[Altered Moment]

There was a study published in The New England Journal of Medicine that has gotten much media attention. I believe the lead author has said that in the media and general public the results have been largely misinterpreted. The study did a meta-analysis of all the pre approval clinical trials done between 1987 and 2004 and covered 12 antidepressants compared to placebo.

The main gist of the study is that big pharma and the FDA cheat. Studies that show positive results are pushed to the fore and published and studies that show negative results are hidden. There is corruption that exists between big pharma and the FDA and I might add Congress too. No big surprise there. That is the main point of the article and what it proves. It doesn’t say anything about why antidepressants work or don’t work. It shows that the original trials don’t paint such a glowing picture. It does not mean antidepressants are ineffective.

In my opinion all of those initial clinical trials whether they were positive or negative are useless because how can you do a 6 to 8 week trial on a drug we now know takes 6 to 8 weeks to work. It tells you nothing about efficacy but does tell you something about safety.

You may see articles titled-
“Why Antidepressants Don’t Work for Treating Depression”
And pointing to the study as the sole source for that statement. This is very misleading and not at all true. In the first place it doesn’t say anything about “why” and it just flatly says they don’t work.

Why Antidepressants Don?t Work for Treating Depression - Dr. Mark Hyman

There are many similar articles that site the study.

New England Journal of Medicine published article on “Selective Publication of Antidepressant Trials and Its Influence on Apparent Efficacy”

Here is the full article-

MMS: Error

The overall meta-analysis showed efficacy to be superior to placebo just not as good as one would have originally been led to believe.

From the article

We wish to clarify that nonsignificance in a single trial does not necessarily indicate lack of efficacy. Each drug, when subjected to meta-analysis, was shown to be superior to placebo. On the other hand, the true magnitude of each drug's superiority to placebo was less than a diligent literature review would indicate.

Interview with lead author by ScienceWatch

Erick Turner - ScienceWatch.com

SW- If the drug is only superior to the placebo in only half of clinical trials, does the drug actually work?

That's where meta-analysis comes in. Meta-analysis lets you combine trials that show a statistically significant difference between drug and placebo with trials that don't. Then you can see whether, for all trials combined, the drug-placebo difference is statistically significant. For each of the 12 drugs we looked at, it was.

Getting back to the point that drug efficacy is not an all-or-none phenomenon, meta-analysis also tells you how big that difference is. In other words, it allows you to put its efficacy somewhere along a continuum. The effect sizes we calculated for each drug based on the FDA data were substantially less than the effect sizes based on the published literature. Whether those effect sizes are clinically significant, in addition to statistically significant, is a matter of debate.

Interview of lead author by Psych Central

This Month?s Expert: Understanding Antidepressant Research by Erick Turner, MD | Psych Central Professional

TCPR: Looking at your paper, some readers, seeing that only half of the studies submitted showed the antidepressant to be effective, might wonder, “Does this mean that these antidepressants basically aren’t effective at all, that it is just a flip of a coin whether a study shows a drug to be effective?” Is that a proper way of looking at it or no?

Dr. Turner: That question comes up a lot. No, that would not be a proper interpretation, because if the drug does not separate from placebo statistically, it might still be numerically better than placebo. In almost every trial we looked at, the drug still had a numerical edge over placebo (there were a few exceptions, trials in which the drug actually did worse than placebo), just not a big enough edge to be statistically significant. Now if you have a lot of trials like that and you combine them through meta-analysis, you get more statistical power, and the overall difference can become significant. And that’s what we found, that each of the 12 drugs, overall, was statistically superior to placebo.The other caveat would be that the results of these trials get reported as means, but each mean value is based upon thousands of individuals, some with very good responses and others with lousy responses. So when you think about how an individual patient in your practice might respond, remember the old saying, “Your mileage may vary.”

To me what really matters is the results after a drug has been on the market for a while. Like I said I don’t give much credence to the original clinical trials. They are too short and have flaws to begin with. We are largely left with our own experience, the anecdotal experience of others, and the anecdotal experience of psychiatrists. The biggest and best study I know of that looked at real world practice and results is the StarD study. It has the problem of not comparing to placebo. There is a very large international study currently being conducted. I think the best evidence so far shows they work in 50 to 60% of cases especially for severe depression.

NIMH · Antidepressants: A complicated picture

But what about long-term effectiveness and true remission of symptoms? In the NIMH-funded Sequenced Treatment Alternatives to Relieve Depression (STAR*D) Study, the outcome measure was remission of depressive symptoms, e.g., becoming symptom-free. This outcome was selected because people who reach this goal generally function better socially and at work, and have a better chance of staying well than do people who only achieve a response but not a remission. STAR*D reported remission rates of 31 percent after 14 weeks and 65 percent at six months. These results may seem modest (placebo response rates are often over 30 percent in antidepressant trials). But STAR*D was not a good test of efficacy or effectiveness because it did not have a placebo comparison. While STAR*D was helpful for comparing antidepressants, in the absence of placebo, one does not know how many people would have been in remission without active medication.

Perhaps the best evidence for efficacy comes from patients who have been treated successfully with antidepressants and are switched in a blinded fashion to placebo. In a meta-analysis of 31 withdrawal studies among more than 4,000 patients, Geddes and colleagues found that 41 percent of patients who were switched to placebo relapsed, compared to 18 percent who remained on an antidepressant.xiii These studies provide compelling evidence that antidepressants are effective for some people.

More on the topic.

Effectiveness of Antidepressants

NIMH · Antidepressants: A complicated picture

Antidepressants: Effectiveness, Trials, Realistic Expectations

NIMH · Questions and Answers about the NIMH Sequenced Treatment Alternatives to Relieve Depression (STAR*D) Study ? All Medication Levels

Are antidepressants really no better than sugar pills? | The Johns Hopkins News-Letter

Robert DeRubeis on anti-depressants | News Center | Stanford Medicine

http://www.nytimes.com/2011/07/10/op...anted=all&_r=0

Study confirms antidepressant efficacy | Yale Daily News

Mild depression: Are antidepressants effective? - Mayo Clinic

Antidepressants

Antidepressants - NHS Choices

Neurogenesis and antidepressants. This means promotion of new neuron growth and new connections. A very promising area of research.

Unraveling the Mystery of How Antidepression Drugs Work - Scientific American

Neuropsychopharmacology - Fluoxetine-Induced Cortical Adult Neurogenesis

Fluoxetine-induced cortical adult neurogenesis. - PubMed - NCBI

Antidepressants increase human hippocampal neurogenesis by activating the glucocorticoid receptor

Chronic Antidepressant Treatment Increases Neurogenesis in Adult Rat Hippocampus

The Future of Depression Treatment: The Neurogenesis Theory

Promoting adult hippocampal neurogenesis: a novel strategy for anti... - PubMed - NCBI

The Neural Plasticity Theory of Depression: Assessing the Roles of Adult Neurogenesis and PSA-NCAM within the Hippocampus

Depression

A Review of the Neuropharmacology of Bupropion, a Dual Norepinephrine and Dopamine Reuptake Inhibitor

How antidepressants spur brain growth
http://www.biologicalpsychiatryjourn...581-6/abstract

http://www.cell.com/trends/pharmacol...2814%2900165-5

Depression, antidepressants and new brain cells

What do you make of this? I'm thinking in simple terms which may not be the scientific view obviously but but it seems to me that if these studies have to be looked at from so many angles it is hard to have any confidence in them. Matter of fact it creates more doubt for me.
On a personal level, my reasons for continuing venlaxefine are as much to avoid withdrawal symptoms as for any therapeutic effect. But I will qualify that statement by admitting that my view of my own depression has changed over time.

[Altered Moment]

It makes it a difficult to navigate. Like I said I think the original clinical trials are useless even if they overall including the hidden ones show they are better than placebo. I don't trust big pharma and its relationship with the FDA and congress and as I said how can you do a 6 to 8 week trial on a med that takes that long to work.

I look for the most recent research on the matter from reliable sources who study these things.

I continue to take Fetzima because it is working very well for me. I can't say how it is working but it is. That is enough evidence for me. To satisfy my scientific side I would like to know how and why it is working. There is lots of research going on that could very well lead to better treatments.

[Altered Moment]

I should point out that I think there are lots of good honest scientist at the FDA and in big pharma. Lots of very beneficial and life saving drugs have come out over the years.

It is the corruption and influence peddling and revolving door at the top decision making process that bothers me. A glaring example is Billy Tauzin. He was chairman of the Energy and Commerce Committee. He announced he was going to resign from Congress. As soon as the Part D Medicare prescription drug bill was passed he resigned and became the top lobbyist for big pharma's trade association. Technically they couldn't call him a lobbyist but he was the top dog for big bucks. Big insurance and big pharma had big influence on that bill. For instance it was stipulated that medicare could not negotiate discount prices on prescription drugs like the VA does. They made sure there was no importation of drugs from Canada.

In a brighter note there have been and are lots of small bio tech companies that patent things and do basic research and come up with beneficial new innovative things. Often they sell out to big pharma or partner with them in order to get approval and marketing. They just don't have the money.

The latest one is a drug called Sovaldi for Hepatitis C by Gilead Sciences in the Bay Area of CA. It has a very high success rate for curing hep C. The word cure has never been used with hep C before. I don't know who owns them or who they are partnered with. There have been lots of bio tech start ups in the Bay Area and in other places. The problem is Gilead wants 80,000 bucks for a course of treatment. Highway robbery. But if you are waiting for a liver and a liver transplant cost 200,000 it may work out. I don't know how insurance companies look at it or if they will cover it. I would think they have priced themselves out of the market but they have record sales.

infohep - Hepatitis C treatment factsheet: Sofosbuvir (<i>Sovaldi</i>)

There will be lots of innovative drugs and treatments coming from the university and bio tech research community in coming years. Hopefully for mental health. It seems to me big pharma has not been in the antidepressant or anti anxiety game for many years. There have been some new antidepressants but I am wiling to bet they started at small companies and then partnered.

[vital]

Originally Posted by George H.

What do you make of this? I'm thinking in simple terms which may not be the scientific view obviously but but it seems to me that if these studies have to be looked at from so many angles it is hard to have any confidence in them. Matter of fact it creates more doubt for me.
On a personal level, my reasons for continuing venlaxefine are as much to avoid withdrawal symptoms as for any therapeutic effect. But I will qualify that statement by admitting that my view of my own depression has changed over time.

Hi George,

Here is Mark Hyman discussing these results

- vital

[Altered Moment]

@Vital
This is why I have a problem with Dr. Hyman's article.

"Why Antidepressants Don’t Work for Treating Depression"

Neither the article or the study says a single word about why antidepressants don't work. So why that title?

In the article he says in the very first sentence.

HERE’S SOME DEPRESSING RECENT medical news: Antidepressants don’t work.

It is a catchy headline and has an opening statement that is not true. I don't see it as being responsible when the opening statement to your article is false.

The author of the study himself says that in the case of all 12 drugs looked at in all the trials looked at they were all significantly statistically superior to placebo.

You have said yourself that you have seen cases here where they do work. I have direct experience of them working along with a great many other people.

So how is it responsible for a doctor such as Dr. Hyman to make a blanket statement like "Antidepressants Don't Work." It is very misleading.

And I have a big problem with the clinical trials in the first place when it comes to antidepressants. The results whether positive or negative don't tell you much since they take six to eight weeks to work. It is real world clinical practice that counts.

I created this thread to point out what the study really found and what it's conclusions were because I saw many different articles that misrepresented the study.

[kiwi33]

Originally Posted by zinco14532323

Dr. Hyman

I think that there are very complex issues here but I am sceptical of anything written by Dr Hyman. He has no professional experience of psychiatric medicine.

On the other hand, he is the owner of an entity called "The UltraWellness Center" - a pretentious label is never a good sign.

The titles of some of his books (none of which seem to have been peer-reviewed) include:

The UltraMind Solution: The Simple Way to Defeat Depression, Overcome Anxiety, and Sharpen Your Mind

The UltraSimple Diet: Kick-Start Your Metabolism and Safely Lose Up to 10 Pounds in 7 Days

The UltraMetabolism Cookbook: 200 Delicious Recipes that Will Turn on Your Fat-Burning DNA

He seems to like the term "Ultra" and the notion of "Fat-Burning DNA" is particularly nonsensical for any evidence-based biomedical scientist.

He looks to me to be just another evidence-free complementary/alternative medicine practitioner who makes money by selling books and other products through his "UltraWellness Center".

[vital]

Originally Posted by kiwi33

I think that there are very complex issues here but I am sceptical of anything written by Dr Hyman. He has no professional experience of psychiatric medicine.

On the other hand, he is the owner of an entity called "The UltraWellness Center" - a pretentious label is never a good sign.

The titles of some of his books (none of which seem to have been peer-reviewed) include:

The UltraMind Solution: The Simple Way to Defeat Depression, Overcome Anxiety, and Sharpen Your Mind

The UltraSimple Diet: Kick-Start Your Metabolism and Safely Lose Up to 10 Pounds in 7 Days

The UltraMetabolism Cookbook: 200 Delicious Recipes that Will Turn on Your Fat-Burning DNA

He seems to like the term "Ultra" and the notion of "Fat-Burning DNA" is particularly nonsensical for any evidence-based biomedical scientist.

He looks to me to be just another evidence-free complementary/alternative medicine practitioner who makes money by selling books and other products through his "UltraWellness Center".

"Turning on your fat burning DNA" is a reference to epigenetics

Epigenetics - Wikipedia, the free encyclopedia

This is a absolutely real, scientifically established thing. You genes can be turned on an off depending on, among other things, what you eat.

As to peer review, both popular and academic books are reviewed by the publisher. This is not exactly the same as the review process for a journal article, but it it completely normal and is not at all a cause for suspicion.

Dr. Hyman does write bestsellers, goes on TV, etc., but this is the only way to have an impact on the health of large numbers of people. He is really trying to help you and your response is just a shame. If you decide you don't like him, you might have a look at Andrew Weil's materials. He has much the same advice on most topics.

- vital

[vital]

Originally Posted by zinco14532323

@Vital
This is why I have a problem with Dr. Hyman's article.

"Why Antidepressants Don’t Work for Treating Depression"

Neither the article or the study says a single word about why antidepressants don't work. So why that title?

In the article he says in the very first sentence.

It is a catchy headline and has an opening statement that is not true. I don't see it as being responsible when the opening statement to your article is false.

I think he just means that antidepressants don't work in the sense of not being a reasonable way to treat someone with depression. The risks outweigh the benefits, in other words. He discusses it further in the video.

Originally Posted by zinco14532323

You have said yourself that you have seen cases here where they do work. I have direct experience of them working along with a great many other people.

I believe you, zinco, and I believe other people who say this. I was particularly impressed by Karen Liberman's story in this video

(an interesting video incidentally) where it took her years of suffering until she and her doctor found the right drug. She was then able to resolve her depression and actually also get off the drug. Unfortunately, there are also many horror stories about this kind of treatment too.

I think that it has to be admitted that Dr. Hyman's approach also has really dramatic success stories and, best of all, the Functional Medicine approach is essentially safe. I think that this should be viewed as wonderful news and a promising thing to try many people in this forum.

- vital

[kiwi33]

Originally Posted by vital

This [epigenetics] is a absolutely real, scientifically established thing.

I know about epigenetics. As part of my day job I taught one of the world leaders in the field (Professor Emma Whitelaw) how to do proper statistical analyses of her epigenetic data. Emma is an outstanding molecular geneticist but I was able to help her out with numerical analysis.

Thanks for drawing my attention to Andrew Weil.

From a look at his Wiki page (Andrew Weil - Wikipedia, the free encyclopedia) he seems to be fairly sensible though I note that a number of his claims have been challenged by evidence-based health professionals, on the grounds that there are no empirical data which support them.

[Altered Moment]

Originally Posted by vital

I think he just means that antidepressants don't work in the sense of not being a reasonable way to treat someone with depression. The risks outweigh the benefits, in other words. He discusses it further in the video.

HERE’S SOME DEPRESSING RECENT medical news: Antidepressants don’t work.

How is a reader of The Huffington Post supposed to know what he might actually mean. If he doesn't mean what he says he shouldn't say it.

And the study he sites actually says the opposite of that statement.

I think that it has to be admitted that Dr. Hyman's approach also has really dramatic success stories and, best of all, the Functional Medicine approach is essentially safe. I think that this should be viewed as wonderful news and a promising thing to try many people in this forum.

- vital

I have no problem at all with functional medicine and nutrition. I think we would all agree that exercise and nutrition are good for you. It should be studied much more than it is.

If his approach has had dramatic success you need to post the scientific studies that prove this.

I am very skeptical in my personal case because when I was in high school I was in the absolute optimal shape and ate are very good whole food diet yet I still had periods of severe depression. I ran two miles a day, 100 push ups, 100 sit ups, 10 sets of ten pull ups, tons of stretching, playing hockey everyday all winter, neighborhood pickup sports all summer, and ate a good whole food diet. Yet I still went into periods of severe depression out of the blue.

I also don't think that functional medicine and nutrition will find a cure for schizophrenia or something like that.

Doctors are always promising all kinds of miracles cures. I mentioned Dr. Oz calling green coffee bean extract a miracle cure and it was based on a 17 person study in India payed for by the company that makes the product.

Half of Dr. Oz?s medical advice is baseless or wrong, study says - The Washington Post

It makes it hard for the general public to know what the hell is going on when there are so many claims that are not backed up by scientific studies. And so many doctors selling supplements. How is one to know unless it is evidence based using the scientific method and peer review? That is the method that has really served us well for centuries in science.

[vital]

Originally Posted by zinco14532323

Doctors are always promising all kinds of miracles cures. I mentioned Dr. Oz calling green coffee bean extract a miracle cure and it was based on a 17 person study in India payed for by the company that makes the product.

Half of Dr. Oz?s medical advice is baseless or wrong, study says - The Washington Post

It makes it hard for the general public to know what the hell is going on when there are so many claims that are not backed up by scientific studies. And so many doctors selling supplements. How is one to know unless it is evidence based using the scientific method and peer review? That is the method that has really served us well for centuries in science.

Here you are (as usual, I have to say), trying to smear Dr. Hyman with some sort of guilt by association. You find some person (Dr. Oz) who you claim has promised a miracle cure. You are implying that Dr. Hyman has also promised a miracle cure. All of Dr. Hyman's work that I have seen is backed up by extensive scientific studies, referenced in his books, for example.

- vital

[Altered Moment]

It was not my intention to smear Dr. Hyman but I think it is hard for the general public to sort this stuff out. I am happy to read any scientific studies if you post them. I haven't seen you post links to scientific peer reviewed studies. I am the first to admit I don't know much about nutrition other than what my two sister in laws have told me. One a dietician, and one a pharmacist, herboligist, and organic farmer. I am learning.

My problem with Dr. Hyman was the opening statement of his article that you have posted multiple times. It is not a true statement and misleading to the general public reading the Huffington Post.

And the study he sites supporting the statement says the opposite. Those are just facts.

Sent from my iPhone using Tapatalk

[vital]

Originally Posted by zinco14532323

And the study he sites supporting the statement says the opposite. Those are just facts.

Sent from my iPhone using Tapatalk

No, that is you stretching his statement in an effort to discredit him somehow.

[Altered Moment]

How am I stretching anything?

He wrote the article-

“Why Antidepressants Don’t Work for Treating Depression”

HERE’S SOME DEPRESSING RECENT medical news: Antidepressants don’t work. What’s even more depressing is that the pharmaceutical industry and Food and Drug Administration (FDA) have deliberately deceived us into believing that they DO work. As a physician, this is frightening to me. Depression is among the most common problems seen in primary-care medicine and soon will be the second leading cause of disability in this country.

The study I’m talking about was published in The New England Journal of Medicine. It found that drug companies selectively publish studies on antidepressants. They have published nearly all the studies that show benefit — but almost none of the studies that show these drugs are ineffective. (1)

I read the study in The New England Journal of Medicine and it didn't say a word about "why" they don't work and it didn't say they don't work. I also quoted the lead author of the study in two separate articles.

Here is the main conclusion of the study-

We wish to clarify that nonsignificance in a single trial does not necessarily indicate lack of efficacy. Each drug, when subjected to meta-analysis, was shown to be superior to placebo. On the other hand, the true magnitude of each drug's superiority to placebo was less than a diligent literature review would indicate.

Go back and read what the lead author wrote.

And that’s what we found, that each of the 12 drugs, overall, was statistically superior to placebo.The other caveat would be that the results of these trials get reported as means, but each mean value is based upon thousands of individuals, some with very good responses and others with lousy responses. So when you think about how an individual patient in your practice might respond, remember the old saying, “Your mileage may vary.”

That statement seems to match real world experience. For some people they work really well and for others not at all.

All of this is based on the initial 6 to 8 week clinical trials. I contend that these trials don't tell us much in the first place since these drugs take 6 to 8 weeks to work in many cases and the early clinical trials are always small. We need to look at the body of evidence since the drugs have been on the market.

To flat out state they do not work is not true based on what is currently known. I do not see it as responsible for a doctor to make that statement is a widely publicized article. That's my opinion but I don't see how you get around it.

Here is a very balanced article that talks about the problems with clinical trials and with real world practice and how the same is true for just about all drugs that have ever hit the market.

Do Antidepressants Really Work? - BrainFacts.org

William Z. Potter, M.D., Ph.D., Foundation of the National Institutes of Health, and Steven M. Paul, M.D., Weill Cornell Medical College, examine the effectiveness of antidepressants in treating severe depression.

Given the relative safety of SSRIs it is now common for someone with the symptoms of depression to be prescribed one by their physician, generally a primary care doctor, even though the clinical trial data tell us that only about 1 in 5 such patients will respond better to the drug than placebo over the ensuing four to six weeks. The doctor, however, has no way of selecting only those patients who will benefit from these SSRIs and, therefore, given the extremely low risk of serious side effects, prescribes the drug and follows the patient to see if he or she is among the 60 to 70 percent who will improve. It is almost impossible however to know in such a real-life setting how many patients would have responded to just placebo.

I have read 40 to 70% in the real world in a whole bunch of different articles.

[kiwi33]

Originally Posted by vital

I think that it has to be admitted that Dr. Hyman's approach also has really dramatic success stories

Has Dr Hyman reported any of his "really dramatic success stories" as case notes in peer-reviewed medical journals?

A case note has this format:

(1) A patient presented to me with [details of clinical signs and symptoms here].

(2) I treated the patient with [clinical details here].

(3) This treatment was successful [clinical evidence here].

If he has published case notes then please provide links to them - that will be credible evidence for what you have asserted.

If you are unable to do that then (with respect) I think that what you have asserted has little credibility.

[Altered Moment]

I think I would like more evidence than that in the form of a scientific study applying the hypothesis and methods of treatment to some number of people (even if small) and the results of the study published in a peer reviewed respectable medical or scientific journal. Then you have something to build on. I know you need funding to do this.

The results of his clinical trials at the Cleveland Clinic will be interesting even though they have nothing to do with mental health.

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[kiwi33]

Zinco14532323, I agree with what you wrote.

Often published case notes (in effect, peer-reviewed anecdotes) can provide valuable clues about something which is worth a more-detailed investigation (for example, a well-designed Randomised Control Trial).

Getting case notes published in the peer-reviewed literature can help in getting funding for more expensive things like RCTs.

[Altered Moment]

I can see that. I certainly think anecdotal evidence is important, or at least an accumulation of it. I know my personal experience is very important to me, and all that I have learned from the personal experience of others here.

How does the FDA's clinical practice reporting system work? Is it only for adverse events or does it include positive outcomes as well?

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[kiwi33]

Zinco, I know very little about how the FDA works but maybe the info here might help: Clinical Trials Guidance Documents .

I am more familiar with the UK system (I worked there for many years). In the UK there is what is called the "Yellow Card" scheme - anybody (patient or clinician) can report a suspected side-effect of a medical procedure: https://yellowcard.mhra.gov.uk/ .

I don't know if there is an American equivalent of Yellow Card.

[Altered Moment]

We do have a similar system I think.

FDA Adverse Event Reporting System (FAERS)

FDA Adverse Event Reporting System (FAERS)

Apparently only for adverse events. I wish there was a system for reporting all outcomes and they would be a large data base with lots of anecdotal info. This system is designed for safety and not efficacy.