The Serotonin Monster Strikes Again

Last Halloween, I discussed the legendary Serotonin Monster, that is, the alleged chemical imbalance that causes depression, anxiety, aggression, and God only knows what else. I ranted briefly and referred interested readers to an excellent article in PLoS Medicine from Jeffrey Lacasse and Jon Leo.

Turns out that Leo and Lacasse are still on the case of the Serotonin Monster. They have a newer article, recently published in the journal Society, that sheds further light on this mysterious creature. The full text of the article is freely available online; I encourage everyone to read it. They are concerned that most people get their information from magazines or newspapers, which they believe presents the overly simplistic "chemical imbalance" theory of depression as if it were based on solid science. Here's what they did to investigate how the media presented such theories:

To determine the evidence behind the media’s claims about chemical imbalances, for approximately 1 year we performed weekly Internet searches of the media for “chemical imbalances” and sent e-mails to the authors asking them for the evidence they were basing their statements on.

Can you guess their results? I bet you can. Think for a minute. OK, here's one example of what they found:

In an article for the Sacramento Bee (3/9/07), about how to handle teenagers with depression, the author states: “Act promptly and accept that they may have a chemical imbalance [italics added] or need help with coping skills.”In reply to our questions, the author mentioned that: psychiatrists would be the best people to talk with about chemical imbalances; mental illnesses have been linked to chemical imbalances; psychiatrists are trained to figure this out through a variety of tests; and that “numerous studies have been done” and “the research is definitely available.” We pointed out to her that, if there are “numerous studies” which are “definitely available,” then it should be relatively easy to cite at least one article. She did not reply. We also mailed a copy of our e-mails to an editor at the Sacramento Bee.

Another example:

In another New York Times article (6/19/07), “On the Horizon, Personalized Depression Drugs,” Richard Friedman, the chairman of psychopharmacology at the Weill Cornell Medical College, stated: “For example, some depressedpatients who have abnormally low levels of serotonin respond to SSRIs, which relieve depression, in part, by flooding the brain with serotonin.” For his evidence he supplied a 2000 paper by Nestler titled, “Neurobiology of Depression,” which focuses on the hypothalamic pituitary system but not on serotonin.

One more:

The Bradenton Herald (3/24/07), published an article entitled, “Seniors Sought for Depression Study.” The primary source for the article was Dr. Andrew Cutler, the director of the Florida Clinical Research Center, who is extensively quoted and referred to by the reporter. “True depression,” Cutler says, “has its roots in a chemical imbalance in the brain.” Neither the reporter nor Dr. Cutler replied to e-mails.

Sidebar: Dr. Cutler. Andrew Cutler has appeared previously on this site.

• One was about a misleading statement he made when stumping for Seroquel. He spoke of a Seroquel trial having several advantageous features, including its inclusion of Bipolar II patients. The problem, however, that was unacknowledged by Dr. Cutler, was that Seroquel was no better than a placebo for this group of patients.
  
• I think that if a researcher makes a statement that "true depression has its roots in a chemical imbalance in the brain," that researcher should respond to emails asking him to back up his argument.
  
• I also found it curious that he noted that he keeps his placebo response low when running clinical trials. Some of his patient recruitment practices also raised potential ethical questions, at least in my mind. These were just questions -- I'm not saying what he was doing was either right or wrong.
• Standard disclaimer: For all I know, Cutler is a great guy. I am not issuing a personal attack here -- Just noticing a few things that raised questions for me.
  

Back to the Article. In the piece, there were several other examples of bogus claims about chemical imbalances in the media. In not a single instance was a journalist able to drum up convincing evidence to support the claims regarding a serotonin deficit. Here are some questions for the media to ponder...

Considering the media’s inability, or unwillingness, to cite evidence in support of their own statements, can the same group really be expected to go one step further and actively investigate these issues? The solution is not simply for the media to modify, or tone down, their own statements about the chemical imbalance theory, but is for them to take a more analytical approach with those who promote the chemical theory as ineluctable truth. In other words, rather than us questioning the media, shouldn’t the media be doing the questioning? It’s almost as if these reporters are blinded by the term, “peer reviewed,” and operate under the mistaken assumption that the words are some sort of stamp declaring that the results are unquestionable and that they can check their skeptical radars at the door when given a press-release mentioning a peer-reviewed article.

The article then mentions that Pfizer tried to pimp the chemical imbalance theory to a reporter who was interested in Lacasse and Leo's prior investigation. To encourage my audience to read the article, I won't discuss it here, but will mention that Leo and Lacasse's dissection of Pfizer's evidence is intriguing, as it involves conflicts of interest, buried data, and other such tricks that have been discussed often on this blog.

Enter Judith Miller. As I was reading this article, I had thoughts of Judy Miller, so I was apparently on the same wavelength as the authors when they wrote toward the end of their paper:

A comparison of the media’s reporting about mental illness to the biased reporting in the New York Times about the events leading up to the Iraq War does not seem far-fetched. In hindsight, as the Times editors now acknowledge, Judith Miller’s war coverage was overly one-sided. Her fundamental flaw could be described as a lack of professional skepticism toward the Bush administration, as she willingly parroted what those pushing for war were saying, while giving little credence to the stance of the other side. Writing in the New York Review of Books, Michael Massing commented that the Times and Miller’s reporting were examples of media “submissiveness.”

This depiction could just as well apply to the media’s reporting of mental health issues. As just one example, in some cases, the media still go to the people responsible for the original problems. For instance, several of the researchers involved with the studies of SSRIs in children are still cited in the press even though the following information has come out about their published studies: they downplayed the suicide risk; they exaggerated the benefits; and the papers published under their names were actually written by ghostwriters paid by the pharmaceutical industry.

Indeed, SSRIs for child/adolescent depression will make fodder for the ages; the role of key opinion leaders/leading lights in child psyshciatry as either "dupes" or willing co-conspirators should be read by EVERYONE (1, 2, 3, 4, 5).

In sum, another nice piece of work from Leo and Lacasse. I understand that being a journalist is not an easy job. Essentially, one is tasked with writing on a wide variety of topics, generally outside of one's areas of expertise. Thus, journalists must rely on their sources, but at the same time, it is quite important that journalists do more than simply accept whatever their sources tell them without any sort of thoughtful evaluation.

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.

Links of Note and a Preview

Many good items have appeared of late and I pass them to you below...

• Adverse drug event reports skyrocket. Furious Seasons has the story.
• AHRP goes after Lilly's potential blockbuster for schizophrenia. AHRP's take on Dr. Lieberman seems a little harsh, but it's still a good read.
• The Last Psychiatrist scores points with a hilarious bit on calculating a commonly used medical statistic (featuring the Flock of Seagulls) and also weighs in on Lilly's hopeful new schizophrenia drug (no Zyprexa pun intended).
• How 'bout some antidepressants for babies? Pharmalot has the scoop.
  
• The discredited chemical imbalance theory of depression rears its head again, courtesy of GSK, as reported by Fiddaman.
• A long overdue link to the Pharma Girls of Reality TV, courtesy of Cary Byrd.

Coming Attractions: There were many other posts of note, and I hope to get to them later. Also, more WikiScanner goodness to pass along in the next day or two. My take on the latest, greatest antipsychotic from Lilly and the next generation of antidepressants, of which "we can expect therapeutic benefits to appear four to five times more rapidly" than current medications, according to one researcher. I also hope to tackle the SSRI-suicide issue in more depth, but that may take some time. Oh, and an example of why I hate psychotherapy research. All that and more (maybe) to come relatively soon.

Chemical Imbalance Watch

I have ranted before about the alleged chemical imbalance in depression. Any time I've seen a commercial for any of the SSRI's, I've just shaken my head (0r banged it against the wall), as the ads love to tout how "experts" (i.e., their marketing department ?) believe that depression is caused by some sort of chemical imbalance. The evidence, as you can read here, is scant, at best, to support such an assertion.

Well, Wyeth is still on the chemical imbalance train with their knockoff of their current bestselling antidepressant Effexor, which may be gracing your pharmacy before long. The new drug is called Pristiq and Wyeth is offering up the following as part of its early PR campaign for the drug:

In the area of depression, Pristiq is expected to improve the balance of serotonin and norepinephrine as compared with serotonin reuptake inhibitors (SSRI) because of its pharmacologic profile as a dual reuptake inhibitor.

Well, whoopee! Will it work any better than antidepressants that attempt to target either norepinephrine or serotonin? Nope. Why? Because a reliable imbalance of either neurotransmitter has never been found in depression. That's right -- never. But Wyeth continues to run with the chemical imbalance program because a lot of people have been indoctrinated, through advertising or perhaps through teachers who themselves lacked much education on the topic, to buy into this whole chemical imbalance deal.

I'm not saying that biology does not impact depression. I am saying that our current level of understanding in this area is much more speculation than it is fact. I do not believe there is a single serious scientist who would stick his/her name behind the simple "chemical imbalance" theory of depression.

And the name Pristiq? It would appear that Wyeth is aiming for a close resemblance to "Pristine," which is a bit ironic given the side effect profile of Pristiq (which will likely resemble that of Effexor closely).

More on Pristiq in an interesting post at Depression Introspection.