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Prozac Backlash

Reviewed by Siegfried Othmer

There is a life cycle for the common psychiatric medications that seems to be regularly repeated, almost like economic cycles. A new type of medication first appears; it is touted strongly by advocates; it gains wide acceptance and becomes "indispensable" to our wellbeing; the story then turns flat as problems crop up; these "side effects" turn out not to be isolated at all; people wonder how the problems could have been missed for so long; regulatory clamps are put on the drugs; they are often relabeled; the drugs fade from the scene, or the are pushed off the stage, as another class of drugs moves into the limelight. With each new kind of drug, the expectation is that the earlier experiences made us wiser; the new drugs avoid the shortcomings of the old, and therefore the new claims can be taken more seriously. We buy in, and then the cycle repeats itself.

Is the class of Prozac-type drugs, the serotonin reuptake inhibitors (SSRIs), different? Apparently not, according to an exhaustive treatment by Harvard psychiatrist Joseph Glenmullen in a book called Prozac Backlash. In chilling recitation from over 600 technical references, Glenmullen pulls together what amounts to a broadside indictment of the SSRIs. In a manner reminiscent of the early paean to cosmetic pharmacology, namely Listening to Prozac, by Peter Kramer, Glenmullen pieces together the story out of his own clinical experience, and then digs into the sometimes obscure clinical literature to gain backup for his emerging suspicions.

In 1993, Kramer wrote: "There is no unhappy ending to this story." But hold on. We may find that the SSRI's will recapitulate the classic life trajectory of earlier classes of psychoactive drugs. Problems surface about ten years in, and are first vigorously denied by apologists for the drug companies. The emerging data become compelling by about twenty years, despite efforts to suppress publication. Then it takes another ten years for regulatory efforts to come up to speed and curtail over-prescribing. "Thus, the cycle from miracle to disaster typically takes thirty years or more." By then the patent has expired and the manufacturer is pushing something else.

This pattern has been observed numerous times in the last century. The first potent antidepressants were cocaine elixirs, which became the most popular prescription medications. Freud wrote three papers touting the use of cocaine. Even Coca Cola used to be a vehicle for its administration, as the name implies. Then came the bromides, the barbiturates, the amphetamines, the narcotics, and the tranquilizers. Each class of drugs, in turn, was hailed as a miracle cure until their dangerous side effects emerged later. Each reached significant penetration into the population.

Glenmullen accumulates evidence for the emergence of tic behavior, the first sign of the development of tardive dyskinesia that was the downfall of the major tranquilizers. The neurological side effects of serotonin boosters turned out to include not only tics but also profound agitation, muscle spasms, and symptoms of Parkinsonism. These problems are not isolated. Agitation, which may involve involuntary feet tapping, etc., can occur in up to 25% of patients.

Mercifully, many of these symptoms are largely reversible when drug treatment is halted. But the similarity of these symptom clusters to what happened with the earlier tranquilizers is sobering. Tics are "the dread side effect of psychiatric medications because no effective treatment exists." Thomas Moore (of the George Washington University Medical Center) laments the "illusion of safety" that comes from the fact that the more serious drug problems tend to be slow and insidious at the outset, and difficult to see early on.

Along with classic Parkinsonism symptoms, there may be fatigue or indifference, a blunted feeling or a disinclination to move. These symptoms are also reminiscent of early Parkinson-type problems. And even if these remediate upon discontinuation of the medication, one must be concerned about long-term vulnerability. The author does not hesitate to use the term brain damage in describing the deficits.

These motor symptoms are largely traceable to the dopamine system, where the major tranquilizers achieved a suppression of dopamine function. The secondary effect of the serotonin boosters may also suppress dopamine function in a similar fashion. Direct measurements have documented a 50% drop in dopamine level in the involuntary motor system with Prozac-like drugs. There appears to be no free lunch. One cannot expect to impact on one neurotransmitter system alone. The history with major tranquilizers may give a clue as to what might be in store. Initially, it was thought that only vulnerable populations were susceptible to the tardive dyskinesia. However, as time went on it became clear that nearly everyone was at risk. Whereas only a third of patients were affected within the first five years, it was a majority after fifteen years, and two-thirds by 25 years. If the SSRI's are recapitulating this history, it will be obvious soon enough.

Additionally, there are significant problems of sexual dysfunctions---beyond mere loss of libido. These problems may affect as many as 60% to 75% of users. They include inhibited sexual arousal; erectile dysfunction; impotence; vaginal anesthesia; delayed or inhibited ejaculation; and paradoxical hypersexuality. The effect on relationships can be larger and more problematic than those of the mild depression that motivated treatment. As it happens, these sequelae are similar to what is observed with the major tranquilizers!

More serious are the reports of suicidality and violence directed outward. The initial findings were reported by Martin Teicher, a respected psychiatrist at the Harvard Medical School. Initially, these reports were dismissed as nothing more than the known vulnerability to suicide seen with all antidepressants during the early phase of recovery. Eventually, it became clear that the suicide risk elicited by the SSRIs was an entirely different phenomenon, associated not so much with depression as with the severe agitation and mania induced by SSRIs. The drugs also tip some patients into paranoia or plain psychosis, both of which can increase the risk of suicidality and violence. According to Teicher, patients showed up with intense, violent, suicidal preoccupations. There was a dramatic change in people, which was out of character for them. The extraordinary degree of violence, and the extremely painful, gruesome behavior exhibited by people on Prozac was atypical of traditional suicidal patients.

When it comes to such rare but severe side effects, there is a sample size problem. These problems don't necessarily show up in formal studies, or they get lost because of poor statistics. Data have to come in from the field as drug usage mounts. David Kessler, former Commissioner of the FDA, estimates that only about 1% of serious events [side effects] are reported to the FDA. With side effects of lesser severity, the reporting incidence is even lower. So the reported data are probably only the tip of the iceberg, or rather one tenth of the tip. But because these data are not gathered systematically, they are attacked by manufacturers as being unscientific. This is clearly disingenuous, in that a formal and systematic study (which they show no inclination to do) could only show up a worse problem.

Glenmullen also describes a variety of withdrawal symptoms. In the psychological realm, these include anxiety, agitation, crying spells, and irritability (and these may not be of garden variety severity). Physical symptoms include disequilibrium, gastrointestinal symptoms, flu-like symptoms, and sleep disturbances. Additional withdrawal symptoms frequently reported include electric shock sensations, dizziness, visual hallucinations, paradoxical weight gain, and rebound anger and irritability. There may be aggressiveness and suicidal impulsivity, and incapacitation for several days is a possibility. Withdrawal symptoms can even show up in a baby that's being breast-fed.

Withdrawal symptoms are of course classic signs of drug dependence and addition. There is confirming evidence of drug dependence of various kinds. Drug effects appear to wear off in 30-40% of patients over time, a phenomenon so well known it is referred to as Prozac poop-out. This is a manifestation of drug tolerance, another feature of addictive drugs. Then there is the phenomenon of sensitization of brain cells by psychiatric drugs, known as supersensitivity. There is a heightened likelihood of relapse after withdrawal from the drug, and that may itself be a consequence of taking the drug. Relapse after successful psychotherapy for depression is 23% over two years; for the SSRI's, relapse after successful treatment is 78% over the same span. Relapse in manic depression comes seven times more quickly than the cycling pattern before the medication. These are clearly drug-induced effects on the competence and stability of the nervous system.

Because of the serious implications of withdrawal symptoms for how these drugs are regarded, a more benign term has been adopted by the industry: "Antidepressant discontinuation syndrome." But dependency it is. Fortunately, there is one unequivocal answer for withdrawal symptoms, and that is reinstatement of the drug regimen!

All these phenomena deserve serious investigation. Regarding doing systematic studies, Donald Klein, professor of psychiatry at Columbia University says "the industry is not interested; the NIMH is not interested; and the FDA is not interested." There can be no doubt that this is a pattern. In over sixty years of administration of stimulant medication to ADHD children, the long-term safety of this approach has never been formally evaluated. Drug company researchers probably already know that formal research could only render concrete all the concerns that are now cropping up in the literature. But there is more.

The model of depression under which Prozac and its relatives are being so liberally administered is no doubt faulty. Sherwin Newland, historian of medicine at the Yale University School of Medicine denounced the hypothesis of serotonin deficiencies and biochemical imbalances as no more than junk science. There is no restoration of appropriate serotonin level. Barry Jacobs, professor of neuroscience at Princeton University points out that most external (drug) manipulation of serotonin levels takes these "beyond the physiological range achieved under [normal] environmental/biological conditions." Boosting serotonin to this degree "might more appropriately be seen as pathologic rather than reflective of the normal biological role of [serotonin]."

Steven Hyman, former Director of the National Institutes of Health, avers that such hyperstimulation triggers "compensatory reactions in the brain in its efforts to achieve "a new adapted state which may be qualitatively as well as quantitatively different from the normal state." Such reactions may explain the phenomena of withdrawal, dependence, tolerance, and supersensitivity. Says Glenmullen: "The unfortunate irony is that drugs heavily promoted as correcting unproven biochemical imbalances may, in fact, be causing imbalances and brain damage." "Future generations may well look back on the last 150 years of these drugs as a frightening human experiment."

Glenmullen challenges the very assumptions of biological psychiatry. To treat all psychiatric symptoms as though they were exclusively biological he sees as unnacceptable reductionism. What should properly be regarded as syndromes are fit inappropriately into the disease model, a model that receives support from the drugs used to treat them. Nevertheless, the model rests on three "pseudo-scientific cornerstones": 1) superficial checklist diagnoses; 2) putative "biochemical imbalances," and 3) alleged genetic determinism.

It appears that in various ways, the trajectory of Prozac mirrors what happened with the major tranquilizers. First of all, they were administered for many of the same conditions as Prozac: mild depression, anxiety, nervousness, and insomnia. Secondly, they made major inroads into the population, just as the SSRI's are doing. Thorazine was administered to some 50M patients in the US by the ten-year mark, 1965, and eventually an estimated 250M were served worldwide. By 1973, some 2000 cases of tic disorder had been identified, and those who raised the issue were denounced as "uninformed alarmists" and "extremists among consumer advocates." But once the issue had come into focus, confirming data accumulated. Nevertheless, "only in 1985, because of intense pressure resulting from media coverage of side effects, did the FDA finally require manufacturers to add a warning to the drugs' labels, alerting doctors and patients to these serious side effects. This was more than thirty years after the introduction of Thorazine and decades of indiscriminate use of the popular drugs." Initially called tranquilizers, after the side effects were documented they were then called major tranquilizers, and more lately antipsychotics and neuroleptics.

There may soon be a backlash against the new medications, as the pervasiveness of the negative long-term implications sink in. Cautions are already being raised. As early as 1992 Van Putten of UCLA compared the Prozac-induced "restlessness, pacing, insomnia, and obsessional suicidality" to that seen with major tranquilizers. Dr. Ronald Pies said in the December 1997 Journal of Clinical Psychopharmacology that Prozac type drugs "should not be prescribed to the 'worried well' or for patients with mild depression." Says Glenmullen: The "behavioral toxicity" of serotonin boosters is too great for them to be used merely as "psychoanalgesics," rather than for major depression. He estimates that 75% of users could radically reduce or even eliminate the SSRIs. Ironically, the anti-depressants were never really tested against major depression, and may not be the best choice there either, vis-à-vis the older tricyclics, for example. It was the larger market of the "worried well" that the drug companies were targeting all along.

And what of drug company behavior throughout all this? The evidence Glenmullen pulls together amounts to a major scandal. The research was not very scientific, and the claims for the research were overblown. Drug companies seem complicit in the suppression of adverse data. Entanglements with the FDA leave a citizen feeling vulnerable. One fears a compounding of crooked science with devious politics and strident propaganda, all lubricated with an unseemly concentration of wealth. The supporting evidence is presented very well in the book, which piles disagreeable anecdote upon contemptible disclosure. The analogy to cigarette companies comes readily to mind: Long-term brain damage doesn't seem to weigh heavily in the scales of near-term financial returns. When all these biased incentives are combined with Managed Care, the result is a "Satanic mix," according to Leon Eisenberg of the Harvard Medical School.

So how is this bombshell of a book being received in the world at large? A review by Jane Allen, a medical writer for the Los Angeles Times, may be indicative. The review finds the science lacking! Astounding, given the 600+ technical references. Allen sounded like a pharmaco-religious acolyte defending to the last the "Church of Prozac." This book is orders of magnitude richer in data than was Listening to Prozac, for example. The review indicates how entrenched mainstream thinking has become, and how difficult it will be to dislodge. Even though we are recapitulating the earlier history of the neuroleptics, we may have to learn the lesson all over again, and perhaps at the same rate.

And then there is Neurofeedback.

Siegfried

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