Why Antidepressant Black-Box Warnings Aren't Enough -- What Doctors and Patients Can Do to Use Antidepressants Safely. A FDA Advisory Committee Recommendation for Stronger Warnings Is a Step Forward, but Not a Solution.  What We Must Do.

    On September 14, 2004, a closely watched FDA Advisory Committee on antidepressant medications recommended black-box warnings in package inserts and other product information about antidepressant medications.  These warnings will alert patients and doctors that these drugs can cause an increased risk of suicidal thinking and behavior.  The Advisory Committee's decision is a helpful and long overdue step, but what will the warnings include?  Will they tell doctors how to prescribe antidepressants more safely, so that these reactions do not occur in the first place?  The Advisory Committee did not address this crucial issue, so it is unlikely such information will be included in the new warnings.

Finally Addressing a Serious, Long-Obvious Problem
    Since the advent of Prozac in 1988, it was obvious that in some people, antidepressant medications could trigger extreme anxiety, physical agitation (akathisia), impaired thought and concentration, impaired judgment, reduced impulse control, and increased suicidal thinking and behavior.  Almost as soon as Prozac was introduced, reports of these problems were swift and compelling.^1-10  Although thought and memory impairment could occur with earlier antidepressants such as Elavil and Tofranil, the problems with Prozac seemed far different, far more worrisome, and more frequent.  One of my first patients became psychotic after just three doses of Prozac.  Another, a highly successful attorney, developed such severe panic attacks, she couldn't function.

    Reports from patients and letters from doctors to medical journals prompted a Congressional hearing in the early 1990s.  It accomplished nothing, and the FDA and drug companies subsequently avoided facing this issue until the British issued a strong warning in March 2004.  Then we learned that drug companies had withheld studies showing increased suicidal thinking in children and adolescents given antidepressants.  This was followed by the revelation that the FDA had suppressed an analysis by one of its own experts demonstrating the same antidepressant-suicidal thinking link.  After public outrage, the FDA finally, albeit sixteen years late, decided to take action.  But is the current action enough?

Positives of the FDA's Actions
    The new warnings will make doctors pause before prescribing antidepressants.  Actually, the effects of previous black-box warnings on other drugs has been mixed.  In many instances, black-box warnings have failed to change doctors' prescribing methods for the better.  However, with so much public attention to antidepressants, most doctors are aware of these issues.  Doctors should pause before writing antidepressant prescriptions for children and adolescents, groups in which antidepressant use has skyrocketed.  Many feel that due to extremely aggressive drug company marketing, these drugs have become the solution for any and all uncomfortable emotions and are vastly overprescribed.

    The traditional approach used to be to obtain counseling or psychotherapy first and then, if necessary, to consider medications.  With managed care, psychotherapy services have been reduced or cut.  It is much easier and cheaper to have a doctor write a prescription than to have a therapist spend a few hours finding out what is really wrong and providing guidance to a youngster and parents.  Now, with greater concern and liability for overprescribing antidepressants, will managed care organizations allow or encourage more talk therapy?  They should.

Concerns
     There is concern among healthcare providers that the new warnings will constrain doctors and scare families from using antidepressants when they are actually needed.  Dr. Albert Melaragno, a pediatrician, stated in the New York Times, "It's raised such a specter with patients that more of the teens who have the need for treatment will be frightened off of using [antidepressants] and suffer more because of that."¹¹

    This is one of the big problems with the FDA's "warnings only" approach.  Side effects with antidepressants can be prevented, but because the FDA Advisory Committee did not recommend any guidelines about how to do so, people and physicians are not reassured.  They do not feel comfortable using these medications even when patients really need them.  And when they do, the same side effects will occur again.  The problem hasn't been solved, so now the pendulum may well swing to the other extreme, with undertreatment equaling overtreatment as a major problem.

How to Prevent Antidepressant Side Effects
    Why do severe side effects occur with antidepressant drugs?  Because the standard dosages recommended by the drug companies are too strong for millions of people.  I published data on this in the Archives of Internal Medicine in 1996¹² and in many subsequent articles and two books.  Just as too much alcohol or coffee will cause predictable side effects, excessive doses of antidepressants will cause all of the side effects the FDA acknowledged in its March 2004 alert: "anxiety, agitation, panic attacks, insomnia, irritability, hostility, impulsivity, akathisia (severe restlessness), hypomania, and mania."¹³

    For example, since 1988, the standard, drug company-recommended starting dose of Prozac has been 20 mg/day.  Yet, even before the drug was introduced, evidence showed that 5 mg helped 54% of patients.¹⁴  There was no information about this effective, lower dose in the information given to doctors.  This meant that even though large numbers of patients only needed 5 mg of Prozac, they all got 20 mg -- 400% more medication -- or even more.  No wonder my patients and so many other patients got immediate, severe reactions.  No wonder this has occurred with so many other antidepressants that are recommended at doses too strong for millions of people.

    This is a problem with many medications, which explains why medication reactions are the #4 leading cause of death year after year.¹⁵  FDA Officer James Cross stated in 2002: "We've seen a lot of situations where drugs are approved by the FDA and subsequent important information about their optimal dose is not determined until afterward."¹⁶  Dr. Carl Peck, a former director of the FDA's drug division, commented: "It's long been known that for individual subjects the dosage listed on a drug label is not necessarily the right one."¹⁶  My counterpart, Dr. Alexander Herxheimer of the U.K., has written: "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."¹⁷  Yet the FDA and drug industry have done nothing.

    Here is how to use antidepressants while minimizing the risk.  Except for severe depressions, treatment should always begin with the lowest, effective doses.  This means, for example, 5 mg or 10 mg of Prozac, 12.5 mg or 25 mg of Zoloft, or equivalent lower doses of other antidepressants.  Even lower initial doses should be considered for people who are small, very young or very old, or those with other medical conditions or taking other medications.  Tiny doses should also be considered for people who are exquisitely sensitive to medications or those who have had many reactions to prescription drugs.  Patients should be followed closely and asked to report any adverse experience to the doctor or nurse.

    Some people respond to low-dose therapy.  For those who don't, the dosage should be increased gradually.  A gradual, stepwise approach frequently leads to a good response with no side effects.  If side effects occur, they are usually mild and can be handled by a slight reduction in dosage.

    Severe depressive disorders may warrant a more intensive approach.  Aggressive treatment with antidepressants should be done in a hospital setting, and hospital staff must be well trained to recognize and intervene if side effects occur.

    My experience is that patients greatly appreciate knowing about the low-dose option, and most patients opt for it.  Most people don't like having to take medications, and if they must, they prefer to use as little as possible.  So a low-dose approach appeals to them.  On the other hand, some patients know that they are not sensitive to medications and prefer to start with a standard dosage.  Either way, careful dosing and careful attention to possible side effects produce excellent results.  My feeling is that antidepressants, if used in an approach that emphasizes safely, can be very helpful.  Moreover, the fact that these decisions are made cooperatively creates a great working relationship.  When side effects occurred with my patients, they understood that I would listen and usually address the problem by adjusting dosages or turning to other, even lower-dose medications.

    My results spoke for themselves.  A much greater percentage of my patients improved with antidepressants than shown in drug company studies.  Equally important, side effects were far fewer and most patients remained in treatment.  After adopting a start-low go-slow approach, I never again saw a severe reaction to antidepressants.  My referral sources, psychologists and counselors, often said I was one of the few doctors they trusted to treat their patients.  I actually began using a start-low go-slow approach in the 1970s with the older, tricyclic antidepressants as well as with many other types of medications.  Tricyclic antidepressants will also be getting new black-box warnings, and just as with the newer antidepressants, most problems can be avoided with a start-low go-slow approach.

    I continued using this approach, when appropriate, through 1990, when I discontinued practice to undertake my present research into the underlying causes of medication side effects and methods of prevention.  Many other doctors before and after me have used a low-dose approach.  This method doesn't apply to all medications.  It should not be used with antibiotics or antifungals, for example.  But with many others, such as drugs for high blood pressure, elevated cholesterol, inflammation, allergies, heartburn, or hormones, a low-dose approach can be used with great success.  Unfortunately, this isn't what the pharmaceutical industry and FDA offer, and this is why medication side effects remain such a serious problem.  It doesn't have to be this way, but it will remain so until the drug industry, FDA, advisory committees, and mainstream medical institutions decide to take a broader look at the problem and finally establish a safety-first model of medication treatment.

Unanswered Questions: Will Drug Surveillance Improve at the FDA?
     The FDA says it will reexamine whether antidepressants can cause adults to become suicidal.  Dr. Janet Woodcock, the agency's deputy commissioner of operations, stated in the New York Times, "I think there might be more to be learned, based on what we learned from the pediatric studies."  I am glad the FDA is taking a second look, but really, many doctors and patients can tell you that antidepressants can indeed trigger all of the same problems in adults.  This has been obvious since 1988.

    Meanwhile, many unanswered questions remain.  Why has it taken so long for the FDA to act?  Must the FDA always be goaded into action by foreign regulatory agencies or embarrassing disclosures of its own mistakes?  Will be FDA now take a stronger, proactive stance on other medications in the future?  Will Congress fund the FDA to do so?  Or will the FDA continue to be understaffed and underfunded?

Will a "Firestone-like Disgrace" Finally Force Drug Companies to Publish All of Their Findings?
    The most scandalous part of this whole antidepressant controversy is that, for many years, the drug companies have hidden studies showing an increased rate of suicidal thinking with these drugs.  Withholding such information from physicians and patients is just as bad as Firestone's withholding information about tire blowouts that injured and killed people.  The only difference is that the Firestone scandal affected less than one hundred people.  The antidepressant scandal has affected thousands.  So why hasn't the drug industry received the public censure that hit Firestone?  Why is the drug industry so immune?  This problem involves more than antidepressants.  It involves many top-selling drugs.

    It has been shown again and again that drug companies readily publish their positive findings, yet often withhold the negative findings.  It has been shown again and again that studies funded by drug companies are far more positive overall than studies undertaken independently.  Because drug company-funded studies dominate the medical literature, physicians get a skewed view of the benefits vs. risks of medications.  This is why so many doctors dismiss patients' complaints about side effects.  We are seeing this same scenario today with statin drugs for reducing cholesterol.  I discuss this at length in my upcoming book, What You Need to Know About Statin Drugs and Their Natural Alternatives (Square One Publishers, Nov. 2004).

    Today, the drug industry is getting a lot of pressure to make all of their studies public.  This would be a positive step.  However, we need to ensure that this also means the publication of all of the findings in their studies.  Drug companies often drop the data they don't like when analyzing the results of studies.  Drug companies may study a drug's effectiveness on ten different scales, but publish only the one or two parameters that showed positive results.  Will we receive all of the data generated from their studies?  We need to read the fine print before congratulating the drug industry for publishing its data.  Even then, full disclosure of drug company studies won't end the side-effect epidemic unless drug companies are required to provide us with the very lowest, safest, effective doses of medications.

FOR FURTHER INFORMATION, SEE:
The October 2004 issue of the Annals of Pharmacotherapy, Dr. Cohen's article: Antidepressants: An Avoidable and Solvable Controversy.  Click here to read.

CHAPTERS 1 AND 4 IN DR. COHEN'S BOOK: Over Dose: The Case Against The Drug Companies.  Prescription Drugs, Side Effects, and Your Health.  Tarcher/Putnam, New York: October 2001.

ON THE MEDICATIONSENSE WEBSITE
In the Apr.-June 2004
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?  A 6-Point Solution.

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 Expose, 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.

REFERENCES
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2.  Louie, AK, Lewis, TB, Lannon, MD.  Use of low-dose  fluoxetine in major depression and panic disorder.  Journal of Clinical Psychiatry 1993;54:435-438.
3.  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(suppl 6):44S-49S.
4.  Schatzberg, AF.  Dosing strategies for antidepressant agents.  Journal of Clinical Psychiatry 1991:52(5, suppl):14-20.
5.  Salzman, C.  Practical considerations in the pharmacologic treatment of depression in the elderly.  Journal of Clinical Psychiatry 1990;59(1 Suppl):40-43.
6.  Fichner, CG, Jobe, TH, Braun, BG.  Does fluoxetine have a therapeutic window?  Lancet 1991;338:520-521.  Letter.
7.  Cain, JW.  Poor response to fluoxetine: underlying depression,  serotonergic overstimulation, or a "therapeutic window"?  Journal of Clinical Psychiatry 1992;53:272-277.
8.  Rakel, RE.  Conn's Current Therapy.  Philadelphia: W.B. Saunders Company, 1993.
9.  Stewart, JW, Quitkin, FM, Klein, DF.  The pharmacotherapy of minor depression.  American Journal of Psychotherapy 1992;46:23-36.
10.  Gram, LF.  Fluoxetine -- review article.  New England Journal of Medicine 1994;331:1354-61. 
11.  Harris, G.  Doctors say they will cut antidepressant use.  New York Times, Sept. 16, 2004:nytimes.com.
12.  Cohen JS, Insel PA.  The Physicians' Desk Reference.  Problems and possible improvements.  Archives of Internal Medicine 1996;156(13):1375?]80.
13.  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\.  Accessed April 12, 2004.
14.  Wernicke, J, Dunlop, SR, Dornseif, BE, Bosomworth, JC, Humbert, M.  Low-dose fluoxetine therapy for depression.  Psychopharmacology Bulletin 1988;24:183-188.
15.  Lazarou, J, Pomeranz, BH, Corey, PN.  Incidence of adverse drug reactions in hospitalized patients: a meta?]analysis of prospective studies.  JAMA 1998;279:1200?]5.
16.  Zuger, A.  Caution: That dose may be too high.  New York Times, September 17, 2002:nytimes.com.
17.  Herxheimer A.  How much drug in the tablet?  Lancet 1991;337:346-8.

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