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.

     Reports of unusual, severe reactions with selective serotonin reuptake inhibitor antidepressant drugs (SSRIs) emerged soon after the first SSRI, Prozac, was introduced in 1988. One of my own patients, a woman with a mild depressive disorder and no history of major psychiatric symptoms, became psychotic after just three days on Prozac. Another woman, a highly successful attorney, developed such severe panic attacks that she couldn't work. Such cases were reported so frequently that Congress held hearings on the issue in the early 1990s. But because the hearings got no further than arguing whether SSRIs cause suicidal and homicidal behavior or not, and never looked at the underlying causes, nothing was accomplished.
     I have never doubted that SSRIs (Prozac, Paxil, Zoloft, Celexa, Lexapro, Luvox, Effexor, Sarafem) can provoke impulsive, violent behavior. Now, sixteen years after the first reports, British regulatory authorities have acted against the use of SSRIs in children because of an increased incidence of suicide. This forced the U.S. Food and Drug Administration to take a second look. In early February 2004, a FDA advisory committee heard powerful testimony from bereaved parents and medical experts and issued a call for stronger warnings on the labels of these drugs. The FDA is considering it.
     Even if the FDA acts, will such warnings make any difference? Not likely. As the FDA has learned, adding warnings to package inserts does little to improve how doctors prescribe drugs.1-3 Doctors kept prescribing Rezulin and Seldane inappropriately despite added warnings, and patients continued dying until the drugs were withdrawn. About 20% of all medications ultimately require additional "black-box" warnings about dangerous side effects discovered after the drugs' approvals,1 yet despite these additional warnings, doctors' prescribing methods remain poor and the incidence of medication-caused hospitalizations and deaths remains high.
     Merely adding warnings to package inserts is inadequate because once doctors begin prescribing a drug, they don't read every updated package insert of every drug they use. Doing so would take hours, and package inserts are long and written in tiny, barely readable script, so new warnings are easily overlooked. Moreover, it usually takes years for such warnings to be added to package inserts, during which time doctors continue prescribing the drugs to millions of people. The fact is, most doctors rely on information provided by the drug companies' legions of sales representatives who accentuate the positive and downplay the negative.
     What should be done? The answer is obvious: look at why these reactions are occurring and impose appropriate solutions.
     My book, Over Dose: The Case Against The Drug Companies (Tarcher/Putnam 2001)4 laid it out and, for doing so, received excellent reviews including the recommendation of the Journal of the American Medical Association. Here is a more succinct explanation of why good drugs cause so much unnecessary harm, and why the medical-pharmaceutical complex allows it to happen again and again.

The Drug Companies
     First rule: it's all about sales. Making profits is the overriding ethic of pharmaceutical companies. What maximizes sales? Marketing that impresses doctors. Although patients like you take the medications, pay the pharmacies, and take the risks, it is doctors who decide which drug and what dosage is used. Doctors are the final decision makers, and once a prescription is written, you have no say in the matter. If your doctor prescribes 50 mg of Zoloft for you, you cannot tell your pharmacist to give you a lower dosage or that you want to get Paxil or Effexor instead.
     Doctors determine which drugs will succeed and which will fail. Drug companies know this and know how to impress doctors with: 1) claims of superior effectiveness; 2) easy-to-use drugs. Superior effectiveness means being able to claim that your drug is better than its competitors in some way. It's very helpful, for example, for a drug company to be able to boast that "our drug helps 72% of patients, yet our competitor's helps only 64%." Although these numbers may have little meaning when it comes to treating individuals, the numbers impress doctors. To achieve superior numbers, drug companies use stronger and stronger drug doses in their studies in order to elicit any little advantage over competitors that they can then market vigorously to doctors. They publish the studies they want the healthcare community to see and untold the ones they don't.
     Drug companies also know that doctors like drugs that are easy to prescribe. One-size-fits-all drugs fit the bill, because their dosages are easy to remember and doctors don't have to take the time to select different doses for different patients. This goes against the basic medical principle of individual variation: that different people require and tolerate different doses of medications (just as with coffee and alcohol). But such methods allow drug companies to promote their drugs with such boasts as "no adjustment needed for the elderly," as if that's a good thing. It isn't -- older people almost always require much lower drug doses -- but most doctors unquestioningly accept drug company guidelines.
     Today's pharmaceutical industry marketing strategy is: Make it strong and keep it simple. This is why Prozac was introduced with a one-size-fits-all starting dose of 20 mg, even though the manufacturer knew that 54% of patients responded to just 5 mg, a 75%-lower dose that caused fewer side effects.5 Other SSRIs with unnecessarily strong starting doses soon followed.
     Strong drug doses work for some people, but they are a sure-fire recipe for major side effects in others, yet the drug companies develop drug after drug in this manner. This is why SSRIs cause sexual dysfunctions in as many as 50% of patients.6-8 Side effects such as anxiety, agitation (akathisia), insomnia, and panic attacks are common and can become so severe that they impair cognitive functioning and judgment, leading to impulsive, destructive behavior by people who never acted in such a way before.9-13

Doctors and SSRI Antidepressants
     Patients have the mistaken impression that doctors understand SSRI drugs. Most doctors don't.
     The drug companies have marketed SSRI antidepressants vigorously not only to psychiatrists, who are supposed to have some expertise with these drugs, but also to family practitioners, pediatricians, gynecologists, internal medicine specialists, and anyone else who can pen a prescription. But this doesn't mean that they possess in-depth knowledge of SSRIs or their actions and toxicities. Many doctors don't know the difference between major and minor (dysthymic) depressions and that the latter responds to much lower SSRI doses. Many doctors don't understand bipolar (manic-depressive) disorder and that overly strong SSRI doses can trigger manic reactions.
     Even worse, many doctors think SSRIs are the best treatment for anxiety symptoms. They aren't. For immediate relief of anxiety, Xanax, Valium, and other benzodiazepines are fast-acting and safe if used in moderation. SSRIs have no immediate anxiety-reducing effects. To the contrary, they can actually provoke anxiety. SSRIs also frequently cause insomnia that is so intractable, doctors prescribe sleep-enhancing drugs, further complicating treatment.
     So why do doctors prescribe SSRIs for anxiety symptoms? Because if taken for awhile -- at a low dosage -- SSRIs can sometimes reduce the development of anxiety symptoms. When used properly, SSRIs can help panic and obsessive-compulsive disorders, but such use means starting with a very low dose and explaining that the benefits may not be seen for weeks. Doctors should also explain to patients that these drugs can worsen anxiety initially. If this happens, patients should contact the doctor, and the dosage should be lowered. Do doctors actually warn patients about this? Rarely. Most doctors don't understand it themselves.
     Even psychiatrists are often appallingly ignorant about how SSRIs work. This was made clear in a January 5, 2004, article in The New York Times titled "A Doctor's Toxic Shock."14 A doctor taking Wellbutrin herself described her reaction: "I developed insomnia, agitation and tremors... panic attacks started... I needed every ounce of energy to concentrate at work.... Sometimes I felt paranoid, and I wondered if I was delusional. When I wasn't working, I was curled in a fetal position, contemplating whether I should hospitalize myself."
     This was a serious reaction, exactly like those that drive some people to violence. Yet the doctor had no clue that it was a dose-related reaction to the very drug she had prescribed for herself. What did she do? Exactly what she and other doctors tell patients to do: stick it out until the drug's benefits kick in. This is ridiculous, dangerous advice, but it's the medical mainstream's party line. Indeed, the doctor described talking to colleagues, who were similarly perplexed by her symptoms. It is very disturbing to think that there are psychiatrists out there who can't recognize the most basic adverse effects of these antidepressants. Every psychiatrist I asked about this immediately identified the symptoms as SSRI side effects and recommended discontinuing the drug or at least decreasing the dosage, so at least some psychiatrists know what they are doing. But not enough, apparently.
     There is no excuse for not recognizing SSRI reactions. There is extensive literature on the dangers with SSRIs 9-13, 15-26, and anxiety and agitation are listed as side effects in the package inserts of most SSRI drugs and Wellbutrin (which although not an SSRI, can cause anxiety.) So it is alarming that so many intelligent, capable doctors are so confused when typical SSRI side effects develop. Yet, if these doctors are relying on the information provided by drug companies and their 90,000 sales reps and drug company-underwritten, expenses-paid seminars and conferences, maybe it isn't so surprising after all.
     Medical educators such as Dr. Jerry Avorn at Harvard and Dr. Roger Jelliffe at the University of Southern California have long sought better training for doctors about medications. Presently, most students get one course that broadly covers the basics on hundreds of drugs, but lacks any depth and fails to teach critical analysis. Raymond L. Woosley, Vice President of Health Services at the University of Arizona wrote to me:

"Only about fifteen of the medical schools today teach formal courses in clinical pharmacology, which is the discipline that emphasizes interindividual variability in response to drugs. This small effort will never counter the overwhelming message from the drug industry that one dosage is all that is needed and everyone will respond nicely without side effects."27

     Dr. Woosley would like to make many changes. So would I. Dr. Jelliffe tried, but was told that medical students' schedules were already filled with more important classes. That's odd, because doctors' most frequent intervention is writing prescriptions. So what could be more important than learning to prescribe drugs properly and recognize side effects promptly?
     Meanwhile, the drug companies have penetrated every corner of medical schools and hospitals today. Medical school faculties and hospital staff are highly reliant on drug company money. The situation is so extreme that in 2000, the editor-in-chief of the New England Journal of Medicine published a disturbing yet all-too-true article titled "Is Academic Medicine for Sale?" Dr. Marcia Angell wrote:

"Academic medical institutions are themselves growing increasingly beholden to [the drug] industry.... Some academic institutions have entered into partnerships with drug companies to set up research centers and teaching programs in which students and faculty members essentially carry out industry research... Young physicians learn that for every problem, there is a pill (and a drug company representative to explain it)." 28

     The drug companies are so entrenched in the education of medical students and the continuing education of doctors, it is no stretch for me to claim that we now have a "medical-pharmaceutical complex." In it, doctors' education and information is so controlled by the drug industry, doctors don't even know how limited their information is. New generations of doctors are taught that they know everything important about medications, when in fact they don't.
     Thus, doctors aren't informed about obvious SSRI reactions and therefore don't warn patients. When reactions occur, doctors cannot identify them. They tell patients to stick with the drugs or increase the doses, making things worse. When patients complain about side effects, many doctors deny, deny, deny. Doctors must decide whether their allegiance is to their patients or to their medications. As I wrote in Over Dose, many doctors over-identify with their drugs, so when the drugs cause side effects, doctors get defensive rather than simply seeing side effects as something that they and their patients can solve together.

The Drugs
     Should Prozac, Paxil, Zoloft, Celexa, Lexapro, Luvox, Effexor, and Sarafem be withdrawn? Some people think so, claiming that SSRIs demonstrate no greater effectiveness than placebo.
     I stand squarely on the side that believes SSRI drugs are helpful to millions of people, including children. I get letters from people who feel very differently, but my experience and my reading of the medical literature convince me that SSRIs have a role in treating depression and other conditions.
     This isn't to say that SSRI drugs are perfect. Any drug that produces benefit can also cause harm. People vary widely in their responses to drugs. This is why it is so important to treat each person individually and, except in acute situations, to start with doses low enough to avoid problems. Such doses may be 5 mg of Prozac, 10 mg of Paxil, 25 mg of Zoloft, 37.5 or 75 mg of Effexor, etc. Some people are ultra sensitive to SSRIs and do well on as well as 2.5 mg of Prozac or 12.5 mg of Zoloft or equivalently tiny doses of other SSRIs.
     If after a week or two, no benefit and no side effects are seen, the doses can be gradually increased. I call this the "Start Low, Go Slow" method. By starting low and increasing gradually, you are guaranteed to get the right amount of medication for you. In this way, risks are minimized. This safety-first method is essential for side effect-prone drugs like SSRIs. Doctors should always start with low doses for people who are old, small, taking other medications, or who have a history of sensitivities to medications. But the start-low go-slow approach is also appropriate for anyone who wants to minimize medication risks.
     This amounts to a lot of people. When I was still treating patients, I explained the benefits and risks of antidepressants and asked patients whether they would prefer starting with a standard, drug company-recommended dose or a lower, safer, proven-effective dose. More than 80% preferred the low-dose approach. Many never needed the full drug company-recommended doses.

Omitted Information = Denial of Your Right of Informed Consent
     The start-low go-slow approach make perfect sense and is easy to initiate -- if drug companies provide information about the lowest, safest drug doses in their package inserts and the Physicians' Desk Reference. Most often, they don't. Without such information, doctors and patients remain mystified when side effects strike. Many doctors mistake side effects for symptoms of the depressive disorder, and rather than reducing the medication, increase it, thereby exacerbating the reactions. People suffer. Needlessly.
     Information is key to inform consent. The American Medical Association Code of Medical Ethics states:

"The patient's right of self-decision can be effectively exercised only if the patient possesses enough information to enable an intelligent choice.... The physician has an ethical obligation to help the patient make choices from among the therapeutic alternatives consistent with good medical practice."29

     If drug companies don't provide you with information about the lowest, safest, effective drug doses, they are denying your right of informed consent. If drug companies don't give doctors full information about SSRI side effects, doctors cannot inform you, and your rights are further infringed. If doctors don't read the information that the drug companies do provide, your quality of treatment and rights of informed consent are again compromised.
Studies have shown that only a small percentage of patients get enough information in doctors' offices to fulfill informed consent.30 With SSRI antidepressants, such negligence can be lethal.

A Six-Point Solution
In a recent newsletter ("An Open Letter to the U.S. Food and Drug Administration on Serotonin-Enhancing Antidepressants," Feb. 2004), I offered a 6-point solution to the SSRI problem:

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. Drug companies must make public all of their data on any drug to be used in humans.

3. Doctors must be trained in the safe use of SSRI antidepressants. Classes and certification should be required for prescribing these drugs. This training should include some basic knowledge of pharmacokinetics, the science of drug metabolism which clearly shows that some patients are slow metabolizers of SSRIs and will develop high blood concentrations even with modest SSRI doses. If doctors understood pharmacogenetics better, they wouldn't be surprised that some people need very low doses of SSRIs and other medications.

4. Doctors must follow patients closely and warn patients about possible SSRI side effects. New patients should be seen frequently until doses are adjusted properly and side effects, if they occur, are handled effectively. Doctors should select SSRIs that come in low doses or as liquids, which allow careful, gradual dose titration.

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 and places patients at unnecessary risk.

6. The FDA must initiate policies requiring drug companies to develop the lowest, safest doses of not only SSRI antidepressants, but all drugs. The FDA must compel drug companies to add warnings to their package inserts promptly when new side effects are reported. For serious adverse effects like SSRI reactions, the FDA must compel manufactures to send warning letters to each doctor. Because even these methods are sometimes ineffective, the FDA must require doctors to report all SSRI reactions and monitor these reports closely, issuing a public statement every six months.

     What is the FDA suggesting instead? Stronger warnings in package inserts -- a strategy the FDA knows is inadequate.
     My 6-point solution would allow drug companies to continue marketing SSRIs, allow doctors to continue prescribing them in appropriate situations, and allow patients to obtain the benefits of SSRIs with minimum risk. This is what needs to be done not only with SSRIs, but with many top-selling drugs. But will it? Not likely in today's medical-pharmaceutical complex in which drug companies set their own prices, collect profits far beyond any other industry, and exert enormous influence on doctors, medical schools, Congress and the FDA -- and society itself.
     The irony is that my proposals would not only help patients, but restore some confidence in the doctor-patient relationship. Even the drug companies would benefit, because by providing better information about side effects and lower, safer medication doses, side effects would be fewer and, if occurring, would be handled properly. This is a much better scenario than today's SSRI scandal that has further tarnished the drug companies' image and hurts SSRI sales.
     Above all, the saddest thing about SSRI-related suicides and homicides is that they are preventable. Most side effects are preventable. When drugs and doses are matched to individual needs and tolerances, benefits are maximized and risks are minimized. Except for acute situations, a start-low go-slow approach guarantees that each person gets the right amount of medication for them, thereby reducing the frequency and severity of side effects. I've been talking about this for thirty years and writing about it for fifteen. But that's not how things are done in today's medical-pharmaceutical complex, where pharmaceutical sales are paramount and patients' safety isn't.

REFERENCES
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