Open Letter to the U.S. FDA on Serotonin-Enhancing Antidepressants in Youngsters:
A 6-Point Solution That Makes Sense Scientifically
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.
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
Do Serotonin-Enhancing Antidepressants
Cause Suicidal and Homicidal Behavior?
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.
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.
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.
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.
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.
reports are enough to ban a drug. The FDA has acted solely on reports many times
Antidepressants Be Banned in Children and Adolescents?
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.
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.
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.
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.
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.
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
best dose of any drug is the least amount that works. Excessive dosing only increases
the risk and severity of side effects.
and SSRI Antidepressants
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”
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.
it right isn't difficult. Here's the method of Dr. Anthony J. Weisenberger, an
excellent psychopharmacologist in Asheville, North Carolina:
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."
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
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
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.
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.
more on this topic, see my article in the Oct.-Dec. MedicationSense Newsletter:
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.
1. Cohen, JS. Over Dose: The Case Against The Drug Companies. Prescription Drugs,
Side Effects, and Your Health. Tarcher/Putnam, New York: October 2001.
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
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)
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
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,
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:
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
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, last checked 4/9/02.
18. Critser, G. Truth:
a Bitter Pill for Drug Makers. Los Angeles Times, Jan. 25 2004: www.latimes.com.
2004, Jay S. Cohen, M.D. All rights reserved. Readers have permission to copy
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