Wednesday, October 31, 2007

Ghosts, Goblins, and Serotonin: Boo!

In an earlier post, I noted that I thought a key opinion leader had contradicted himself across two articles regarding the role of serotonin in depression. One reader posted a comment that challenged my assertion, to which I reply via this post. The reader, “Alan,” stated, in part, that
He only said what he said -- that [serotonin] is clearly disordered and deficient in many if not most people with depression. And he is right. There's overwhelming evidence for that. (There's also great evidence for the therapeutic value of serotonergic interventions in depression, which he did not mention.) That's not to say that other things are not playing a role, or that serotonin is the sole problem area -- the "single fundamental neurobiological defect". He only said what he said. And this blogger is jumping all over him. Why?

Okay. Two issues here. One: Did the key opinion leader (Charles Nemeroff) contradict himself? Two: Is serotonin deficient in depression? This post will deal with issue two – people can read the old post and decide for themselves if Nemeroff’s statements were contradictory or if I was in error. You decide.

Part 1: Does a Serotonin Deficiency Cause Depression?

Let’s break this thing down to make it really simple to understand. Statement 1 from Alan: [serotonin] is clearly disordered and deficient in many if not most people with depression... There's overwhelming evidence for that.

Really? Drug companies certainly use serotonin to market their antidepressants, but is there solid evidence for a serotonin imbalance in depression? Actually, no.

Despite making excellent marketing copy, studies have found no consistent abnormality in serotonin in depressed people. Doubt me? Read this excellent article by Lacasse and Leo (published in PLoS Medicine) that describes the gap between the marketing of serotonin in depression and the scientific literature.

One quote from the PLoS Medicine article:

Consider the medical textbook, Essential Psychopharmacology, which states, “So far, there is no clear and convincing evidence that monoamine deficiency accounts for depression; that is, there is no ‘real’ monoamine deficit” [44]. Like the pharmaceutical company advertisements, this explanation is very easy to understand, yet it paints a very different picture about the serotonin hypothesis.

But since SSRI’s impact depression and also impact serotonin, depression must be due to a serotonin deficiency. Um, no. Again, I’ll leave it to Lacasse & Leo:

With direct proof of serotonin deficiency in any mental disorder lacking, the claimed efficacy of SSRIs is often cited as indirect support for the serotonin hypothesis. Yet, this ex juvantibus line of reasoning (i.e., reasoning “backwards” to make assumptions about disease causation based on the response of the disease to a treatment) is logically problematic – the fact that aspirin cures headaches does not prove that headaches are due to low levels of aspirin in the brain. Serotonin researchers from the US National Institute of Mental Health Laboratory of Clinical Science clearly state, “[T]he demonstrated efficacy of selective serotonin reuptake inhibitors…cannot be used as primary evidence for serotonergic dysfunction in the pathophysiology of these disorders” [12].

I could quote the article extensively, but I’d prefer that you read it yourself. Whether you have a scientific background or not, it’s easy to understand and it shows that the serotonin emperor is wearing no clothes. Don’t take my word for it. After you’ve read the article, if you’d like to do your own independent investigation on the topic, go ahead. Please report your findings showing a strong link between serotonin dysfunction and depression right here in the comment section. I’m waiting.

It is true that variations in the serotonin transporter gene can predispose people toward experiencing depression. I don’t deny that. And given that our understanding of the brain is still rather primitive, there may be some point where we figure out that serotonin plays a certain role in depression. But at this point, there is no evidence supporting a specific serotonin deficiency in depression. Again, please correct me if you disagree.

Part 2: Do SSRI’s Work?

Another piece from Alan’s comment:

There's also great evidence for the therapeutic value of serotonergic interventions in depression.

Like what? Try that about 80% of the drug effect is replicated by placebo – there is about a 20% difference in efficacy between placebo and antidepressant (Kirsch et al., 2002). Is that “great evidence” of efficacy? It’s more encouraging than 0% better than placebo, but I remain less than fully convinced. And about those sexual side effects and increased risk of suicidal thinking and suicide attempts… If depression was really due to poor serotonin function, then one would expect treatments that increase serotonin transmission would have a much stronger advantage over placebo.

I appreciate Alan’s comment as well as its timing. It is only appropriate on Halloween, I should discuss the serotonin-depression link, as it is about as well supported scientifically as many of the ghost stories often told on such a holiday.


John A. said...

You and your readers may already be aware of this...

Psychiatrist's Undisclosed Financial Ties Prompt Reproval - NYT

"Dr. Nemeroff, a former president of the American College of Neuropsychopharmacology, favorably described the products in which he has significant financial interests while describing the competitors' products as "disappointing." Dr. Nemeroff's financial ties were documented in company documents filed with the federal securities and exchange commission."

Follow the blood-stained money, good doctors.... follow the money.

Also, please visit and for information on SSRI-induced horror stories.

Andrea Roberts' brother,

Anonymous said...

Can I suggest:

1 SSRI's have a profound positive effect on some people with depression but dont help others (possibly most).

2 Identification of this subset is not in Big Pharmas interest as it "reduces the size of the market".

As an analogy I would use the leukotriene antagonists in asthma. They are marvellous in a small subset of asthma patients, but ineffective in many.

Herb said...

Hi Doc,

“It is true that variations in the serotonin transporter gene can predispose people toward experiencing depression. I don’t deny that. And given that our understanding of the brain is still rather primitive, there may be some point where we figure out that serotonin plays a certain role in depression. But at this point, there is no evidence supporting a specific serotonin deficiency in depression. Again, please correct me if you disagree.” --- CL PSYCH

And I couldn’t possibly agree with you more especially about “And given that our understanding of the brain is still rather primitive…”

And while you and your colleagues “understanding of the brain is still rather primitive” what is the patient and me, as a support person and care giver, to do for my charge?

“Like what? Try that about 80% of the drug effect is replicated by placebo – there is about a 20% difference in efficacy between placebo and antidepressant (Kirsch et al., 2002). Is that “great evidence” of efficacy? It’s more encouraging than 0% better than placebo, but I remain less than fully convinced.” --- CL PSYCH

You may recall you and I had a little discussion about what you felt were poor test results from the VNS Therapy study. You felt the response rate was essentially no better than placebo and yet several hundred leading psychiatric professionals felt what they were reading was kind of remarkable especially for the patient population that was being treated since absolutely nothing worked previously. Even more astonishing is what I am reading and knowledgeable is what I refer to as the MCPE. Multi-year Continuous Placebo Effect being experienced by a number of these same patients and I’ll also ask of you. Please site for me in the medical literature any information describing any such phenomenon as MCPE. Charles Donovan who self-published his book and experiences “Out of the Black Hole” answered me when I cited Drs. Lurie and Wolf’s assertions that the effects of VNS were nothing more than a placebo effect. Charlie stated and I’ll paraphrase, “Well, then I must be having one-year continuous placebo effects for the past 6 years.” The same more or less holds true for my spouse and a number of others.

The point of all this is that I am fully in agreement with you that your understanding and that of your fellow professionals, of the brain is primitive and far less so for the mood disorders it creates. Yet, I as a lay person must look to people like you for guidance and direction and be forced to experiment with what I often refer to as the “Trial and Error Approach to Wellness” until such time as you and your associates and colleagues can offer up definitive answers and directions.

Until such time I shall continue to enjoy or cringe and muse at your offerings and share with others my opinions as to the importance of being relatively educated about these illnesses and treatment options and the need for newer more effective therapies while I also encourage hope and persistence until you guys/gals can state, 1 + 1 = 2.

As always, thanks for your thoughts and contribution to my continued skepticism and education.


Alex Chernavsky said...

Excellent post. And I think that you're being rather generous when you state that antidepressants have a 20% advantage over placebo. See, for example, "Antidepressants Versus Placebos: Meaningful Advantages Are Lacking" (a short commentary published in Psychiatric Times in 2002).

One of the best books on the subject of the biological basis of mental disorders is, Blaming the Brain: The Truth About Drugs and Mental Health, by Elliot Valenstein, PhD (Free Press, 1998). The book is somewhat dated now but is still an excellent resource for those who take a skeptical view of psychopharmacology.

What I particularly like about Blaming the Brain is that Elliot Valenstein is in no way a crank or a fringe figure (unlike some other anti-psychiatry authors). At the time he wrote the book, Valenstein was a respected neuroscientist at the University of Michigan. He has since retired apparently, but he continues to write books.

OK, I'll provide one more citation, and then I'm done with this post. Another good article about antidepressants is, "Is it Prozac? Or Placebo?", from Mother Jones magazine, of all places.

Keep up the good work.

CL Psych said...


If your spouse has experienced a notable positive change since receiving VNS, then I'm quite glad to hear it. For any individual patient, it always boils down to trial and error. It would be nice if our current set of treatments worked better, particularly in the long-term, but we're left with treatments that often fail, despite all the marketing hype.

CL Psych said...


Valenstein's book is indeed excellent. Thanks for citing it and linking to it. It has my highest recommendation.

You are indeed correct that a 20% advantage is likely generous. When one considers active placebo controlled trials, the advantage for antidepressants falls to 10% at best, from my recollection. Notice how nobody has done an active placebo controlled trial in a long time. Gee, I wonder why...

But I wrote 20% to give the benefit of the doubt to the drugs, to show that I am indeed fair and balanced when it comes to reporting.

Kevin Thompson, Ph.D. said...

Many interesting comments here. Let me add some of my own.

First, I most definitely agree that equating "cause of depression" to "low serotonin" is nonsensical, as per the analogy with headaches and aspirin. To the extent that serotonergic medications alleviate depression, they may conceivably do so for many reasons other than a patient's low serotonin levels.

Second, the fact that medications such as Wellbutrin, which act on neurotransmitters other than serotonin, can alleviate depression should put a nail through the coffin of a pure serotonin hypothesis for depression.

Third, the response rate of individual antidepressants is indeed disappointing. Whether the figure is 10%, 20%, or (the figure I see most often) 30%, there is no denying that they work far less well than one would wish.

Yet, as Herb said, what else are we going to do? Not try antidepressants for depression, because the response rate is poor?

I could argue that a 20% response rate to a given medication predicts that trying 5 of them gives good odds of success, especially when they come from different chemical families and have different mechanisms. In fact, many people do try multiple medications before finding good results, which I find a more compelling reason to believe that antidepressant medications can be effective.

The main issue I have with the entire debate over antidepressant efficacy is that I suspect the unspoken assumption underpinning the debate is simply wrong. The central assumption is that there is such a thing as depression, and I firmly believe that this is not the case at all.

By this statement, I do not mean that people do not suffer from the symptoms that define depression in the DSM. What I mean is that there is no identified underlying disorder that uniquely gives rise to these symptoms. The diagnosis of "depression," then, is misleading, to the extent that it suggests that there is a single specific and identified etiology behind the symptoms.

It seems far more reasonable to me that "depression" is like "fatigue," a set of symptoms that may arise from a wide variety of causes. Indeed, given that depression is associated with conditions as widely varied as hypothyroidism and Parkinson's disease, I consider this almost a certainty.

If it is true that many different causes (even restricting attention to neurochemistry) can produce the set of symptoms known as depression, it is hardly surprising that individual antidepressants have a low success rate. Indeed, if the average antidepressant works 20% of the time, and there are (say) five different causes for depression, it might be that a given antidepressant is very effective for one of those conditions!

The fact that we can have a debate like this shows how poorly we understand the causes of mood disorders. Until science gives us better explanations, I imagine we'll continue these debates. In the meantime, trial-and-error as a technique for helping the individual patient is still a large improvement over doing nothing.

Herb said...

Hi doc Thompson,

I just caught your comments and I’d like to say I like your apparent caring and compassionate thoughts too.

I got my wife’s psychiatrist involved and trained in the use of VNS Therapy because he’s a progressive doc and truly looking to do the best he can for his patients and he sought me out. At first he was extremely skeptical of me and certainly the study results for this therapy.

He’s no longer skeptical of me and my knowledge and he found in his clinical practice the therapy benefiting some of his most difficult to treat population of patients despite poor study results. He in turned then turns around and tells me to respond to other skeptical professionals, “Well what other alternatives do you suggest.”

Here it is more than 4 decades into my experiences as a support person and care giver and I learn from blogs such as this one that the profession is offering the patient treatment options often no better than placebo. Treatment options that appear to have been finessed and massaged to get FDA approval and for those who suffer serious debilitations from these mood states, like my spouse, we are offered nothing more than what I refer to as the “Trial and Error Approach to Wellness” although the professionals would never accept this marketing terminology.

After some 36 years we’ve been fortunate to have a treatment regimen that is not only working for my spouse but yielding long-term remission but I can also tell you, it didn’t come easy.

One approach not often discussed in these circles is withdrawal, abstinence and starting from scratch. I read of individuals coming off medications also reporting improving mood states. So while we are lacking in definitive answers such as mechanisms of action and causation I feel the patient in cooperation with a caring and knowledgeable health care professional should not leave any stones unturned even if the percentages appear to be no better than placebo. For the lucky patient despite those low percentage figures he/she may have hit the jackpot.


Discover What You Think said...

Serotonin Medications: Do the Risks Outweigh Any Benefits?

Presently, for the treatment of depression and other mental disorders, some of these disorders are questionable regarding thier existence, the preferred choice of medicinal treatment are a class of medications called selective serotonin reuptake inhibitors, referred to as SSRIs, as they are the drugs of choice by most prescribers. Such meds, meds that affect the mind, are called psychotropic medications. SSRIs also include a few meds in this class with the addition of a norepinephrine uptake inhibitor added to the SSRI, and these are referred to SNRI medications. Examples of SNRIs are Effexor and Cymbalta. Presently, some compare the usage and popularity of these classes of meds as that of the usage of tranquilizers decades ago.
Some Definitions:
Serotonin is a neurotransmitter thought to be associated with mood. The hypothesis was first suggested in the mid 1960s that this neurotransmitter may play a role in moods and emotions in humans. Yet to this day, the serotonin correlation with such behavioral and mental conditions and diseases is only theoretical. In fact, the psychiatrist’s bible, which is called the DSM, states that the definite etiology of depression remains a mystery and is unknown. So a claim of a chemical imbalance in the brain as a reason for depression is not proven to be the cause of this and other mood disorders, it is only suspected based on limited science, which may or may not be valid. Observation by one's doctor is usually the determining factor for such a diagnosis.
Norepinephrine is a stress hormone, which many believe help those who have such mood disorders as depression. Perhaps this is now added to SSRIs for additional efficacy for those treated with these medications.
And depression is only one of those mood disorders, yet possibly the most devastating one. Once again, an accurate diagnosis of these mood conditions lack complete accuracy as they can only be defined conceptually, so the diagnosis is dependent on subjective criteria, such as questionnaires, as there is no diagnostic testing available to conclude objective diagnosis of such disorders. However, the diagnosis of depression in patients has increased quite a bit over the decades. While most likely a real disease, most will agree, misdiagnosis does occur due to the subjective assessment that determines the disease, as perhaps one out of every four people diagnosed with depression is inaccurate.
Several decades ago, less than 1 percent of the U.S. population were thought to have depression. Today, it is believed that about 10 percent of the population have depression at some time in their lives. Why this great increase in the growth in the assessment of this condition remains unknown and is subject to speculation. What is known is that the psychiatry specialty is the one specialty most paid to by certain pharmaceutical companies for various forms of support, as this industry clearly desires market growth of their psychotropic products, such as SSRIs, since clearly this is part of their nature and objective as a pharmaceutical company. Regardless, SSRIs and SRNIs are the preferred treatment methods if depression or other certain mood disorders that may be suspected by a doctor.
Over 30 million scripts of these types of meds are written annually, and the franchise is around 20 billion dollars a year, with some of the meds costing over 3 dollars per tablet. There are about ten different SSRI/SRNI meds available, many of which are now generic, yet essentially, they appear to be similar in regards to their efficacy and adverse events. The newest one, a SNRI called Pristiq, was approved this month and is expected to be promoted primarily for the treatment for menopause. Conversely, the first one of these SSRI meds was Prozac, which was available in 1988, and the drug was greatly praised for its ability to transform the lives of those who consumed this medication in the years that followed. Some termed Prozac, ‘the happy pill’. As years passed, this drug was preferred for children with depression. Also, a book was written praising Prozac as a euphoric entity for all to experience.
Furthermore, these meds have received additional indications for really questionable conditions, such as social phobia and premenstrual syndrome. With the latter, I find it hard to believe that a natural female experience can be considered a treatable disease. With social phobia, many would say that is a personality trait and, in my opinion, is synonomous with shyness, which probably should not be labeled a treatable disease as well. There are other indications for certain behavioral manifestations with the different SSRIs or SRNIs. So the market continues to grow with these meds- assisted by thier manufacturers. Yet, it is believed that these meds are effective in only about half of those who take them. Also, the makers of such meds create such conditions for utilization of these types of medications, in my opinion, and are active with related support groups who are funded by the makers of such drugs, such as sponsoring screenings for the indicated and not indicated conditions of their meds, including children and adolescents in particular, it is believed. Yet depression, which has clearly has been proven to be devastating to the victim, such screenings are controversial due to possible bias involved in seeking those with mental illness in this manner.
More concerning, however, is the adverse effects associated with SSRIs and SRNIs, which include suicidal thoughts and actions, as well as violence, including acts of homicide and aggression. The associations with these actions have been established with these types of meds. While most are approved for use in adults only, prescribing these meds to children and adolescents has drawn the most attention to others through the media. The reasons for this attention are the off-label use of these meds in this population, and the association with suicide. What may be most shocking is the fact that some of the makers of these meds did not release clinical study information about the risks of suicide as well as the other adverse events and true efficacy of certain types of SSRI meds, including the decreased efficacy of SSRIs, which is believed to be only less than 10 percent more effective than a placebo, until ultimately the makers of such drugs were forced to do so. Paxil, for example, caught the attention of the government regarding these issues some time ago for hiding and not presenting such important information to others, for example.
And there are very serious questions about the use of SSRIs in children and adolescents regarding the effects of these meds on them. For example, do the SSRIs correct or create brain states considered not within normal limits, which in effect may worsen thier mental state? Are adolescents depressed, or just experiencing what was once considered normal teenage angst? Do SSRIs have an effect on the brain development and their identity? Do adolescents in particular become dangerous or bizarre due to SSRIs interfering with the myelination occurring in their still developing brains? No one seems to know the correct answer to such questions, yet the danger associated with the use of SSRIs does in fact exist. It exists in some who take such meds, but not all who take these meds. Yet more need to be aware of such possibilities, some say.
Finally, if SSRIs are discontinued by those who have taken them for certain periods of time, withdrawals have been reported to be quite brutal, and may be a catalyst for suicide in itself, as not only are these meds habit- forming, but discontinuing these meds leaves the brain in a state of neurochemical instability, as the neurons are recalibrating upon discontinuation of the SSRI after being altered by the med to some degree. This occurs to some level with any psychotropic med, yet the withdrawals can reach a state of danger for the victim in some classes of meds such as the case with SSRIs.
SSRIs and SRNIs have been claimed by doctors and patients to be extremely beneficial for the patient’s well -being regarding the patient’s issues involved with thier mental illness suspected, such as depression, yet the risk factors associated with this class of medications may outweigh any perceived benefit for the patient taking such a drug, and this may want to be explored more by others. Considering the lack of efficacy that has been demonstrated objectively, along with the deadly adverse events with these meds only recently brought to the attention of others, other treatment options should probably be considered at the discretion of your prescriber.

“I use to care, but now I take a pill for that.” --- Author unknown

Dan Abshear