The New Antidepressant Warnings: Not Enough to Prevent Further Harm.

After Finally Issuing Warnings 16 Years Late, British and U.S. Authorities Fail to Tell Doctors and Patients How to Actually Prevent Serious Side Effects, Leaving Millions at Further Risk. What Should Be Done?

On March 22, 2004, the U.S. Food and Drug Administration issued an advisory for the use of antidepressants in children and adults.1 This advisory, which followed a U.K. advisory, was long overdue. Sixteen years overdue: Prozac was marketed and immediately revealed problems in 1988. The new warnings covered 10 top-selling antidepressant drugs: Celexa (citalopram), Effexor (venlafaxine), Lexapro (escitalopram), Luvox (fluvoxamine), Remeron (mirtazapine), (Paxil (paroxetine), Prozac (fluoxetine), Serzone (nefazodone), Wellbutrin (buproprion), and Zoloft (sertraline). The advisories finally warned doctors that these drugs are clearly linked to severe side effects, but they failed to provide vital information about how doctors can prevent severe reactions from occurring.

1. Key Information Omitted
First, isn’t it amazing that the FDA had to caution “physicians, their patients, and families and caregivers of patients about the need to closely monitor both adults and children with depression.” Aren’t doctors supposed to pay close attention to their patients, especially when starting new medications? Aren’t they supposed to follow-up in a timely fashion? The FDA was right to advise this, but the fact it was necessary is a stinging critique of today’s healthcare system.
In fact, aren’t doctors supposed to warn patients and children’s parents about possible side effects and what to do if they occur? It’s called informed consent, a basic right of every patient. Yet very few medication patients receive informed consent these days, which is a big part of the antidepressant problem.
Why is close scrutiny necessary? Because, as the FDA states, these antidepressants can provoke “anxiety, agitation, panic attacks, insomnia, irritability, hostility, impulsivity, akathisia (severe restlessness), hypomania, and mania.” It is difficult to believe that 16 years after Prozac’s entry, many doctors still don’t know this. So when these reactions occur, rather than reducing the dosage or stopping the drug, some doctors actually increase the dose, worsening the reactions and sometimes triggering destructive behavior.
The British advisory in early March addressed this important point: “There is evidence that increasing the dose in this situation may be detrimental.” Yet the FDA omitted this important warning, which is a huge oversight because doctors will continue to make the same mistake. The fact is, many doctors don’t know how to prescribe antidepressants properly. One reason is that the drug industry, with its saturation advertising and 90,000 sales reps, has vigorously pushed antidepressants at family practitioners, pediatricians, gynecologists, and anyone else who can pen a prescription. Many of these doctors are inadequately trained to handle antidepressants, which are tricky drugs because patients respond so differently to them. This is why the lead author of a new study challenging the effectiveness and safety of these antidepressants in children2A told the New York Times, “We strongly want to say that non-child psychiatrists should not be initiating the prescribing” of SSRI antidepressants for children or adolescents.

2. Failure to Define the Role of Antidepressants in Anxiety Disorders
The drug industry’s aggressive marketing methods are no different than other industries pushing their products. The more, the better. To accomplish this, the drug companies have convinced doctors that these drugs are not only useful for depression, but that some antidepressants are also useful for anxiety symptoms. Yet, these drugs are nothing like Valium or Xanax. Antidepressants have no immediate anxiety-reducing effects. To the contrary, they can actually cause severe anxiety, agitation, insomnia, mania, and the other reactions the FDA listed. Some antidepressants do have a longer-term role in treating anxiety disorders such as panic or obsessive-compulsive disorders, but their effects take weeks to work. And some patients, especially panic sufferers, are extremely sensitive to these drugs and must be started with very low doses. The U.S. and U.K. advisories say nothing about this.

3. Failure to Inform Doctors and Patients about Lower, Safer, Effective Antidepressant Doses
This is the most egregious omission of the U.S. and U.K. advisories. These agencies know that antidepressant doses one-half and one-quarter the standard starting amounts work.3-5 Dr. Robert Temple, the FDA’s top drug expert, acknowledged this about Prozac in his debate with me on March 26, 2004, in front of 400 pharmacologists at the meeting of the American Society for Clinical Pharmacology and Therapeutics. Lower doses of Zoloft, Paxil, Effexor, Wellbutrin, and the others also work for millions of people.
There’s a reason that serious reactions, as the U.K. advisory acknowledged, occur when patients are first prescribed these drugs. The reason is that the standard, one-size-fits-all starting doses are too strong for millions of people. These doses are derived from averaged results from studies, which may be meaningful statistically, but are misleading when treating individual patients. Giving all patients the same standard starting doses of antidepressants is like giving all shoe purchasers a size 10 and then telling them to come back in a month if the fit isn’t right. Such methods ignore the obvious broad variation among us and are guaranteed to provoke problems.
As every medical textbook states, variation in medication response isn’t the exception, but the rule. Yet the drug companies — and regulatory agencies — ignore this basic medical principle because they are more interested in pushing new drugs to the widest populations possible. The result: high sales — and high side-effect statistics. Medication side effects cause more than 106,000 deaths and 1 million hospitalizations annually, and are the fourth leading cause of death in America. More than 75% of these adverse effects are dose-related:6 the problem isn’t the drugs themselves, but excessively strong doses. Consider what Dr. Carl Peck, a former director of the FDA’s drug division, said recently:

“It’s long been known that for individual subjects the dosage listed on a drug label is not necessarily the right one.7”

And what my friend and counterpart, Dr. Alexander Herxheimer of the U.K., wrote:

“Drugs are often introduced at a dose that will be effective in around 90% of the target population, because this helps market penetration. The 25% of patients who are most sensitive to the drug get much more than they need.8”

This is why so many people react so severely to the initial doses of antidepressants: the drug-company recommended, FDA-approved initial doses are too strong for millions of people.

There are studies proving that much lower doses work, some conducted by drug companies. When one of my patients got psychotic in 1988 after just three doses of Prozac, I searched the medical literature. I’d prescribed her the standard 20-mg dose that the drug rep assured me was the lowest, safest dose. Yet I found a large study, conducted by Prozac’s manufacturer, showing that just 5 mg — 75% less medication — helped 54% of patients.9 But this information was omitted from the package insert, PDR, advertising, or rep’s info. Despite many subsequent articles on the effectiveness of low-dose Prozac,10-14 today most patients are still started at the 20-mg dose of Prozac and similarly strong doses of other antidepressants — and many people react like my patient.
FDA: A Reactive Model Instead of a Preventive Model
Some people do require strong doses of these drugs. But others don’t and get severe reactions when treated in this one-size-fits-all way. The FDA and British agencies know this. Why didn’t they advise us? Or would they look bad by finally admitting that the doses they originally approved were wrong?
Some FDA officers already acknowledge the problem. FDA Officer James Cross stated in 2002: “We’ve seen a lot of situations where drugs are approved by the F.D.A. and subsequent important information about their optimal dose is not determined until afterward.7” Antidepressants are a perfect example. Yet the FDA still won’t admit this publicly and has again failed to offer a proactive, preventive approach for patients and doctors. Instead, we are left with the same reactive model that allows patients to get serious side effects. And some doctors will still misdiagnose the reactions, some will increase drug doses, and other doctors, not knowing what to do, will switch patients from one strong antidepressant to another and another with the same negative results. This is a wasteful, outdated method that does not put patients’ safety first.
Solutions
What must be done? The 16-year controversy about antidepressant medications was entirely avoidable. The problem isn’t the drugs, but a system that perpetuates a methodology guaranteed to cause unnecessary harm. Even with the new warnings, problems are going to continue and patients will become ever more fearful of using these drugs even when they are indicated. I agree with Dr. Laurence Greenhill, a professor of clinical psychiatry at Columbia University, who told the New York Times that neither side of this intense debate had a monopoly on the truth: “I think that these medications are neither as much of a silver bullet as the advocates would have it nor as terrible as the critics would say.2B” So how do we use these drugs appropriately and safely?
In earlier newsletters, I outlined a 6-point plan for allowing people to get antidepressant therapy with minimum risk. Here’s an abbreviated version:

1. For serious depressions, standard antidepressant doses should be used with close monitoring.

2. Most depressive disorders are not acute, so patients must be given the option of starting with lower, safer, effective doses. The failure of the drug industry and regulatory agencies to provide this information constitutes a failure of informed consent. Patients and their doctors deserve the opportunity to discuss different doses and treatment options.

3. Doctors must become more knowledgeable about how to prescribe antidepressants, follow patients, and recognize and handle side effects. Doctors who prescribe antidepressants should be required to take a brief course or prove competence in using these drugs effectively and safely and in informing patients about potential risks.

4. Drug companies must define the lowest effective doses of antidepressants and must make this information readily available to patients and doctors.

5. The FDA must initiate policies requiring drug companies to develop the lowest, safest doses of not only antidepressants, but of all drugs.

6. The FDA must require doctors to report all serious antidepressant reactions. This is the only way we will learn the full scope of the problem.

Maybe all of these steps aren’t practical today, but in a healthy healthcare system they would be automatic. Lower, safer doses would be encouraged. Doctors would follow patients closely and would handle side effects effectively. It’s not asking a lot.
The Dose Makes the Difference
Paracelsus said it six centuries ago: “The right dose differentiates a poison and a remedy.” A standard medical school textbook, Goth’s Medical Pharmacology, says the same thing: “Many adverse reactions probably arise from the failure to tailor the dosage of drugs to widely different individual needs.15” Ultimately, it doesn’t matter whether you need a low dose or high dose — what matters is that you get the right dose for you. Except in emergencies or other acute situations, there usually is no reason to start with the strong, standard, drug-company recommended doses of antidepressant drugs.
That’s why I’ve long advocated a start-low go-slow approach for most patients. Even if you ultimately need a higher antidepressant dosage, starting low and increasing gradually is a good strategy because it triggers fewer side effects than starting immediately with a high dose.
The issue here is about informed consent. It is about the failure of the drug industry to provide drugs to be used flexibly according to each patient’s needs and tolerances. It is about allowing marketing strategies for maximizing sales to override medical science that maximizes safety. The FDA and U.K. advisories are welcome steps forward, although long overdue and incomplete. New advisories should be issued that explain why so many serious reactions occur at the beginning of treatment and should inform patients and healthcare providers about low-dose options that can actually prevent these reactions.
Other Recent Articles on Antidepressants Reactions
In the Apr.-June 2004 E-Newsletter
The Underlying Cause of Suicides and Homicides with SSRI Antidepressants: Is It the Drugs, the Doctors, or the Drug Companies? How a dysfunctional medical-pharmaceutical complex causes and perpetuates unnecessary harm.

In the Jan.-Mar. 2004 E-Newsletter
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.

Antidepressant Side Effects: In A New York Times Exposé, A Doctor Describes Her Own Reaction To An Antidepressant Drug. But She Doesn’t Explain Why Antidepressant Side Effects Occur and How to Prevent Them. This Article Does.

In the Oct.-Dec. 2003 E-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.

And in:
Cohen, JS. Over Dose: The Case Against The Drug Companies. Prescription Drugs, Side Effects, and Your Health. Tarcher/Putnam, New York: October 2001. (Highly recommended by all major reviewers including the Journal of the American Medical Association.)
References
1. FDA Talk Paper. FDA Issues Public Health Advisory on Cautions for Use of Antidepressants in Adults and Children. U.S. Food and Drug Administration, March 22, 2004:www.fda.gov\.
2. Braddock, CH, Edwards, KA, Hasenberg, NM, Laidley, TL, Levinson, W. Informed Decision Making in Outpatient Practice: Time to Get Back to Basics. JAMA 1999;282:2313-20.
2A. Jureidini, JN, Doecke, CJ, Mansfield, PR, et al. Efficacy and safety of antidepressants for children and adolescents. BMJ 2004;328: 879-883.
2B. Harris, G. Study advises against drugs for children in depression. New York Times, Apr. 9, 2004:nytimes.com.
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, 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 2001;161:880-85.
5. Cohen, JS. Do Standard Doses of Frequently Prescribed Drugs Cause Preventable Adverse Effects in Women? JAMWA 2002;57:105-110.
6. Lazarou, J, Pomeranz, BH, Corey, PN. Incidence of adverse drug reactions in hospitalized patients: a meta-analysis of prospective studies. JAMA 1998;279(15):1200-5.
7. Zuger, A. Caution: That dose may be too high. New York Times, September 17, 2002:nytimes.com.
8. Herxheimer A. How much drug in the tablet? Lancet 1991;337:346-8.
9. Wernicke, JF, Dunlop, SR, Dornseif, BE, et al. Low-dose fluoxetine therapy for depression. Psychopharmacology Bulletin 1988;24(1):183-188.
10. Schatzberg AF, Dessain E, O’Neil P, Katz DL, Cole JO. Recent studies on selective serotonergic antidepressants: trazodone, fluoxetine, and fluvoxamine. Journal of Clinical Psychopharmacology 1987;7(6):44S-49S.
11. Salzman C. Practical considerations in the pharmacologic treatment of depression in the elderly. Journal of Clinical Psychiatry 1990;59(1 Suppl):40-43.
12. Schatzberg AF. Dosing strategies for antidepressant agents. Journal of Clinical Psychiatry 1991:52(5suppl):14-20.
13. Cain, JW. Poor response to fluoxetine: underlying depression, serotonergic overstimulation, or a “therapeutic window”? Journal of Clinical Psychiatry 1992;53(8):272-277.
14. Louie, AK, Lewis, TB, Lannon, MD. Use of low-dose fluoxetine in major depression and panic disorder. Journal of Clinical Psychiatry 1993;54(1):435-438.
15. Clark, WG, Brater, DC, Johnson, AR. Goth’s Medical Pharmacology. 13th Edition. St. Louis: The C.V. Mosby Company, 1992.

NOTE TO READERS: The purpose of this E-Letter is solely informational and educational. Theinformation herein should not be considered to be a substitute forthe direct medical advice of your doctor, nor is it meant to encourage the diagnosis or treatment of any illness, disease, or other medical problem by laypersons. If you are under a physician’s care for any condition, he or she can advise you whether the information in this E-Letter is suitable for you. Readers should not make any changes in drugs, doses, or any other aspects of their medical treatment unless specifically directed to do so by their own doctors.

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