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Dr. Bob is Robert Hsiung, MD,
bob@dr-bob.orgShown: posts 84 to 108 of 139. Go back in thread:
Posted by linkadge on April 9, 2006, at 14:34:05
In reply to Re: Drugs versus Psychotherapy - Backlash? » linkadge, posted by ed_uk on April 9, 2006, at 12:51:29
Its all about doing your best.
Linkadge
Posted by linkadge on April 9, 2006, at 14:46:50
In reply to Re: Drugs versus Psychotherapy - Backlash?, posted by SLS on April 9, 2006, at 13:20:51
> Perhaps placebo responce to drugs goes down as severe depression goes up, but so does responce to active drugs.
What I mean was...responce to active drugs goes down as sevarity of depression goes up. But then I already see you disagree.
I would think that is the same with a lot of severe mentall illnesses. Ie severe schizophrenia generally has a poor long term outcome with drugs. Severe bipolar and severe parkinsons generally fare poorly on drugs alone.
I guess I don't really have data on that claim, I would just assume.
Linkadge
Posted by linkadge on April 9, 2006, at 14:49:18
In reply to Re: Drugs versus Psychotherapy - Backlash?, posted by SLS on April 9, 2006, at 13:24:25
I just have a hard time thinking that these drugs are solving underlying biochemical abnormalities when we don't know the underlying abnormalities in "endogenious" depression.
Linkadge
Posted by Squiggles on April 9, 2006, at 14:52:35
In reply to Re: Drugs versus Psychotherapy - Backlash?, posted by linkadge on April 9, 2006, at 14:49:18
> I just have a hard time thinking that these drugs are solving underlying biochemical abnormalities when we don't know the underlying abnormalities in "endogenious" depression.
>I'm not sure they are solving them - that would
be taking you to a perfectly "normal" state - but
they are taking you out of depression and
allowing you to cope and live a moderately
comfortable life, with the exception of a few
bad moments or days, or months sometimes.Squiggles
Posted by SLS on April 9, 2006, at 15:12:42
In reply to Re: Drugs versus Psychotherapy - Backlash?, posted by linkadge on April 9, 2006, at 14:46:50
> What I mean was...responce to active drugs goes down as sevarity of depression goes up.
Perhaps, but that the active compound separates itself from placebo becomes clear.
- Scott
Posted by SLS on April 9, 2006, at 15:20:25
In reply to Re: Drugs versus Psychotherapy - Backlash?, posted by linkadge on April 9, 2006, at 14:49:18
> I just have a hard time thinking that these drugs are solving underlying biochemical abnormalities when we don't know the underlying abnormalities in "endogenious" depression.
>
> Linkadge
That's why we must rely on empirical observations. That's basically what the DSM is all about and why must rely on blinded studies with placebo controls.It is frustrating dealing with a black box.
- Scott
Posted by Caedmon on April 9, 2006, at 15:25:52
In reply to Re: Drugs versus Psychotherapy - Backlash?, posted by linkadge on April 9, 2006, at 14:46:50
> What I mean was...responce to active drugs goes down as sevarity of depression goes up. But then I already see you disagree.
>
> I would think that is the same with a lot of severe mentall illnesses. Ie severe schizophrenia generally has a poor long term outcome with drugs. Severe bipolar and severe parkinsons generally fare poorly on drugs alone.
Severe schizophrenia and bipolar have a poor prognosis in general. I'm sure that meds + therapy increase remission or response at least to a degree but primary Tx modality in both cases are drugs. Or anyway, ideally is.(Yes, I know they did some work on CBT and schizophrenia. Longitudinal studies show CBT does very poorly for psychosis. Actually, it does poorly for anxiety disorders too, but that's another story.)
I don't understand the Parkinson's reference. Being a progressive, degenerative neurological movement disorder, I don't know why it's included. (Unless you're talking about comorbid depression?) That's like saying that dementia doesn't respond well to drugs long-term. Well, of course not, it doesn't respond well to *anything* long-term.
- C
Posted by Squiggles on April 9, 2006, at 15:30:20
In reply to Re: Drugs versus Psychotherapy - Backlash?, posted by Caedmon on April 9, 2006, at 15:25:52
That's interesting - it is probably the reason
my doctor said I don't need a psychiatrist.But even in psychotic disorders like bipolar
or brain disorders like amnesias, Alzheimer's
etc., I think that instead of cognitive therapy,
a sympathetic ear might do wonders. People
are still people even when they are sick.Squiggles
Posted by linkadge on April 9, 2006, at 19:45:56
In reply to Re: Drugs versus Psychotherapy - Backlash?, posted by Caedmon on April 9, 2006, at 15:25:52
I guess the connection is that, like with mood disorders, drugs for Parkinson's don't really attack the underlying disease. They may be kickstarting a poorly working system. So if there is such thing as progressive dopaminergic degeneration, why could this not exist with other neurotransmiiter systems. Maybe chronic depression is actually due to progressive dammage to the serotonergic system. (Now I know nothing like that has been proven, but its possible)
There is some evidence that certain treatments for neurological disorders can actually worsen certain of the detectable underlying abnormalities. Ie, Dopa for Parkinsons, Haldol in Schizophrenia.
We are discovering things about the drugs now that we didn't know before. For instance, the TCA's have been avilable for a while, but only recently have warnings been put forward regarding possible exacerbation of suicidality in certain populations.
People just assume that if it has been around long enough that it is safe. Hopefully new technology can verify our assumptions, but perhaps they will verify our fears?
Linkadge
Posted by linkadge on April 9, 2006, at 19:51:39
In reply to Re: Drugs versus Psychotherapy - Backlash? » Caedmon, posted by Squiggles on April 9, 2006, at 15:30:20
Its the same story with drugs like Aricept. Alzheimers is due to plaques and tangles isn't it? Acetylcholinsterase inhibitors only offer symptomatic improvement. If thats your only option then fine, but we do know that other (proactive strategies) can actually put off Alzheimer's onset. Thats more significant.
I hate the idea of becoming a Darth Vader (more machiene now than man). I remember when I was taking like 6 drugs at one point, I was told I'd never see the light of day off drugs. I felt like a freak. My poor brain.Linkadge
Posted by Phillipa on April 9, 2006, at 20:22:47
In reply to Re: Drugs versus Psychotherapy - Backlash?, posted by ed_uk on April 9, 2006, at 12:56:30
Ed I love you my adopted Son and listen to you most of the time. Love PJ XXXXXXXX
Posted by Caedmon on April 9, 2006, at 21:18:11
In reply to Re: Drugs versus Psychotherapy - Backlash? » Squiggles, posted by linkadge on April 9, 2006, at 19:51:39
> Its the same story with drugs like Aricept. Alzheimers is due to plaques and tangles isn't it? Acetylcholinsterase inhibitors only offer symptomatic improvement. If thats your only option then fine, but we do know that other (proactive strategies) can actually put off Alzheimer's onset. Thats more significant.
There is a way to significantly put off dementia? Although I should only think it will provide short-term (i.e. a few years) worth of protection.
Why is that *more* significant? Is it more significant when you are finally an Alzheimer's patient? I don't understand, the dichotomy seems false. Regards,
- C
Posted by ed_uk on April 10, 2006, at 13:44:09
In reply to Re: Drugs versus Psychotherapy - Backlash? » ed_uk, posted by Phillipa on April 9, 2006, at 20:22:47
Thanks PJ! But what did I do?
Ed xxx
Posted by Phillipa on April 10, 2006, at 19:17:56
In reply to Re: Drugs versus Psychotherapy - Backlash? » SLS, posted by ed_uk on April 7, 2006, at 17:24:29
Ed just agreed that excercise is a form of an antidepressant no biggie. Love PJ XXXXX
Posted by linkadge on April 11, 2006, at 15:43:24
In reply to Re: Drugs versus Psychotherapy - Backlash?, posted by Caedmon on April 9, 2006, at 21:18:11
(Don't really know what you are saying)
We do know that certain lifestyles seem to delay the onset of Alzheimer's disease. For instance, lifetime coffee drinkers apparently display lower rates, and less severe onset of dimentia and Alzheimers. Whether this habit has any ability to prevent the underlying structural abnormalities is not certain.
I guess what I am saying is that many of the current treatments do not seem to actually prevent and of the structural changes evident in Alzheimers.
Researchers are following certain leads to try and uncover why the plaques are forming. For instance, GSK-3b inhibitors appear influence some enzyme that is responsible for the formation of the plaques and tangles. Lithium (a GSK-3b inhibitor) appears to block the formation of plaques and tangles in a mouse model of Alzheimers) This would be a more significant treatment option since attacking the underlying progression should lead to less functional impariment.
There is no evidence that aceylcholinsterase is high in Alzheimers. The drugs boost cholinergic neurotransmission in attempts to kickstart remaining circutry.
The same arguments could be made about depression. We know it can be neurodegenertitive, ie involving loss of hippocampal volume, but we don't fully know why. Many studies attempting to link depression to the levels of the serotonin transporter (SERT) have not been conclusive. Same thing goes for the norepinephrine transporter (NET). Some studies actually show that the levels of these transporters are already low in depressive states.
I guess what I am saying is that, while I might believe an antidepressant will work temporarily, it would be more comforting and reassuring to know that the drug was correcting an idenified abnormality. That case might guarentee a more than temporary symtomatic improvement.
Would you not agree that a more satisfying answer is the right answer?
Linkadge
Posted by linkadge on April 11, 2006, at 15:51:59
In reply to Re: Drugs versus Psychotherapy - Backlash? » Caedmon, posted by linkadge on April 11, 2006, at 15:43:24
The same thing goes for schizophrenia. The idea that schizophrenia is due to too much d2 activation is interesting but not conclusive.
In addition, the drugs' usage can lead to increased number of d2 receptors and a loss of effect accompanied by rebound psychosis upon withdrawl. So it is evident that they are not fixing the problem. It would be more satisfying to actually cure schizophrenia.
How does that relate to drug use overall? If there is evidence to suggest that an antidepressant will only work for a certain period of time, and lead to subsequent dependance and significant withdrawl, in addition to only providing symptomatic improvement for a disease that often remits on its own has made some people carefully consider all treatment options.
Linkadge
Posted by SLS on April 18, 2006, at 8:01:38
In reply to Re: Drugs versus Psychotherapy - Backlash?, posted by SLS on April 9, 2006, at 13:20:51
The following citation demonstrates what I have seen elsewhere in medical literature over the years.
This is the finding that leads me to the following hypothesis:
> It seems that if one limits the study population to those who have the severest of depressions that meet DSM criteria for MDD, antidepressants look more like wonder drugs. If, on the other hand, you were to give an antidepressant to a population of people whose mood depends entirely on how they think, a biological intervention will do little to affect them. In this case, the response rate is similar to placebo. Unfortunately, antidepressant trials in the past have included subjects with a psychologicaly driven depression. That's why the placebo rate is so high. Many of these people are very susceptible to suggestion.
>
> It is my guess that the preponderance of people with severe depression have a biological disorder while those with mild to moderate depressions are more likely to have a strong psychological component. This is why I keep questioning what we mean when we use the word "depression". People whose depression evolves from a psychogenic diathesis are far more apt to demonstrate a placebo effect because it is their expectation that they will be helped. I believe this expectation changes their outlook and therefore changes their mood. With psychogenic depressions, you can change the way you feel by changing the way you think. With biogenic depressions, this is not true. The way you think is determined by the way you feel.
>
> It would be ideal to identify the difference between an endogenous versus an exogenous depression when choosing a treatment modality. However, things are not that simple. I believe that there is an affective spectrum within which are an array of psychobiologies. At either end of the spectrum lie people whose depressions are either entirely biological or entirely psychological. In between lie those whose depressions are driven by a mix of both biological and psychological contributions. I find this framework appealing because it works well to explain the phenomenology of depression as a syndrome rather than a single illness. I find that the inferences that can be drawn from this model explains much about what we see happening in the diagnosis and treatment of depression.
Posted by zeugma on April 20, 2006, at 6:11:52
In reply to Re: Drugs versus Psychotherapy - Backlash? » Caedmon, posted by linkadge on April 11, 2006, at 15:43:24
Many studies attempting to link depression to the levels of the serotonin transporter (SERT) have not been conclusive. Same thing goes for the norepinephrine transporter (NET). Some studies actually show that the levels of these transporters are already low in depressive states.
>>Some have suggested that the transporters downregulate in an attempt to compensate for the pathological condition:
-z
Posted by SLS on April 20, 2006, at 6:53:04
In reply to Re: Drugs versus Psychotherapy - Backlash? » linkadge, posted by zeugma on April 20, 2006, at 6:11:52
"The decreased binding of [3H]nisoxetine to NETs in the LC in major depression may reflect a compensatory downregulation of this transporter protein in response to an insufficient availability of its substrate (norepinephrine) at the synapse."
That's very interesting. I would love to know if there is any biological precedence for their conclusion that the transporter would downregulate in the absence of neurotranmitter. Has this phenomenon been documented elsewhere? I can't imagine that no one has measured the amounts of NE to be found in the LC of suicide victims.
Can you think of a dynamic in circuitry that would explain this?
I gotta think about this one.
I see that the authors have published other papers studying NE and 5-HT function in major depression and Alzheimers. They all seem to corroborate each other and indicate that dimished neurotransmission is accompanied by reductions in transporter and increases in autoreceptors and the enzymes that produce neurtransmitter.
Ah. I get it. I suppose there must be a certain amount of neurotransmitter in the synaptic cleft to maintain a partial depolorization (prevent a static hyperpolarization) of the postsynaptic membrane.
- Scott
Posted by linkadge on April 20, 2006, at 8:09:44
In reply to Re: Drugs versus Psychotherapy - Backlash? » linkadge, posted by zeugma on April 20, 2006, at 6:11:52
Ok so suppose the NET transporter lowers itself to compensate for a deficiancy of norepinephrine. Then still, the pathelogical condition is not an abnormality in NET but rather an abnormality in norepinephrine availabilty.
Ie, I cant see how taking these depressed patients who's brains respond to low norepinephrine by decreasing NET, and exposing them to a drug that decreases it further, is going to remedy the situation, or make their brains function more like the contol brains.
Linakdge
Posted by linkadge on April 20, 2006, at 8:15:27
In reply to Re: Drugs versus Psychotherapy - Backlash? » zeugma, posted by SLS on April 20, 2006, at 6:53:04
In either case, I don't really see the problem as lying in a malfunctioning uptake system.
I remember reading somewhere that a fair portion of tested depressed patients had an abnormality in the TPH-2 gene (tryptophan hydroxylase)(or something like that) which coded for a much lower level of serotonin synthesis. That might explain things better.
Posted by zeugma on April 20, 2006, at 8:38:06
In reply to Re: Drugs versus Psychotherapy - Backlash? » zeugma, posted by linkadge on April 20, 2006, at 8:09:44
> Ok so suppose the NET transporter lowers itself to compensate for a deficiancy of norepinephrine. Then still, the pathelogical condition is not an abnormality in NET but rather an abnormality in norepinephrine availabilty.
>
> Ie, I cant see how taking these depressed patients who's brains respond to low norepinephrine by decreasing NET, and exposing them to a drug that decreases it further, is going to remedy the situation, or make their brains function more like the contol brains.
>
> Linakdgeif the downregulation of NET in response to abnormality in NE neurotransmission is a result of a homeostatic process, then amplifying the brain's own response with a NET inhibitor would be a strengthening of this response (possibly enough to compensate for the dysregulation).
The key is that 'normal' neurotransmission may be achieved by different routes. The brain is a highly 'degenerate' system; there are numerous ways to get the same functional result (definition of degeneracy i am using: "In physics two or more physical states are said to be degenerate if they are both at the same energy level." -Wikipedia). The use of a NET inhibitor might bring noradrenergic function in line with that of an individual who was unmedicated but euthymic despite the very different configurations of NET/NE systems in each.
-z
Posted by zeugma on April 20, 2006, at 9:02:56
In reply to Re: Drugs versus Psychotherapy - Backlash?, posted by linkadge on April 20, 2006, at 8:15:27
> In either case, I don't really see the problem as lying in a malfunctioning uptake system.>>
The evidence seems to be that the uptake systems are associated with drug response, if not with the disorder itself:
I suppose the key is the ability to attain a homeostatic state that has the same functionality as an euthymic individual's.
>
> I remember reading somewhere that a fair portion of tested depressed patients had an abnormality in the TPH-2 gene (tryptophan hydroxylase)(or something like that) which coded for a much lower level of serotonin synthesis. That might explain things better.>>
>There are likely abnormalities at all levels of neurotransmission. At some point psychiatrists will stop using trial and error and use genomic evidence to treat particular patients. I believe very strongly that the current pharmocopoeia is not used to maximum benefit because this information is not routinely used to guide treatment. It is certainly easier to study gene effects on treatment response, than to design new drugs.
-z
>
Posted by SLS on April 20, 2006, at 10:20:16
In reply to Re: Drugs versus Psychotherapy - Backlash? » linkadge, posted by zeugma on April 20, 2006, at 9:02:56
So, then, what's the deal?
Is the reduction in the numbers of NET reported in the previous study you cited the result of inadequate gene expression, or is it the result of a compensatory mechanism?
- Scott> > In either case, I don't really see the problem as lying in a malfunctioning uptake system.>>
>
> The evidence seems to be that the uptake systems are associated with drug response, if not with the disorder itself:
>
> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15939518&query_hl=211&itool=pubmed_docsum
>
> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16005136&query_hl=212&itool=pubmed_docsum
>
> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15993855&query_hl=215&itool=pubmed_docsum
>
> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15337646&query_hl=230&itool=pubmed_docsum
>
>
> I suppose the key is the ability to attain a homeostatic state that has the same functionality as an euthymic individual's.
> >
> > I remember reading somewhere that a fair portion of tested depressed patients had an abnormality in the TPH-2 gene (tryptophan hydroxylase)(or something like that) which coded for a much lower level of serotonin synthesis. That might explain things better.>>
> >
>
> There are likely abnormalities at all levels of neurotransmission. At some point psychiatrists will stop using trial and error and use genomic evidence to treat particular patients. I believe very strongly that the current pharmocopoeia is not used to maximum benefit because this information is not routinely used to guide treatment. It is certainly easier to study gene effects on treatment response, than to design new drugs.
>
> -z
> >
>
>
Posted by zeugma on April 20, 2006, at 10:57:59
In reply to Re: Drugs versus Psychotherapy - Backlash? » zeugma, posted by SLS on April 20, 2006, at 10:20:16
So, then, what's the deal?
Is the reduction in the numbers of NET reported in the previous study you cited the result of inadequate gene expression, or is it the result of a compensatory mechanism?>>
Definitely not inadequate NET gene expression, but compensation for inadequate gene expression downstream:
Daily treatment of rats with DMI (10 mg/kg, i.p.) for 3 or 14 days significantly increased postmortem cerebral TH mRNA in the locus coeruleus (LC) area by 47-68%. Again, TH protein concentrations in LC decreased at 3 and 14 days, by 25-40%, with transient significant reduction in amygdala tissue after 3 days of treatment that were not sustained. These findings indicate that DMI exerts complex, typically opposite and perhaps compensatory, gradually evolving effects on the expression of TH protein (decreases) and its message (increases), possibly in response to increased synaptic availability of NE.
it is possible that the reduction of NET in the other studies is an attempt to upregulate inadequate gene expression (of tyrosine hydroxylase), and that the inhibitor facilitates this process. I think that antidepressants, when they work, probably build on the brain's own compensatory mechanisms.then again, I am just speculating. What do you think?
-z
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