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Excerpts from Toxic Psychiatry
Chapter 11
by Peter R. Breggin, M.D.

Xanax - Approved for Panic Disorder

The news was announced in 1990 in headlines in Upjohn's eight-page gaudy color advertisements in psychiatric journals: XANAX: THE FIRST AND ONLY MEDICATION INDICATED FOR PANIC DISORDER. Panic disorder (see chapter 10) was officially classified as a distinct psychiatric entity for the first time in 1980 by the APA's Diagnostic and Statistical Manual. The recent FDA approval of Xanax as the one and only treatment for this popular diagnosis will catapult the drug to even greater domination of the market.

Yet what is there to distinguish Xanax from the rest of the benzodiazepines? We've already found that there's little or no difference among these drugs in regard to their clinical impact. The same is true in regard to side effects - except that Xanax is short-acting and more tightly bound to its receptors, and therefore, as already discussed, more likely to cause severe withdrawal symptoms and addiction.

Xanax is one of the more dangerous minor tranquilizers. Joe Graedon and Teresa Graedon warn about Xanax in their October 1989 syndicated column "The People's Pharmacy":

Xanax, one of the most commonly prescribed medications in the country, has been associated with confusion, paranoia, depression, hostility and forgetfulness while a person is taking it. Sudden withdrawal from such antianxiety agents can be living hell for some people. We have received letters from readers reporting nerves "jumping," muscle twitching, feelings of disorientation, fear, insomnia, anxiety, agitation and even seizure.

Death from Xanax in combination with alcohol or other sedatives has been a special problem, as reported by Chad Carlton in 1990 in the Lexington Herald-Leader: "A commonly prescribed tranquilizer, introduced nearly a decade ago as a safer alternative to Valium, has become increasingly linked to overdose deaths, addiction and street-drug sales in Central Kentucky." It had played a role in ten deaths in a six-month period in Lexington alone. "Doctors are handing it out like candy," says Mark Hyatt, chief of psychiatry at the local Veterans Affairs Medical Center.

The Xanax Studies

On reading Upjohn's eight-page advertisements in psychiatric journals about its FDA studies, I was struck by something odd. At the top left of one page is a statement that drug evaluations were made at "weeks 1, 2, 3, 4, 6, and 8 of therapy." This gave the immediate impression that Xanax must have been proven effective at eight weeks. But the chart beneath this statement records only the first four weeks. Nowhere in the advertisement is there any discussion of the results after the full eight weeks. Then, at the bottom of the page, there is this explanation: "Because of the high rate of placebo dropouts, week 4 (the last evaluation point where the majority of patients remained in the placebo treatment group) was considered the study 'end point' for efficacy analyses."

In other words, Upjohn was counting only the first four weeks of the study and discarding the final results at eight weeks. Why would Upjohn want to do this?

I was shocked at what I found when I studied the original research report. By the end of the eight weeks, the sugar-pill patients were doing about as well as the drug patients. Indeed, the placebo patients were far better off, because they did not suffer the severe withdrawal and rebound reactions, including an increase in anxiety and in phobic responses, plus a 350 percent greater number of panic attacks.

In an unusually negative reaction to a highly touted study, an international group of eleven psychiatrists and psychologists, led by Isaac M. Marks from the Institute of Psychiatry in London, wrote a two-page letter in the July 1989 Archives of General Psychiatry criticizing and largely dismissing the Xanax study. They point out that "at the last week after taper [drug withdrawal], patients receiving alprazolam were in a worse state than patients receiving placebo, in terms of panic (350% worse, in table I of the article by Pecknold et al.), phobias and Hamilton anxiety (other measures were not reported)."

In summary, the FDA Xanax study really shows that most patients were better off if they had never taken the drug. None of this is obvious in reading the actual study by James C. Ballenger and his colleagues. In the introductory abstract, no mention is made of Xanax's effect beyond four weeks. And yet the abstract describes the drug as an unqualified success.

Faced with their own negative results, the Xanax investigators came up with statistical manipulations to show how the data really should have - but didn't - come out at eight weeks; but apparently they were embarrassed by these efforts, and they limited the summary and conclusion of their report to data from the first four weeks. As noted, the drug company, with whom they were working closely, followed suit.

In their lengthy critique of the study in the Archives of General Psychiatry, Marks and his colleagues point out that a few weeks of relief is hardly worth the consequences of withdrawal and worsening symptoms, especially when the patients had been suffering from anxiety problems for an average of nearly nine years.

Furthermore, they point out that any hoped-for benefit must be balanced against known and unknown dangers of long-term use, including the possibility (see above) of brain shrinkage from chronic benzodiazepine use.

Marks and his colleagues summarize, "The unqualified conclusions about efficacy based solely on short-term partial gains in a chronic condition seems biased and arguable."

More Problems with the Xanax Study

As discussed in chapter 8, most people think that FDA drug trials extend for many months or years rather than a few weeks. According to Ballenger and his colleagues, most psychiatrists were giving Xanax for a period of three months to a year before tapering or discontinuing it. Yet Upjohn itself limited its data analysis on efficacy to a mere four weeks. It merits reemphasis: FDA approval does not mean that the drug has been tested with controlled studies for anywhere near the length of time that it typically is prescribed by doctors.

The size of the sample is also a problem, especially in regard to testing for negative side effects. While most people think that FDA-approved drugs have been tested on thousands or tens of thousands of patients, the actual sample size is described in Upjohn advertisements as "more than 500 patients." In fact, only 226 patients took Xanax for the length of the main study. That is hardly a sufficient number to test for relatively infrequent but potentially serious side effects. For example, a side effect that causes death in 0.5 percent of drug patients could easily escape showing up in such a small sample, but it would kill five thousand of the first one million people to take the drug. And, of course, a side effect that doesn't appear until after eight weeks would be missed completely.

Xanax's addictive effects became a serious problem even during short, eight-week trials. J. C. Pecknold and his associates found that even a gradual four-week period of withdrawal did not prevent a "worsening of symptoms" and that "some, in fact most, patients experienced relapse." Thirty-five percent of the patients had "mild to moderate" withdrawal symptoms. Thus after only two months of treatment, a large percentage of the patients were becoming addicted to the drug.

The warning given by Upjohn for Xanax in the 1991 PDR states: "If benzodiazepines are used in large doses and/or for extended periods of time, they may produce habituation and emotional and physical dependence." However, the data actually indicate that physical dependence very frequently develops without "large doses" and before "extended" periods of treatment. Furthermore, there is no hint in the PDR that Xanax is especially addictive.

Writing in The New Harvard Guide to Psychiatry, George Vaillant indicates that the public is unaware of the addictive qualities of minor tranquilizers, including Xanax: "Contrary to popular belief, physical dependence on diazepam (Valium), chlordiazepoxide (Librium) and especially alprazolam (Xanax) does occur" (p. 711). Because the public is relatively ignorant of the problem and because Xanax is "especially" likely to addict, Upjohn should have made the danger as emphatically clear as possible.

Pecknold and his colleagues recommend that treatment with Xanax be routinely extended for six months, to be followed by very slow withdrawal. This adds up to a minimum period of treatment approaching one year. In short, the authors recommend many months of treatment for a drug whose beneficial effect over a placebo was shown to decline to nothing at eight weeks! Furthermore, as Pecknold and associates admit, the increased length of treatment could be expected to worsen the addiction and withdrawal problems. A genuine concern for the patients should have led these investigators to the opposite recommendation: that in order to avoid withdrawal and addiction, the drug should be used for very short periods of time (such as a few days) or not at all.

Xanax as Alcohol in a Pill

The similarity between Xanax and any other addictive sedative, including alcohol, was verified in the FDA studies. Russell Noyes, Jr., and his associates report that 61.7 percent of the subjects suffered from sedation during the first week and that by the last week 38.7 percent were still aware of the effect. At some time during the treatment, 77 percent reported "at least mild sedation." Clinical experience with alcoholism and drug addiction, as well as the Golombok study of minor tranquilizers, indicates that people taking sedatives tend to deny their drug-induced sedation. People who are sedated often do not appreciate that they are thinking more slowly, getting muddled, forgetting things, slurring their words, or losing their coordination. As almost everyone has noticed at parties where people get "drunk," or from TV and radio ads encouraging us to take the car keys away from our inebriated friends, denial of impairment is typical of people experiencing sedation. It is virtually certain that the patients on Xanax were far more sedated than they reported.

In addition to sedation, other "drunken" symptoms were commonly reported by the patients, including ataxia (muscular incoordination), fatigue, slurred speech, and amnesia.

One wonders how the drug would have compared to alcohol, rather than to an inactive placebo, in its "beneficial" and its toxic side effects.

In another study, after only six days' use, Xanax was found to cause sufficient memory problems to potentially impair educational learning. The investigators warned against taking Xanax before school examinations.

How did Xanax get such an edge on the other benzodiazepines, first by taking the lead in the market and then by becoming the first drug approved for panic disorder? Apparently not on the basis of scientific studies, which show that Xanax is ineffective beyond four weeks, frequently produces sedation and mental dysfunction, and often causes withdrawal problems. In chapter 15 we shall examine how Upjohn's financial support of the psychiatric profession may have influenced the drug's acceptance.

Is There Any "Therapeutic Role" for the Minor Tranquilizers?

Don't people have a right to escape anxiety at times? To use shortcuts if necessary, including sedative drugs? Yes, they surely do. But should doctors encourage this approach to life? I don't think so, except under the most limited circumstances. Because people cannot obtain minor tranquilizers without a doctor's prescription, I don't fault physicians who occasionally prescribe them to help patients get through a difficult few days or to get a good night's sleep; but their usefulness for more than a few days is highly questionable. Even the prodrug literature has not been able to show a beneficial impact beyond a few weeks, when tolerance and withdrawal symptoms develop.

Minor tranquilizers, like any sedative, can be harmful in the long run not only because they are habit-forming and addictive, but because they cover up anxiety by suppressing the capacity of the brain to generate feelings. The brain, as usual, tries to overcome the suppression and reacts in ways we cannot begin to predict or fully comprehend. As we have seen, drug-induced rebound anxiety is one common effect.

The drugged individual with a suppressed and confused anxiety signal system lives under a considerable handicap. At the least, feelings are pushed down, and with that, self-awareness is muted. More seriously, as the brain reacts against the drug, natural anxiety responses are muted but abnormal rebound anxiety reactions begin to flare up.

What about people who are so overwhelmed by anxiety that they cannot cope at all? The doctor who offers medication is likely to reinforce the patient's feelings of helplessness. If psychotherapy is being attempted, the drug induced insensitivity to self can inhibit progress. When a patient has an acute anxiety attack in the midst of a psychotherapy session, for example, it's prime time for understanding the problem and showing the patient various ways to handle it.

Without drugs, severely anxious patients often can be helped rather quickly to overcome the worst of their anguish (see chapter 10). Over a longer period they can learn new approaches to living relatively free of anxiety.

But success in psychotherapy is not guaranteed. Failure may result from a faulty delivery of therapy or from a poorly motivated client, or from a bad "chemistry" between client and therapist. Whatever the cause of the failure, what about drugs as an alternative?

I would rather urge a client to try another therapist, or several other therapists, as well as other approaches, such as group therapy, self-help groups, self-help books, self-hypnosis, relaxation techniques, deep massage, or meditation and other spiritual exercises, rather than to turn to drugs.

Improvement while on drugs is rarely a psychologically clean affair; the improvement almost always leaves an aftermath of persistent personal helplessness. The individual is unable to say with confidence, "I overcame my anxiety and I know how I did it." There is always the lingering suspicion that "the drugs did it."

Even prescribing medications on an occasional basis can interfere with and undermine the real work of psychotherapy.

After a session, a client called me in the evening to request a telephone prescription for a few minor tranquilizers.

"What's up?" I asked.

"Sorry to bother you, Peter. I can't sleep. I just want something to sleep for a few nights."

"How come you didn't bring it up in the session today'?" I asked.

"Hey, Doc, you were hardly listening to me today. You seemed in another world yourself"

In an instant I knew he was right. I'd received distressing news by telephone moments before his session, and without realizing it at the time, I hadn't shaken off the effect.

"Thanks for telling me," I said. "if you can come in tomorrow morning, I'll give you a free session to make up for it."

"It's a deal. And forget the drugs. Good-night."

If I had readily acquiesced to the request for a prescription, the patient's real feelings never would have surfaced. Giving drugs runs the risk of distracting from the work of psychotherapy, not only for the client but for the therapist.

Scientific Studies of Efficacy

By now, I hope, the reader will approach the question of "scientific studies" in psychiatry with a large measure of skepticism, and even cynicism. In regard to the minor tranquilizers, there are some blanket endorsements, such as this one from the American Psychiatric Press's Textbook of Psychiatry: "The efficacy of the benzodiazepines in the treatment of anxiety, including the symptoms of worry, psychic anxiety, and somatic symptoms (gastrointestinal and cardiovascular), has been clearly and repeatedly demonstrated in many well-controlled studies" (p. 810). On the other hand, there is a detailed review of the literature by Ronald Lipman in Seymour Fisher and Roger Greenberg's The Limits of Biological Treatments for Psychological Distress (1989). Lipman finds that, except for the very short-term treatment of generalized anxiety, there is little evidence for the efficacy of these medications. Most reviews suggest that use should be short term and that long-term use is generally dangerous and unwarranted.

Peter R. Breggin, M.D. founded The International Center for the Study of Psychiatry and Psychology (ICSPP) as a nonprofit research and educational network concerned with the impact of mental health theory and practices upon individual well-being, personal freedom, and family and community values. For 25 years ICSPP has been informing the professions, media and the public about the potential dangers of drugs, electroshock, psychosurgery, and the biological theories of psychiatry.

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