March 30

Are Drugs Always Needed for Schizophrenia? What does the Scientific Evidence Show?

“This study investigates the question of whether short periods of medication-free research in early episode schizophrenia result in demonstrable long-term harm to human subjects. A meta-analysis of published quasi-experimental and random assignment studies that had a majority of first or second-episode schizophrenia spectrum subjects, at least 1 initially unmedicated group, and a minimum of 1-year results was conducted. Only 6 studies, with 623 subjects, met inclusion criteria. The initially unmedicated groups showed a small, statistically nonsignificant long-term advantage (r = _0.09). Incorporating only random assignment studies into a composite effect size produced a similar near-zero result (r = 0.01). Good-quality evidence is inadequate to support a conclusion of long-term harm resulting from short-term postponement of medication in early episode schizophrenia research. A categorical prohibition against such research should be reconsidered.” [1]

For decades, the psychiatry’s opinion leaders have admonished clinicians against waiting before starting patients who first present with psychotic symptoms on antipsychotics: “Delaying treatment, may damage the brain.”

However, these pillars of schizophrenia research provided no evidence–other than their "expert" opinion, and resolutely avoided examining patients long-term outcome which would reveal whether the drug-centered paradigm of treatment improves patients lives. That drug-paradigm has not been put to the test of science; it rests on a single speculative article by Dr. Richard Wyatt, an influential psychiatrist at NIMH. [2]

Dr. Bola notes, “'The most striking observation in this review is the dearth of evidence that addresses the long-term effects of initial treatment.''

Dr. William Carpenter, director of the University of Maryland's Psychiatric Research Center and the editor of the Schizophrenia Bulletin, said that while antipsychotics are central to treatment in most cases the field's aggressive use of the drugs leaves ''little maneuvering room'' to try different options, like drug-free periods. ''It's a very controversial issue, and I thought it was important to get it out there.''

The drugs cause severe, irreversible harm—including diabetes, hyperglycemia, and early death–they carry Black Box warnings. Though not approved for use in children, a new report by Vanderbilt University reveals that 40 of every 1,000 children were prescribed antipscychotics off-label in 2002–that's 2.5 million children. [3]  

The Times reports, “Studies suggest that 10 percent to 40 percent of people with symptoms of psychosis can manage without medication.”
One has to wonder what exactly is the evidence referred to when practicing psychiatrists  claim to be practicing, “evidence-base medicine?” What criteria are used for making a risk / benefit assessment?

The response to Bola’s article by several key opinion leaders in psychiatry has been hostile—even irrational:  “experts warned that the new report's conclusions were dangerous.”  When told of the Bola review, Dr. Jeffrey Lieberman, chairman of psychiatry at Columbia University and director of NYS Psychiatric Institute, exclaimed: “not treating with medication is a huge mistake that risks the person's best chance at recovery. It's just flat-out nuts.''  

Dr. Lieberman, however, did not point to any evidence to back up his “emphatic” position despite the fact that the NIMH CATIE study—which he led—comparing the treatment effects of the new and older schizophrenia drugs, found that within 18 months, 64% to 82% of patients stopped taking the drugs because they were dissatisfied. [4]

Indeed the drugs’ adverse effects on patients’ metabolic system is so severe—changes in blood glucose, cholesterol, triglycerides, acute humongous weight gain–psychiatrists refer to drug-induced phenomena as “The Evolution of Metabolic Syndrome.”
[Dr. Henry Nasrallah, University of Cincinnati, Nordic Psychiatry conference, Jan. 2006]

Dr. Thomas McGlashan, Yale psychiatrist acknowledges the double edged sword of the atypical antipsychotic drugs:
 ''Medication can be lifesaving in a crisis, but it may render the patient more psychosis-prone should it be stopped and more deficit-ridden should it be maintained.''

The drugs are triggering chronic debilitating disease, increasing drug dependency, diminishing the quality of life, and lowering life expectancy.  The Times correctly reports,  “antipsychotic medication also induces significant changes in brain function that are not well understood. The drugs numb brain cell receptors to the activity of dopamine, a neural messenger that appears to circulate at high levels when people are in the grip of psychosis.”

Our oft repeated criticism—directed in particular at science reports in the Times—is failure to inform readers about financial ties of the experts quoted—so that the conflicts of interest are made visible:

In a Medscape interview, Dr. Lieberman disclosed that he has received grants for clinical research or educational activities from AstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline, Janssen, and Pfizer. He has served as an advisor or consultant to AstraZeneca, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Janssen, Johnson & Johnson, Novartis, and Pfizer. Dr. Lieberman also holds a patent from Repligen. See:

Following the Times article—lacking financial disclosure information—is a commentary by prize winning science writer, Robert Whitaker, who first analyzed the FDA pre-marketing data and reported the signs that foreshadowed the debilitating effects of the atypical antipsychotics. His findings have never been contested nor contradictory evidence presented. Neither has anyone from the psychiatric establishment stepped to the plate in a public debate. Mr. Whitaker is the author of: Mad in America (Perseus, 2001), Mapmakers Wife (Basic Books, 2004), Twelve Condemned to Die (Crown, 2007).

1.John Bola Schizophrenia Bulletin, 2006, Vol 32(2): 288-296.
2. Wyatt RJ. Neuroleptics and the natural course of schizophrenia. Schizophr Bull. 1991;17:325–351.
3. Cooper, et. al. Trends in Prescribing of Antipsychotic Medications for U.S. Children,  Ambulatory Pediatrics, 2006;6:79–83.
4. Lieberman JA, Stroup TS, McEvoy JP, et al. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med. 2005;353:1209-1223. Abstract

Contact: Vera Hassner Sharav  
Revisiting Schizophrenia: Are Drugs Always Needed?
March 21, 2006

The only responsible way to manage schizophrenia, most psychiatrists have long insisted, is to treat its symptoms when they first surface with antipsychotic drugs, which help dissolve hallucinations and quiet imaginary voices.

Delaying treatment, some researchers say, may damage the brain.

But a report appearing next month in one of the field's premier journals suggests that when some people first develop psychosis they can function without medication — or with far less than is typically prescribed — as well as they can with the drugs. And the long-term advantage of treating first psychotic episodes with antipsychotics, the report found, was not clear.

The analysis, based on a review of six studies carried out from 1959 to 2003, exposes deep divisions in the field that are rarely discussed in public. In the last two decades, psychiatrists have been treating people with antipsychotic drugs earlier and more aggressively than ever before, even testing the medications to prevent psychosis in high-risk adolescents.

The studies demonstrate that the drugs are the most effective way to stabilize people suffering a psychosis. Millions of people rely on them, and the new report is not likely to alter the way psychiatrists practice anytime soon.

But some doctors suspect that the wholesale push to early drug treatment has gone overboard and may be harming patients who could manage with significantly less medication, perhaps because they have mild forms of the disorder. About three million Americans suffer from schizophrenia, and a vast majority of them take antipsychotic drugs continually or periodically.

''My personal view is that the pendulum has swung too far, and there's this knee-jerk reaction out there that says that any period off medication, even for research, is on the face of it unethical,'' said Dr. William Carpenter, director of the University of Maryland's Psychiatric Research Center and the editor of the journal Schizophrenia Bulletin, which will publish the article on April 1, along with several invited commentaries.

Dr. Carpenter said that while antipsychotics are central to treatment in most cases the field's aggressive use of the drugs leaves ''little maneuvering room'' to try different options, like drug-free periods under close observation after a person's first episode of psychosis. ''It's a very controversial issue, and I thought it was important to get it out  there,'' he said.

Other experts warned that the new report's conclusions were dangerous, and  represented only one interpretation of the evidence.''I am usually a pretty moderate person,'' said Dr. Jeffrey Lieberman, chairman of psychiatry at Columbia University Medical Center and director of the New York State Psychiatric Institute. ''But on this I am 110 percent emphatic: If the diagnosis is clear, not treating with medication is a huge mistake that risks the person's best chance at recovery. It's just flat-out nuts.''

In the report, John Bola, an assistant professor of social work at the University of Southern California, reviewed six long-term studies involving 623 people who had symptoms of psychosis. All of these men and women entered the studies soon after their psychosis was diagnosed, after a first or second break from reality. In the studies, roughly half of the patients were promptly treated with antipsychotic drugs while the other half went without the medication for periods ranging from three weeks to more than six months.Those who functioned well without medication remained drug free in several of the studies. Those who relapsed received drug treatment.

Two studies found that after a year or more the patients on a full course of medication performed better on measures of social interaction, work success and the risk of rehospitalization than those who were initially drug-free.

The other four studies found the opposite: that the less-medicated group did slightly better. Over all, the findings of the studies were a wash, showing no significant advantage for either group. The patients on full medication were taking older antipsychotics, like Haldol; similar studies have not been carried out with newer drugs, like Risperdal.

''The most striking observation in this review,'' Dr. Bola wrote in the paper, ''is the dearth of evidence that addresses the long-term effects of initial treatment.''

Previous reviews concluding that drugs provided significant benefits included many studies that did not have a comparison group of people who were not on medication, he found.  ''My hypothesis is that there is a subgroup of patients who are drug-free responders, probably because they have a mild form the disorder,'' Dr. Bola, who has argued against aggressive drug treatment in the past, said in an interview. ''I think the implications of this are that we need to be additionally careful about medicating people after their first psychotic episode if there's reason to think they could'' function without medication.

Studies suggest that 10 percent to 40 percent of people with symptoms of psychosis can manage without medication. But there is no test to identify these people, and psychiatrists say that withholding drugs after a full-blown psychotic episode is highly risky. Psychotic episodes tend to become worse over time when untreated, they say, and the effect of the experience on the brain is still unknown.

''The psychotic state is a crisis, an emergency; people do irrational things, dangerous things, and the initial treatment has to be with what works best — medication — along with an attempt to get them into a talking relationship,'' said Dr. Thomas McGlashan, a professor of psychiatry at Yale.

The issue is most important to patients and their families. First episodes of psychosis, which often strike in high school or college, can derail young people at a crucial point in their lives and even lead to suicide. John Caswell, 50, a writer and an artist living in Lebanon, N.H., said he tried to kill himself twice after going off medication.

''Once I was driving around and having hallucinations, listening to a gospel station, and I had this strong feeling that I should die and would wake up after that and start life anew,'' he said in an interview. He purposely drove his car off the road and into a guardrail, he said.

Since then, Mr. Caswell has managed his symptoms with Risperdal, an antipsychotic he takes daily. He says he relies on the drug, ''like a diabetic needs insulin.''

Yet a large, study in 2005 comparing the schizophrenia drugs found that over 18 months, about three-quarters of people stopped taking the medications they were on because they were dissatisfied. The drugs have significant side effects: older medications can induce Parkinson's disease-like tremors and the movement disorder known as tardive dyskinesia; some of the newer drugs also induce weight gain and increase the risk of diabetes; and in elderly people, both classes of drugs have
been linked to higher rates of premature death.

Antipsychotic medication also induces significant changes in brain function that are not well understood. The drugs numb brain cell receptors to the activity of dopamine, a neural messenger that appears to circulate at high levels when people are in the grip of psychosis.

Ever adaptable, the body responds by manufacturing more dopamine receptors, which could make the brain more sensitive to future dopamine onslaughts that are untreated, experts say.

''Medication can be lifesaving in a crisis, but it may render the patient more psychosis-prone should it be stopped and more deficit-ridden should it be maintained,'' Dr. McGlashan of Yale wrote in a commentary that accompanied Dr. Bola's report.

For these reasons, many former psychiatric patients have challenged the wisdom of treating psychosis aggressively and early, especially for high-risk patients who have not yet shown full-blown psychotic symptoms.

''If I had stayed on medication, I don't think there's any way my life would be as together as it is now,'' said Will Hall, 40, a mental health advocate in Northampton, Mass., who was hospitalized 14 years ago and put on antipsychotics for about four months after a suicide attempt.

Mr. Hall said that he still heard voices, machine sounds and imaginary conversations but that the hallucinations had become less threatening over time. ''I am very careful about the early warning signs, the noises, the sounds, and I make sure to talk to people and resist the urge to isolate myself,'' he said in a telephone interview. ''People can learn tricks, ways of dealing with symptoms so they don't get overwhelmed.''

Several programs have helped people manage psychotic symptoms with minimal use of medication. In one, researchers in Finland found that intensive family therapy helped more than 40 percent of patients with early symptoms of psychosis recover significantly without antipsychotics — and they have remained off the drugs, for more than two years.

Another program, in Sweden, also has found that many people do well when treated with low doses of antipsychotic medications, or none at all, after their first psychotic break.  

But both countries have health care systems in which psychotherapy and in-hospital care are readily accessible. In the United States, psychiatrists say, taking patients off medication would leave them vulnerable to life-altering relapses without sufficient support. Only in research settings, with carefully informed consent, are doctors likely to allow people suffering from a first psychosis to go drug free, they say.

''My bottom line is that this is a very challenging illness, every patient is different, and we need more research to inform decisions about how to individualize care,'' said Dr. John Kane, chairman of the psychiatry department at Zucker Hillside Hospital in Glen Oaks, N.Y. With certain patients, he added, ''We have to be very careful about making blanket statements about which treatment is best.''

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Commentary by Robert Whitaker:

The story by the New York Times just cracks open the door a bit on a question that psychiatry has avoided addressing at all costs: If you take people newly diagnosed with schizophrenia, and treat them either with drugs or with a placebo, which group will do better over the long run?

Now Bola, as he reviewed the data, could only find seven studies since the introduction of neuroleptics that could be seen as well designed, and with a total of only 623 subjects, that addressed this question. And the placebo group in these studies is of this sort: Patients are not immediately put on the drugs. Those who don't get better after a period of time (3 to 6 weeks) are then put on the drugs. So you could say that the placebo group, over the long term, involves selective use of the drugs. Now here are the results form the seven studies:

Wirt and Simon, 1959. This one involved 80 first-admission patients treated in a VA hospital, and it found that one year later, the drug-treated group had somewhat better social functioning and slightly  lower work ratings. I should note that when I wrote Mad in America, I skipped this study because the NIMH, when it conducted its first big  study in the early 1960s, basically concluded that all earlier studies were poorly designed, lacked statistical significance, etc.

The NIMH collaborative research study. This is the 1960s study which found that while drug-treated patients at six weeks fared better than placebo patients, at one year a smaller percentage of the placebo patients had been rehospitalized. So even on the target symptom of psychosis, patients treated initially without drugs (and some never got drugs) did better.

The next was the May study, also done in the 1960s, which is a very complicated study because it had four arms: electroshock, drug, psychotherapy without drug, and placebo. Again, over the short-term, the drug-treated patients, in terms of remission of psychotic symptoms, did better than either of the two groups treated without drugs. And over the long-term, the psychotherapy patients didn't do well, and so this study became to be cited as showing why you couldn't treat patients without drugs. However, and this point is never noticed, 59% of patients in the placebo group–no drugs and no therapy sessions with a psychiatrist–were successfully discharged in the initial study period, and this group "functioned over the (long-term) at least as well, if not better, than the successess from the other treatments."

In other words, 3 of every five patients, if treated with placebo (but not with psychotherapy), got well enough to leave the hospital, and it was this group that arguably had the best long-term outcomes of any group in the study.

Now the remaining four studies Bola looked at were all more recent studies (1970s to 2000), and all involved providing the placebo patients with some sort of environmental support (rather than just giving them no drugs in a hospital setting).  And in each of these studies, the group treated experimentally–as Bola reported–did better. They had lower relapse rates and higher social functioning. Moreover, if you look at those studies, somewhere between 37% and 65% of the patients treated initially with placebo never went on the drugs during the follow-up periods, which I think ranged from one to five years.

So what does this body of research actually show?

It shows that if you treat first-episode patients without drugs in a supportive environment, these patients–as a group–will do better over the long term, even on the target symptom of psychosis. And of course those patients who never go on the drugs–37% to 65% of the patients–will not suffer all the physical side effects from the drugs, the emotional dampening, etc., and this group will be the best functioning group as well. That's what all four experimental programs have reported.

It was good and even brave, given the prevailing wisdom in society about drugs and schizophrenia, that the NY Times dared to suggest that some people so diagnosed might do better without the drugs. But the article only hinted at the real story here, and that is that the science shows that such experimental care, which involves not immediately putting people on drugs so you can see who might do well without them, would provide better outcomes than what we see today with our drug-everybody approach.

I should note that Bola, in his article, didn't frame the question quite this way, as it would have been too radical. Instead, he framed it as a question of whether newly diagnosed people can be treated without drugs for a period of time in order to do "research." And so he concludes that yes, you can. What is scandalous, of course, is that we have this body of evidence showing a better way, and we can't even discuss it. It's considered beyond the pale, or as Dr. Lieberman would have it, "nuts."  He, of course, has been a big-time consultant for the drug companies, and in so labeling this notion "nuts," is not speaking about what the science shows, but what ideas money will support.

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