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#1
04-10-2011, 10:40
RoboCodeine7610
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Depression: Death to the serotonin hypothesis

Robo was watching a documentary on the overprescription of antidepressants and other psychiatric drugs to children, and heard that the serotonin hypothesis of depression has pretty much no evidence for it apart from the efficacy of SSRIs.

That would have been enough for me, except for the fact that apparently 57% of the SSRI trials funded by the pharmaceutical industry failed to show a significant difference between drug and placebo.

Here are a few links on the subject:

http://phineasgage.wordpress.com/200...in-hypothesis/

http://neuroscientificallychallenged...rogenesis.html

http://www.plosmedicine.org/article/...l.pmed.0020392

I'd really appreciate all of your opinions on this.These articles really do seem to make a valid point, but then again, the euphoric effects of XTC seem to be induced by serotonin release so it would make sense that a gradual decrease in serotonin re-uptake would increase one's happyness.

Robo
#2
04-10-2011, 14:18
Troussman
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Re: Depression: Death to the serotonin hypothesis

What documentary did you watch? Was it "Generation RX" cause that one talks about same issue.
#3
04-10-2011, 17:55
RoboCodeine7610
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Re: Depression: Death to the serotonin hypothesis

Quote:
 What documentary did you watch? Was it "Generation RX" cause that one talks about same issue.
Yeah, that was the one.Any thought on the subject?
#4
04-10-2011, 18:19
WhiteDobe
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Re: Depression: Death to the serotonin hypothesis

The "serotonin hypothesis" would probably be considered entirely disproven by the medical community and society as a whole if it weren't so profitable to big pharma. Studies have shown that artificially raising/lowering the amount of serotonin in the brain shows no significant effect on mood. In clinical trials, the effect of antidepressents against placebos has shown very little difference over both short term and long term use.

On the other hand, antidepressants can actually be very harmful. Like many prescription drugs, the list of side effects is practically endless, most notably, including a significantly hightened risk of suicide ideation and violence, which is precisely what they're prescribed to prevent. I personally believe that antidepressants cause more trouble in the average patient than they avert and I've seen them "push many people over the edge," so to speak.

Anti-depressants can be very dangerous, afoaf was prescribed low dose lexapro to help deal with depression, these caused him far worse misery and downright insanity than he had ever experienced without them.

In conclusion, these can be placebos at best and a cause of suicide, homicide or other disturbing act of violence at worst. I can guarantee you that whatever program you watched about the "serotonin theory" was not hard enough on it.

Post Quality Reviews:
 What you "personally believe" means nothing compared to actual data. SSRIs are relatively safe, much more so than most drugs, and many other serotonergic antidepressants are very effective.
#5
04-10-2011, 19:58
RoboCodeine7610
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Re: Depression: Death to the serotonin hypothesis

Quote:
 The "serotonin hypothesis" would probably be considered entirely disproven by the medical community and society as a whole if it weren't so profitable to big pharma. Studies have shown that artificially raising/lowering the amount of serotonin in the brain shows no significant effect on mood. In clinical trials, the effect of antidepressents against placebos has shown very little difference over both short term and long term use. On the other hand, antidepressants can actually be very harmful. Like many prescription drugs, the list of side effects is practically endless, most notably, including a significantly hightened risk of suicide ideation and violence, which is precisely what they're prescribed to prevent. I personally believe that antidepressants cause more trouble in the average patient than they avert and I've seen them "push many people over the edge," so to speak
What I don't understand is that normally, drugs and their effects are discovered through clinical trials like viagra, for example, that was originally intended to be an anti-hypertensive drug and while running the clinical trial showed it's effects on erectile dysfunction.

So how did this serotonin myth actually begin?Why claim that SSRIs have antidepressant effects if there was absolutely no reason to believe they did?

Robo
#6
04-10-2011, 20:08
 Synaps Silver Member Join Date: 27-07-2010 Male from Norway Posts: 210
Re: Depression: Death to the serotonin hypothesis

SSRI did not cure my depression, but it helped me regain the control over my thoughts. During the most severe phase of my depression, thinking rationally was impossible because every thought I conjured in my mind developed into bad memories and depressive thoughts. I could not think. Thanks to SSRI I was able to go through therapy.

SSRI + Cognitive Behavioural Therapy has well documented efficacy. In my opinion, the issue is that SSRI's are too often described by itself as a wonder drug against depression, which it clearly is not. It is a tool to make therapy possible. All studies point to this, and it baffles me that there are still doctors out there that do not understand this.

Post Quality Reviews:
 excellent point about SSRIs efficacy when concomitant with CBT.
#7
04-10-2011, 21:46
staples
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Re: Depression: Death to the serotonin hypothesis

To keep things brief, an obvious thing to point out here is that supposing SSRIs (hell, supposing all serotonergic substances) never show any statistically-significant efficacy over placebo, then in the context of the serotonin hypothesis, we've simply failed to reject the null hypothesis. It doesn't mean that serotonin is not implicated by depression. In other words, this is not sufficient to conclude that the serotonin hypothesis is wrong.

This topic has come up in other threads so I'd like to point this thread towards the research I posted here and the points I raised here (note: I think it'd be appropriate at this point to reply to either of these posts in this thread, if you'd like to reply to one or both).
#8
04-10-2011, 22:06
Crazy Insane Sanity
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Re: Depression: Death to the serotonin hypothesis

The serotonin deficiency hypothesis was proposed as a cause for depression because nearly all anti-depressants, up until recently, increased levels of serotonin and are known to help a lot of people deal with their depression (not everyone, though). The reasoning here is obviously flawed for making any conclusive claims, but it's just a hypothesis. As Staples pointed out in his post, there is a good deal of evidence to suggest dysfunction of the serotonergic system in at least some people suffering from depression.

It is true that SSRI's don't work very well on their own...but studies show a statistically significant benefit over placebos for severely depressed patients. When paired with therapy the effects seem to be even greater. Since SSRI's have less severe side effects than previously used antidepressants, they have largely replaced their usage.

In more recent times, antidepressants have been discovered that do not affect serotonin levels, but still manage to get the job done. DNRI's like bupropion, dissociatives like ketamine, or 5-HT1a partial agonists like buspirone are some examples. This has led researchers to consider some other type of underlying cause. It is possible that increasing levels of serotonin has an indirect effect on whatever this issue is. Just think of MDMA's effects on mood...MDMA doesn't just inhibit the serotonin transport protein, but reverses it, causing serotonin to spill into the synapse.

It's really up in the air right now as to what exactly causes depression. One interesting new development involves levels of brain-derived neurotrophic factor. Only time will tell what developments will unfold.

Keep in mind though, that just because you, or someone you know didn't benefit from SSRI's, doesn't mean that there aren't people who do benefit from them. Our understanding of depression is only in it's infancy, and the drugs to treat it are limited in their efficacy, but that doesn't mean we should just do away with what little treatments we have. I myself have had a horrible reaction to an SSRI. On the other hand, I know a couple of people who have had success with cognitive behavioral therapy only after being placed on SSRI's. Anecdotal reports are a piss poor measurement for a drugs efficacy (or anything, for that matter), and the fact is that studies suggest a slight, but statistically significant benefit in severely depressed patients.

Post Quality Reviews:
 This was a good post, right to the point, making a lot of good points.. Excellent info and good point about how it depends on person
#9
04-10-2011, 22:53
Dog Rockets
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Re: Depression: Death to the serotonin hypothesis

Quote:
 Originally Posted by Synaps SSRI did not cure my depression, but it helped me regain the control over my thoughts. During the most severe phase of my depression, thinking rationally was impossible because every thought I conjured in my mind developed into bad memories and depressive thoughts. I could not think. Thanks to SSRI I was able to go through therapy. SSRI + Cognitive Behavioural Therapy has well documented efficacy. In my opinion, the issue is that SSRI's are too often described by itself as a wonder drug against depression, which it clearly is not. It is a tool to make therapy possible. All studies point to this, and it baffles me that there are still doctors out there that do not understand this.

This. Take it from someone who has been to the very brink of death via suicide and is now a much happier person due to extremely high dosages of SSRIs combined with relatively small amounts of benzodiazapines and lots and lots of therapy.

Drugs, of any kind, are rarely if ever the answer to one's problems. However they can be extremely valuable if used correctly and in conjunction with other treatment modalities and life changes.

I may only be a sample of one but something in my treatment dramatically changed my brain chemistry and/or how it functions. It might have been the SSRIs, benzos, therapy, something else, all/none of these. What I do know is that I'm still alive many years later and my psychiatrist/psychologist seem to be a big part of that.

Post Quality Reviews:
 excellent post based on personal experience
#10
05-10-2011, 00:55
Troussman
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Re: Depression: Death to the serotonin hypothesis

What disturbs me the most is how psychiatrists are prescribing SSRI's, Anti-Psychotics and amphetamines like Focalin to young kids. Kids that are as young as 4 years old are taking these drugs on a daily basis. It is not like it is a small amount of children subject to this. Tons of children are diagnosed with ADD/ ADHD and depression at very early ages. Whether SSRI's work or not, it certainly isn't healthy to be loading a young developing brain up on drugs. I'm a product of this as I grew up when Ritalin hit the market.
#11
05-10-2011, 07:51
Dog Rockets
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Re: Depression: Death to the serotonin hypothesis

Quote:
 Originally Posted by Troussman What disturbs me the most is how psychiatrists are prescribing SSRI's, Anti-Psychotics and amphetamines like Focalin to young kids. Kids that are as young as 4 years old are taking these drugs on a daily basis. It is not like it is a small amount of children subject to this. Tons of children are diagnosed with ADD/ ADHD and depression at very early ages. Whether SSRI's work or not, it certainly isn't healthy to be loading a young developing brain up on drugs. I'm a product of this as I grew up when Ritalin hit the market.
This we can agree on. It's one thing to drug the absolute shit out of someone like myself, who clearly needs it, and a kid who is disruptive in class. It was my impression that the DSM did not really recommend diagnosing minors with mood disorders as they are, well, kids. And god knows how these drugs affect brain development!
#12
05-10-2011, 09:05
psyche

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Re: Depression: Death to the serotonin hypothesis

Quote:
 Originally Posted by Crazy Insane Sanity Since SSRI's have less severe side effects than previously used antidepressants, they have largely replaced their usage.
Agree with your post, except for this part. Reversible MAOI's like moclobemide are as well tolerated as SSRI's and effective. I just got a prescription and had a brief talk with the doctor about the drugs, and I ended up wondering why moclobemide wouldn't be in common use today. I had a hunch of my own, but wouldn't want to espouse it without knowing for sure. I was happy to hear my doctor himself attribute it honestly to the marketing & making money.

Personally I find MAOI's true antidepressant in the sense that they do just what they need to do, nothing more, nothing less: elevate the mood and make life worth living again. In contrast, SSRI's can be great in less nondirect way that goes better with therapy, by offering intra/interpersonal clarity and stability. SSRI's probably have a wider range of applications, they might suit people less stable or with more complex disorders than depression/anxiety.

Last edited by psyche; 05-10-2011 at 18:43.
#13
05-10-2011, 14:25
lillianni
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Re: Depression: Death to the serotonin hypothesis

Having been treated 3 times in the past for depression successfully with Fluoxetine, my last episode has developed into something quite different. Initial doses and subsequent increases of Fluoxetine did nothing apart from make me quite ill due to side effects so I was changed to Citalopram which again did nothing. My diagnosis was changed to bi-polar 2 disorder and I was started on Quetiapine and finally put on Venlafaxine. I am happy to report that I have improved and stabilised to the point where my psychiatrist has discharged me back to the care of my GP. Venlafaxine is a serotonin and noradrenaline re-uptake, Quetiapine is an atypical antipsychotic. I also occasional take Diazepam and Zopiclone to still my very busy mind.

My point is, do not expect medication to miraculously make you better, particularly with regard to mental health. Often it just relieves the symptoms but the cause will remain, usually only discovered during therapy. It took a long time to get a psychiatric referral and then I used insider knowledge to make statements that weren't necessarily true but which I knew would get the results I wanted.

If you are prescribed medication then you should take it but make sure that some form of "talking" therapy is arranged alongside.
#14
05-10-2011, 16:47
RoboCodeine7610
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Re: Depression: Death to the serotonin hypothesis

Quote:
 To keep things brief, an obvious thing to point out here is that supposing SSRIs (hell, supposing all serotonergic substances) never show any statistically-significant efficacy over placebo, then in the context of the serotonin hypothesis, we've simply failed to reject the null hypothesis. It doesn't mean that serotonin is not implicated by depression. In other words, this is not sufficient to conclude that the serotonin hypothesis is wrong.
Well, the reason why I suggested that the ineffectiveness of SSRIs could prove wrong the serotonin hypothesis was because, as said in "generation Rx" (not completely sold on the info there), the effectiveness of these drugs were the only available evidence to support the serotonin hypothesis.

Quote:
 In more recent times, antidepressants have been discovered that do not affect serotonin levels, but still manage to get the job done. DNRI's like bupropion, dissociatives like ketamine, or 5-HT1a partial agonists like buspirone are some examples. This has led researchers to consider some other type of underlying cause. It is possible that increasing levels of serotonin has an indirect effect on whatever this issue is. Just think of MDMA's effects on mood...MDMA doesn't just inhibit the serotonin transport protein, but reverses it, causing serotonin to spill into the synapse.
That's pretty interesting.After reading your post I'm really starting to see how depression isn't as simple as serotonin deficiency in the brain.It really seems to be a lot more complicated than that and, as good a point as you make about our understanding of depression being at it's infancy, we'll get some conclusive answers in the near future.After all, depression is really where the money is when it comes to drug research.

Quote:
 It's really up in the air right now as to what exactly causes depression. One interesting new development involves levels of brain-derived neurotrophic factor. Only time will tell what developments will unfold
Brain-derived neurotrophic factor?Sounds interesting.

Quote:
 What disturbs me the most is how psychiatrists are prescribing SSRI's, Anti-Psychotics and amphetamines like Focalin to young kids. Kids that are as young as 4 years old are taking these drugs on a daily basis. It is not like it is a small amount of children subject to this. Tons of children are diagnosed with ADD/ ADHD and depression at very early ages. Whether SSRI's work or not, it certainly isn't healthy to be loading a young developing brain up on drugs. I'm a product of this as I grew up when Ritalin hit the market.
That is, in fact, very disturbing.If you think about it, this has already happened once in history.Back in the 19th century, children were often put to sleep with laudanum or morphine syrups and grew up with severe mental deficits.Now stimulants in the amphetamine class are generally more neurotoxic than opiates are, which leads me to wander if the neurological deficits, depending on the dosages prescribed, might be even worse...
#15
05-10-2011, 17:26
psyche

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Re: Depression: Death to the serotonin hypothesis

This is a common rap, but still: I wonder what would happen if FDA began to require a new drug to be more efficient than the previous one or to have less side-effects, instead of just working better than placebo. The day the majority of drug-companys money goes to research, and only advancements, not advertisements, are financially rewarded, then the serious research begins.

Last edited by psyche; 05-10-2011 at 18:47. Reason: sentence clarification
#16
05-10-2011, 18:17
Dog Rockets
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Re: Depression: Death to the serotonin hypothesis

Quote:
 Originally Posted by RoboCodeine7610 That's pretty interesting.After reading your post I'm really starting to see how depression isn't as simple as serotonin deficiency in the brain.It really seems to be a lot more complicated than that and, as good a point as you make about our understanding of depression being at it's infancy, we'll get some conclusive answers in the near future.After all, depression is really where the money is when it comes to drug research.
This is very true. So many treatments work/don't work depending on the person. For example, I am SHOCKED that anti-psychotics have been found to be efficacious for depression in some treatment resistant cases. I've never been on an anti-psychotic, but have been on seizure meds and wouldn't wish that on anyone. To me, these types of drugs reduce one to a stoooopid vegetable. And it made me more unhappy at that!

Quote:
 Originally Posted by RoboCodeine7610 That is, in fact, very disturbing.If you think about it, this has already happened once in history.Back in the 19th century, children were often put to sleep with laudanum or morphine syrups and grew up with severe mental deficits.Now stimulants in the amphetamine class are generally more neurotoxic than opiates are, which leads me to wander if the neurological deficits, depending on the dosages prescribed, might be even worse...
Preach on RoboCodeine. The DEA stresses just how destructive drugs like meth are while conveniently "forgetting" to mention that it's a schedule II prescription medication as well as a street drug. How the hell you prescribe amphetamines to an eight year old is beyond me.
#17
05-10-2011, 18:58
staples
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Re: Depression: Death to the serotonin hypothesis

Quote:
Originally Posted by RoboCodeine7610
Well, the reason why I suggested that the ineffectiveness of SSRIs could prove wrong the serotonin hypothesis was because, as said in "generation Rx" (not completely sold on the info there), the effectiveness of these drugs were the only available evidence to support the serotonin hypothesis.

Quote:
 In more recent times, antidepressants have been discovered that do not affect serotonin levels, but still manage to get the job done. DNRI's like bupropion, dissociatives like ketamine, or 5-HT1a partial agonists like buspirone are some examples. This has led researchers to consider some other type of underlying cause. It is possible that increasing levels of serotonin has an indirect effect on whatever this issue is. Just think of MDMA's effects on mood...MDMA doesn't just inhibit the serotonin transport protein, but reverses it, causing serotonin to spill into the synapse.
Wouldn't efficacy of buspirone support the serotonin hypothesis?

My understanding is that bupropion has very low affinity for DA and NA receptors and the risk of seizure puts it behind SS(N)RIs as a first line of defense, regardless; isn't Buproprion not accepted as a treatment for depression in the UK? and in the US it's typically prescribed alongside an SSRI in clinical practice... But even beyond that point, notice that the exact converse conclusion of the above quote could be the fact of the matter: perhaps non-serotonergic medications which improve symptoms of depression have a distal effect on serotonergic nerves? Or perhaps depression needs more (ways of identifying) subtypes such that we can know when SSRIs are implicated rather than a DRI, vice versa, or a combination of the two.

As for the effectiveness of drugs being the only available evidence to support the serotonin hypothesis, please at least take a look at these three papers from the post I mentioned earlier:

Note: At least the first paper presumes an understanding of the difference between a receptor and an autoreceptor, and the circumstances that would cause an increase or decrease in either. Also take note of such wordings as "alterations of serotonergic neurons", implying a component of time (to both develop and correct said alterations).

Indeed I think the entire issue of just how complex and varied depression is/can be is unfortunately taken for granted in movies like Generation RX. Have you read Prozac Nation?

Post Quality Reviews:
 Excellent, thorough post; you're a real asset 'round here! continuing to add useful insight to the thread
#18
05-10-2011, 20:11
Elfenlied
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Re: Depression: Death to the serotonin hypothesis

Quote:
 Originally Posted by RoboCodeine7610 That would have been enough for me, except for the fact that apparently 57% of the SSRI trials funded by the pharmaceutical industry failed to show a significant difference between drug and placebo.
The problem with the criticism that there was a small statistical significance but not a clinical significance, is that these industry studies were carried out to meet the FDA criteria for significance. Industry will opt for short-term cheap trials if that's sufficient to meet the targets. Most studies only lasted 6 weeks or less. They didn't use strict criteria to select test subjects. Basically, they look for the cheapest and fastest way to get the drug approved. So using these trials to judge the clinical significance of SSRI's will likely give disappointing results.

As for the serotonin hypothesis, I think that maybe depression is a case of the brain being stuck in some kind of negative thought patterns, and breaking out of these can be achieved in various ways, by increasing serotonin, by electroshocks, by reducing serotonin (SSRE or selective serotonin reuptake enhancer), by psychotherapy and so on.

Post Quality Reviews:
 Very good point on what FDA trial results do (and do not) say...
#19
05-10-2011, 20:21
RoboCodeine7610
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Re: Depression: Death to the serotonin hypothesis

Quote:
 This is very true. So many treatments work/don't work depending on the person. For example, I am SHOCKED that anti-psychotics have been found to be efficacious for depression in some treatment resistant cases. I've never been on an anti-psychotic, but have been on seizure meds and wouldn't wish that on anyone. To me, these types of drugs reduce one to a stoooopid vegetable. And it made me more unhappy at that!
I have to say that I'm also impressed at the fact that antipsychotics help depression in some cases...And about the anti-seizure meds, it really depends on what you're on.I know someone who's on a daily dose of valproic acid and doesn't seem to be impaired by it.Then again, she's been on it for the most part of her life.

Quote:
 My understanding is that bupropion has very low affinity for DA and NA receptors and the risk of seizure puts it behind SS(N)RIs as a first line of defense, regardless; isn't Buproprion not accepted as a treatment for depression in the UK? and in the US it's typically prescribed alongside an SSRI in clinical practice... But even beyond that point, notice that the exact converse conclusion of the above quote could be the fact of the matter: perhaps non-serotonergic medications which improve symptoms of depression have a distal effect on serotonergic nerves? Or perhaps depression needs more (ways of identifying) subtypes such that we can know when SSRIs are implicated rather than a DRI, vice versa, or a combination of the two.
And apparently it's also a 5HTa1 partial agonist, which seems to confirm the fact that it mediates party by modulating serotonin.

Quote:
 As for the effectiveness of drugs being the only available evidence to support the serotonin hypothesis, please at least take a look at these three papers from the post I mentioned earlier:
As I said earlier, it seemed rather far-fetched that there was no other evidence for the serotonin hypothesis.Very interesting reads, thanks for the links.I'll read them thoroughly when I have more time.

Quote:
 Indeed I think the entire issue of just how complex and varied depression is/can be is unfortunately taken for granted in movies like Generation RX. Have you read Prozac Nation?
Do you recommend it?I have been looking for an interesting read, if you know where I can get a pdf that'd be great.

Robo

RoboCodeine7610 added 4 Minutes and 24 Seconds later...

Quote:
 The problem with the criticism that there was a small statistical significance but not a clinical significance, is that these industry studies were carried out to meet the FDA criteria for significance. Industry will opt for short-term cheap trials if that's sufficient to meet the targets. Most studies only lasted 6 weeks or less. They didn't use strict criteria to select test subjects. Basically, they look for the cheapest and fastest way to get the drug approved. So using these trials to judge the clinical significance of SSRI's will likely give disappointing results.
Had no idea.Always assumed pharmaceutical companies would condition the trials to give the greatest statistical significance to their claims.But if these trials only lasted 6 weeks or less, obviously the results would be disapointing, nice catch.

Quote:
 As for the serotonin hypothesis, I think that maybe depression is a case of the brain being stuck in some kind of negative thought patterns, and breaking out of these can be achieved in various ways, by increasing serotonin, by electroshocks, by reducing serotonin (SSRE or selective serotonin reuptake enhancer), by psychotherapy and so on.
Can't say I've suffered from any severe depression before, but that hypothesis does make sense.Still, as I stated previously this is a very well researched topic and I'm sure we'll have more specific knowledge on this in the near future.

Robo

Last edited by RoboCodeine7610; 05-10-2011 at 20:21. Reason: Automerged Doublepost
#20
09-10-2011, 08:10
Elfenlied
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Re: Depression: Death to the serotonin hypothesis

Quote:
 Originally Posted by RoboCodeine7610 Had no idea.Always assumed pharmaceutical companies would condition the trials to give the greatest statistical significance to their claims.But if these trials only lasted 6 weeks or less, obviously the results would be disapointing, nice catch.
That was at least how I remembered it, did some searching when I came across such a study a while ago. Wasn't too sure about the details so I checked again.

The most prominent meta-analyses on ssri studies (and the ones that attracted most media attention) are the two by Irving Kirsch.
• First one in 1998 with Sapirstein G: Listening to Prozac but hearing placebo: : A meta-analysis of antidepressant medication. Prevention and Treatment.
• Second one in 2008 with Deacon BJ, Huedo-Medina TB, Scoboria A, Moore TJ: Initial severity and antidepressant benefits: A meta-analysis of data submitted to the Food and Drug Administration.
The 1998 study examined published pre-approval trial results, the 2008 study added the unpublished trial results (requested from the FDA under the Freedom of Information Act), all trials relating to four SSRI's: Fluoxetine, nefazodone, paroxetine and venlafaxine. (sertraline and citalopram excluded because some trials didn't report the necessary data)

Here are the (in my opinion) most important points :
info comes from the study itself, and online articles about the study, sentences and sections with * express my own opinions and arguments

Info on the trials:
• There were a total of 47 trials (including the ones for sertraline and citalopram).
• Thirty-three trials were of 6-wk duration, six trials were 4 wk, two were 5 wk, and six were 8 wk.
• Thirty-nine trials focused on outpatients, three included both inpatients and outpatients, three were conducted among the elderly and two were among patients hospitalized for severe depression.
• Replacement of patients who investigators determined were not improving after 2 wk was allowed in three fluoxetine trials and in the three (excluded) sertraline trials.
• The use of other psychoactive medication was reported in 25 trials. In most trials, a chloral hydrate sedative was permitted in doses ranging from 500 mg to 2,000 mg per day. Other psychoactive medication was usually prohibited but still reported as having been taken in several trials.
• Improvement was judged by a list of factors, like mood, insomnia, lack of appetite, using the Hamilton Depression Rating Scale (HRSD).

The main findings of the study:
• Most of the improvement was due to placebo effect. On the Hamilton rating scale, weighted mean improvement was 9.60 points for patients on SSRI and 7.80 points for those on placebo.
• The difference between SSRI's and placebo was not clinically significant. The criterion for clinical significance used by the National Institute for Clinical Excellence (NICE) (UK) is a three-point difference in HRSD scores or a standardized mean difference of 0.50 . While the 1.80 difference was statistically significant, it did not meet the NICE criterium of 3.00 for clinical significance. The standardized means changes were 1.24 for SSRI and 0.92 for placebo, the difference of 0.32 not meeting the NICE criteria of 0.5
• Drug efficacy did not change as a function of initial severity, whereas placebo efficacy decreased as initial severity increased.
For patients with HRSD baseline scores exceeding 28, the difference between drug and placebo effect became clinically significant (0.50 standardized mean difference).
• Most small studies had higher baselines and showed larger effects.

Conclusions of the study: "We find that the overall effect of new-generation antidepressant medications is below recommended criteria for clinical significance. We also find that efficacy reaches clinical significance only in trials involving the most extremely depressed patients, and that this pattern is due to a decrease in the response to placebo rather than an increase in the response to medication."

As part of the licensing process, the FDA requires drug companies to report “all controlled studies related to each proposed indication” (emphasis in original). Thus, there should be no reporting bias in the dataset we analyze.

The FDA requires that rigorous standards be followed for the conduct of all efficacy trials for marketing approval and also sets specific agency standards for clinical trials of antidepressant drugs. In addition, the FDA independently reviews the clinical trial methods, statistical procedures, and results.

FDA reviewers sought a completion rate of 70% or better for these typically 6-wk trials. Only four of the trials reported reaching this objective, and completion rates were not reported for two trials. Attrition rates were comparable between drug and placebo groups. Of those trials for which these rates were reported, 60% of the placebo patients and 63% of the study drug patients completed a 4-, 5-, 6-, or 8-wk trial.

In-depth opinion article reporting the results:
removed

Criticism:
• The whole study is based on pre-approval trials, carried out 15 to more than 20 years ago. Fluoxetine was approved in 1987, venlafaxine was introduced in 1993, nefazodone was first marketed by Bristol-Myers Squibb in 1994, discontinued in 2004 because of rare cases of liver failure, (generic version still available in some countries)*. Paroxetine was first marketed in 1992*.
• Given the widespread use of these drugs, much more data and (maybe better) studies are available today. Eli Lilly and Co (prozac) points to over 12000 patients in clinical trials and thousands of scientific papers on Prozac. GlaxoSmithKline (Seroxat) says the analysis has only examined a small subset of the total data available.
• The FDA requires at least two placebo-controlled trials with positive results to authorize a drug indication, regardless of how many trials fail to demonstrate the drug's superiority to placebo. Companies rushing to get medications to market have had an incentive to run quick, sloppy trials.
• Kirsch used a standardized means difference of 0.50 for clinical significance, a norm no longer used by NICE.
• The study fails to mention that for paroxetine and venlafaxine the difference between drug and placebo effect was larger than three HRSD points, meeting the NICE standard for clinical significance.
• The Kirsch et al.'s meta-analysis suffered from important flaws (errors) in the calculations.
• Statements on the combined results are based on the absolute values (3 point standard), statements about the decrease in placebo effect, not an increase in SSRI effect as a reason for the results in severely depressed patients are based on standardized means; if the absolute values are compared, the placebo effects remain the same and the SSRI effects increase.
• The study shows a clinically significant effect beginning at a baseline score of about 28 HRSD points; when judged by the 3 point standard, this would instead begin 2 points lower.
• The authors overstate the placebo effect by ignoring that some depressed patients will recover without treatment*.
• The brain concentration of fluoxetine and its metabolites keeps increasing through at least the first five weeks of treatment, what would explain why fluoxetine showed lower effectivity in short trials than paroxetine and venlafaxine.*

So, if we add these comments to the "what did the researchers found?" section of the study*:

"They confirmed first that the overall effect of these new generation of antidepressants was below the recommended criteria for clinical significance. - the overall effect of both paroxetine and venlafaxine was clinically significant, nefazodone has been withdrawn and fluoxetine takes a long time to reach steady state concentrations making short duration studies ill-suited to examine the effects. - Then they showed that there was virtually no difference in the improvement scores for drug and placebo in patients with moderate depression - only two studies, both with fluoxetine focused on patients with mild and moderate depression - and only a small and clinically insignificant difference -according to outdated criterion, no longer used by NICE- among patients with very severe depression - using the same criteria they based their first statement on, a clinically significant difference was shown starting at HRDS scores of 26, and that group of patients is, based on the same criteria, not significantly different clinically from patients with moderate depression (dubious argument maybe... depending on which definition is used, that's a bit unclear, see next section "RDS as tool..") ,-. The difference in improvement between the antidepressant and placebo reached clinical significance, however, in patients with initial HRSD scores of more than 28—that is, in the most severely depressed patients - see previous comment - Additional analyses indicated that the apparent clinical effectiveness of the antidepressants among these most severely depressed patients reflected a decreased responsiveness to placebo rather than an increased responsiveness to antidepressants." - using the same criteria as before, responsiveness to placebo stayed the same, responsiveness to antidepressants increased -

HRSD as tool to measure severity and improvement*

The HRSD questionnaire: attached

Most often only the first 17 questions are used (HRSD-17). Linking the score to severity is a bit of a problem*. I've seen sources for HDRS-17 that define:
• mild depression starting at 10, moderate at 14 and severe at 18
• mild starting at 7, moderate at 18 and severe at 25
• severe as 20 or more
• 10 – 13. Mild. 13 – 17. Mild to Moderate. > 17. Moderate to severe.
• at least 19 for severe depression (apparently based on the Handbook of psychiatric measures published by the American Psychiatric Association)
A 1996 European Neuropsychopharmacology Consensus Meeting report about the lack of an accepted criterium for severe depression mentions that 25 or 28 for HRSD-17 and 28 for HRSD-21 are often used.

HDRS bias in favor of sedating and weight gain side-effects*

HDRS has been criticized as being biased in favour of tricyclic AD's since 3 questions for a maximum of 6 points are related to insomnia. If you add the two questions with maximum 5 points about loss of appetite and loss of weight, it would seem a safe bet that TCA's or anti-psychotic medication like seroquel will lower HDRS scores, the only obvious disadvantage being 2 points related to loss of energy, fatigue*.

_______

Reactions to the criticisms listed should perhaps have been included, but this post is already long enough...

Final note: Kirsch is professor emeritus of psychology; he is the originator of response expectancy theory (1985) and most of his published work is about expectancy, suggestibility, hypnosis, placebo-effect and their use in medical treatment*.

Links removed since I can't post them

Post Quality Reviews:
 This is an excellent & exemplary post full of substance; precisely the kind of post we're interested in seeing. Please keep posting in EB! Impeccable post! Impressive and thorough amalgamation of major points from the cited meta-analyses tied neatly together with some critical thinking. Very well done! a highly detailed post, with sources, attachments, and the works. Clearly you put a lot of effort into this response. Very interesting and detailed information.
Attached Files
 HAMD.pdf (49.0 KB, 3 views)

Last edited by Elfenlied; 09-10-2011 at 08:46. Reason: minor changes
#21
09-11-2011, 16:21
chibi curmudgeon
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Join Date: 26-11-2008
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Re: Depression: Death to the serotonin hypothesis

Quote:
 Originally Posted by Elfenlied HDRS bias in favor of sedating and weight gain side-effects* HDRS has been criticized as being biased in favour of tricyclic AD's since 3 questions for a maximum of 6 points are related to insomnia. If you add the two questions with maximum 5 points about loss of appetite and loss of weight, it would seem a safe bet that TCA's or anti-psychotic medication like seroquel will lower HDRS scores, the only obvious disadvantage being 2 points related to loss of energy, fatigue*.
I kind of take issue with this; I'm not sure how much the HAM-D has been revised, or maybe I'm confusing it with another scale, but I've seen ones that use either weight loss OR gain, as well as hypersomnia and/or insomnia (I know all too well it's possible to have both...)

I don't know if I'd call this bias in favor of TCAs as much as an example of why scales aren't a replacement for clinical judgement: someone who goes from a normal appetite to constant "comfort eating" is obviously deteriorating, and even if someone's been losing weight due to depression, gaining 30 lbs of fat is never an improvement.

Just my \$0.02. I doubt the serotonin hypothesis is going anywhere, it just needs further refinement.

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