Jay S. Cohen M.D.       http://medicationsense.com      1337 Camino Del Mar   Suite C       Del Mar, CA 92014       Phone: 858.345.1760       Fax: 858.509.8944


An Open Letter to the U.S. Food and Drug Administration on Serotonin-Enhancing Antidepressants in Youngsters: A 6-Point Solution That Makes Sense Scientifically.



There is a reason that serotonin-enhancing antidepressants are repeatedly linked to suicides and homicides, and there is a solution to this problem. I have been saying this since 1988 and publishing about it since 1996.

I am board certified in psychiatry. I am also an expert on medication side effects with two books 1,2 and more than a dozen articles published in top medical journals (Archives of Internal Medicine, Annals of Pharmacotherapy, etc.) 3-12 on why medication reactions occur and how they can be avoided. My most recent book, Over Dose: The Case Against The Drug Companies , was highly recommended by every major reviewer as well as the Journal of the American Medical Association .13 I have spoken widely on adverse drug reactions including being the keynote speaker at the 2002 Annual Science Day at the U.S. Food and Drug Administration Clinical Pharmacology Division. Next month I will debate Dr. Robert Temple, the FDA's top drug expert, at the annual conference of the American Society for Clinical Pharmacology and Therapeutics. This is our fourth debate. My research has been featured in every major newspaper and magazine in America, and I have been on National Public Radio. Most of all, I have no ties to the drug industry and have never taken money from it.

Do Serotonin-Enhancing Antidepressants Cause Suicidal and Homicidal Behavior?
Yes. From 1988, when one of my patients became psychotic after just three days on Prozac, and with subsequent case reports and studies showing a clear link, I've never doubted that these drugs -- Prozac, Zoloft, Paxil, Effexor, Lexapro, Celexa, Luvox -- can cause such intense side effects that some patients act impulsively and violently. Almost everywhere I go, someone has a story about a wicked reaction to these drugs.

A telltale sign is that these reactions typically occur in the initial phase of treatment. Medical science has a term for this: first-dose reactions . When these reactions occur, it indicates a person who is getting much more medication than they can tolerate. This isn't surprising with SSRI antidepressants: I've long written that the standard starting doses of these drugs are much too strong for a substantial proportion of patients. That's why the side-effect rates for these drugs are so high, as high as 50% or more.

In addition, excessive doses of any antidepressant can cause mental confusion and disorganization in thinking. These side effects also occurred with older antidepressants like Elavil and Tofranil. But unlike the older drugs, SSRIs cause another adverse effect that can make mental impairments particularly dangerous. SSRIs can cause a form of severe agitation known as akathisia. People become extremely anxious, panicky, physically agitated. Some become irritable or angry, and their personalities change. The akathisia can become so unbearable that, coupled with mental disorganization or impaired judgment, people act rashly.

If this is so, then why didn't the American College of Neuropsychopharmacology, after evaluating studies of more than 2,000 youngsters, find statistically significant increases in suicidal thinking or attempts in children taking SSRIs ?14 Does this report exonerate SSRI drugs? Absolutely not.

First, six of the ten doctors involved in this report have direct ties to the pharmaceutical industry .14 But even if they maintained some objectivity, the key words in their report are "statistically significant." Infrequent side effects are often difficult to pin down statistically. SSRI-associated suicidal and homicidal acts aren't frequent, but this doesn't mean they aren't real. The cholesterol-lowering drug Baycol, the antihistamine Seldane, and the weight-loss drug Redux were all withdrawn for causing severe side effects and deaths. Yet these reactions never attained statistical significance in studies.

Compelling reports are enough to ban a drug. The FDA has acted solely on reports many times before.

Should Serotonin-Enhancing Antidepressants Be Banned in Children and Adolescents?
SSRI antidepressants help too many people including youngsters to be banned. Yet they cause too much harm to be used as indiscriminately and ignorantly as they are used now. There is a reason these reactions are occurring. This is what the FDA should be addressing.

First, these side effects are dose-related: the culprits aren't the drugs themselves, but drug company-recommended doses that are far too strong for too many people. Drug companies like to market strong doses because they can advertise that their drug helps more people than competitors' drugs. And by using a strong dose that covers the majority of patients, they can keep dosaging simple, which doctors like. This improves sales, but it reduces safety.

Safety is further eroded when drug companies omit information about the effectiveness of lower, safer doses from package inserts and the Physicians' Desk Reference (PDR) 15 Before Prozac was approved and marketed at a one-size-fits-all initial dose of 20 mg, it was proven that 5 mg -- 75% less medication! -- was effective for a majority of patients .16 Yet there wasn't a word about this in the package insert when Prozac was introduced in 1988, and the package insert still lacks adequate information today.

Similarly, many patients respond to doses that are one-half or one-quarter those recommended by the manufacturers of Zoloft, Paxil, Effexor, and others. Some people are slow metabolizers of these drugs. They lack enzymes for breaking down these drugs, so high blood levels persist. Yet, package inserts contain scant information about treating slow metabolizers safely. Other people have mild depressions that don't require the same strong doses used for major depression, but drug company guidelines usually don't make this vital differentiation, so people with mild conditions get major doses of SSRI drugs.

This problem is compounded by the fact that doctors get almost all of their information directly or indirectly from the drug industry. Patients and other consumers are also kept in the dark because most consumer drug references are based on the PDR. Without adequate information about the lowest, safest drug doses, patients are denied their right of informed consent, and doctors never think to use lower doses for people who are small, elderly, or medication-sensitive, or even for people having trouble at standard doses. These problems occur not only with antidepressants, but with statins, antihypertensive and anti-inflammatory drugs, and many others.

As I have told the drug industry directly, they must provide information on the very lowest, safest doses of their drugs. Failing to do so is negligent. And I have told the FDA directly that they must require drug companies to perform adequate dose studies, to identify the lowest effective doses, and to provide information and pills that make using these doses possible. Failing to do so is a dereliction of duty.

The best dose of any drug is the least amount that works. Excessive dosing only increases the risk and severity of side effects.

Doctors and SSRI Antidepressants
Doctors also play a role in this tragedy. There are too many doctors who prescribe these drugs without adequate information about their risks. There are too many doctors who do not advise patients about side effects or who fail to recognize and act promptly when side effects occur. In fact, doctors aren't adequately trained to identify and handle side effects. In a report titled "Very Few Students in American Medical Schools Receive Training about Adverse Drug Events," the U.S. Department of Health and Human Services stated, "Only 16 percent of internal medicine clerkship programs include formal lectures about adverse drug events .17

Moreover, the great majority of prescriptions for SSRIs are written by family physicians, pediatricians, internists, and gynecologists. According to the Los Angeles Times, SSRI manufacturers targeted these types of doctors with their advertising, promotions, and sales representatives, because these doctors far outnumber psychiatrists, and getting them to prescribe SSRIs would greatly increase sales .18 This is exactly what has occurred, yet few of these doctors are properly trained for using psychiatric drugs. And many psychiatrists mishandle SSRIs, too.

Doing it right isn't difficult. Here's the method of Dr. Anthony J. Weisenberger, an excellent psychopharmacologist in Asheville, North Carolina:


"When antidepressant treatment fails, it's usually the doctor's fault, not the patient's. I always explain that I am starting with the lowest doses in order to test their sensitivity and minimize side effects. I discuss specific doses with my patients and common side effects. Because they understand the process and are participants in the decisions, most patients are very cooperative and do well."


In fact, if you ask patients whether they prefer starting with a standard drug company dosage or with a 50%-75% lower dose that works, most patients choose the safer approach. Most people don't like taking medications, would prefer taking as little as possible, and are far more concerned about side effects than their doctors. Patients and parents of children-patients have a right of informed consent, which includes knowing all of the effective doses of drugs and having some choice in the matter. They are the ones taking the drugs, paying the costs, and running the risks.

A 6-Part Solution
The use of SSRI antidepressants in adults and especially in children should be controlled, not banned. When automobile safety became an issue in the 1960s, we didn't ban cars, but required manufacturers to make them safer with seat belts, air bags, bumpers that actually protected, frames that didn't collapse, gas tanks that didn't explode, and many other modifications. With prescription drugs, we need major improvements in research, review, and usage. Here's what must be done:


1. Except for acute situations, patients must be started at the lowest, safest, effective doses of SSRI antidepressants.

2. Drug companies must define these doses, provide information in package inserts and the PDR, and produce pills and liquids that make using low doses possible.

3. Doctors must be trained in the safe use of SSRI antidepressants. Classes and certification should be required for prescribing these drugs.

4. Doctors must follow patients carefully. New patients should be seen frequently until doses are adjusted properly and side effects, if they occur, are handled properly.

5. Patients, including parents of children-patients, must be fully informed about the potential risks of SSRIs. Patients can play a critical role in recognizing early signs of serious side effects. The failure to provide adequate information constitutes a denial of patients' rights of informed consent.

6. The FDA must initiate policies requiring drug companies to develop the lowest, safest doses of not only SSRI antidepressants, but all drugs. And drug companies must also be compelled to add warnings to their package inserts promptly about newly recognized side effects.


It is well known that different people respond to different doses of medications. This is a basic medical principle. We need drugs that can be individualized to the highly varying needs of patients. We need doctors who understand this and who are well trained about side effects and how to intervene effectively. And we need a pharmaceutical industry that recognizes that its long-term prosperity depends not only on boosting sales, but also on ensuring safety.

For more on this topic, see my article in the Oct.-Dec. MedicationSense Newsletter: Suicides and Homicides in Patients Taking Paxil, Prozac, and Zoloft: Why They Keep Happening -- And Why They Will Continue. Underlying Causes That Continue to Be Ignored by Mainstream Medicine and the Media.

References
1. Cohen, JS. Over Dose: The Case Against The Drug Companies. Prescription Drugs, Side Effects, and Your Health. Tarcher/Putnam, New York: October 2001.
2. Cohen, JS. Make Your Medicine Safe: How To Prevent Side Effects From The Drugs You Take. New York: Avon Books, 1998.
3. Cohen, JS. Dose Discrepancies between the Physicians' Desk Reference and the Medical Literature, and Their Possible Role in the High Incidence of Dose-Related Adverse Drug Events. Archives of Internal Medicine , April 9, 2001:161:957-64.
4. Cohen, J.S. Ways To Minimize Adverse Drug Reactions: Individualized Doses and Common Sense Are Key. Postgraduate Medicine 1999;106:163-72.
5. Cohen, JS. Adverse Drug Reactions: Effective Low-Dose Therapies for Older Patients. Geriatrics Feb. 2000;55(2):54-64.
6. Cohen JS, Insel PA. The Physicians' Desk Reference. Problems and possible improvements. Archives of Internal Medicine 1996;156(13):1375-80.
7. Cohen, JS. Do Standard Doses of Frequently Prescribed Drugs Cause Preventable Adverse Effects in Women? JAMWA (The Journal of the American Medical Women's Association) 2002;57:105-110.
8. Cohen, JS. Adverse drug effects, compliance, and the initial doses of antihypertensive drugs recommended by the Joint National Committee vs. the Physicians' Desk Reference. Archives of Internal Medicine , March 26, 2001;161:880-85.
9. Cohen, JS. Comparison of FDA Reports of Patient Deaths Associated with Sildenafil (Viagra) and with Injectable Alprostadil (Caverject). Annals of Pharmacotherapy , March 2001;35:285-88.
10. Cohen, JS. Is the Product Information on Sildenafil (Viagra) Adequate to Facilitate Optimal Therapeutics and to Minimize Adverse Events? Annals of Pharmacotherapy , March 2001;35:337-42.
11. Cohen, JS. Why Aren't Lower, Effective, OTC Doses Available Earlier by Prescription? Annals of Pharmacotherapy 2003;37(1):136-142.
12. Cohen, JS. Should Patients Be Given a Low Test Dose of sildenafil (Viagra) Initially? Drug Safety July 2000;23:1-10.
13. Findlay, SD. Review: Over Dose, The Case Against The Drug Companies. JAMA , Nov. 6, 2002;288(17).
14. Cato, J. Report casts doubt on drug, suicide link. The Herald Online , Jan. 23, 2004: http://www.heraldonline.com/local/story/3264586p-2918424c.html.
15. Physicians' Desk Reference , 57th Edition. Montvale, N.J.: Medical Economics Company, 2003.
16. Wernicke, JF, Dunlop, SR, Dornseif, BE, Bosomworth, JC, Humbert, M. Low-dose fluoxetine therapy for depression. Psychopharmacology Bulletin 1988;24(1):183-188.
17. Very Few Students in American Medical Schools Receive Training about Adverse Drug Events. U.S. Agency for Healthcare Research and Quality, U.S. Department of Health and Human Services, Sept. 4, 2001 :www.ahcpr.gov/news/press/pr2001/studntpr.htm, last checked 4/9/02.
18. Critser, G. Truth: a Bitter Pill for Drug Makers. Los Angeles Times, Jan. 25 2004: www.latimes.com.






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