemicals that help regulate the immune system. As an essential amino acid, L-Tryptophan is required for your body to work properly.
> Even though L-Tryptophan and 5HTP are metabolized to serotonin along the same biochemical pathway, individual differences in metabolism can cause significant differences in effectiveness.
>
> L-Tryptophan 5HTP
> Body regulates conversion to serotonin Conversion is unregulated
> Body controls WHERE conversion occurs Partially converts to serotonin in the gut and blood, not the brain
> Cross the blood-brain barrier in sickness and health Disease blocks the absorption process
> L-Tryptophan is an essential amino acid 5HTP is not essential
> Utilized in many body functions Can convert to serotonin only"
>
> (I am not suggesting that serotonin alone can fully treat many anxiety disorders, but merely that it can play a role in anxiety. For instance, I don’t think SSRIs are sufficient to treat many anxiety disorders (although they help some people), and therefore other options are often necessary e.g. benzos, MAOIs, etc. (I also personally don’t prefer the SSRIs due to emotional numbness, anhedonia, akathesia, sexual side effects, etc., although some people find them tolerable.) )
>
> Note: to anyone considering trying l-tryptophan, I think it might tend to poop out after a month or so. So it might be best used periodically, perhaps...
>
> Another interesting note: I don’t know if this is true or not, but “For about 11 years now, Dr. Ann Blake Tracy (Prozac: Panacea or Pandora?), persistently warns the public against raising serotonin levels. Doctor Tracy has taught us that an increase in serotonin produces rushes of insulin dropping sugar levels and chemically inducing hypoglycemia (low blood sugar) in this way. Furthermore it has been established that too much serotonin damages blood vessels, particularly in the lungs, and may also harm heart valves. This would be due to the fact that serotonin is a powerful vasoconstrictor.” So, if this is true, perhaps it is unhealthy to vastly raise serotonin solely instead of raising it in moderation with several other neurotransmitters.
>
> Amy
>
>
Posted by steve12 on September 28, 2004, at 15:06:45
In reply to Re: Cymbalta honeymoon is over » steve12, posted by alesta on September 16, 2004, at 12:14:42
See below:
>
> so you're saying that the main neurotransmitters involved with anxiety are serotonin and norepinephrine? you are discounting lots of current research on the importance of dopamine and gaba.
>
> and concerning norepinephrine's role in anxiety, i have compared the success rate of effexor and the success rate of prozac (an SSRI) for anxiety, and it was *exactly that same*. if norepinephrine played a significant role then you would expect the success rate to increase with effexor. but i admittedly am still unsure about norepinephrine...
>But that data is all from the drug companies, right? Can you trust that? Plus, if NE leads to anxiety, anxiety would be *higher* with Effexor, which many clinicans report is, in fact, the case.
Posted by steve12 on September 28, 2004, at 15:08:47
In reply to Re: Cymbalta honeymoon is over » steve12, posted by alesta on September 16, 2004, at 17:44:05
I value your thoughts! Let's face it, at this point it's all trial and error in AD's b/c we really have little idea of how they work :)
> > I'm on my 5th week of Cymbatla (60 mgs). Initially, Cymbalta had few side effects and controlled my anxiety. But within the past 10 days, the side effects have really picked up (sexual, sweating [a lot!]) and I feel anxious. In some ways I'm not suprised -- each new AD comes along with a lot of promises that generally don't pan out. I'm meeting with my doc next week and I'm considering 3 different routes:
> >
> > 1. Reduce Cymbalta to 40 mgs;
> > 2. Return to Effexor
> > 3. Go to Prozac -- which worked great for me in the past but I had a lot of side-effects (but I was on a high dose then, I wouldn't need that now)
> >
> > What do people think?
>
> hi, steve,
> i just reread your original post again. i am very fuzzy here lately due to food-deprivation (over the last 48 hours), so sorry about that. for that reason i think i'm gonna take a break from posting, lol. most of my views on the neurotransmitters still stand, but, anyway, looking at your personal situation, you had indicated that you had done well on an SSRI and cymbalta previously, so..to reanswer your question according to the options you listed, i would reduce to 40 mg first. i doubt you're still interested in my opinion at this point, but i just wanted to share that anyway. i was wrong not to take your personal response to these drugs into account. i should probably say more, but i honestly can't think at this point..
>
> amy:)
>
Posted by alesta on September 29, 2004, at 3:53:34
In reply to Re: Cymbalta honeymoon is over » alesta, posted by steve12 on September 28, 2004, at 15:08:47
hi, steve,:)
thanks for your replies! i appreciate that.:) this is an interesting discussion...:)
yes, i absolutely agree, as i said in my last post, SSRIs can work well for anxiety. (although not effective enough for some.) i just
wondered if it was due to the emotional numbness or to the serotonin. that's why i wanted to seek more evidence with serotonin enhancers that didn't have the emotional numbness as a side effect.i'm not totally sure about dopamine, either.:) and i have no idea whether all these studies are from the drug companies or not. is there any way to tell which ones are by the drug cos.? (sorry if that is a dumb question.:)) although, studies aside, here is some strong evidence in favor of dopamine's role in anxiety. on remedyfind (which has patient ratings of various meds), parnate has an *excellent* rating for anxiety disorders.
it got a whopping 9.5 rating for effectiveness! check it out. while imipramine only rated a 4.5 and effexor rated a 6.4 (effexor might be more "high-powered" than imipramine). imipramine and effexor affect serotonin and norepinephrine. (the only difference between them and parnate is the lack of effect on *dopamine*.)
also, here is a great post i saw on PB from kregpark. it talks specifically about social anxiety. i don't know how much merit there is to these studies and such, but it is interesting!.."One more on DOPAMINE:
More evidence linking SP with low DOPAMINE:
Those with SP are 5 times more likely to
get Parkinson's in later life, according to
at least one large well done study I saw.Two studies looking at brains (Couldn't say how
the 2nd but first was MRI I think) showed SP
folks had dysufnctional (causing low dopamine)
D2 receptors in striatum in 1 study and don't
recall the other study exactly.SMOKING: 5 times lower rate of Parkinson's in
heavy smokers (lung cancer get them instead!!!)
This is well established in AMA books etc.CAFFIENE: Recent studies (made Newsweek cover or
was it US NW Report?) show more coffee each
day lower Parkinson's risk with heaviest coffee
drinkers 5 times LESS likely to get Parksinson's.
(I've always LOVED LOTS of caffiene - am I
self medicating low dopamine levels?)(Rick: I recall that you don't benefit much or
maybe negatively from caffiene? I thought you
mentioned some panic type symtoms occasionally
also? Anyway my comment was just that studies
show than PANIC DISORDER patients respond with
ANXIETY TO CAFFIENE and SOCIAL PHOBIA patients
(no panic disorder) DO NOT normally get anxiety.Also Panic Disorder responds to imipramine
(no DOPAMINE++, SP does not), but BOTH respond
to Nardil very well (similar to imipramine but
with DOPAMINE ++ ).KregPark"
<As for Dr. Tracy's statements -- has this been supported in peer reviewed journals? There are a lot of anti-pharm books out there that, in my opinion, are simply trying to make a $. Are we really to believe that use of SSRI's is strongly associated with hypoglycemia and... then diabetes? I'm not aware of a single study that has shown this to be true.
good point, steve! i don't know.
> and concerning norepinephrine's role in anxiety, i have compared the success rate of effexor and the success rate of prozac (an SSRI) for anxiety, and it was *exactly that same*. if norepinephrine played a significant role then you would expect the success rate to increase with effexor. but i admittedly am still unsure about norepinephrine...
<But that data is all from the drug companies, right? Can you trust that? Plus, if NE leads to anxiety, anxiety would be *higher* with Effexor, which many clinicans report is, in fact, the case.
no, that data is not from drug companies. it is from my comparisons of patient ratings on remedyfind. also, i didn't say that NE leads to anxiety, only that i don't think it *helps* anxiety.
<I value your thoughts!
thanks..i value yours, too! this thread has been very educational!
you take care,:)
amy
Posted by theo on September 30, 2004, at 9:33:33
In reply to Re: serotonin's role in anxiety, posted by steve12 on September 28, 2004, at 14:59:47
How do you like Concerta? Have you ever tried Adderall XR?
I've never taken a stimulant and my pdoc is going to start me on one or the other and with anxiety, I want the one least likely to cause it. Any input?
Posted by mxrider on October 1, 2004, at 9:24:36
In reply to Re: serotonin's role in anxiety » steve12, posted by theo on September 30, 2004, at 9:33:33
> How do you like Concerta? Have you ever tried Adderall XR?
>
> I've never taken a stimulant and my pdoc is going to start me on one or the other and with anxiety, I want the one least likely to cause it. Any input?Sorry to butt in...I have SP as well, I am on a trial of Concerta 18mg/ day to help w/ ADD symtoms. I had some mild anxiety in the first day or two, but other than that it seems very smooth and easy to tolerate.
Hope this helps.
Posted by alesta on October 1, 2004, at 15:10:39
In reply to Re: Cymbalta honeymoon is over » steve12, posted by alesta on September 29, 2004, at 3:53:34
> yes, i absolutely agree, as i said in my last post, SSRIs can work well for anxiety. (although not effective enough for some.) i just
> wondered if it was due to the emotional numbness or to the serotonin.
concerning the quote of what i wrote above:
i just wanted to make it very clear to anyone who reads this thread that i am *not* a big fan of the SSRIs..just because they can somewhat help anxiety does not mean they're a great med..they raise serotonin at the expense of dopamine..not cool, in my opinion. to name one alternative, parnate is awesome for anxiety disorders (maybe not *quite* as good for social anxiety), as well as klonopin and other benzos. parnate is i think about 30% more effective than the SSRIs for most anxiety disorders.amy:)
Posted by Dave001 on October 3, 2004, at 20:54:55
In reply to serotonin's role in anxiety, posted by alesta on September 28, 2004, at 12:04:34
> way. Furthermore it has been established that too much serotonin damages blood vessels, particularly in the lungs, and may also harm heart valves. This would be due to the fact that serotonin is a powerful vasoconstrictor.” So, if
Although this could theoretically be of concern with 5-HTP supplementation, anti-depressant drugs such as the SSRIs are active in the CNS but don't affect peripheral serotonin concentrations or activity. Thus, you don't need to worry about SSRIs causing the above problems.
Dave
Posted by steve12 on October 3, 2004, at 21:14:51
In reply to Re: serotonin's role in anxiety » steve12, posted by theo on September 30, 2004, at 9:33:33
I like Concerta -- never tried Adderall. My advise whichever you choose is to start on a small dose (Concerta = 18 mg). Good luck!
> How do you like Concerta? Have you ever tried Adderall XR?
>
> I've never taken a stimulant and my pdoc is going to start me on one or the other and with anxiety, I want the one least likely to cause it. Any input?
Posted by steve12 on October 3, 2004, at 21:17:40
In reply to just 1 more comment for clarity to anyone reading, posted by alesta on October 1, 2004, at 15:10:39
Understood (re: SSRI), but does not Parnate raise 5HT levels as well? Perhaps it's not 5HT, but the mechanism by which its raised?
>
> > yes, i absolutely agree, as i said in my last post, SSRIs can work well for anxiety. (although not effective enough for some.) i just
> > wondered if it was due to the emotional numbness or to the serotonin.
>
> concerning the quote of what i wrote above:
> i just wanted to make it very clear to anyone who reads this thread that i am *not* a big fan of the SSRIs..just because they can somewhat help anxiety does not mean they're a great med..they raise serotonin at the expense of dopamine..not cool, in my opinion. to name one alternative, parnate is awesome for anxiety disorders (maybe not *quite* as good for social anxiety), as well as klonopin and other benzos. parnate is i think about 30% more effective than the SSRIs for most anxiety disorders.
>
> amy:)
Posted by alesta on October 3, 2004, at 21:46:43
In reply to Re: serotonin's role in anxiety, posted by Dave001 on October 3, 2004, at 20:54:55
hi, dave,:)
i'm sure glad I added the phrase "I don’t know if this is true or not" when i added that quote. :)
thank you very much for providing info concerning this topic!
take care!:)
amy
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