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Re: Dr. Tracy on SSRIs.. » linkadge

Posted by Larry Hoover on December 16, 2005, at 15:28:13

In reply to Re: Dr. Tracy on SSRIs.., posted by linkadge on December 16, 2005, at 13:12:47

I really want to simplify. I'm exhausted from shovelling snow with one arm.

> >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.

> Perhaps they may cause compensentory changes with the 5-ht system. Downregulation of 5-ht2 receptors? That can be done with 5-ht2a antagonists, surprisingly. It can also be done with melatonin, which acts functionally as a 5-ht2a antagonist. It may just be a consequence of normalized HPA axis function. Surmontil produces the same adaptive changes in receptor systems as other tricyclic antidepressnats, yet has no effect on monoamine uptake. So I argue, if serotonin uptake is unneccesary, might tampering with it cause problems ?

Drugs that cause immediate increases in synaptic serotonin concentration, e.g. Ecstacy or powerful agonists e.g. LSD, stand in somewhat stark contrast from the serotonergic antidepressants, which take weeks for most of the effects to appear. (There are exceptions, but I'm just wanting to make a simple point.) So, serotonin receptor mediated events that lead to changes in regulatory behaviour in the neuron are most likely what makes an antidepressant an antidepressant.

I once posted an overview of changes in RNA concentration following antidepressant exposure. There were many dozens of significant changes, up to 20-fold. Just looking at permutation, we're already being forced to consider something like 10^17 possible meaningful interactions of those changes. I wish I could think of what the paper was called.

That's why I go back to empirics. We put this drug into a mysterious processor, and we observe these common outputs. How, why, why not.....I'll never pretend to know.


> >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=15>993855&query_hl=2

> Another argument against the widespread use of agents that affect the system in only one way.

But they don't affect the system one way. http://kidb.cwru.edu/pdsp.php


> >I think it's premature to make anything out of >this finding. We don't know if the gene is >pleiotropic, for example.

> I think it is a great place to start. It indicates to use that the system is much more complex than the drug commercials make it out to be.

Commercials. They ought to make them stop direct marketing drugs.

But, Tracy falls in the same level of scientific truth. That's the problem with her.


> >The thing I keep having to point out, Ian, is >that a theory is proof of nothing. Where are the >data?

> You are right. We are devoid of many long term studies on the safety of SSRI's. That is a big problem. Just like we don't really have many studies on the issue of "antidepressant poop out". I am sure you are able to accept the presence of antidepressant poop out, for instance, without a randomized double-blind, placebo controlled study indicating it occurs. If somebody got on the radio and said antidepressants poop out occurs, I wouldn't scoff the notion based on the absence of stringent trials. It is important to use our eyes and ears too.

Saying what happens is one thing. That is data collection, and description. That's empiricism. Of course poop out occurs, but if anyone tries to explain why, that's over the line.


> I'm not so sure that all the side effects of this drug are adequately collected or reported. A lot of clicial trial information reports that sexual dysfunction happens in <14% of people treated with say lexapro. I'd be inclined to think that it happens in more than half. Let me guess. Where's my data?

No, those data are available. Post-marketing surveillance puts the rate at about 3 times that, off the top of my head. Clinical trials of efficacy are not designed to collect information that might be personal or embarassing. I may not mention my erectile dysfunction, but I'd surely mention hallucinations.

Here's the study I was thinking of:

J Clin Psychiatry. 2001;62 Suppl 3:10-21.

Comment in:
J Clin Psychiatry. 2002 Feb;63(2):168.

Incidence of sexual dysfunction associated with antidepressant agents: a prospective multicenter study of 1022 outpatients. Spanish Working Group for the Study of Psychotropic-Related Sexual Dysfunction.

Montejo AL, Llorca G, Izquierdo JA, Rico-Villademoros F.

University Hospital of Salamanca, Psychiatric Teaching Area, University of Salamanca, School of Medicine, Spain. angelluis.montejo@globalmed.es

BACKGROUND: Antidepressants, especially selective serotonin reuptake inhibitors (SSRIs), venlafaxine, and clomipramine, are frequently associated with sexual dysfunction. Other antidepressants (nefazodone, mirtazapine, bupropion, amineptine, and moclobemide) with different mechanisms of action seem to have fewer sexual side effects. The incidence of sexual dysfunction is underestimated, and the use of a specific questionnaire is needed. METHOD: The authors analyzed the incidence of antidepressant-related sexual dysfunction in a multicenter, prospective, open-label study carried out by the Spanish Working Group for the Study of Psychotropic-Related Sexual Dysfunction. The group collected data from April 1995 to February 2000 on patients with previously normal sexual function who were being treated with antidepressants alone or antidepressants plus benzodiazepines. One thousand twenty-two outpatients (610 women, 412 men; mean age = 39.8 +/- 11.3 years) were interviewed using the Psychotropic-Related Sexual Dysfunction Questionnaire, which includes questions about libido, orgasm, ejaculation, erectile function, and general sexual satisfaction. RESULTS: The overall incidence of sexual dysfunction was 59.1% (604/1022) when all antidepressants were considered as a whole. There were relevant differences when the incidence of any type of sexual dysfunction was compared among different drugs: fluoxetine, 57.7% (161/279); sertraline, 62.9% (100/159); fluvoxamine, 62.3% (48/77); paroxetine, 70.7% (147/208); citalopram, 72.7% (48/66); venlafaxine, 67.3% (37/55); mirtazapine, 24.4% (12/49); nefazodone, 8% (4/50); amineptine, 6.9% (2/29); and moclobemide, 3.9% (1/26). Men had a higher frequency of sexual dysfunction (62.4%) than women (56.9%), although women had higher severity. About 40% of patients showed low tolerance of their sexual dysfunction. CONCLUSION: The incidence of sexual dysfunction with SSRIs and venlafaxine is high, ranging from 58% to 73%, as compared with serotonin-2 (5-HT2) blockers (nefazodone and mirtazapine), moclobemide, and amineptine.


> >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.

> Evidence for efficacy does not equate to proven theory, and a theory that has not been proven, is unproven.

Ya, I think.

> >We have discovered that they work. We have not >discovered why.

> We have discovered that they work sometimes. We have discovered that oftentimes they perform worse than placebo. We have discovered that often times we need 8 trials to show the drug performs better than the placebo. Those are truths.

Maybe. Placebo response is the bugbear of mood disorder treatment. Placebo response in e.g. positive symptom schizophrenia is estimated at < 3%. Here is an excellent article about the difficulties in interpretation that arise because of the clinical trial system for medication being inappropiate for mood disorder treatments.
http://www.psychiatrictimes.com/p000429.html


> >I'm offended.

> I am sorry. Did I, for one minaute, try to dismiss your manic reaction to Luvox; to say that it was not due to Luvox at all? Perhaps you had "other" things going on.

Exactly. Perhaps I did. It certainly took place. The role of Luvox is not clearly defined.


> >A study with N=1 proves nothing.

> Similarly, your manic reaction to Luvox proves nothing. (Now you no I don't believe that)

You've confused me again, with your parenthetical remark. Nothing was proven, but it would be prudent for me to avoid that drug, in future.


> I again bring up Healy's arguments against the merrit we have on the efficacy of these drugs.

That's why they did these studies. Healy's an author on the first one.

A meta-analysis of 702 clinical trials....
http://bmj.bmjjournals.com/cgi/content/full/330/7488/396

And, another, of 477 more....
http://bmj.bmjjournals.com/cgi/content/full/330/7488/385

And, a huge real-life observational study...
http://bmj.bmjjournals.com/cgi/content/full/330/7488/389

 

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poster:Larry Hoover thread:587690
URL: http://www.dr-bob.org/babble/20051211/msgs/589611.html