Posted by Larry Hoover on December 15, 2005, at 23:07:13
In reply to Re: Dr. Tracy on SSRIs.., posted by linkadge on December 15, 2005, at 19:01:44
> >I read it. There was no evidence presented that >the pre-synaptic neuron would release identical >amounts of serotonin under both transporter >conditions, nor any evidence presented that COMT >or MAO-A concentrations were the same.
> But the point is that the level of the protein is reduced.
They measured one variable in a complex (i.e. multivariate) system.
> If our theory of depression is that the *5-ht* reuptake mechanism is too active in depression, then this is information to suggest against it.
But that's not a common theory. (I've never heard it before, myself.) Rather, the integrated serotonin signal in a pathway or pathways is believed (by some) to be weaker in depression. In order to strengthen the signal, without resorting to indiscriminate serotonin release, existing signals may be amplified by extending the half-life of serotonin in the synapse. The hope is to enhance the magnitude of pre- and post-synaptic receptor response, contributing to the integrated signal across that neural network. If I recall correctly, the increase in half-life is measured in fractional seconds. That's one theory. <shrug>
> Of course there could be compensatory changes in MAO-A, but this could also happen in patents treated with SSRI's.
That's one of *my* arguments, against your theory. You can't just measure reuptake transporter protein, and fail to simultaneously measure MAO-A concentration, COMT concentration, and total serotonin released into the synapse. And then do the same with an antidepressant present. And then do it again, two weeks later. And so on.
The whole idea that SSRIs function by flooding the brain with serotonin is patently absurd. Reuptake inhibition takes place immediately, whereas physiological antidepressant response takes weeks. It couldn't possibly be the explanation.
And, for the same reasons, global excess serotonin is equally absurd.
> >There is no evidence to reach that conclusion. >It is a conceivable hypothesis, but it has never >been tested.
> Scientists like to study one gene at a time. It makes sence to see if the 5-ht transporter is associated with depression or not. It's just like if you found low acetylcholinsterase in Alzeimer's disease, then it might make one rethink the model.
Scientists must also delay promoting their pet theories until such time as they have evidence to describe the relationship between multiple variables upon which their theories rest.
Did you see the recent work on SERT polymorphism? Out of 96 subjects, they found 27 variants, 21 of which were previously unknown. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15993855&query_hl=2
In such complex systems, I simply avoid mechanistic arguments altogether. I don't even pretend to have a clue.
> >The only easily tested hypothesis which arises >from this heterogeneity of SERT promoter regions >is to determine if SSRI response is different >under the three natural populations. It may well >explain why SSRIs don't work for everybody. Or >part of the why.> One researcher found that individuals with the long varients of the transporter responded better to SSRI's than did those with the short varients.
Babblemail me a good email address, and I'll send you the full-text of the above article.
> >SSRIs are depressogenic?
> Yes, I would argue that they can be for certain individuals. Mood may be maintained by a very delicate ballence between serotonin and dopamine. If you get too much serotonin, I think it can cause depression. I experienced a distinct worsening of all core symptoms of depression on paxil.
I meant generally. You can't project your experience without bias. It's a poor strategy because it fools you. Now, to say something can happen can be proven with but a single case. Amongst the (probably) billions of doses of SSRIs, I would argue that the most general conclusion is that SSRIs are not depressogenic.
You cannot apply that general conclusion to an individual. But that same argument cuts both ways. You cannot generalize from individual experience.
> >Suicide rates are falling.
> >http://www.afsp.org/statistics/USA.htm> But to associate this with SSRI use may not be accurate.
It's easy to use the word "may". What I would look for, though, is evidence for that anti-suicide agent that must be present for the initial thesis (SSRIs induce suicide) to be true. To argue that SSRIs induce suicide, while the evidence for a population shows an inverse relationship, requires that one demonstrate an independent variable of greater suicide reduction potential than the putative SSRI suicide inductive effect.
> >There is no autopsy evidence for SSRI >potentiation of suicide. But alcohol? Huge. >Widely available, without a prescription.
> I don't think that autopsy information is necessary.
Perhaps not necessary, but informative. It makes the SSRI-suicide link look a tad anemic. 40-45% of suicides positive for alcohol. Ever seen a suicide warning on a can of beer? Just a couple of examples...
Forensic Sci Int. 2005 Jan 17;147 Suppl:S25-8.
Fatal suicide cases from 1991 to 2000 in Szeged, Hungary.Havasi B, Magori K, Toth A, Kiss L.
Department of Forensic Medicine, University of Szeged, 6722 Szeged, Kossuth L. sgt. 40, Hungary. havasi@anat-fm.szote.u-szeged.hu
The aim of this study is to analyze the fatalities due to suicide in the period of 1991-2000. The autopsy reports of 719 suicide cases during that period of the Department of Forensic Medicine, University of Szeged were reviewed retrospectively. The victim's age, sex, way of commitment, place of death, the presence of alcohol and drug influence and survival time were recorded. Five hundred and one of the (69.6%) total 719 suicide fatalities were men and 218 (30.4%) were women. The largest age groups were 41-50 in men, in women we experienced a 'double-peak' of age groups 41-50 and 71-80. The most frequent way of committal was hanging (46%). The results revealed that 38.8% of the 474 victims whose blood and/or urine alcohol concentration measurement were carried out consumed alcohol prior to the act. The presence of licit drugs in 12% of not drug-related cases were experienced.
Forensic Sci Int. 1996 Apr 2;78(2):157-63.
Pathoanatomic findings and blood alcohol analysis at autopsy (BAC) in forensic diagnoses of undetermined suicide. A cross-cultural study.Ferrada-Noli M, Ormstad K, Asberg M.
Department of Clinical Neuroscience, Karolinska Institute, Karolinska Hospital, Stockholm, Sweden.
In Sweden, ca. 25% of unnatural deaths ascribed to self-inflicted injury are finally recorded as 'undetermined suicide' (abbreviated UMSA), i.e. the forensic pathologist has not been able to establish whether the fatality was an accident or a suicide. In the present study, a series of UMSA cases was investigated with the aims to study the impact of immigrant status, and alcohol abuse on the occurrence of this forensic diagnosis on the mode of death. The alcohol issue was addressed by focusing on blood alcohol concentrations at autopsy (BAC) and post mortem signs of alcohol-related organ pathology. The results can be summarised as follows: Positive BAC occurred at an equal rate in the UMSA group and in definite suicides, i.e. about 45%. Among non-Swedish UMSA victims positive BAC was more common (50%) than among the Swedish (41%), whereas no difference was found in the definite suicide group. The level of BAC at autopsy was significantly higher in Finnish immigrants than in other ethnic groups. Organic signs of chronic alcohol abuse were found in 13 of 40 cases testing positive for BAC; thus, presence of alcohol at autopsy may reflect incidental intake rather than habitual overconsumption.
> >No, it doesn't. It links a homozygous gene to >those events. Not SSRIs.> I realize that. It is not a direct link, but it is something that has really baffled a lot of researchers. I emailed Dave on www.biopsychiatry.com and asked him what he thought about the issue of the serotonin transporter, and some of the recent findings. He said to me, that sometimes in psychiartry you will find things that don't fit the mold. Sometimes the findings will seem to indicate the exact opposite.
I don't know what you mean by your closing sentence. And, I was refuting any connection between the gene findings and SSRI effects. It is petitio principii, begging the question, to accept that the SERT promoter polymorphism tells us anything about SSRIs. It certainly isn't a conclusion obtainable from the evidence presented.
> SSRI's may *work* through a different mechanism alltogether. We have serotonin uptake inhibiting drugs that have no antidepressant potential whatsoever. All of the currently available SSRI's increase the activity of the gabaergic neurosteroid allopregnalone, some 20 fold.
I have absolutely no doubt that reuptake inhibition is possibly a tiny, and perhaps even inconsequential, aspect of their mechanism of effect. I'm sure we'll keep finding more and more effects, that we never anticipated finding.
> >Or Tianeptine might work on homozygous short->short SERTs?
> Well this is it. I was just more surprised by the fact that the study seemed to suggest that the most chronically depressed posessed the double short varient.
I think it's premature to make anything out of this finding. We don't know if the gene is pleiotropic, for example.
> >I strongly reiterate. There is no pathological excess serotonin state.> I strongly reiterate. Some researchers think that excessive serotonergic function in certain areas of the brain result in anxiety.
You're starting to come off the Tracy position. The key is *localization* of the serotinergic activity. And the activity in that locality is a relative finding.
> There are researchers who believe that certain generalized anxiety disorders are due to elevated serotonin activity. Some think high serotonergic neurotransmission may be involved in anorexia.
> http://www.mhsource.com/expert/exp1041502a.html
This example is nothing more than a poor explanation to a layperson.
The key point, I state for the umpteenth time, is localized serotinergic activity. There is no global excess serotonin state.
> >Getting back to how this phrase came into our >discussion, Tracy claims that this "excess >serotonin" state causes premature aging. You >seem to have just contradicted that, quite >explicitly.> I don't see what you mean.
You clipped it. You said:"If any drug were capable of mimicing some the catastrophic alterations in cognition an sentience that are evident in old age, I'd like to know about it."
If SSRIs cause this excess serotonin state, which causes premature aging (all her language), then your contention that there is no drug that could cause that certainly absolves SSRIs of any possibility of doing so, eh?
> There are theories out there as to how SSRI's may advance aging. The melatonin theory sounds convincing. I can see how chronically lowering melatonin might acellerate aging. There are other theories too.
Which is it, then? SSRIs to blame, or no drug can do it (mimic aging)?
The thing I keep having to point out, Ian, is that a theory is proof of nothing. Where are the data?
> >No, not potentiation. "...all data were >compatible with additivity of effects rather >than true potentiation."> The article says that fluoxetine substituted for LSD in certain paradigms.
You said potentiation. That is not potentiation. The dogs were preconditioned (read their normal receptor function was altered). It wasn't a naturalistic observation, this somewhat congruent drug effect.
> >The one above was about dogs. I wonder just what >the dogs said to describe their experiences.> This is about findings that may confirm some of the experiences that people have had.
I don't think it does anything of the sort.
I'll say it as often as I have to. That there are adverse events, serious adverse events, is not in question. With the billions of doses of these drugs consumed, it would be inconceivable for there not to be such events.
Do you have any idea what the death rate is from NSAIDs, each year? It exceeds the rate of suicide, from all causes, let alone from SSRIs. Context.
> >And, individual idiosyncratic reactions happen >all the time.
> It is not an idiosyncracy.
"An abnormal susceptibility to some drug, protein or other agent". Normal being all the rest.
> Both agents potently stimulate certain sertonin receptors.
Few people hallucinate on SSRIs. Using COSTART terminology, the reaction is uncommon to rare.
> We have no problem accepting that GI effects may be due to excess 5-ht3 stimulation, but yet cannot believe that people have had perceptual disturbances consistant with excess 5-ht2a agonism ?
I believe it happens. It's uncommon. When it does happen, the offending agent may be discontinued, and relief is then sought elsewhere.
> There are some documented cases of antidepressant induced perception disorder on www.biopsychiatry.com in addition to expert explainations of the events.
I am not arguing "never", Ian.
> >How? Who the heck knows that?
> Exactly. We can pop a pill based on unproven theory,
I have never popped a pill based on unproven theory. Not ever. I have, however, taken pills based on evidence for efficacy, notwithstanding the potential for idiosyncratic reactions.
> yet we start wars in defence of drugs based on unproven theory. She is not the only one who has attacked the theory behind SSRI medications.
I fail to follow the import of your argument. Empiricism is the basis of all pharmacological treatment. Theories of mechanism are to calm those who don't trust empiricism. Or something. We have discovered that they work. We have not discovered why.
> >That's what I meant earlier about mechanistic >arguments. They really are pointless.
> So what good is it to say that she is devoid of proof, when we have no proof of the opposite. Her proof may be our lack of proof.
Proof would be data. Empirical data. Not theory. You can throw words at something for days, and it will remain a mystery. Measure it, however, and you have data. She claims blood sugar relationships to mental illness. It should be blessedly easy to come up with supporting data. Same with her magic oils. Data?
> >Other people, with different beliefs, discovered >salicylic acid in willow bark, derived a >synthetic form, and made a near-bankrupt German >dye chemist named Bayer very rich.
> True, but we later learned how aspirin causes more deaths each year than any other drug (I believe). I am not going to try and dismiss the information that points to the dangers of aspirin.
But that's empiricism. That's my point, all along. Red willow spirit mechanism arguments won't stop someone from bleeding to death due to gastric perforation.
BTW, aspirin would never make it to market today, as a prescription drug. That it is an over-the-counter remedy is a quirk of history. It is still legal today to do trans-orbital frontal lobotomies, under the same sort of grandfathering legislation.
> >That's not hyperbole.> Did I say it was ?
Please be more careful with your editing. You might as well have left those bits out, considering the context was already taken away.
> >And we don't know why. But we do know that they >work. Empirical evidence.> It is a truth that the drug company can still market a drug when only 1/8 of the studies show any benefit.
Yes, it is a truth. Not because they have a theory. Because they have empirical evidence sufficient to convince the regulatory authorities that having the drug is better than not having it.
> >How about promoting better medical management. >More personal interaction with caregivers. >Providing critical information for true informed >consent. No fear-mongering required.
> Fair enough.
Good. Tracy, go away.
> >Post hoc ergo propter hoc is a fallacious >interpretation, a good part of the time.
> >You may have other medical concerns.> I'm sorry I brought it up. I didn't know you were going to be one of those people.
I'm offended.
A study with N=1 proves nothing. It *may* disprove some things. Your argument is affirmative, and therefore inherently indeterminate.
> >Sometimes, they do. And if appropriate >precautions had been taken, and corrective >action initiated at the first sign of trouble, I >think that many of the most serious outcomes >would simply never have happened.
> For certain individuals, the kind of monitoring necessary is not tangable. Monitoring cannot prevent all potential problems. Monitoring cannot prevent T.D. for instance, with neuroleptic use.
I did not say all. Monitoring can, in fact, minimize chronic TD in neuroleptic use, with prompt discontinuation.
> >I didn't listen to the whole interview.> I know
Biblical prophecy, remember? There is no science in that. Vague generalizations, anecdote, and biblical references attest to her quality of argument. Oh, and that gooey glossy stuff.
> >I have read through some of the complete >clinical trial data for some of the SSRIs.
..
> > If you want to see that, I'll dig it up and show >it to you.> You are one individual. Other individuals have analayed similar data, and have come to different conclusions.
Again, I resent the implication. I already presented expert verification of my prior work.
http://www.dr-bob.org/babble/20051211/msgs/588011.htmlThe data are the science. I verified the data. The faulty summaries are not the science.
> >All else is interpretation.
> Thats the problem. The argument in support of these drugs is interpretation.
The argument in support of these drugs is empirical. Raw statistical data for efficacy.
> The mechanisms are theoretical.
I'm glad you've picked up on that.
> When you don't know why they work, and why they fail, then interpretation becomes more tangable.
This sentence is confusing to me. We don't know why they work, and we don't know why they fail, and you can argue about it forever and be no closer to settling it. You need appropriate data. Data that have not yet been collected.
> >Link, I have very closely followed the research. >I read every study on this subject. The recent >Healy and Martinez studies were rather >compelling. If there is a suicidal signal, it is >brief, early, and small. Medical management can >handle these issues.
> Lar, dispite your independant research, you are not the final say.
I'm offended again. I am encouraging debate. I'm sorry if you struggle with the arguments I raise. The data in support of Tracy (and others) are absent. Theories have been bandied around as if they were fact.
> And you have not read every study on the subject. (oh I know I'm going to get banned)
My apologies, for failing to use the word 'recent', i.e. last six years, and some earlier stuff.
> >She's in the ballpark. She's the candy floss.
> ?
It was metaphorical.
> >I was meaning her evidence. Her hypotheses are >not directly connected to evidence. I'm being >generous. Myrrh oil? All mental illness is sugar >related? (or something like that)
> From my school of thought, if somebody argues something, and another has evidence to support it, then it becomes his evidence.
Fine. Please give empirical support for essential oils and blood sugar regulation in the successful treatment of mood disorders.
> >It's far from closed. And I am not trying to >shut the door. I'm trying to lay a solid >foundation of empirical evidence, and put to >rest hyperbole and fear-mongering.
> Fear mongering wakes people up. Bad things can happen behind closed doors, and sometimes raising appropriate concern is a good thing.
Appropriate concern raises its own attention.
> Where her arguments are not appropriate, I do not support them.
> Linkadge
Chacun a son gout.
poster:Larry Hoover
thread:587690
URL: http://www.dr-bob.org/babble/20051211/msgs/589483.html