October 26

Next Phase in Psychiatry? Or, NIMH Effort to Rescue Bad Drugs – WSJ

Next Phase in Psychiatry? Or, NIMH Effort to Rescue Bad Drugs – WSJ

Fri, 29 Jul 2005

The Wall Street Journal uncritically reported: “The results of the largest studies ever conducted of depression and schizophrenia will be released in coming months, potentially transforming the way patients are treated and shaking up some of the drug industry’s most lucrative markets.”

These studies were sponsored by the National Institute of Mental Health, presumably to test the efficacy of various psychotropic drug combinations for the treatment of depression, bi-polar disorder (a.k.a. manic-depression), schizophrenia, and depression in adolescents.

It is significant that when the data from company-controlled clinical trials was analyzed independently, the drugs failed to demonstrate clinically significant benefits–such in any way improving the lives or recovery of patients–to justify either the risks associated with these drugs, or the cost. 

But thanks to advertising hype and the concealment of the most severe risks–such as an increased suicide risk–antidepressants and antipsychotics became blockbuster profit makers: ranking third and fourth among drug classes in the US (after cholesterol and heartburn medicines). US sales last year reached $20.7 billion–mostly paid by US taxpayers.

Facts not addressed by the WS Journal – which should have been a component of any evaluation of the efficacy of psychotropic drugs:

Second generation antidepressants (the SSRIs) and the so-called atypical antipsychotics now carry Black Box warnings reserved for the drugs carrying the most severe, life-threatening risks of harm:

SSRI labels carry black box warnings (since October 2004) about the increased risk of drug-related suicidal behavior in adolescents.

Antipsychotic drug labels carry black box warnings (since 2003) about the potential increased risk of cerebrovascular events, including stroke and an increased risk of death from stroke, and the risk of drug-induced, potentially fatal diabetes mellitus. See: www.fda.gov/cder/drug/advisory/antipsychotics.htm.

The ineffectiveness of antidepressants and antipsychotics is demonstrated by the fact that psychiatrists have to resort to polypharmacology–that is, they prescribe “drug cocktails” in the hope that one drug will mask the adverse effects of the other, and that together the drugs might produce a beneficial effect that none have produced singly.

But polypharmacology is an experimental unproven treatment approach that physicians are generally wary about because this approach increases risks for patients. Polypharmacology adds confusion to the equation, making it that much more difficult to detect and isolate the source of life-threatening adverse effects. There is no scientific legitimacy for prescribing multiple psychotropic drugs of the same class plus drugs of related classes. Such prescribing is an effort to overcome the lack of effectiveness of these much advertised drugs.

Patients who are prescribed multiple psychotropic are unwitting subjects of an uncontrolled experiment.

Dr. Jeffrey Lieberman, the principal investigator of the NIMH schizophrenia study (known as CATIE), is quoted in the WS Journal stating: “Clinicians are just basically practicing seat-of-their-pants pharmacology based on their experience with patients.”

Clinicians are indeed skating on thin ice by prescribing drugs whose ill effects outweigh any perceived benefit–mostly attributable to the placebo effect. The prescribing of these drugs widely and in multiples–all at public expense–lacks clinical justification.  

According to the Wall Street Journal, even before the schizophrenia trial results have been fully analyzed for publication, “one striking fact has already emerged: nearly 70% of patients in the study didn’t do well on their first drug, and switched to another.”

Thus, the NIMH appears to have undertaken the task of salvaging psychiatry¹s failed drugs whose severe adverse effects should have precluded their wide use, inasmuch as they may trigger severe irreversible illness. These NIMH trials appear to be a last ditch effort to salvage the drugs by lending legitimacy to polypharmacy – an expensive and risky practice.

An investigation by the Office of the Inspector General is in order to stop the waste in public financing for failed dangerous treatments.

See two most recent critiques: Joanna Moncrieff, MD and Irving Kirsch, PhD analyze published reports of SSRI efficacy in the July 2005 BMJ.

Efficacy of antidepressants in adults by Moncrieff and Kirsch BMJ. July 2005; 331: 155-157.

 “The continuing concern that selective serotonin reuptake inhibitors may increase the risk of suicidal behaviour1, 2 means there needs to be further consideration of evidence for the efficacy of antidepressants in adults as there has been in childrenŠ.Current approaches to depression should be re-evaluated and alternatives to drug treatment should be developed further.”

In an interview with Reuters Health, Dr. Moncrieff said: “I do not think there is such a thing as a drug that will specifically relieve depression. I think so-called antidepressants are just drugs that do other things, such as sedating or stimulating people.” In fact, she continued, “I am skeptical as to whether there is a biochemical syndrome of depression despite the portrayal by the drug companies and some psychiatric literature.”

See also, “Rethinking Psychiatric Drugs : A Guide for Informed Consent,” by Grace Jackson, MD, (soon to be released book ) that promises to provide a critical appraisal of the three classes of medications – antidepressants, antipsychotics and psychostimulants – which an estimated 20% of Americans consume on a regular (and sometimes involuntary) basis. 

Grace Jackosn, MD, a board certified psychiatrist who graduated summa cum laude from California Lutheran University with a Bachelor of Arts in Political Science and a Bachelor of Science in Biology, as well as a Masters Degree in Public Administration.  She earned her Medical Degree from the University of Colorado Health Sciences Center in 1996 and completed her internship and residency while in the U.S. Navy.  Following her service as a staff psychiatrist at Bethesda Naval Hospital, she worked in the North Carolina prison system.

Contact: Vera Hassner Sharav


Some goals of the NIH’s trials on major mental illnesses:

€Compare the safety and efficacy of different drugs and treatment regimens

€Gather long-term data about efficacy and side effects of psychiatric drugs

€Compare the cost- effectiveness of various branded and generic drugs

€Offer guidance on treatment strategies if the first drug fails

€See a list of some common treatment strategies for depression

The Next Phase in Psychiatry

Largest Ever Studies on Drugs for Depression,
Schizophrenia Could Transform Treatment
July 27, 2005; Page D1

The results of the largest studies ever conducted of depression and schizophrenia will be released in coming months, potentially transforming the way patients are treated and shaking up some of the drug industry’s most lucrative markets.

The federally funded studies are part of a six-year push by the mental-health division of the National Institutes of Health to come up with reliable scientific data on the differences between drugs and treatment strategies for the major psychiatric illnesses. The project comprises four trials, in serious depression, bipolar disorder, schizophrenia and adolescent depression.

The aim is to fill the information gap that plagues psychiatry, and hurts the quality of care given to patients. Clinical trials that companies do to get drugs approved aren’t designed to provide the answers that doctors say they really need. For one, these trials don’t compare one drug with another, because they are designed to show only whether a particular drug is effective against an illness. Thus, psychiatrists have little guidance on whether one drug works better than another or has fewer side effects than another.

Also, at eight to 12 weeks long, drug-company trials are too short to reveal how patients fare or what side effects crop up long-term. And, in order to stay focused on a drug’s efficacy on one illness, they exclude the sickest patients and people with co-existing diseases.

The paucity of quality information about drugs has been a major issue in recent years as concerns have emerged about side effects, and drug companies have been criticized for hushing up unfavorable study results.

So, the NIH-funded trials aim to compare treatments to discover both positive and negative impacts of the drugs, and to mimic the real world with all of its imperfections. All kinds of patients are included and they are followed for years. The trials — which include thousands of participants, versus the hundreds in a typical drug-company trial — are conducted all over the country and include community clinics and primary-care offices, not just academic medical centers. As part of the $140 million effort, the NIH is also collecting data on the cost effectiveness of the various treatments and pitting older drugs, which are available as cheaper generics, against newer blockbusters.

Grayson Norquist, a former NIH psychiatrist who played a big role in conceiving the trials, says they aim to answer the main question doctors face every day. “Of the several drugs I have to choose from,” says Dr. Norquist, now at the University of Mississippi Medical Center, “which one should I use for the person sitting in front of me?”

Enormous amounts of money are at stake if the trials reveal differences in the safety and efficacy of various drugs. Antidepressants and antipsychotics are the third- and fourth-biggest classes of drugs in the country after cholesterol and heartburn medicines, with U.S. sales of $20.7 billion last year. Much of that cost is borne by government health-care plans. Both health-care payers and Wall Street investors are anxiously awaiting the results of the two trials in coming months. (Results from the first arm of the project, on adolescent depression, came out in August 2004 and showed that a combination of antidepressants and therapy was the most effective treatment. The study of bipolar disorder ends in September, and results will be published after the analysis is completed.)

In addition to comparing drugs, the trials are trying to fill another gap in the scientific literature: what to do with the many patients who don’t get better on their first drug. Psychiatrists do a lot of switching patients from one antidepressant to another and tinkering with drug combinations. None of this is backed up with good evidence, and it can take months to find the right regimen. Practices and outcomes vary widely among doctors.

Steve Miller saw a dozen doctors before finding the drugs that alleviated his schizophrenia. The 45-year-old from Cedar Rapids, Iowa, first had hallucinations as a freshman in college, and took haloperidol, an older-generation antipsychotic, for years. He remained so anxious and depressed he contemplated suicide. A newer antipsychotic, Clozaril, worked better. But it was only when his doctor added Zyprexa to the mix that he finally recovered.

“Clinicians are just basically practicing seat-of-their-pants pharmacology based on their experience with patients,” said Jeffrey Lieberman, the principal investigator on the schizophrenia study, which is known as CATIE. “When they look for hard data in the scientific literature to base their decisions on, they can’t find it.”

The problem is especially acute in depression — about half of patients don’t respond to standard antidepressant therapy. The depression study, called STAR*D, tests whether the subsequent treatment strategies doctors typically use for these patients actually work. It included 3,940 patients across the country who were followed for five years.

All of the patients first take the antidepressant Celexa, from Forest Laboratories Inc., which belongs to a class of drugs known as selective serotonin reuptake inhibitors. Those who don’t get better can choose whether to try therapy or switch to other antidepressants — either Pfizer Inc.’s Zoloft, another SSRI, or GlaxoSmithKline PLC’s Wellbutrin or Wyeth’s Effexor, which work by different mechanisms in the brain. In the third and fourth stages of the study, people who don’t get better cycle through various antidepressants and combinations of drugs.

The CATIE schizophrenia study pits eight antipsychotic drugs against each other to determine their comparative effectiveness and safety. About 1,600 patients were enrolled and followed for 18 months.

In the first stage, patients are given either perphenazine (an older, generic antipsychotic medication) or one of four newer drugs: Eli Lilly & Co.’s Zyprexa, Johnson & Johnson’s Risperdal, AstraZeneca PLC’s Seroquel or Pfizer’s Geodon. If they don’t get better or encounter side effects, they are switched to other antipsychotics, including the newest, Abilify from Bristol-Myers Squibb Co.

One of the big benefits to patients of the CATIE trial will be high-quality, rigorous information about the comparative side effects of psychiatry medications. Concerns have emerged in recent years that some of the newer medicines, known as atypical antipsychotics, can cause extreme weight gain, worsen cholesterol and lead to diabetes. Although the Food and Drug Administration required that all atypical antipsychotics carry a warning about these side effects, the NIH trial might actually reveal whether certain drugs in the class are worse than others.

The CATIE investigators are now analyzing the results and preparing them for publication in September. But one striking fact has already emerged: nearly 70% of patients in the study didn’t do well on their first drug, and switched to another.

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