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Although it is often possible to help depressed people through caring, enthusiastic psychotherapy (see chapters 6 and 16), biopsychiatrists typically reject psychological approaches and instead make extraordinary claims for the efficacy of drugs.
One antidepressant, Prozac, recently generated a Newsweek cover story, leaped to the top of the drug charts, and then ran into a storm of controversy. Sales figures for August, September, and October 1990 show that more than 400,000 new prescriptions for Prozac are being written each month in the United States. Total sales in 1991 are expected to reach one billion dollars. Meanwhile, a flood of lawsuits is pending against the manufacturer, Eli Lilly. * This chapter will provide an analysis of the actual effects and potential dangers of the drug.
Antidepressants: Widespread and Growing Usage
Antidepressants are very much in vogue, but they have been around for a long time. Elavil (amitriptyline) and Parnate (tranylcypromine), for example, have been in use for three decades. In 1984, thirty-four million prescriptions were written for antidepressants, placing them a distant second behind the minor tranquilizers; but the Prozac craze is narrowing the lead. More than two-thirds of antidepressant prescriptions are for women.
The great majority of antidepressant prescriptions are written by nonpsychiatric physicians. Psychiatrists, however, set the tone for the widespread use of these agents. Right now psychiatrists are advocating their use for a variety of disorders, from depression and anxiety to eating problems, premenstrual tension, phobias, and obsessions and compulsions. They have become a jack-of-all-trades drug. This in itself should warn us not to trust the claims being made.
Prozac: The Most Recent "Miracle Drug"
Prozac (fluoxetine), introduced in January 1988, is one of the latest of a new generation of antidepressants. The March 26, 1990, Newsweek sports the picture of a huge Prozac capsule on the cover - a kind of "pill of the year" award. Beneath the giant PROZAC headline, the subhead announces A BREAKTHROUGH DRUG FOR DEPRESSION.
The story sports a photo of a smiling woman, captioned "I'm nowhere near perfect, but it's a big, big improvement." Without embarrassment, Newsweek reports how one patient exclaimed to her doctor, "I call myself Ms. Prozac." The story anticipates that "these breakthrough drugs may change the lives of millions."
At a recent picnic I met a woman who had just been prescribed Prozac - by another psychiatrist at the previous party she'd attended. Apparently he wrote out a prescription on the basis of the brief "consultation." Another woman on Prozac explained that her psychiatrist said he himself was taking the drug, even though he wasn't depressed; it just made him feel better.
Surprisingly, recent psychiatric textbooks and many experts take the position that Prozac is no more effective than any other antidepressant, and maybe even less so. The 1988 American Psychiatric Press's Textbook of Psychiatry gives it a dubious endorsement: "studies show it to be as efficacious as imipramine in the treatment of depression." Imipramine (Tofranil) is among the oldest antidepressants and is one of those old standbys whose entire credibility is being challenged by researchers like Greenberg and Fisher. Similarly, the 1989 Comprehensive Textbook of Psychiatry observes that Prozac is "at least as effective as standard antidepressants."
The most sophisticated analysis, found in the four-volume Treatments of Psychiatric Disorders, by the American Psychiatric Association, finds that expectations for the newer generation of antidepressants, specifically including Prozac, have not panned out: ". . . it is apparent that no currently available agent at the time of this writing either offers enhanced efficacy or is free of toxicity limitations. " Speaking of Prozac it warns, "Whether this agent's spectrum of efficacy will be more favorable than that of other antidepressants remains to be observed" (p. 1799).
Rarely do psychiatric textbooks display such uniformly conservative evaluations of a new drug. It's a disconcerting contrast to the feverish promotion being generated by the drug industry through the media.
Prozac seems especially exciting to doctors, patients, and the press because it is described as selectively affecting the neurotransmitter serotonin. It is suggested that this selectivity for serotonin somehow makes Prozac more limited in its impact on the brain and mind, and less likely to produce complex or dangerous side effects. These are false conclusions. Serotonin nerves spread throughout most of the brain - including the emotion-regulating limbic system and frontal lobes - and are thus involved in multiple functions that defy our current understanding or imagination. Prozac makes serotonin more available by inhibiting its removal from the synaptic region between nerves.(1) When this biochemical imbalance is created, many other related neurotransmitter systems, such as dopamine, are forced to undergo changes as well, creating more widespread disruptions. There should be no comfort associated with the idea that Prozac is selective for serotonin. The brain, an integrated organ blessed with harmonies and balances beyond our ken, is thrown out of balance by any such biochemical intrusion.
The relative safety of Prozac is acclaimed by the Newsweek cover story; but in reality it's too early to hold out such hopes. Nor does the literature confirm such positive expectations. For example, an August 1989 report in the Journal of Clinical Psychiatry compared Prozac with a much more thoroughly tried antidepressant, Desyrel (trazodone). It found no therapeutic advantage to Prozac and no fewer adverse symptoms. Forty-three percent of the Prozac patients complained of two or more side effects, including headache (29 percent), nausea (24 percent), and somnolence (19 percent). It is also well-known that Prozac causes anxiety and agitation, as well as insomnia and bizarre dreams, in a large percentage of patients. It can also result in loss of appetite, diarrhea, dry mouth, sweating, dizziness, impotence, inability to achieve orgasm, seizures, and rash. It can cause hypoglycemia with anxiety, chills, cold sweats, confusion, weakness, and other symptoms of low blood sugar. On rare occasion, a severe rash develops with symptoms of fever, joint pain, and swollen lymph nodes. A "Prozac syndrome" may develop, with hot flashes and flushing, agitation, nausea, muscle tremors, and sweating. Using tryptophan can increase the risk of Prozac syndrome. Convulsions and a few deaths have been reported from massive overdoses. Combination with MAOI antidepressants and other drugs can be dangerous. From the initial studies, it was also apparent that a small percentage of Prozac patients become psychotic. And as we shall see, there are still more ominous problems associated with Prozac, including serious neurological and psychiatric disorders.
The PDR warns that Prozac has not been systematically studied for its potential to cause withdrawal reactions. Earlier in this chapter, I described a patient with such severe withdrawal symptoms that she felt compelled to resume taking the drug. The PDR further states, "it is not possible to predict on the basis of this limited experience the extent to which [Prozac] will be misused, diverted, and/or abused once marketed." That is, the drug may yet turn out to be habit-forming or addictive.
Murder and Suicide Associated with Prozac
Newspaper and scientific reports are pointing to an association between Prozac and compulsive self-destructive and murderous activities in a growing number of patients.(2) In "Murder Trials Introduce Prozac Defense" in the February 7, 199 1, Wall Street Journal, Amy Dockser Marcus reports, "A spate of murder trials in which defendants claim they became violent when they took the antidepressant Prozac are imposing new problems for the drug's maker, Eli Lilly & Co." An article by Natalie Angier on the same day in the New York Times declared in its headline, "Suicidal Behavior Tied Again to Drug: Does Antidepressant Prompt Violence?"" On February 28, 1991, a "Donahue" TV talk show put together a group of individuals who had become compulsively self-destructive and murderous after taking Prozac and the clamorous telephone and audience response confirmed the problem.
The clinical literature also displays a growing number of reports of compulsive suicidal behavior in people taking Prozac. An article by Martin Teicher and others in the February 1990 American Journal of Psychiatry described six cases of obsessive, violent suicidal thoughts after starting Prozac, 10 and more recently a variety of individual case reports have reinforced these initial observations. I am personally familiar with several cases of compulsive suicidal or violent feelings developing after taking Prozac. Recently I presented a seminar on Prozac and its dangers at the psychiatric grand rounds of a hospital. After I concluded, one of the psychiatrists in the audience summarized a case of his own in which a highly responsible corporate executive had unexpectedly become very violent one week after starting to take Prozac. The patient had no prior history of violence and described the impulse as taking him over. He had to be subdued by several men after he attacked a stranger without provocation during a minor quarrel.
How Prozac Could Cause Seemingly Paradoxical Reactions
As noted in chapter 7, some researchers believe they have found an association between diminished or sluggish activity of serotonin and impulsive acts such as suicide and murder." While Prozac is supposed to enhance serotonin neurotransmission, the brain in fact reacts to the first dose by reducing serotonergic activity, including that to the emotionregulating centers. Researchers for the pharmaceutical company itself, Ell Lilly, first described this reaction before the drug was even named. In Life Sciences (1974), Ray Fuller and colleagues from the Lilly Research Laboratories reported that one dose of Prozac (then called Lilly 110140) caused a marked drop in serotonin nerve activity for more than twenty-four hours. They suggested that this was the result of a "compensatory mechanism" in reaction to initial overstimulation. As further documented by Claude de Montigny and his team in the December 1990 journal of Clinical Psychiatry and by Pierre Biler et al. in the 1988 Navnyn-Schmiedeberg's Archives of Phannacology, Prozac and similar drugs initially cause a suppression of serotonergic neurotransmission that gradually returns to normal over a three-week period. In a phone call interview with me in early 1991, Montigny agreed that this compensatory serotonergic shutdown mechanism could possibly account for the out-of-control destructive reactions to initially taking the drug; but he considered the suggestion "speculative." However, it is no less speculative than the drug company's claim that Prozac alleviates depression by enhancing serotonergic neurotransmission.
Prozac can also produce a relative shutdown of serotonergic neurotransmission during long-term use through another mechanism called down-regulation. When neurotransmitter systems are overstimulated, some of them tend to become relatively nonreactive. One way this occurs is through a reduction in the density of the receptors for the neurotransmitter. Prozac-induced down-regulation occurs and is even mentioned in the 1991 USP DI Drug Information for the Health Care Provider, but without indicating the potentially disastrous outcomes associated with it.
Prozac as a Stimulant
There are still other ways of understanding how Prozac could produce both murderous and suicidal behavior. Prozac often affects individuals as if they are taking stimulants, such as amphetamine, cocaine, or PCP. When testing a drug for amphetaminelike or stimulant qualities In animal research, the two main criteria are an energizing effect and an appetite suppression effect - and Prozac has both. Indeed, this stimulant quality may be the main reason for Prozac's popularity.
Although Lilly makes no mention of Prozac's stimulant profile in the PDR or in its advertising, the response of many Prozac patients is indistinguishable from reactions to the amphetamines or cocaine - "elevation of mood, a sense of increased energy and alertness, and decreased appetite." Like amphetamines or cocaine, Prozac can produce the whole array of stimulant effects, such as sleeplessness, increased energy, jumpiness, anxiety, artificial highs, and mania. Some patients taking Prozac do indeed look "hyper" or "tense," and even aggressive, without realizing it. The 1990 PDR states that "abnormal dreams and agitation" are "frequent. " Prozac also has other side effects frequently associated with stimulants, including loss of appetite, tremors, various abnormal bodily movements, sweating, and headache. Indeed, the FDA's internal review of Prozac side effects by psychiatrist Richard Kapit twice mentions the drug's "stimulant" effects, but these important observations were not included in the final labeling requirements.
The PDR lists the symptoms of Prozac overdose - "agitation, restlessness, hypomania, and other signs of CNS excitation," as well as seizures-and these are similar to stimulant overdose. Consistent with this, there are many published reports of patients becoming "manic" or otherwise psychotic on Prozac. I suspect that violence in individuals taking Prozac may sometimes be associated with amphetaminelike psychoses. And finally, there is already one published report by Mark Pollach and Jerrold Rosenbaum in the January 1991 Joumal of Clinical Psychiatry that shows that some patients can use Prozac to withdraw from cocaine. We must await further animal and human studies to learn to what degree Prozac can actually substitute for cocaine and other stimulants.
The public has begun to catch on that Prozac is a stimulant. It is being referred to in the popular press as "the Yuppie Upper" and in the January 1991 Life (p. 96) as "Prozac, the new Puppie [sic] Upper."
Some people react paradoxically to uppers by becoming depressed. More important, in psychopharmacology "what goes up must come down," and we would expect some patients to crash after being high on Prozac, producing still another potential for depressed, suicidal behavior.
Are there precedents for stimulant and other addictive drugs that initially were greeted with unbounded enthusiasm? Yes. Amphetamines for weight reduction and depression were an enormous fad before doctors and the public caught on to the danger of addiction, psychosis, and bizarre behavior. Minor tranquilizers were at first dispensed freely because they were thought to be relatively safe and nonaddictive. They turned out to be very dangerous in combination with other drugs and highly addictive (see chapter 11).
Permanent Depression from Prozac?
Laboratory research in animals shows that subsensitivity can become permanent after exposure to other antidepressant drugs, and while there is as vet no direct evidence for this danger, I fear that Prozac will prove no exception. In some cases the brain may end up iieeding increasing amounts of Prozac to compensate for the subsensitivity. Are we creating a permanent need for Prozac in some patients - a virtual addiction? Although we do not yet have research confirmation, it seems highly probable to me. If Prozac can indeed alleviate depression by making more serotonin available in the brain, then with time it may produce incurable depression by making the brain relatively unresponsive to any amount of serotoniin.(3) While Prozac does not commonly produce dulling effects on the mind as obviously as the tricyclic antidepressants do, it does disrupt serotonin neurotransmission to the frontal lobes and cerebral cortex. If subsensitivity becomes permanent in that region of the brain, Prozac may also end up causing subtle irreversible lobotomylike effects.
Other Potential Long-Term Risks
Although I've not seen it discussed elsewhere, I also fear there is a potential danger of permanent neurological disorders with the long-term use of Prozac. The drug can produce temporary neurological reactions similar to those caused by neuroleptics. In the September 1989 Journal of Clinical Psychiatry, Joseph Lipinski, Jr., reports on five cases of akathisia caused by Prozac. The symptoms were objectively and subjectively indistinguishable from those produced by neuroleptics, including "severe anxiety and restlessness," floor pacing and sleeplessness, severe "jerking of extremities," and "bicycling in bed or just turning around and around."
Prozac-induced akathisia may also contribute to the drug's tendency to cause self-destructive or violent tendencies. Akathisia is very disturbing, especially if the individual does not realize what is happening. Akathisia can become the equivalent of biochemical torture and could possibly tip someone over the edge into self-destructive or violent behavior.
The PDR describes akathisia and numerous other abnormal neurological reactions as "infrequent" (occurring at a rate between 1/100 and 1/1000); but as we learned in studying tardive dyskinesia, psychiatrists typically fall to notice neurological reactions in their patients. The June 1990 Health Newsletter, produced by the Public Citizen Health Research Group, reports, "Akathisia, or symptoms of restlessness, constant pacing, and purposeless movements of the feet and legs, may occur in 10-25 percent of patients on Prozac." The Health Letter also notes that Prozac can exacerbate parkinsonism, and attributes both the akathisia and the parkinsonism to interference with dopamine neurotransmission.
Lipinski also believes that Prozae causes akathisia by indirectly suppressing dopamine, eventually causing dopamine supersensitivity or byperreactivity. Animal studies indicate that Prozac can suppress dopamine activity, and clinical reports confirm that, like the neuroleptics, it can produce not only parkinsonism and akathisia, but dystonias (muscle spasms of neurological origin).
We know that direct dopamine suppression by neuroleptics, followed by hyperreactivity, produces permanent neurological disorders, such as tardive dyskinesia, tardive akathisia, and even tardive dementia (chapter 4). What will the future show about Prozac's capacity to produce permanent neurological disease through its indirect suppression of dopamine?
The FDA and Prozac
When I ask patients or audiences, "How lengthy do you think the studies or trials were before Prozac was approved by the FDA?" most people guess several years or more. Aware of how long it sometimes takes to get FDA approval, some people assume that the drugs are tested for ten years. No one guesses the truth - that the Prozac scientifically controlled testing trials lasted a mere five or six weeks. Following that, the FDA is largely dependent on unscientific follow-up studies and anecdotal reports spanning a year or two. Once approval of the drug is then given, there is no reliable mechanism at the FDA for keeping track of dangerous effects that turn up with long-term use. Instead the FDA relies on information from the drug company itself. The FDA must keep track of so many reports that it scans them with a computer looking for unusual clusters of adverse effects. In my interviews with several past and present FDA administrators, it became apparent that long-term follow-up at the FDA is a low priority, largely because it is not demanded by the public and the Congress, which is more concerned with the initial approval process.
People assume that FDA approval and the widespread distribution of a drug - with many patients taking it for months or years- means that long-term studies have found it safe in regard to side effects, drug interactions, dependency, addiction, and withdrawal. Thus FDA approval grossly misleads the public, lulling it into an unfounded security.
The PDR also admits that Prozac's effectiveness has not been tested in controlled trials of "more than 5 or 6 weeks" and that "long-term" usefulness has therefore not been demonstrated. Yet by now many patients have been on the drug for more than a year, never imagining that it has not been tested or approved for long-term or continuous use.
Do the Antidepressants Accomplish Anything?
Despite the difficulty of showing any useful effect in the hundreds of studies thus far conducted, the antidepressants do have an impact on the mind.
Most obviously they reduce emotional responsiveness. This is why they are being used, however inappropriately, in a variety of severe anxiety disorders, such as insomnia, panic attacks, bulimia, obsessions and compulsions, various phobias in adults, and school phobia and attention deficit disorder in children. They are even used for chronic pain and for the control of aggression in brain-damaged and mentally retarded individuals. The blunting effect probably is due to a general toxicity as well as to the impact on specific neurotransmitter systems. Both the tricyclics and Prozac disrupt neurotransmission to the frontal lobes of the brain.
In many of their uses, the tricyclics are substitutes for the chemically related phenothiazine neuroleptics and their lobotomizing impact. Since the neuroleptics produce a more severe motor retardation-including a flat facial expression and restrained bodily movements-they would look as if they were worsening the symptoms of depression. Therefore the antidepressants, which cause less motor slowing, are preferred by psychiatrists as flattening agents for depressed people.(4)
Most antidepressants also have a tendency to rev up the brain, sometimes producing euphoria and more rarely delusions and hallucinations. These effects are most unwanted when trying to control an already excited "schizophrenic" individual. For that purpose, the stupefying, muscleparalyzing effects of the neuroleptics are preferred.
The antidepressants also tend to produce an organic brain syndrome or delirium - the brain's response to generalized damage from any source, such as toxic drugs, viral encephalitis, or electroshock. It is characterized by memory difficulties, confusion, disorientation, impaired judgment, mood instability, and generalized intellectual malfunction. As we'll document in the next chapter, this is exactly what happens in electroshock and provides the so-called antidepressant effect of that treatment as well. A patient typically is rendered unable to stay depressed during an episode of organic brain dysfunction, because depression requires a relatively I 'ficially euphoric intact brain and mind. Rendered either apathetic or arti by brain dysfunction, the patient is evaluated as "improved."
In their mild delirium, patients themselves will say they are improved, due to the temporary high or euphoria associated with the initial stages of brain dysfunction and delirium. This is a familiar phenomenon that occurs frequently during the early stage of alcoholic intoxication. As in intoxication with alcohol, mild degrees of drug-induced delirium may be undetected by the patient or other observers and yet impair the individual's capacity to feel anything, including depression.(5)
In a study entitled "Confusional Episodes and Antidepressant Medication" in the July 1971 American Journal of Psychiatry, Robert Davies and a team from Yale examined the charts of 150 consecutive patients receiving relatively small doses of antidepressants on a thirty-bed intensive treatment psychiatric ward. They looked for symptoms of delirium, including "evening restlessness and pacing, followed by sleep disturbances" and progressing to "forgetfulness, agitation, illogical thoughts, disorientation, increasing insomnia, and, at times, delusional states."
The average drug-induced episode lasted a week, with a range of three to twenty days, which again is typical of shock treatment as well. It afflicted more than one-third of the patients over age forty, the average percentage of patients usually judged improved by antidepressant treatment. The authors themselves note that the onset of the acute organic brain syndrome-two to four weeks after the start of drug treatment - coincides exactly with the period when drug-induced relief from depression usually begins.
Unhappily, the authors completely fail to connect the brain dysfunction with the supposed recovery from depression. We shall find the same failure when we examine the relationship between brain dysfunction and supposed recovery after electroshock.
In summary, the antidepressants probably have no specific antidepressant effect. Their clinical impact derives from any one of, or a combination of, at least four factors: (1) enhanced placebo effect, (2) emotional blunting, (3) an energizing or stimulant effect, and (4) the artificial euphoria or apathy associated with an organic brain syndrome. With it all, there is little evidence that they are of net benefit to depressed people.
Dispensing with Antidepressants?
Depression is routinely treated by many psychotherapists working with individuals, families, and groups. Many psychotherapists wouldn't dream of prescribing a drug for anything so obviously psychological and spiritual in origin. They would resist blunting the passions of the already "out of touch" or suppressed person.
Even in a full-time lifetime general practice of psychiatry it's possible to offer help without ever starting a patient on antidepressants. Depressed people don't tend to hurt themselves when they have a good relationship with a therapist and some hope of improvement. I try to help individuals experience their feelings, to understand the sources of their despair, and to overcome hopelessness, while providing a caring, morale-building relationship and guidance toward more effective ways of living. Often this involves the client learning new, more positive values and a more daring, creative approach to life.
Nor do I think that I am more effective as a therapist than many others in the field. There are no "great therapists," only great clients. From my conversations with nonmedical therapists - such as psychologists, social workers, counselors, and family therapists - I find that many of them work successfully with severely depressed clients without ever referring them to a physician for drugs or electroshock.
Furthermore, the vast majority of people overcome depression without resort to any mental health services. They do so by virtue of their own inner strength, through reading and contemplation, friendship and love, work and play, religion, art, travel, beloved pets, and the passage of time-all of the infinite ways that people have to refresh their spirits and to transcend their losses.
Since the antidepressants frequently make people feel worse, since they interfere with both psychotherapy and spontaneous improvement by blunting the emotions and confusing the mind, since most are easy tools for suicide, since they have many adverse physical side effects, since they can be difficult to withdraw from, and since there's little evidence for their effectiveness - it makes sense never to use them.
1. This is called blocking re-uptake of serotonin.
2. See chapter 7 for my criticism of directly associating particular biochemical alterations with specific behaviors.
3. This tendency to produce the very symptoms that it seeks to cure is similar to what we have seen with the neuroleptics. 'Me neuroleptics initially suppress psychotic symptoms, but the long-term effect is to produce permanent psychoses that make it difficult or impossible to remove the patient from the drugs (chapter 4).
4. Nonetheless, many patients on antidepressants do develop a zombielike reaction.
5. The patient's failure to recognize toxicity also will be discussed in regard to lithium and minor tranquilizers.
Peter Breggin's Home Site - 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.
Brain-Disabling Treatments in Psychiatry : Drugs, Electroshock, and the Role of the FDA Today! by Peter R. Breggin, M.D.
The Manufacture of Madness : A Comparative Study of the Inquisition and the Mental Health Movements by Thomas S. Szasz, M.D., Professor
Law, Liberty, and Psychiatry : An Inquiry into the Social Uses of Mental Health Practices by Thomas S. Szasz, M.D., Professor
The Limits of Biological Treatments for Psychological Distress by Seymour Fisher and Roger P. Greenberg
Psychiatric Drugs: Hazards to the Brain by Peter R. Breggin, M.D.
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