November 19

Depression-Serotonin: How Did So Many Smart People Get it So Wrong?_WSJ

One after another of psychiatry’s theoretical constructs and therapeutic armamentarium have been knocked down and relegated to the dust-heap of pseudo-scientific history. None of psychiatry’s claims have withstood the test of scientific scrutiny.  The very core upon which psychiatry’s practice guidelines are based–using drugs to restore a "chemical imbalance" in the brain– has been shown to be nothing but unsubstantiated speculation.

Jeffrey Lacasse and Jonathan Leo, Ph.D., the authors of "Serotonin and depression: A disconnect between the advertisements and the scientific literature," published in PLoS Medicine, have delivered a decisive blow to psychiatry’s unubstantiated claim about a "chemical imbalance" in the brain of people who suffer from depression –or other psychological / emotional ailments.

The article, by a professor of anatomy and a doctoral student,  is receiving wide attention both in the general and medical news media–Nature, WebMD, Medscape, UPI, New Scientist, the Wall Street Journal.  

When confronted with evidence refuting this mantra of biological psychiatry, Wayne Goodman, chair of the FDA’s psychopharmacologic advisory committee admited in The New Scientist, that the "chemical imbalance" story is but a "useful metaphor."

WSJ health columnist, Sharon Begley, points out that "For many, SSRIs help little, if at all. To do better, we have to get the science right."

But instead of science, the public and health care professionals have been fed a bill of goods:
 "Prozac, Zoloft, and Paxil ads and glowing accounts in the press have turned patients with depression into veritable pharmacologists, able to rattle off" the serotonin chemical imbalance script they have been fed by SSRI drug manufacturers and the psychiatric establishment.   But Lacasse and Leo found that: "Not a single peer-reviewed article … support[s] claims of serotonin deficiency in any mental disorder."

"Low serotonin levels no more cause depression than low aspirin levels cause headache.”
Yet, not only company advertisements but leading psychiatrists have deluded the public for decades with such false claims:

To cite but two examples:
NYU Child Study Center website assures families:
"Our faculty and staff have special expertise in dealing with all aspects of Depressive Disorders."  Then proceeds to state: "Depression is most likely due to an inherited predisposition to a chemical imbalance in the brain." See: <>   

Columbia University College of Physicians and Surgeons Kreichman PET Center lists two courses offered by John Mann, MD.

"4294 PET Mapping of Serotonin Transporters …Find out if / what changes in brain chemistry can cause an episode of depression.  Serotonin is an important chemical in the brain and deficiency of serotonin is thought to underlie major depression."

3752 In Vivo PET Imaging of the Serotonin Transporter (SERT) and 5HTiA Receptor in Bipolar Disorder. Identify changes in brain chemistry that may cause an episode of depression and/or be associated with suicidal behaviors." For more information, please contact Dr. Mann at 212-543-5571.

In 1995, the American Foundation for Suicide Prevention Research Award went to Dr. Mann "for his breakthrough research on serotonin levels as a predictor of suicide risk. Dr. Mann’s research has helped to uncover the chemical imbalances that occur in depressed patients, and his work on hormonal abnormalities in suicidal patients has fostered the development of tests that predict suicide risk. His studies of the different tests measuring perturbations in the brain’s secretion of the hormone serotonin have contributed substantially to recent advances in the field."

Begley correctly observes that the false "chemical imbalance" premise is misdirecting patients away from potentially better therapeutic options: "The hegemony of the serotonin hypothesis may be keeping patients from a therapy that will help them more in the long term. The relapse rate for patients on pills is higher than for those getting cognitive-behavior psychotherapy."  

Indeed, unsubstantiated pronouncements by psychiatry’s leadership gave the mental health industry and its patient advocacy front groups pseudo-scientific arguments with which to equate mental illness to physical illnesses–such as diabetes (for which insulin is needed to balance blood-sugar level).

This patently false comparison gave the psychotropic drug lobby–which includes the National Institute of Mental Health and state mental health agencies–ammunition with which to lobby for drug budget parity. They lobbied for the latest, most expensive medicines to restore a "chemical imbalance" in mental disorders–a claim that Dr. Goodman acknowledges is nothing but "a useful metaphor."  

That "useful metaphor" was used to deceive patients and the public and to divert health care funds from essential medicines to pay for drugs whose benefit is now largely in doubt, and whose severe adverse effects are undermining patients’ physical and mental health.

Dr. Goodman admits that he has never revealed the truth to his patients– "I can’t get myself to say that."
The fact is the psychiatric establishment has been concealing the truth about the lack of scientific evidence behind all of its theoretical constructs and armamentarium.

Contact: Vera Hassner Sharav <>

Some Drugs Work To Treat Depression, But It Isn’t Clear How
November 18, 2005; Page B1

Hardly any patients know how Lipitor lowers cholesterol, how Lotensin reduces blood pressure, or even how ibuprofen erases headaches. But when it comes to Prozac, Zoloft and Paxil, ads and glowing accounts in the press have turned patients with depression into veritable pharmacologists, able to rattle off how these "selective serotonin reuptake inhibitors" keep more of the brain chemical serotonin hanging around in synapses, correcting the neurochemical imbalance that causes depression.

There is only one problem. "Not a single peer-reviewed article … support[s] claims of serotonin deficiency in any mental disorder," scientists write in the December issue of the journal PLoS Medicine.

Indeed, a steady drip of studies have challenged the "serotonin did it" hypothesis. A 2003 mouse experiment suggested that SSRIs work by inducing the birth and growth of new brain neurons, not by monkeying with serotonin. In March, a review of decades of research concluded that something other than "changes in chemical balance might underlie depression." And as Jeffrey Lacasse and Jonathan Leo write in PLoS Medicine, although ads for SSRIs say they correct a chemical imbalance, "there is no such thing as a scientifically correct ‘balance’ of serotonin."

How did so many smart people get it so wrong? Medicinal chemist Derek Lowe, who works in drug development for a pharmaceutical firm, offered an explanation in his "In the Pipeline" blog. "I worked on central nervous system drugs for eight years, and I can confidently state that we know just slightly more than jack" about how antidepressants work.

It is not for lack of trying. In 1965, psychiatrist Joseph Schildkraut of Harvard University suggested that a deficiency of a brain chemical causes depression. With the success of drugs that block the reuptake of these chemicals, that idea started to look pretty good.

Yet the evidence was always circumstantial. You can’t measure serotonin in the brains of living human beings. The next best thing, measuring the compounds that serotonin breaks down to in cerebrospinal fluid, suggested that clinically depressed patients had less of it than healthy people did. But it was never clear whether depression caused those low levels, or vice versa. A 2002 review of these early experiments took them to task for such flaws.

There had always been data that don’t fit the serotonin-imbalance theory. Depleting people’s serotonin levels sometimes changed their mood for the worse and sometimes didn’t. Sending serotonin levels through the roof didn’t help depression, a study found as early as 1975.

There is little doubt that the SSRIs do what their name says, keeping more serotonin in the brain’s synapses. But the fact "that SSRIs act on the serotonin system does not mean that clinical depression results from a shortage of serotonin," says Dr. Leo, professor of anatomy at Lake Erie College of Osteopathic Medicine, Bradenton, Fla. No more so, anyway, than the fact that steroid creams help rashes means that rashes are caused by a steroid shortage.

A clue to how SSRIs do work comes from how long they take to have any effect. They rarely make a dent in depression before three weeks, and sometimes take eight weeks to kick in. But they affect serotonin levels right away. If depression doesn’t lift despite that serotonin hit, the drugs must be doing something else; it’s the something else that eases depression.

The best evidence so far is that the something else is neurogenesis — the birth of new neurons. When scientists led by Rene Hen of Columbia University and Ronald Duman of Yale blocked neurogenesis in mice, SSRIs had no effect. When neurogenesis was unimpeded, SSRIs made the mice less anxious and depressed — for rodents. As best scientists can tell, SSRIs first activate the serotonin system, which is somehow necessary for neurogenesis. That is what takes weeks.

Claiming that depression results from a brain-chemical imbalance, as ads do, is problematic on several fronts. Patients who believe this are more likely to demand a prescription. If you have a disease caused by too little insulin, you take insulin; if you have one caused by too little serotonin, you take serotonin boosters.

Most people treated for depression get pills rather than psychotherapy, and this week a study from Stanford University reported that drugs have been supplanting psychotherapy for depressed adolescents. Clinical guidelines call for using both, and for psychotherapy to be the first-line treatment for most kids. Psychotherapy "can be as effective as medications" for major depression, concluded a study in April of 240 patients, in the Archives of General Psychiatry. Numerous other studies find the same.

The hegemony of the serotonin hypothesis may be keeping patients from a therapy that will help them more in the long term. The relapse rate for patients on pills is higher than for those getting cognitive-behavior psychotherapy.

Some 19 million people in the U.S. suffer from depression in any given year. For many, SSRIs help little, if at all. To do better, we have to get the science right.

Write to Sharon Begley at <> <>  

Television adverts for antidepressants cause anxiety
    12 November 2005
    From New Scientist Print Edition.
ADVERTS that claim depression is caused by a chemical imbalance, and that antidepressants correct it, are false and should be banned, say two mental health specialists.

Popular antidepressants such as Prozac and Celexa block the uptake of the neurotransmitter serotonin and have been shown to be slightly better than placebo in treating depression. But low serotonin levels are no more the cause of depression than low aspirin levels are the cause of headaches, argue Jonathan Leo at Lake Erie College of Osteopathic Medicine in Bradenton, Florida, and Jeffrey Lacasse at Florida State University in Tallahassee (Public Library of Science Medicine, DOI: 10.1371/journal.pmed.0020392).

"It has become an absolute mainstay of popular culture," says Leo. "But there’s very little support for this. We really don’t know what chemicals are involved."

Wayne Goodman, chair of the psychopharmacologic advisory committee of the US Food and Drug Administration admits they have a point. He calls the chemical imbalance story a "useful metaphor" but says it is never one he uses when talking to patients. "I can’t get myself to say that."

The Irish Medicines Board, the equivalent of the FDA in Ireland, recently banned GlaxoSmithKline from making similar claims in information for patients. Leo and Lacasse want the FDA to follow suit.

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