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Why Are We More Stressed and Depressed Than Ever?


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We Have Happy Pills, Anxiety Drugs, and Therapists Galore: So Why Are We More Stressed and Depressed Than Ever?


July 3, 2012 Psychotherapy Networker / By Andrew Weil



More of us than ever are discontented and not experiencing optimum emotional well-being. Why is the vast enterprise of professional mental health unable to help us feel better?


In 1980, the American Psychiatric Association radically revised the Diagnostic and Statistical Manual–III (DSM-III) to be in accord with the biomedical model. As a consequence, the role of psychiatrists went from being facilitators of insight in patients to being dispensers of drugs to modify brain chemistry. Although some psychiatrists still rely on talk therapy, of all medical specialties, the profession as a whole is the most dominated and, to my mind, hobbled by blind faith in biomedicine. Psychiatrists were easily seduced because of a collective inferiority complex with regard to their place in the medical hierarchy. Still referred to as witch doctors and shrinks (from headshrinkers), they themselves have a history of questioning whether they are real doctors and whether they need the same basic medical training as cardiologists and surgeons. With the spectacular rise of biomedicine, their discomfort increased, and, not wanting to be left behind, they looked for ways to be even more biologically correct than their colleagues in other specialties. They saw their ticket to acceptance in the new and rapidly developing field of psychopharmacology—the study of the effect of drugs on mental and emotional disorders.


In 1921, Otto Loewi (1873–1961), a German pharmacologist, demonstrated that nerve cells (neurons) communicate by releasing chemicals. Prior to that time, neuroscientists thought nervous communication was electrical. Among the many important breakthroughs that followed from Loewi’s work were the identification of neurotransmitters and the discovery of receptors on cell surfaces that bind them. Neurotransmitters are chemicals made within the body, stored in tiny sacs clustered within a neuron and released into the synapse, the gap between the neuron and a target cell, which might be another neuron (the postsynaptic neuron) or a muscle or glandular cell. The released molecules then bind to receptors—specialized proteins on the surface membrane of the target cell—causing changes in that cell, making it more or less likely to produce an electrical signal (in the case of a neuron), to contract (in the case of a muscle), or to secrete a hormone (in the case of a glandular cell). Later, the neurotransmitters can separate from their receptors and be taken up by presynaptic cells for reuse or be broken down by enzymes into inactive metabolites. Neuroscientists have now compiled long lists of neurotransmitters, described their actions, and identified many types and subtypes of receptors.


Three of the most studied neurotransmitters are norepinephrine, dopamine, and serotonin, all very relevant to the subject at hand because they influence our moods and emotions. For example, dopamine is involved in what is known as the reward system of the brain; drugs that affect it can alter our experience of pleasure. Cocaine is such a drug. It blocks reuptake of dopamine back into the presynaptic neuron, effectively increasing its action at the synapse to produce an intense pleasurable response. With prolonged use of cocaine, postsynaptic neurons become less responsive to dopamine, leading to depression and dependence on the drug to relieve it. The dopamine hypothesis of schizophrenia attributes psychosis to overactivity of this neurotransmitter. Norepinephrine regulates both reward and arousal. Disturbances in that neurotransmitter system are associated with anxiety disorders. And serotonin affects our moods and sleep.


The most widely used psychiatric drugs today influence the production and effects of these major neurotransmitters. Psychopharmacologists made their first big breakthrough in the 1950s from work with antihistamines, used to quell allergic symptoms. Although antihistamines are best known for blocking the effects of the compound responsible for certain immune responses, they also affect the brain, often making people groggy, sleepy, and depressed. By tinkering with these molecules, chemists produced a new class of psychoactive drugs—the phenothiazines—that blocked dopamine transmission. Thorazine and other phenothiazines were successfully marketed as major tranquilizers and antipsychotics and quickly revolutionized the treatment of schizophrenia. Psychiatrists hailed them as magical compounds that cured psychosis, while critics argued that they simply made psychotic people groggy, sedated, and easier to manage, even as outpatients. Energized by this achievement, psychopharmacologists then turned their attention to depression. Over the past sixty years, they have come up with a number of drugs to treat it.


The efforts of psychopharmacologists give us an opportunity to evaluate the usefulness of the biomedical model in psychiatry. In practice, psychiatric medicine today is synonymous with psychopharmacology. The credo of that field is “There is no twisted thought without a twisted molecule.” (The words of the American neurophysiologist Ralph Gerard, 1900–1974). The biomedical model explains depression as the result of a chemical imbalance in the brain, specifically of neurotransmitters affecting our moods. How well does that explanation enable us to describe, predict, and control depressive illness? In other words, just how effective are the antidepressant drugs that psychopharmacologists have developed, that the big pharmaceutical companies sell such quantities of, and that so many people today take? The answer, I’m afraid, is not very.


The first antidepressant drug was discovered serendipitously in 1952. Iproniazid, an antimicrobial agent being studied as a possible treatment for tuberculosis, was found to affect mood, making even terminally ill patients cheerful and optimistic. Investigation of a possible mechanism for this unexpected psychoactivity revealed that the drug blocked enzymatic breakdown of all three major neurotransmitters: norepinephrine, dopamine, and serotonin. Pharmaceutical chemists then looked for other drugs with this action and soon after produced a different class of antidepressant drugs by modifying the phenothiazine tranquilizers. These became known as tricyclic antidepressants, of which amitriptyline was the prototype; Merck pharmaceutical company gave it the brand name Elavil. In 1961, the FDA approved Elavil for the treatment of major depression, and it quickly became a bestselling drug. The tricyclics appeared to work by blocking presynaptic reuptake of norepinephrine and serotonin without affecting dopamine.


Because all of the early antidepressants had unpleasant side effects and serious potential interactions with other drugs and medications, pharmaceutical chemists continued their search for better ones with more specific action. But what specific action should it be? Some thought deficiency of norepinephrine was the biochemical cause of depression. Others argued for a serotonin hypothesis of depression and looked for compounds to prevent its breakdown or reuptake. The proponents of the serotonin hypothesis would win the day; their big discovery came in the 1970s, again, interestingly enough, as a result of work with an antihistamine.


Very likely you have taken Benadryl (diphenhydramine) at some point in your life. It is one of the oldest and most widely used antihistamines, the first such drug to be approved by the FDA for prescription use, in 1946. Benadryl is so sedating that it is now sold over the counter as a sleep aid. In the 1960s, this tried-and-true drug was found to have an action independent of its effect on histamine: it selectively inhibited the reuptake of serotonin. By modifying this molecule, scientists at Eli Lilly and Company in the 1970s came up with the first safe and effective selective serotonin reuptake inhibitor, fluoxetine, much better known by its brand name Prozac. The rest is history. Today the accepted biomedical explanation of depression is that it results from a deficiency of serotonin at synapses in key areas of the brain; therefore, boosting the activity of this neurotransmitter with drugs that block its reuptake will treat or cure the problem.


It’s a good bet that thirty years ago, not one American in a thousand had heard of this neurotransmitter—or any neurotransmitters, for that matter. Today, when you Google serotonin, about 11 million results appear, and Amazon sells nearly three thousand books with the word in the title (including The Serotonin Solution: The Potent Brain Chemical That Can Help You Stop Bingeing, Lose Weight, and Feel Great). “Serotonin” is the name of a professional wrestling team and an album by the British rockers The Mystery Jets. You can even proclaim your autumn blues to friends by way of a greeting card that reads, “The leaves and my serotonin levels are falling.” A once-obscure neurochemical has become pop-culture currency, and increasing levels of this feel-good compound has turned into a public obsession.


None of this just happened on its own. In order to sell antidepressant medications, drug manufacturers launched a relentless worldwide marketing and public-relations campaign promoting serotonin as the distilled biochemical essence of happiness. The message was that selective serotonin reuptake inhibitors—SSRIs—increase synaptic levels of serotonin in the brain by slowing its rate of reabsorption by presynaptic neurons, ending depression. Psychiatrists and other physicians got the technical version of this message, while consumers got a simplified one, often reduced to the rallying cry “Boost serotonin!”


The only problem is that it probably isn’t true.


Like the dopamine hypothesis of schizophrenia and other attempts to attribute complex mental phenomena to simplistic biochemical causes, the serotonin hypothesis of depression is shaky at best. Several studies have established that lowering serotonin levels does not negatively impact mood. In fact, a new pharmaceutical known as tianeptine—sold in France and other European countries under the trade name Coaxil—has been shown to be as effective as Prozac. Tianeptine works by lowering synaptic serotonin. As psychology professor Irving Kirsch of the University of Hull in England told Newsweek, “If depression can be equally affected by drugs that increase serotonin and by drugs that decrease it, it’s hard to imagine how the benefits can be due to their chemical activity.”


It is, indeed, especially as evidence accumulates that, in most cases, SSRIs work no better than placebos to boost mood. The first such analysis, published in 1998, looked at thirty-eight manufacturer-sponsored studies that included more than three thousand depressed patients. It found negligible differences in improvement between those on the drugs and those on dummy pills. At least 75 percent of the benefit from this class of antidepressants seemed to be a placebo effect. This finding has since been confirmed by other research.


To say that biomedically minded physicians have been reluctant to accept this finding or modify their prescribing habits as a result would be a great understatement. Both professional and popular media have tried to play down the significance of this new research and in some cases have misreported the findings. In April 2002, the Journal of the American Medical Association (JAMA) published the results of a large randomized controlled study sponsored by the National Institutes of Health to evaluate a popular herbal treatment for depression, St. John’s wort (Hypericum perforatum). Its effect was compared with that of the widely prescribed SSRI Zoloft (sertraline) and a placebo in 340 patients with major depressive disorder. The conclusion that made front-page news around the world was that St. John’s wort worked no better than the placebo at relieving depression. Television news shows featured reporters in health-food stores pointing to St. John’s wort products and advising consumers not to waste their money on natural remedies whose supposed benefits were nothing more than old wives’ tales.


Never mind that St. John’s wort is not indicated for the treatment of major depression, making the point of the study questionable. The finding from this well-designed trial that should have made front-page news was that Zoloft also worked no better than the placebo. In fact, the placebo treatment was acually more effective in these very depressed patients than either Zoloft or St. John’s wort!


Irving Kirsch summarized the growing body of evidence against SSRIs in his 2010 book, The Emperor’s New Drugs: Exploding the Antidepressant Myth, which I recommend. In response, proponents of the drugs and the serotonin hypothesis retreated to a more defensible position: SSRIs may owe much of their apparent benefit to patients’ belief in them, they admit, but they still have a real biochemical effect that makes them useful in the treatment of severe depression. Unfortunately for those proponents, the most recent analysis, published in the January 6, 2010, issue of JAMA, rates the real biochemical effect of SSRIs as nonexistent to negligible even in most cases of severe depression. Only in patients with very severe symptoms can researchers detect a statistically significant drug benefit compared with that of a placebo. About 13 percent of people with depression have very severe symptoms. One of the authors of the JAMA paper, Steven D. Hollon, Ph.D., of Vanderbilt University, has said, “Most people [with depression] don’t need an active drug. For a lot of folks, you’re going to do as well on a sugar pill or on conversations with your physicians as you will on medication. It doesn’t matter what you do; it’s just that you’re doing something.”


I would argue that the dismal performance of Prozac, Zoloft, Paxil, and other antidepressant drugs relative to placebos not only leaves the serotonin hypothesis of depression without a leg to stand on but also exposes the failure of the biomedical model to further our understanding of and ability to manage emotional disorders. I firmly believe that the nature of depression will never be revealed solely in studies of brain biochemistry that are isolated from the rest of human experience. Like coronary heart disease, depression is a multifactorial health problem, rooted in complex interactions of biological, psychological, and social variables, best understood and managed through a broader biopsychosocial model of the sort proposed by George Engel.


Loneliness, for example, is a powerful predictor of depression. Numerous studies show that people with few intimate social contacts are more likely to be depressed than those who enjoy a rich network of friends and family. Reductionists might argue that being part of a social group boosts serotonin, but I am confident that there is something in a successful social life that transcends any effect on brain biochemistry, at least insofar as we currently understand that biochemistry. In other words, a happy family life probably raises serotonin in some people, lowers it in others, and leaves it unaffected in still others. Yet it makes them all more comfortable, serene, and relatively immune to mood disorders through a body-mind-social interaction that can’t be reduced to its constituent parts.Read More.

Edited by Altostrata
added date of publication

As always, LISTEN TO YOUR BODY! A proud supporter of the 10% (or slower) rule.


Requip - 3/16 ZERO  Total time on 25 years.


Lyrica: 8/15 ZERO Total time on 7 or 8 yrs.

BENZO FREE 10/13 (started tapering 7/10)  Total time on 25 years.


Read my intro thread here, and check the about me section.  "No matter how cynical you get, it's almost impossible to keep up." Lily Tomlin



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"Happy pills" GRRRRR}}}}}


Good article. It confirmed my suspicion about TCAs.

Pristiq tapered over 8 months ending Spring 2011 after 18 years of polydrugging that began w/Zoloft for fatigue/general malaise (not mood). CURRENT: 1mg Klonopin qhs (SSRI bruxism), 75mg trazodone qhs, various hormonesLitigation for 11 years for Work-related injury, settled 2004. Involuntary medical retirement in 2001 (age 39). 2012 - brain MRI showing diffuse, chronic cerebrovascular damage/demyelination possibly vasculitis/cerebritis. Dx w/autoimmune polyendocrine failure.<p>2013 - Dx w/CNS Sjogren's Lupus (FANA antibodies first appeared in 1997 but missed by doc).

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Great article by Dr. Weil. Sums it all up pretty well.


I would also add those awful corporate jobs do their part in adding to stress, depression, overload, and physical inactivity.

This is not medical advice. Discuss any decisions about your medical care with a knowledgeable medical practitioner.

"It has become appallingly obvious that our technology has surpassed our humanity." -- Albert Einstein

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I know doctors who find Weil a reliable authority.


When I first got off and was trying supplements for cog fog my Dr. FG would frequently refer to Weil's site to get the skinny on a compound he was not familiar with. FG is very aware of 'mainstream' and in his bias would lump say Peter Breggin and Tom Cruise into the 'quacko-wacko' basket. But Weil was a trusted authority.

"Well my ship's been split to splinters and it's sinking fast
I'm drowning in the poison, got no future, got no past
But my heart is not weary, it's light and it's free
I've got nothing but affection for all those who sailed with me.

Everybody's moving, if they ain't already there
Everybody's got to move somewhere
Stick with me baby, stick with me anyhow
Things should start to get interesting right about now."

- Zimmerman

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