Question from an IM resident: What's this about SSRE (not SSRI) for depression?

[QuantumX]

Long prelude:

Maybe a year ago I read an article on the web about SSRE's, or selective serotinin reuptake enhancers, being used for depression, asthma , premature ejaculation and some other diseases. Tianeptine, or trade name stablon is approved in Europe but not in the US. My uncle asked me about it at that time and I had no clue, I had to look it up.

I have always thought the mechanism of action of SSRI's is this: inhibiting the reuptake of seroronin making it more available at the neurosynapse. But something always did not add up: Why did some SSRI's work and others didn't for some patients? Correct me if I'm wrong, but serotonin's concentration in the synapse does increase from day 1, but the effect (anti-depressant, for eg) cannot be appreciated for 2-3 weeks, right? Which means, according to theory, that new neuronal connections have to be established (or at least that is the reason of the delay). So then, what is teh role of serotonin? I asked the above question in bold to a few psychiatrists, they didn't know.

So now with SSRE's (here's a link from wikipedia, google for more ( http://en.wikipedia.org/wiki/Tianeptine), HOW DO antidepressant SSRI's or SSRE's work?

Surely it is not serotinin mediated. I just find it funny that they still have serotonin in the acronym SSRI/E, when a serotonin's uptake can't be both enhanced and inhibited AND cause the same result: eg better mood.

Any input?

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[sunlioness]

The short answer is no one knows how SSRIs work. We know that they do, but not why/how.

 

[QuantumX]

The short answer is no one knows how SSRIs work. We know that they do, but not why/how.

Thanks for the answer, lioness.. Frankly the fact that we don't know how most drugs work in psychiatry made me shy away from applying to the specialty 2 years ago. As much as it is exciting to work in a field that is constantly having important scientific achievements, the lack of a solid pathophysiological basis for understanding differenr disease entities can be a bit frustrating.

Well maybe "lack" isn't the word I'm looking for, but "less of" compared to say, what we know about liver disease. Or heart disease.. Anything related to the brain is so darn complicated..

 

[Someguy2007]

If I remember correctly, and that's a big "if", considering that the lecture was during my first year of medical school... it takes a while for the transcriptional/translational downstream effects of a bump in serotonin to become apparent. But even with that explanation, 2-3 weeks is quite a while...

 

[Anasazi23]

The short answer is no one knows how SSRIs work. We know that they do, but not why/how.

I wouldn't quite put it like that. It offers no value to the volumes of data we have on the neurotransmitter receptor hypothesis of antidepressant action at best, and makes the science of psychiatry to appear flippant and not useful at worst.

All antidepressants thus far work eventually to alter monoamine neurotransmission receptors or enzymes. It's way beyond the scope of this post to elucidate the details of the neurotransmitter receptor hypothesis of antidepressant action or to go into detail about gene transcription/expression and its role in BDNF.

To address the original question about why some SSRIs work for some patients and not for others...this is also an answer beyond the scope of the post. Suffice it to say that gene-encoding proteins vary between people. Small variations in chemical structure of antidepressants therefore will work differently for different patients.

This is not dissimilar to the hypertensive or arrythmic patient responding to one particular antihypertensive (B-blockier, ACE, Ca receptor blocker, etc) or antiarrhthmic versus another.

Lots of stuff in the newer psychiatric literature on this.

 

[sunlioness]

That's the longer answer. But we still don't know. And I personally don't think that takes anything away from the field of psychiatry. We know that they work, we know what they do, we know that they are safe. We just haven't quite got the connections sorted out yet. I think in the realm of the mind/brain (whichever term you prefer) that's really not bad.

 

[Adam_K]

To address the original question about why some SSRIs work for some patients and not for others...this is also an answer beyond the scope of the post. Suffice it to say that gene-encoding proteins vary between people. Small variations in chemical structure of antidepressants therefore will work differently for different patients.

This is not dissimilar to the hypertensive or arrythmic patient responding to one particular antihypertensive (B-blockier, ACE, Ca receptor blocker, etc) or antiarrhthmic versus another.

So, why are placebos equally efficacious?

 

[Anasazi23]

So, why are placebos equally efficacious?

Another complex question with no easy answer. The short answer is that they're not equally efficacious when examining most large clinical trials. For the studies that do show similar efficacy, we can point to PET studies that demonstrate brain changes even with the administration of placebo, or you could speak on the literature regarding long-term outcome differences. The latter stretches not only to SSRIs, but to older antipsychotics and even lithium.

 

[whopper]

sorry double post

 

[whopper]

That's the longer answer. But we still don't know. And I personally don't think that takes anything away from the field of psychiatry. We know that they work, we know what they do, we know that they are safe. We just haven't quite got the connections sorted out yet. I think in the realm of the mind/brain (whichever term you prefer) that's really not bad.

Depends on what level of proof you want.

For example one could argue that science hasn't 100% definitively proven that smoking causes cancer. I think we would though all agree that enough evidence has been presented for us to accept this as virtual fact.

Science journals in general accept a paper with 95% validity, not 100% and 100% may in several respects be impossible.

While you are technically correct in a purist sense, this can also be argued with almost every aspect of medicine, and if you say these exact same words to a patient, its not exactly comforting or attracts their desire to get treatment from you.

"Your son is depressed and we're going to give him a med and no one knows how it works". Isn't exactly the right thing to say to someone.

Though you also are right in one sense.

 

[sunlioness]

For example one could argue that science hasn't 100% definitively proven that smoking causes cancer. I think we would though all agree that enough evidence has been presented for us to accept this as virtual fact.

That's not quite the same analogy though. I didn't say we don't know that SSRIs work. We absolutely do. We also have a good understanding of what they do. We just aren't precisely sure yet if what we see them doing is why they work. So it's more akin to saying, "I know smoking causes cancer. And I know smoking causes X, Y, and Z in the body, but I don't know exactly if it causes cancer through X, Y, Z or some combination of these."

And yes, I would say that to a patient. Much more likely to be able to explain that to a patient than go into those studies that are too complicated to go into in a forum full of physicians.

 

[Therapist4Chnge]

Small variations in chemical structure of antidepressants therefore will work differently for different patients.

This is not dissimilar to the hypertensive or arrythmic patient responding to one particular antihypertensive (B-blockier, ACE, Ca receptor blocker, etc) or antiarrhthmic versus another.

Lots of stuff in the newer psychiatric literature on this.

I understand where QuantumX is coming from, but I think that is what makes psychology/psychiatry that much more interesting....it is still very much a growth area for research, and we as professionals can really contribute to accelerating our understanding and knowledge in the field. I really think pharmacogenomics is the next major step, albeit a big one for the field. It is an area I've gotten really interested in the last couple of years, and I think it shows some promising opportunities.

-t

 

[Demosthenes]

(Disclaimer: tonight I feel as though I should be singing "If I Only Had A Brain..." If this is unintelligible -- well, just don't tell me. I'll never know the difference. It is so past my bedtime.)

I read something pretty recently suggesting the answer to how SSRIs work is that the downregulation of 5HT receptors increases neurotransmission at some of the DA receptors. Basically, that SSRIs might work by normalizing the ratio of 5HT and DA. Ironically, i read a paper the same week about the effects of methylphenidate on DAT knockout mice -- it seemed to work through upregulation of 5HT receptors. Made me smile and cross my eyes -- Ritalin works by its actions on 5HT, while Prozac does its magic on DA? Interesting, if true.

Aside from everything involving the genetics of receptors -- whichever receptors are controlling my typing tonight are apparently way out of whack, by the way -- I've always thought that the reason some drugs work for some pts, is that what we call "depression" is probably a constellation of disease states which result in symptoms which look similar. Certainly, that might help explain melancholic versus atypical, or why some people respond to one AD rather than another.

Personally, it seems to me that tolerabiility has a lot more to do with why some pts are successful on one rather than another. Some pts are much more sensitive to certain side effects, so they can't tolerate the drug. Just an observation, for whatever it's worth. (Not much, tonight, I'm afraid.)

'Night, all. I'm off to LumLand.

 

[whopper]

I read something pretty recently suggesting the answer to how SSRIs work is that the downregulation of 5HT receptors increases neurotransmission at some of the DA receptors. Basically, that SSRIs might work by normalizing the ratio of 5HT and DA.

Yes, and that is the current most accepted theory, however its still just a theory.

As is almost everything in medicine, however because psychiatry is much more "touchy feely" than the other branches, you're going to get a lot more naysayers.

You even get other doctors on the board occasionally troll here to basically diss our field even though theirs have the same holes.

Its funny. There's a lot more data backing a lot of psychotropics vs for example a lot of chemotx meds, but you don't get entire organizations trying to refute chemo meds as much as you do psychotropics.

Be careful how you word things, though you also need to be honest. Aside from the Scientologists out there trying to discredit anything we do, our field has poor compliance rates to begin with. You're doing your patients a disservice if you don't attempt to strongly motivate them to take meds (of course only if you feel the meds are justified).

 

[sunlioness]

I agree with you. I know people are more resistant to taking psychotropics than they are to other meds and I try very hard to explain that taking something for depression is really no different than taking something for high blood pressure.

I also agree with whoever it was that said the stuff we don't know in psychiatry is a good part of why it is so exciting to work in this field. We're learning new things all the time.

 

[normality]

Just to fancy my own curiousity, How does one transition from your typical SSRI medications to an SSRE such as Stablon...

Seems easy enough with a slow taper and then completely off the current medication, but what if doing so would put the patient in really bad shape.

The mechanism of action seems to counteract each other and taking an SSRE directly after an SSRI seems to be bad news.

Could be wrong on this, but what are some suggestions on how to transition from an SSRI to an SSRE...

 

[michaelrack]

Why did some SSRI's work and others didn't for some patients? ?

Despite being called "selective", SSRI's have other effects besides serotonin reuptake inhibition. For exampe, paxil has some anticholinergic effects and prozac has some mild noradrenergic effects (from the metabolite norfluoxetine). THE SSRI's are different from one another, so a patient may respond to one SSRI and not another.

 

[michaelrack]

Tianeptine, or trade name stablon is approved in Europe but not in the US. My uncle asked me about it at that time and I had no clue, I had to look it up.

HOW DO antidepressant SSRI's or SSRE's work?

Surely it is not serotinin mediated. I just find it funny that they still have serotonin in the acronym SSRI/E, when a serotonin's uptake can't be both enhanced and inhibited AND cause the same result: eg better mood.

Any input?

that's interesting about stablon http://en.wikipedia.org/wiki/Stablon

Don't got a good explanation of why it would work- hopefully Stahl will produce some pretty pictures soon that will give a rational hypothesis

 

[Encephalopathy]

Keep in mind that there is only one medication representing SSREs, so you can't call it a class effect yet. Hitting multiple receptors is common, and it's possible that tianeptine has other pharmacologic properties that could result in it's antidepressant action.

 

[Faebinder]

Why do SSRIs not work on all depression cases? Similar to why do beta blockers not work on all HTN cases?

The depressive disorders is a collection of disorders that exhibit similar symptoms that we don't really have "all" the eitology:

a) Some eitologies are branched out and clearly defined. Depressive D/O due to GMC is usually the label when they are well defined (such as depressive disorder due to hypothyroidism).

b) Some eitologies are now being separated from the haystack such as deficits in trimonoamine neurotransmitter synthesis attempted to be treated via Deplin (in theory it looks like a good eitology that explains depression in some people, but it's not proven).

The haystack is made worse by other things that look like depression (Bipolar disorder, chronic substance abuse especially opiods like Percocets, Borderline Personality Disorder). This make it even harder to determine who really has depression.

In otherwords, defining depression is hard and thus getting a treatment that works for this vague definition is hard.