"Psychopharmacology is in crisis"

When are all the new drugs for psychiatric disorders coming along? Probably not in your lifetime.

Schizophrenia Bulletin, Fibiger (2012)

"Psychopharmacology is in crisis. The data are in, and it is clear that a massive experiment has failed: despite decades of research and billions of dollars invested, not a single mechanistically novel drug has reached the psychiatric market in more than 30 years. Indeed, despite enormous effort, the field has not been able to escape the “me too/me (questionably) better” straightjacket. In recent years, the appreciation of this reality has had profound consequences for innovation in psychopharmacology because nearly every major pharmaceutical company has either reduced greatly or abandoned research and development of mechanistically novel psychiatric drugs. This decision is understandable because pharmaceutical and biotechnology executives see less risky opportunities in other therapeutic areas, cancer and immunology being the current pipeline favorites. Indeed, in retrospect, one can wonder why it took so long for industry to abandon psychiatry therapeutics. So how did we get here and more importantly, what do we need to do to find a way forward?            

The discovery of all three major classes of psychiatric drugs, antidepressants, antipsychotics, and anxiolytics, came about on the basis of serendipitous clinical observation. [Also known as dumb luck.] At the time of their discoveries, the mechanisms by which these molecules produce their effects were unknown, and it was only later that antipsychotics were shown to be D2 receptor antagonists, antidepressants monoamine reuptake inhibitors, and anxiolytics GABA receptor modulators. It is interesting and perhaps instructive to consider whether any of these classes of drugs could have been discovered by current drug discovery strategies. For example, what genetic or preclinical data exist that point to the D2 dopamine receptor as a likely target for antipsychotic activity? Presently there are no genetic data that suggest that this receptor is expressed or functions abnormally in psychotic disorders. And without the benefit of the prior clinical validation, it is difficult to see how preclinical data alone would point to the D2 receptor as an interesting potential target for the treatment of psychotic disorders. The same can be said for monoamine transporters with respect to depression where, like psychosis, there are no animal models based on disease pathophysiology and no compelling preclinical data pointing to these as potential targets for antidepressant drugs. This raises a troubling question: if in retrospect the three major classes of currently prescribed psychiatric drugs would likely never have been discovered using current drug discovery strategies, why should we believe that such strategies are likely to bear fruit now or in the future?               

In order to recapture industry’s investment in psychiatric drug development, major changes in psychiatry will need to take place. These changes are necessary along the entire value chain, including both preclinical and clinical domains. What the field lacks is sufficient basic knowledge about normal brain function and how its disturbance underlies the pathophysiology of psychiatric disease. Because of this, as the record now clearly shows, it remains too early to attempt rational drug design for psychiatric diseases as currently conceived. The most obvious solution here is expanded investment in neuroscience. By necessity, this will be driven primarily by the efforts of clinical and basic scientists in academic settings because industry no longer has the appetite or the resources to engage in such activities. It is worth emphasizing that industry is in the business of making drugs, knowledge sometimes being a fortuitous byproduct. Academia is in the business of generating knowledge, and knowledge is what is needed at present. If we are successful in making the necessary changes, given the enormous level of unmet need left by existing psychiatric drugs, there is no doubt that industry will return and reinvest.                 

A major barrier to progress is the current state of nosology in psychiatry. A new taxonomy is a prerequisite for meaningful progress. Today, few would argue that syndromes such as schizophrenia and depression are single, homogeneous diseases. And yet when it comes to clinical research, including clinical trials, both are still almost always treated as such. For example, studies continue to be published on the genetics of both of these syndromes despite the fact that there never will be a robust genetics of either condition as the nature and severity of specific symptoms are too heterogeneous across individuals to have any consistent genetic correlates. Similarly, while DSM conceptualizations of psychiatric disease may have utility in current clinical practice, when it comes to research, they too are a barrier to progress. A different approach would be to break these syndromes down into their component subsyndromes or symptoms and investigate the neurobiological substrates of these more precisely defined components. As an example, although there will never be a coherent biology of schizophrenia (any more than there ever could have been be a meaningful biology of cancer as it was understood 30 years ago), the chances seem better that there will be a biology of subsyndromes such as negative symptoms, delusions, or hallucinations (just as it is now understood that there are distinct biologies underlying different cancers). Advances in knowledge about the biological mechanisms underlying different cancers are were a prerequisite for the huge current investment in developing novel cancer therapeutics. Psychiatry should learn from this example.                 

Given that there cannot be a coherent biology for syndromes as heterogeneous as schizophrenia, it is not surprising that the field has failed to validate distinct molecular targets for the purpose of developing mechanistically novel therapeutics."

Jail Suicide Attributed to Paxil, to the tune of $11.9 million

Can't say I'm as anti-biological psychiatry as Peter Breggin, but I'm glad he's writing his books.

Ithaca, NY (PRWEB) October 06, 2016

"A jury has awarded $11.9 million in a suicide case involving the antidepressant Paxil (paroxetine). The patient killed himself in jail after a psychiatrist restarted him on the SSRI antidepressant.

The $11.9 million award was one of the largest jury awards of its kind in an antidepressant-related suicide case which concluded September 15, 2016.

The defendant was PrimeCare and several of its practitioners and staff who provided services at the jail. The jury determined that the company and most of the defendants acted with deliberate indifference to the patient’s medical needs.

Psychiatrist Peter R. Breggin MD testified, according to court documents, about the negligence and callous indifference of the psychiatrist and the psychologist who treated the 46 year old patient, Mr. Mumun Barbaros. In addition, Dr. Breggin testified about causation in respect to the actions of the psychologist and psychiatrist, as well as the nursing staff and administration.

According to court documents Dr. Breggin testified that restarting the patient on his regular dose of the SSRI antidepressant Paxil 30 mg, despite a hiatus of least four days without the medication, was a direct cause of the suicide later on the same day. He explained further that the patient had difficulty several years earlier when starting the medication, even though the initial dose was only 10 mg. Restarting him on Paxil 30 mg, when most of the drug was out of his system caused akathisia (agitation with hyperactivity) and suicide. He also found that the doctor and the psychologist were negligent in several other ways, including their failure to evaluate the patient and to order careful monitoring."

The jury award included $2.8 million for negligence, $1.06 million for federal deliberate indifference and $8 million for punitive damages.

The attorney for the plaintiff was Brian Chacker of Philadelphia. The case is Ponzini et al. v. Monroe County et al., case number 3:11-cv-00413, in the U.S. District Court for the Middle District of Pennsylvania in Scranton.

Captagon - Drug of Choice for Syrian fighters

The Guardian

"As Syria sinks ever deeper into civil war, evidence is starting to emerge that a brutal and bloody conflict that has left more than 100,000 people dead and displaced as many as two million is now also being fuelled by both the export and consumption of rapidly increasing quantities of illegal drugs.

Separate investigations by the news agency Reuters and Time magazine have found that the growing trade in Syrian-made Captagon – an amphetamine widely consumed in the Middle East but almost unknown elsewhere – generated revenues of millions of dollars inside the country last year, some of which was almost certainly used to fund weapons, while combatants on both sides are reportedly turning to the stimulant to help them keep fighting.

Captagon, the trademark name for the synthetic stimulant fenethylline, was first produced in the 1960s to treat hyperactivity, narcolepsy and depression, but was banned in most countries by the 1980s as too addictive. It remains hugely popular in the Middle East; Saudi Arabia alone seizes some 55m tablets a year, perhaps 10% of the total thought to be smuggled into the kingdom.

The drug is cheap and simple to produce, using ingredients that are easy and often legal to obtain, yet sells for up to $20 a tablet. A Lebanese psychiatrist, Ramzi Haddad, said that Captagon had "the typical effects of a stimulant", producing "a kind of euphoria. You're talkative, you don't sleep, you don't eat, you're energetic."

Those effects explain why fighters from most of the warring parties in the conflict – with the exception of al Qaida-linked groups, which mostly hold to a strict interpretation of Islamic law – are now said to be making extensive use of Captagon, often on night missions or during particularly gruelling battles. But doctors and psychiatrists say use of the drug is also becoming widespread among Syria's increasingly desperate civilian population."

Oh wait, Paxil is no better than placebo in teens, and it increases suicide risk

More generally, you know what stinks about these clinical drug trials for antidepressants? Their use of the terribly lame HAM-D as the primary outcome measure. I suspect that they don't use the MMPI-2 because the scores would be too stable from Time 1 to Time 2.

NYT

"Fourteen years ago, a leading drug maker published a study showing that the antidepressant Paxil was safe and effective for teenagers. On Wednesday, a major medical journal posted a new analysis of the same data concluding that the opposite is true.

That study — featured prominently by the journal BMJ — is a clear break from scientific custom and reflects a new era in scientific publishing, some experts said, opening the way for journals to post multiple interpretations of the same experiment. It comes at a time of self-examination across science — retractions are at an all-time high; recent cases of fraud have shaken fields as diverse as anesthesia and political science; and earlier this month researchers reported that less than half of a sample of psychology papers held up....

...The dispute itself is a long-running one: Questions surrounding the 2001 study played a central role in the so-called antidepressant wars of the early 2000s, which led to strong warnings on the labels of Paxil and similar drugs citing the potential suicide risk for children, adolescents and young adults. The drugs are considered beneficial and less risky for many adults over 25 with depression.

Over the years, thousands of people taking or withdrawing from Paxil or other psychiatric drugs have committed violent acts, including suicide, experts said, though no firm statistics are available. Because many factors could have contributed to that behavior, it is still far from clear who is at risk — and for whom the drugs are protective....

...The original study began in the late 1990s, when antidepressant makers started testing the drugs in young people. Antidepressant trials are an extremely tricky enterprise, in part because anywhere from a third to more than half of subjects typically improve on placebo. Choices about how to measure improvement — and how to label side effects — can make all the difference in how good a drug looks.

And so it was in the Paxil study. The original research, led by Dr. Martin Keller of Brown University, tracked depression scores over eight weeks in three groups of about 90 adolescents each, one taking Paxil, one on placebo pills and one taking imipramine, an older generic drug for depression. The Paxil group did no better than the other two groups on the study’s main measure — a standard depression questionnaire — but did rate higher on other, “secondary” measures, like another scale of mood problems, the authors reported.

Researchers consider secondary measures like these as akin to circumstantial evidence, potentially meaningful but not as strong as the primary ones....

...Prescriptions of antidepressants to young people surged in the wake of the study, increasing by 36 percent between 2002 and 2003, according to one analysis. The growth slowed after regulators ordered the black-box warnings on labels.

...The reanalysis delivers the same critique as before — no clear effectiveness, and mislabeling of serious side effects — only from the inside, using voluminous data from the study itself. ...

...In an interview, Dr. Healy said that five of six adverse events labeled “emotional lability” in the original study involved suicidal thinking or behavior but were not presented as such. The patient-level files provided detail on what, exactly, happened in those cases: One teenager was hospitalized after taking 80 Tylenol tablets. Another overdosed on Paxil and other medications after a “disagreement with her mother.” Others suffered “severe suicidal ideation,” and one was “admitted due to severe suicidal and homicidal ideation, towards his parents.” No completed suicides occurred."

The Neuroscience of Despair -- Michael W. Begun

New Atlantis

"Pharmaceutical companies sold the idea of depression as much as the drugs themselves, promoting the belief that depression stems from a chemical imbalance in the brain, with a marketing apparatus rival in scope to national political campaigns. (By 2000, pharmaceutical companies were spending over $2 billion in direct-to-consumer advertising. By comparison, spending by candidates in the 2000 presidential election totaled a mere $343 million.) This marketing effort played no small part in shaping the public’s understanding of depression.

The sales of antidepressant drugs increased in kind. According to a 2002 article in the Journal of the American Medical Association, “patients treated for depression were 4.8 times more likely to receive an antidepressant in 1997 than in 1987.” And a 2005 article in Health Affairs reported that in a period of merely five years, between 1996 and 2001, overall spending on SSRIs and other new antidepressants rose from $3.4 billion to $7.9 billion. Edward Shorter writes in A History of Psychiatry (1997) that antidepressants became so popular that “patients began to view physicians as mere conduits to fabled new products rather than as counselors capable of using the doctor-patient relationship itself therapeutically.” While this description may overstate things, it seems likely that the growing popularity of antidepressants and other psychoactive drugs began to reshape our conventional notions of mental disorders.

A Deficient Theory

"It is really not known how drugs alleviate the symptoms of mental disorders,” wrote neuroscientist Elliot S. Valenstein in his book Blaming the Brain (1998), “and it should not be assumed that they do so by correcting an endogenous chemical deficiency or excess.” Valenstein was referring to chemical deficiency (or chemical imbalance) theories of depression, which postulate that depression results from low concentrations of certain neurotransmitters in the brain. Valenstein’s words remain true today: every time a new neurobiological theory seems like it might explain depression, evidence comes along to demonstrate the theory’s inadequacies. The last half century of attempts to formulate such a theory can be summed up by Kafka’s remark: “Like a path in autumn: no sooner is it cleared than it is once again littered with fallen leaves.”

The original chemical deficiency theory of depression dates back to 1965, when Harvard psychiatrist Joseph J. Schildkraut hypothesized that low levels of catecholamines — a kind of neurotransmitter, or brain chemical — were associated with depressive disorders, with high levels corresponding to feelings of elation. The paper remains one of the most frequently cited in the history of psychiatry. While the hypothesis may appear rudimentary today, it laid the groundwork for current chemical imbalance theories of depression.

Schildkraut inspired the development of the monoamine hypothesis, which postulates that deficiencies in certain neurotransmitters such as serotonin and dopamine cause depression. (Monoamines are a class of neurotransmitters that includes serotonin, dopamine, and catecholamines, such as norepinephrine.) In contrast to early antidepressant drugs, which were discovered serendipitously, the later SSRIs were designed on the basis of the monoamine hypothesis. They were expressly engineered to increase the amount of serotonin available in synapses, the junctions between neurons. While SSRIs have proven to be more effective than most other antidepressant drugs, we know little about how they work beyond their immediate biochemical effects. One particular problem scientists have tried to understand is that while the physical effects of SSRIs and other antidepressant drugs transpire within minutes after consumption, the psychological effects typically take nearly two weeks to manifest. This difficulty has prompted further hypotheses and speculative modifications to the monoamine theory, but no empirically bulletproof explanation has thus far been found.

Evidence suggests that nothing close to the simple chemical deficiency hypothesis can be right. Despite intense efforts to correlate serotonin deficiencies with depression, most studies have been unable to do so. The same goes for other monoamines, too. Only about 25 percent of depressed patients actually have low levels of serotonin or norepinephrine, according to Valenstein, suggesting that other processes are involved.

These shortcomings have not stopped the chemical imbalance theory from shaping popular discourse about depression and mental illness in general. Advertisements for antidepressants and anti-anxiety medications have frequently appealed to the chemical imbalance hypothesis, sometimes cartoonishly depicting the deficiency in neurotransmitters that was supposed to cause depression. A Prozac advertisement that ran in Newsweek, Time, and other popular magazines around 1997 and 1998 explained:

When you’re clinically depressed, one thing that can happen is the level of serotonin (a chemical in your body) may drop. So you may have trouble sleeping. Feel unusually sad or irritable. Find it hard to concentrate. Lose your appetite. Lack energy. Or have trouble feeling pleasure.... To help bring serotonin levels closer to normal, the medicine doctors now prescribe most often is Prozac.®

The advertisement respects FDA regulations against false drug advertising statements by including the qualification “one thing that can happen,” though it presents a seductive explanation of a whole range of woes we experience on a daily basis. The mismatch between the empirical status of the chemical deficiency hypothesis and its portrayal in pharmaceutical advertisements led a 2005 paper published in PLOS Medicine to conclude: “The incongruence between the scientific literature and the claims made in FDA-regulated SSRI advertisements is remarkable, and possibly unparalleled.” This kind of aggressive advertising on the part of the pharmaceutical companies (among other practices like political lobbying, incentivizing doctors to prescribe their products, and promoting screening for depression) has led many authors to lambast the pharmaceutical industry for selling the idea of depression just as much as its treatment.

The chemical deficiency hypothesis may itself be deficient, but it helped make possible a new subdiscipline, biological psychiatry, in which mental disorders are understood as arising from facts about the biology of the person. Most psychiatrists today point to more complex explanations than those offered by Schildkraut in the 1960s. For instance, in a 2011 letter to the New York Review of Books, two psychiatrists wrote of “recent advances in neuroscience research that demonstrate that depression is not a disease of a single neurotransmitter system or brain region but probably a disorder that involves multiple neural circuits and neurotransmitters.” Schildkraut himself stressed that his chemical imbalance hypothesis was “undoubtedly, at best, a reductionistic oversimplification of a very complex biological state,” and that it was properly regarded as a heuristic rather than a sufficient explanation of the neurobiology of depression. Yet the form of explanation, in which a mental disorder is related to a neuronal abnormality, has not changed since Schildkraut’s hypothesis first took hold, and today we seem ever more committed to neurobiological explanations of mental illness. How far can they go?"

Adderall Abuse After College

If Calvin took Ritalin.

 

 

 NYT

"The number of stimulant misusers who become addicted is unclear. But supply has risen sharply: About 2.6 million American adults received A.D.H.D. medication in 2012, a rise of 53 percent in only four years, according to Express Scripts, the nation’s largest prescription-drug manager. Use among adults 26 to 34 almost doubled.

Most experts say a proper evaluation for the disorder typically requires an extensive inquiry into a patient’s history of impulsivity and inattention. Yet misusers routinely described brief chats with doctors to get a prescription. Two lawyers in Houston said wearing a suit to their appointments guaranteed no scrutiny.

Those lawyers said they and dozens of young colleagues at their firms had casually traded pills to work into the night and billed hundreds of extra hours a year in the race for partnerships.

One said he had originally taken 20 milligrams of Adderall a day, moving up to 100 milligrams — almost double the highest dose recommended by the Food and Drug Administration — by getting prescriptions from multiple doctors, a felony in Texas. His productivity, he said, thrilled his unquestioning bosses and clients.

Then came the downside: rapid heartbeat, profuse sweating and acute anxiety due to sleep loss. These overwhelmed any positive effects on his work performance, he said, and transformed his personality to the point that his wife divorced him. After he lost his job, he spent six weeks at a drug treatment center."

The article includes a link to this research article which reviews the research on ADHD medication: 1) they don't improve the academic performance (e.g., GPAs) of students taking the drugs (but they do reduce behavioral disruptions); and, 2) they don't enhance the cognitive abilities of people without ADHD. If you need to stay up and study during this exam week -- have a cup of coffee.

Two Thirds of People on Antidepressants Aren't Clinically Depressed

What Dr. Forman (below) doesn't say is that the main reason patients are taking antidepressants even when they are not needed is that many physicians actually believe the "chemical imbalance" theory of depression. Primary care physicians should be referring patients to a mental health expert (e.g., clinical psychologist) to make the diagnosis and recommend treatment options.

Medical Daily

"A new study published in The Journal of Clinical Psychiatry reports some 69 percent of people taking selective serotonin reuptake inhibitors (SSRIs), the primary type of antidepressants, have never suffered from major depressive disorder (MDD). Perhaps worse, 38 percent have never in their lifetime met the criteria for MDD, obsessive compulsive disorder, panic disorder, social phobia, or generalized anxiety disorder, yet still take the pills that accompany them.

In a society that is increasingly self-medicating itself, capsules, tablets, and pills are turning from last resorts to easily obtained quick fixes. Between 1988 and 2008, antidepressant use increased nearly 400 percent. Today, 11 percent of the American population takes a regular antidepressant, which, by the latest study’s measure, may be a severe inflation of what’s actually necessary.

“I think while psychotherapy is another option to helping people obtain better mental health, there are roadblocks,” said Dr. Howard Forman, medical director of the Addiction Consultation Service at Montefiore Medical Center. Forman, who wasn’t involved with the study, points toward cost, availability of experts, and time demands as the main reasons people may decide to pursue alternatives."

Source: Takayanagi Y, Spira A, Bienvenu O, et al. Antidepressant Use and Lifetime History of Mental Disorders in a Community Sample: Results From the Baltimore Epidemiologic Catchment Area Study. The Journal of Clinical Psychiatry. 2015.

Review of Jeffrey Lieberman's Shrinks: The Untold Story of Psychiatry

Excerpt from a great review by Gary Greenburg.

Book Forum

"I may be critical of psychiatry, but as a clinician, I would be thrilled if the portrait Lieberman paints of the mental health field bore a closer resemblance to reality. If a scientific medicine of the brain were truly available, I’d be glad to avail myself of it. At the very least, I’d be relieved not to worry that every time I sent a patient to a psychiatrist, she might return with a fistful of prescriptions, little idea of how the drugs work (for no one really knows) or what side effects she may suffer, and no guarantee that she will get better. Lieberman’s apologetics suffer from his cheerleading, from a tendency to gloss over history that would perhaps suggest a less sanguine conclusion than his.

...

But it’s not just the distant past that Lieberman leaves unrecounted. He minimizes or entirely overlooks such unsavory recent chapters as the widespread diagnosis, against the criteria of the DSM, of bipolar disorder in the very young and their subsequent treatment with powerful (and untested in children) antipsychotic drugs—an episode that occasioned Senate hearings and front-page exposés. He never acknowledges that the “serotonin imbalance” that antidepressants supposedly rectify does not exist—or if it does, it has yet to be discovered—and his lock-and-key image belies the much less certain clinical reality, in which antidepressants are routinely prescribed for anxiety disorders, antipsychotics for mood disorders, and anti-anxiety drugs for a wide range of complaints—and all on a trial-and-error basis. He fails to mention that no new psychiatric medications have been discovered in the past quarter century, or that none of the newer ones have proved more effective than the drugs discovered in the 1950s (although some of them do have fewer side effects). And he vastly overestimates the current state of neuroscience, which is only beginning to unravel the mysteries of how the billions of neurons and trillions of connections among them turn into consciousness."

Homeopathy not effective for treating any condition, Australian report finds

Of course homeopathy is just placebo -- they are selling you a bottle of distilled water, for goodness sakes. But why do people go to homeopaths? (And why does the National Health Service of Great Britain pay for it?) Well, unlike actual physicians, a homeopath will actually sit down with you and listen to you talk about your symptoms. In other words, they will pay attention to you and treat you like a human being. Maybe if physicians tried that, they wouldn't have so much competition from quacks.

Guardian

"Homeopathy is based on the belief that “like cures like” and that the dilution of a medicine – homeopaths call the process “potentiation” – renders it not weaker but stronger. As both of these assumptions fly in the face of science, critical thinkers have always insisted that few things could be more implausible than homeopathy.

But plausibility is not everything. In Exeter, we conducted trials, surveys and reviews of homeopathy in the faint hope that we might discover something important. What we did find was sobering

 

• Our trials failed to show that homeopathy is more than a placebo.
• Our reviews demonstrated that the most reliable of the 230 or so trials of homeopathy ever published are also not positive.
• Studies with animals confirmed the results obtained on humans.
• Surveys and case reports suggested that homeopathy can be dangerous.
• The claims made by homeopaths to cure conditions like cancer, asthma or even Ebola were bogus.
• The promotion of homeopathy is not ethical.

                                             

....The Australians then considered this evidence carefully and have now published their final report. It arrived at the same conclusion as the previous document. If anything, it went one step further by pointing out that “people who choose homeopathy may put their health at risk if they reject or delay treatments for which there is good evidence for safety and effectiveness”. Personally, I would go another step further and remind pharmacists who sell homeopathic remedies to the unsuspecting public that it is unethical to pretend they are more than placebos."

 

 

 

Psy-feld class brings psychiatry training to a new low

 

NJ.com

"It’s 9 a.m. on a Tuesday morning at Robert Wood Johnson University Hospital and 10 medical students sit around a conference table covered by coffee cups and clipboards. Preparing to start their morning rounds, the students chat about what they watched on television the night before.

“Jerry’s girlfriend doesn’t like George,” third-year student Marlene Wang says, referring to the iconic 1990s sitcom "Seinfeld." “And he just couldn’t live with the idea of this person not liking him.”

This isn’t a discussion about nothing. More than 15 years after the final episode, "Seinfeld" is the basis for “Psy-feld,” a teaching tool designed to help medical students identify and discuss psychiatric disorders."

Personally, I find this horrifying. This is training in psychopathology, I suppose, but for bright high school juniors -- not psychiatry residents. I wonder if part of the reason for this approach is that most of the psychiatry residents are foreign born? Watching American sit-coms might help them learn some idioms. But when they practice, all they are going to do is diagnose you as "bipolar," give you (oddly) an antidepressant, and when that doesn't work, add an antipsychotic. If they like you, they'll give you Xanax, too. Oh, and ADHD meds for the kiddies.

Ketamine (Special K) for Depression

"Yup, I pretty much have my depression under control. Just keep dosing me with that horse tranquilizer."

NYT

"It is either the most exciting new treatment for depression in years or it is a hallucinogenic club drug that is wrongly being dispensed to desperate patients in a growing number of clinics around the country.

It is called ketamine — or Special K, in street parlance.

While it has been used as an anesthetic for decades [for HORSES!], small studies at prestigious medical centers like Yale, Mount Sinai and the National Institute of Mental Health suggest it can relieve depression in many people who are not helped by widely used conventional antidepressants like Prozac or Lexapro.

And the depression seems to melt away within hours, rather than the weeks typically required for a conventional antidepressant.

But some psychiatrists say the drug has not been studied enough to be ready for use outside of clinical trials, and they are alarmed that clinics are springing up to offer ketamine treatments, charging hundreds of dollars for sessions that must be repeated many times.

... 

Dr. David Feifel, a professor of psychiatry at the University of California, San Diego, said that what is essentially a psychedelic trip is over quickly after the treatment is ended. 

“More often than not, they really like it,” said Dr. Feifel, who is one of the only academic psychiatrists to offer ketamine as a treatment, as opposed to in a clinical trial, though only to people who have exhausted other options. He said that if he did not offer the drug, “I’m consigning you to lose another decade until ketamine might be ready. I just don’t feel that presumptuous.” 

One of his patients, Maggie, said that when she got her first infusion she was aware enough to change the tunes on her iPod, albeit slowly, but was “transported into a completely different dimension.” She added, “Everything there is completely vibrant or molten.” 

The trip ended quickly, but within hours, a lifetime of depression began to lift."

Have a problem? Take a pill!

Telegraph

"Hundreds of thousands of people drinking half a bottle of wine a night are to be put on the first ever drug to help reduce alcohol consumption, under plans announced by the National Institute for Health and Care Excellence (NICE).  

Men drinking three pints of beer and women drinking two large glasses of wine per night and who do not cut down within two weeks should be prescribed a new drug, NICE has said.  

There are an estimated 750,000 people in the UK who would be eligible for nalmefene who show no overt symptoms associated with their drinking.  

The plans mean GPs will actively ask patients about their alcohol consumption even when they see them for unrelated health matters such as low mood, inability to sleep, diabetes and high blood pressure.  

...

Prof Mark Bellis, alcohol lead for the Faculty of Public Health said there were relatively simple alternatives that would reduce alcohol consumption without the need to medicate the middle classes such as reducing advertising of alcohol and introducing a minimum price per unit.  

... 

The drug, which costs £3 per tablet, is taken when people feel the urge to have a drink and stops them from wanting more than one. In clinical trials the drug helped people to cut their alcohol consumption by about 60 per cent from 13.5 units a day to five units. 

However this was only 1.8 units more than those receiving just counseling."

Why not just pump it into the water supply, like fluoride?

This is actually a really old drug (1970s) that is not even sold anymore in the U.S. If it works anywhere near as well as the other opioid-antagonists, like its cousin, Naltrexone, then I'm pretty confident that it doesn't work at all. (Not that I'm all that sanguine about the benefits of counseling in this regard, either.) There's a big difference between demonstrating positive effects in a clinical trial and success in the real world. How many patients do I know who've kicked opiates with Naltrexone? None.

Pushing Lexapro: Costs more than Celexa, and it's not any better!

 

 

NYT

 

September 2, 2009

Document Details Plan to Promote Costly Drug

By GARDINER HARRIS

 

The pharmaceutical industry has developed thousands of medicines that have saved millions of lives, but it has also used its marketing muscle to successfully peddle expensive pills that are no more effective than older drugs sold at a fraction of the cost.

No drug better demonstrates the industry’s salesmanship than Lexapro, an antidepressant sold by Forest Laboratories. And a document quietly made public recently by the Senate’s Special Committee on Aging demonstrates just how Forest managed to turn a medicinal afterthought into a best seller.

The document, “Lexapro Fiscal 2004 Marketing Plan,” is an outline of the many steps Forest used to make Lexapro a success. Because of concerns from Forest, the Senate committee released only 88 pages of the document, which may have originally run longer than 270 pages. “Confidential” is stamped on every page.

But those 88 pages make clear that one of the principal means by which Forest hoped to persuade psychiatrists, primary care doctors and other medical specialists to prescribe Lexapro was by finding many ways to put money into doctors’ pockets and food into their mouths.

Frank Murdolo, a Forest spokesman, said the company was “aware” that its marketing plan was circulating around the Senate.

“We’re aware of it but I can’t give you any other comment on it,” he said.

In February, federal prosecutors in Boston announced a civil lawsuit against Forest claiming that the company illegally marketed both Lexapro and a closely related antidepressant, Celexa, for use in children and paid kickbacks to doctors to induce them to prescribe the medicines to children.
It is illegal to pay doctors to prescribe certain medicines to their patients. It is not illegal to pay doctors to educate their colleagues about a medicine. In recent years, federal prosecutors have accused many drug makers of deliberately crossing that line.

Lexapro was the sixth drug in a class of medicines that includes Prozac, Paxil, Zoloft, Luvox and Celexa. Forest licensed Celexa from Lundbeck of Denmark and introduced the medicine into the United States in 1998. But because Celexa’s patent life was relatively short, the company quickly developed a new version of Celexa by tinkering with the molecule in a way that is standard in the industry. The company called the new medicine Lexapro and introduced it into the United States in 2002.

Forest’s executives and paid consultants have long implied that Lexapro is superior to Celexa and other antidepressants. But the Food and Drug Administration did not require Forest to test this theory in any statistically valid way. The F.D.A. views the two medicines as so interchangeable that the agency recently approved Lexapro’s use in depressed adolescents based in part on the results of a study Forest conducted using Celexa.

Lexapro had $2.3 billion in sales in 2008 even though generic versions of Celexa and every other drug in the class sell for a fraction of Lexapro’s price. For example, a month’s supply of 5-milligram tablets of Lexapro costs $87.99 at drugstore.com, compared to $14.99 for a month’s supply of a generic version of Prozac. Forest has recently been raising the price of Lexapro to make up for a decline in its use.

Many doctors say they believe that Lexapro is the best antidepressant, so they prescribe the drug despite its cost.

It is impossible to unpack all of the reasons for these prescriptions, but some industry critics say one reason could be the money doctors make from Forest. Psychiatrists make more money from drug makers than any other medical specialty, according to analyses of payment data. And Forest gives more money and food to doctors than many of its far larger rivals. Vermont officials found that Forest’s payments to doctors in 2008 were surpassed only by those of Eli Lilly, Pfizer, Novartis and Merck — companies with annual sales that are five to 10 times larger than Forest’s.

Forest’s 2004 plan for marketing Lexapro offers detailed information about how the company planned to direct this money to doctors.

Under “Rep Promotional Programs,” the document said the company planned to spend $34.7 million to pay 2,000 psychiatrists and primary care doctors to deliver 15,000 marketing lectures to their peers in one year.

“These meetings may be large-scale dinner programs with a slide presentation, small roundtable discussions or one-on-one advocate lunches,” the document states.

Under “Lunch and Learns,” the company intended to spend $36 million providing lunch to doctors in their offices. “Providing lunch for a physician creates an extended amount of selling time for representatives,” the document states.

An entire section of the marketing plan, titled “Continuing Medical Education,” outlines how the company intended to use educational seminars for doctors to teach them about Lexapro. The Senate’s Special Committee on Aging held a hearing in July on whether industry funding of medical education classes leads to tainted talks.

“At our recent hearing we asked the question, ‘Is the line between medical education and marketing blurred?’ ” said Senator Herb Kohl, a Democrat from Wisconsin who is chairman of the committee on aging. His panel was given the Lexapro document by the Senate Finance Committee, which has long been investigating drug maker marketing efforts. “These documents show that for these companies, there is no line,” Mr. Kohl said.


 

Antidepressants or Exercise?

The Atlantic

 

 

 

Percent of patients in each condition six months after treatment.(Psychosomatic Medicine)

Depression is the most common mental illness—affecting a staggering 25 percent of Americans—but a growing body of research suggests that one of its best cures is cheap and ubiquitous. In 1999, a randomized controlled trial showed that depressed adults who took part in aerobic exercise improved as much as those treated with Zoloft. A 2006 meta-analysis of 11 studies bolstered those findings and recommended that physicians counsel their depressed patients to try it. A 2011 study took this conclusion even further: It looked at 127 depressed people who hadn’t experienced relief from SSRIs, a common type of antidepressant, and found that exercise led 30 percent of them into remission—a result that was as good as, or better than, drugs alone.

Though we don’t know exactly how any antidepressant works, we think exercise combats depression by enhancing endorphins: natural chemicals that act like morphine and other painkillers. There’s also a theory that aerobic activity boosts norepinephrine, a neurotransmitter that plays a role in mood. And like antidepressants, exercise helps the brain grow new neurons.

But this powerful, non-drug treatment hasn’t yet become a mainstream remedy. In a 2009 study, only 40 percent of depressed patients reported being counseled to try exercise at their last physician visit.
Instead, Americans are awash in pills. The use of antidepressants has increased 400 percent between 1988 and 2008. They’re now one of the three most-prescribed categories of drugs, coming in right after painkillers and cholesterol medications.

Sedating Kids in Foster Care with Antipsychotics

Wall Street Journal

Overseen by state and local governments, foster care provides temporary placement for minors unable to remain in their own homes. They can live in individual foster homes, in group homes, or other institutional settings. Nationwide, there were approximately 400,000 children in foster care in 2012, according to the Department of Health and Human Services.

Antipsychotics, drugs dispensed for a broad array of diagnoses, have ignited a wave of debate—most recently over their use in poor children and the billions that they cost the Medicaid and Medicare systems annually.

Most scrutiny centers on a new class of antipsychotics sold under such brand names as Abilify, Seroquel, Risperdal and Zyprexa.

Based on 2009 data from Medicaid and private insurers, Stephen Crystal, a professor of health-services research at Rutgers University, estimates that 12% to 13% of kids in foster care take these medicines. That compares with about 2% for children on Medicaid but not in foster care and about 1% for those with private insurance.

While originally hailed as safer and more tolerable than predecessor drugs such as Thorazine and Haldol, the newer generation of antipsychotics, often called atypicals, has spawned a growing body of research about potential side effects. These, say researchers, can include sudden and severe weight gain, increased risk for diabetes and movement disorders.

Atypicals, with their strong sedative powers, were originally intended for the narrow segment of adults with psychotic conditions like schizophrenia.

The Food and Drug Administration only sanctions their use for kids diagnosed with schizophrenia and conditions such as bipolar disorder and irritability associated with autism. But physicians can also prescribe these medicines "off label" to combat behavioral issues in children—some as young as two years old.

Some doctors stress that the drugs are helpful in treating children with certain aggression and behavior illnesses. Yet many are concerned that the use of antipsychotic drugs, particularly among those in custodial care, has gone too far.

According to Prof. Crystal's research, the largest diagnostic groups receiving the drugs in foster-care in 2009 were those with disruptive-behavioral disorders and attention-deficit/hyperactive disorders.

"These diagnoses involve difficulty focusing attention or controlling behavior—but that is different from not being in touch with reality," a key element of psychosis, he says.

To be sure, some doctors see considerable value in the use of antipsychotics on children in custodial care. Dr. Christoph Correll, professor of psychiatry at Hofstra University's Zucker Hillside Hospital, maintains that antipsychotics can effectively combat the violent, aggressive behavior some foster kids display. The drugs "generally work fast, which is often desired when kids are at risk of being suspended from school for their behaviors," says Dr. Correll. "In these situations, having to wait for a therapy appointment is not an option." [Let's be clear that this is merely managing behavior by administering a heavily sedating drug, and not anything therapeutic.]

The popularity of such drugs helps to account for their blockbuster sales. In 2011, antipsychotics rang up $18.5 billion in U.S. revenues, according IMS Health, rising from $12.9 billion in 2007. Sales dipped in 2012 as cheaper generics came on the market.

Of all prescription drugs sold in the U.S., Otsuka Pharmaceutical Co.'s Abilify boasts the biggest sales by dollar, ringing up $5.87 billion in sales in 2012, according to IMS Health.

In September, the American Psychiatric Association urged its members to prescribe antipsychotics only to kids with serious psychotic disorders.

Fifty years from now, I sincerely hope that the abnormal psych textbooks treat our society's widespread drugging of children with as much contempt as we regard the forced sterilization of Carrie Buck.

Is ADHD overdiagnosed?

New York Times

[R]ecent data from the Centers for Disease Control and Prevention show that the diagnosis had been made in 15 percent of high school-age children, and that the number of children on medication for the disorder had soared to 3.5 million from 600,000 in 1990. He questioned the rising rates of diagnosis and called them “a national disaster of dangerous proportions.”

“The numbers make it look like an epidemic. Well, it’s not. It’s preposterous,” Dr. Conners, a psychologist and professor emeritus at Duke University, said in a subsequent interview. “This is a concoction to justify the giving out of medication at unprecedented and unjustifiable levels.”       

The rise of A.D.H.D. diagnoses and prescriptions for stimulants over the years coincided with a remarkably successful two-decade campaign by pharmaceutical companies to publicize the syndrome and promote the pills to doctors, educators and parents. With the children’s market booming, the industry is now employing similar marketing techniques as it focuses on adult A.D.H.D., which could become even more profitable.

Few dispute that classic A.D.H.D., historically estimated to affect 5 percent of children, is a legitimate disability that impedes success at school, work and personal life. Medication often assuages the severe impulsiveness and inability to concentrate, allowing a person’s underlying drive and intelligence to emerge.

But even some of the field’s longtime advocates say the zeal to find and treat every A.D.H.D. child has led to too many people with scant symptoms receiving the diagnosis and medication.

Antipsychotic medications used to control behavior in poor children?

 Consumer Reports

The number of children taking powerful antipsychotic drugs has nearly tripled over the last 10 to 15 years, according to recent research. The increase comes not because of an epidemic of schizophrenia or other forms of serious mental illness in children, but because doctors are increasingly prescribing the drugs to treat behavior problems, a use not approved by the Food and Drug Administration (FDA). And a disproportionate number of those prescriptions are written for poor and minority children, some as young as age 2.

Doctors are prescribing antipsychotics even though there’s minimal evidence that the drugs help kids for approved uses, much less the unapproved ones, such as behavioral problems. And to make matters worse, the little research there is suggests the drugs can cause troubling side effects, including weight gain, high cholesterol, and an increased risk of type-2 diabetes.

Doctors can legally—and commonly do—write prescriptions for any medication they see fit to treat a condition. (See here for more details on off-label prescribing)

But overuse of antipsychotic drugs has become worrisome enough that the American Psychiatric Association recently announced that doctors should not routinely prescribe the drugs as first-line treatment to children and adolescents for any reason other than psychotic disorders such as schizophrenia or severe tic disorders. The association is so concerned that it chose to include this issue as part of Choosing Wisely, an initiative in which Consumer Reports has jointed the ABIM Foundation and national medical societies to identify tests and treatments to question.

Antipsychotic drugs do have a place in psychiatric treatment, even in children and teens. They can help manage disabling symptoms caused by severe mental illness or developmental disorders. But for many kids taking the drugs, the benefits probably don’t outweigh the risks.

“What’s not known about the long-term effects is very troubling,” Christopher Bellonci, M.D., assistant professor at Tufts University School of Medicine in Boston, said. “The younger you go, the more you can affect the developing brain.”

So, what’s behind the antipsychotic boom? Our investigation, based on an analysis by the American Society of Health-System Pharmacists, uncovered several factors, including overly aggressive drug marketing and a lack of access to quality mental health care. Caught in the middle are families who often have insufficient resources to deal with complex emotional, psychological, and behavioral problems.

“There’s a societal trend to look for the quick fix, the magic bullet that will correct disruptive behaviors,” David Rubin, M.D., associate professor of pediatrics at the Perelman School of Medicine at the University of Pennsylvania in Philadelphia, said. “But for those looking for a quick solution to escalating behaviors at home, the hard truth is there is unlikely to be a quick fix.”

The rise of antipsychotic drug use

 

Certain antipsychotic drugs have been approved by the FDA to treat schizophrenia and bipolar disorder in adolescents and teens, as well as extreme irritability in children 5 and older with autism who could be a danger to themselves and others. (See the table below for a summary).

But the majority of kids prescribed antipsychotic drugs don’t take them for one of those reasons. Schizophrenia is rarely diagnosed until adulthood, for example. Bipolar disorder is estimated to affect less than 3 percent of teens, according to the National Institute of Mental Health, but the exact prevalence is unknown because of its difficulty to diagnose in children. That’s partly because the symptoms are less clear and may overlap with other conditions such as ADHD. And while about one in 110 children have some form of autistic disorder, only about 30 percent are affected by the aggressive impulse behavior antipsychotic drugs have been approved to treat.

Table 1. Antipsychotic Medications and Their Approved Uses

Brand Name (generic name)	FDA-approved uses for children
Abilify (aripiprazole)	Approved for use by adolescents with schizophrenia, adolescents with bipolar disorder mixed or manic episodes, and irritability associated with autism.
Clozaril, Fazaclo (clozapine)	None
Saphris (asenapine)	None
Fanapt (iloperidone)	None
Zyprexa, Zyprexa Zydis (olanzapine)	Approved for use by adolescents with schizophrenia, and adolescents with bipolar disorder mixed or manic episodes.
Invega (paliperidone)	None
Seroquel, Seroquel XR (quetiapine)	Approved for use in treatment of children with manic episodes in bipolar disorder, and adolescents with schizophrenia.
Risperdal (risperidone)	Approved for use by adolescents with schizophrenia, adolescents with bipolar disorder mixed or manic episodes, and for irritability associated with autism.
Geodon (ziprasidone)	None

Over the last decade or so, doctors have increasingly prescribed the drugs for “off-label” uses, particularly in ADHD and disruptive behavior disorder, a broad diagnosis that encompasses a range of behaviors from attacking other children to temper tantrums and defying authority.

Those disorders affect a much larger pool of children. About 10 percent of kids aged 3 to 17 are affected by either behavior problems or ADHD.

Increasingly, kids are prescribed antipsychotic medications at their pediatrician’s office, rather than by a psychiatrist. The number of prescriptions for the drugs written by pediatricians has increased steadily over the last several years and is up nearly 25 percent since 2006.

“What started out as a treatment with some level of evidence for a small sub-group of youth with significant development disabilities, for example, has been extended to cognitively normal kids without any strong evidence,” Rubin said.
 

 

Two studies provide a window on just how much things have changed. In the first, researchers looked at prescribing practices from 2005 to 2009 and those of a decade earlier. Results, published online Aug. 6, 2012, by the Archives of General Psychiatry showed that antipsychotic use increased about 85 percent in children and adolescents—at a much higher rate than in adults—and that the drugs are now used very differently in younger patients. For example, in adults, doctors prescribe antipsychotic drugs mostly for bipolar disorder, depression, or schizophrenia and more often to women; in children and adolescents, the drugs are most commonly prescribed to treat disruptive behavior disorder in boys.

Another analysis found that antipsychotic prescriptions for children age 2 to 5 doubled between 2001 and 2007. Most of the children were 4- and 5-year-old boys, with ADHD and disruptive behavior disorder among the most frequent diagnoses.

Behind the trend

 

Use of all psychiatric drugs has increased in children, not just antipsychotic drugs. One reason is a growing awareness of mental health problems in kids and an honest desire to treat them. But the system is not always set up to provide the best care.

For one thing, an approach that combines nondrug measures such as parent training and cognitive behavior therapy with medication if necessary may work best. But many kids taking antipsychotic drugs have never seen a mental health professional. “Use is really high among kids in the Medicaid system where decent non-drug services may be difficult to find,” says Rubin, who also points out that even kids with private insurance often don’t have coverage for psychiatric care or counseling.
And it doesn’t help that drug companies might overhype the benefits of the drugs while playing down the risks.

Antipsychotics have become huge moneymakers for the drug industry. In 2003, annual U.S. sales of the drugs were estimated at $2.8 billion; by 2011, that number had risen to $18.2 billion. That huge growth was driven in part by one company—Janssen Pharmaceuticals— and its aggressive promotion of off-label uses in children and elderly patients, relying on marketing tactics that according to the federal government, crossed legal and ethical lines.

In November, Janssen Pharmaceuticals and two other subsidiaries of the behemoth drug manufacturer Johnson & Johnson agreed to pay more than $2.2 billion to settle criminal and civil claims stemming from deceptive marketing of the antipsychotics risperidone (Risperdal) and other products. According to claims made by the U.S. Department of Justice, the companies marketed two antipsychotics for uses that were never proved safe and effective using tactics that allegedly included downplaying serious risks and paying kickbacks to physicians and pharmacies for prescribing and promoting the drugs.

Important questions

 

There’s been little official research into the use of antipsychotic drugs in kids, particularly off-label uses of the drugs. But, in effect, widespread off-label use of the drugs means that many kids are involved in a sort of large, poorly controlled experiment. That has left a lot of questions, even some basic ones, unanswered:
 

Do they help? Even for approved uses, the evidence is limited to a few short-term studies; it’s still unclear how well the drugs work and whether they remain effective over the long-term. All total, studies of the drugs have involved fewer than 3,000 children, most followed for eight weeks or less.
 

Are they safe? Newer antipsychotic drugs are turning out to carry more risk than initially thought. “The atypical versions were thought to be safer (than older antipsychotic drugs), but we are seeing a different set of side effects,” Bellonci said.

One of the most common side effects is weight gain. Studies lasting six to eight weeks show that children and teens can gain an average of 2 to 9 pounds, depending on the drug, and current research suggests that weight gain may continue as long as children take the drugs. In addition, some antipsychotic drugs can adversely affect cholesterol and increase blood sugar levels and their risk of type-2 diabetes.

Although the newer antipsychotic medications used commonly today are less likely to cause movement disorders than older versions of the drugs, some studies have found that kids taking certain drugs are still at slightly higher risk of abnormal body movements, including muscle twitches, tremors, and spasms than those receiving a placebo.
 

What happens when drugs are combined? Even less is known about what happens when kids take two or more of the drugs at the same time, something that doctors often prescribe. For example, in one study of a large Medicaid program, 7 percent to 8 percent of children and adolescents treated with antipsychotic drugs received two or more of the drugs for an average of about six months. And in the preschool study cited earlier, nearly 80 percent of children prescribed antipsychotic drugs were taking one or more additional psychiatric drugs.
 

How do they work? The exact mechanism is not well understood. Scientists know that antipsychotic drugs affect neurotransmitters, brain chemicals that play important roles in behavior and cognition, as well as sleep, mood, attention, memory and learning. This might be how the drugs reduce psychotic symptoms, such as hallucinations, delusions, disorganized thinking, and agitation as well as the tendency to hurt oneself or others.

A cautious approach

 

Although there may be a place for limited off-label use of antipsychotic drugs in children, the group of kids who could benefit needs to be better defined and the drugs should be more carefully managed than they often are today.

“In the end, what I’m bothered most by is those who would say we have to do it this way because we don’t have enough mental-health resources," said Helen Egger, M.D., Chief of Child and Family Mental Health and Developmental Neuroscience in the Department of Psychiatry and Behavioral Sciences at Duke University Medical Center in Durham, North Carolina. "That’s not good enough. The answers on how best to use these drugs will come from instituting evidence-based standards of care.”

Eggers and others advocate for a multifaceted approach to behavioral, emotional, and developmental issues, in which medications, if used at all, would comprise only one part of treatment. While there is no cookie-cutter formula for families dealing with complex and often very difficult issues, following steps outlined below can help people navigate the health care system and get the best possible care for their child.



 

The "devastatingly effective myth" of psychopharmacology

The New Yorker

[P]sychopharmacology...is...deeply indebted to...a remarkable series of accidental discoveries made in the fifteen or so years following the end of the Second World War.

In 1949, John Cade published an article in the Medical Journal of Australia describing his discovery that lithium sedated people who experienced mania. Cade had been testing his theory that manic people were suffering from an excess of uric acid by injecting patients’ urine into guinea pigs, who subsequently died. When Cade diluted the uric acid by adding lithium, the guinea pigs fared better; when he injected them with lithium alone, they became sedated. He noticed the same effect when he tested lithium on himself, and then on his patients. Nearly twenty years after he first recommended lithium to treat manic depression, it became the standard treatment for the disorder.

In the nineteen-forties and fifties, schizophrenic patients in some asylums were treated with cold-induced “hibernation”—a state from which they often emerged lucid and calm. In one French hospital, the protocol also called for chlorpromazine, a new drug thought to increase the hibernation effect. One day, some nurses ran out of ice and administered the drug on its own. When it calmed the patients, chlorpromazine, later named Thorazine, was recognized in 1952 as the first drug treatment for schizophrenia—a development that encouraged doctors to believe that they could use drugs to manage patients outside the asylum, and thus shutter their institutions.

 

In 1956, the Swiss firm Geigy wanted in on the antipsychotics market, and it asked a researcher and asylum doctor, Roland Kuhn, to test out a drug that, like Thorazine, was an antihistamine—and thus was expected to have a sedating effect. The results were not what Kuhn desired: when the schizophrenic patients took the drug, imipramine, they became more agitated, and one of them, according to a member of the research team, “rode, in his nightshirt, to a nearby village, singing lustily.” He added, “This was not really a very good PR exercise for the hospital.” But it was the inspiration for Kuhn and his team to reason that “if the flat mood of schizophrenia could be lifted by the drug, then could not a depressed mood be elevated also?” Under the brand name Tofranil, imipramine went on to become the first antidepressant—and one of the first blockbuster psychiatric drugs.

American researchers were also interested in antihistamines. In 1957, Leo Sternbach, a chemist for Hoffmann-La Roche who had spent his career researching them, was about to throw away the last of a series of compounds he had been testing that had proven to be pharmacologically inert. But in the interest of completeness, he was convinced to test the last sample. “We thought the expected negative pharmacological results would cap our work on this series of compounds,” one of his colleagues later recounted. But the drug turned out to have muscle-relaxing and sedative properties. Instead of becoming the last in a list of failures, it became the first in a series of spectacular successes—the benzodiazepenes, of which Sternbach’s Librium and Valium were the flagships.

By 1960, the major classes of psychiatric drugs—among them, mood stabilizers, antipsychotics, antidepressants, and anti-anxiety drugs, known as anxiolytics—had been discovered and were on their way to becoming a seventy-billion-dollar market. Having been discovered by accident, however, they lacked one important element: a theory that accounted for why they worked (or, in many cases, did not).

...

Despite their continued failure to understand how psychiatric drugs work, doctors continue to tell patients that their troubles are the result of chemical imbalances in their brains. As Frank Ayd pointed out, this explanation helps reassure patients even as it encourages them to take their medicine, and it fits in perfectly with our expectation that doctors will seek out and destroy the chemical villains responsible for all of our suffering, both physical and mental. The theory may not work as science, but it is a devastatingly effective myth.

Whether or not truthiness, as one might call it, is good medicine remains to be seen. No one knows how important placebo effects are to successful treatment, or how exactly to implement them, a topic Michael Specter wrote about in the magazine in 2011. But the dry pipeline of new drugs bemoaned by Friedman is an indication that the drug industry has begun to lose faith in the myth it did so much to create. As Steven Hyman, the former head of the National Institute of Mental Health, wrote last year, the notion that “disease mechanisms could … be inferred from drug action” has succeeded mostly in “capturing the imagination of researchers” and has become “something of a scientific curse.” Bedazzled by the prospect of unraveling the mysteries of psychic suffering, researchers have spent recent decades on a fool’s errand—chasing down chemical imbalances that don’t exist. And the result, as Friedman put it, is that “it is hard to think of a single truly novel psychotropic drug that has emerged in the last thirty years.”

Despite the BRAIN initiative recently announced by the Obama Administration, and the N.I.M.H.’s renewed efforts to stimulate research on the neurocircuitry of mental disorder, there is nothing on the horizon with which to replace the old story. Without a new explanatory framework, drug-company scientists don’t even know where to begin, so it makes no sense for the industry to stay in the psychiatric-drug business. And if loyalists like Hyman and Friedman continue to say out loud what they have been saying to each other for many years—that, as Friedman told Times readers, “just because an S.S.R.I. antidepressant increases serotonin in the brain and improves mood, that does not mean that serotonin deficiency is the cause of the disease”—then consumers might also lose faith in the myth of the chemical imbalance.