A Schizophrenia Mystery Solved?


One of the enduring mysteries in schizophrenia research circles has been the disparity in outcomes between schizophrenia patients in “developing countries” and those in “developed” countries. The mystery arose in 1979 when World Health Organization investigators announced that, in a five-year study, patients in developing countries had fared better than those in the United States and other “developed” countries. A second study then produced the same startling results. In developing countries, the WHO researchers concluded, schizophrenia patients enjoyed “an exceptionally good social outcome,” whereas living in a developed country was a “strong predictor” that a person would never fully recover.

But today, according to a recent report by Eli Lilly investigators who are conducting a study of 17,000 schizophrenia outpatients in 37 countries, that disparity in outcomes has largely disappeared. And therein, I believe, lies a clue to solving the original mystery.

WHO’s Hypothesis

After the first study, the WHO researchers naturally speculated about the causes of the disparity in outcomes, and one of their hypotheses was this: Perhaps the patients in the developing countries were more medication compliant. This hypothesis made sense — antipsychotics presumably improved long-term outcomes — and so the WHO researchers, in the second study, assessed medication usage. However, they found that in the three developing countries-India, Colombia, and Nigeria-only 16% of the patients were regularly maintained on antipsychotics, compared to 61% of the patients in the developed countries. Outcomes were better in countries where patients weren’t regularly maintained on the drugs.

Once the WHO researchers had this data in hand, they turned their attention to cultural differences as the likely source of the disparity in outcomes. Perhaps patients in the poor countries are not as isolated and are better able to find work. Any thought that a variance in medical treatment might be the cause of the disparity in outcomes was mostly forgotten. But, if we return to their initial hypothesis today, it seems fair to raise this long-neglected question: Is it possible that a paradigm of care that involves selected, limited use of antipsychotics would produce better long-term outcomes?

The Outcomes Literature for Antipsychotics

Thorazine was introduced into asylum medicine in 1954, and so there is a 50-year history of outcomes studies that can be tracked to determine how the drugs affect the long-term course of schizophrenia. Here are just three of the many surprises to be found in that history:

    •    When Boston University’s Courtenay Harding studied the long-term outcomes of 168 chronic schizophrenics discharged from Vermont State Hospital in the 1950s and early 1960s, she found that 34% were recovered 20 years later. This meant they were “asymptomatic and living independently, had close relationships, were employed or otherwise productive citizens, were able to care for themselves, and led full lives in particular.” All of the people in this recovered group shared one thing in common: They all had “long since stopped taking medications,” Harding told the APA Monitor. It was a “myth,” she concluded, that people with schizophrenia “must be on medication all their lives.”

    •    During the mid 1990s, MRI studies found that antipsychotics can cause basal ganglion structures and the thalamus to swell, and the frontal lobes to shrink. Then, in 1998, Raquel Gur at the University of Pennsylvania reported that the swelling of the basal ganglia and thalamus was “associated with greater severity of both negative and positive symptoms.” In other words, this research showed that the drugs cause morphological changes in the brain that are associated with a worsening of the very symptoms the drugs are supposed to treat.

    •    In 2007, Martin Harrow reported on the 15-year outcomes of a group of 64 schizophrenia patients he had been following since the 1980s. Forty percent of those off meds were in recovery (and more than 60% were working), whereas only five percent of those taking antipsychotics were in recovery (and few were working.) Only 28% of those off meds still suffered psychotic symptoms at the end of 15 years, versus 64% of those still on meds. “I conclude that patients with schizophrenia not on antipsychotic medication for a long period of time have significantly better global functioning than those on antipsychotics,” Harrow said at the 2008 annual meeting of the American Psychiatric Association.

At the very least, these three studies provide support for the idea that selective, limited use of the medications would produce better long-term outcomes than a “continual use for all patients” paradigm of care.

Two Experiments

Now if we wanted to test whether the different medication usage in the WHO studies was a key reason for the disparity in outcomes, we would like to see two experiments run. We would want a developed country to use antipsychotics in a selective, limited manner, and see how their patients fared over the long term. Then we would want a developing nation to use antipsychotics in a more comprehensive manner, and see how their patients fared. Fortunately, we now have evidence of both types.

Since 1992, the medical community in the western Lapland region of northern Finland has been using antipsychotics in a selective, cautious manner. At the end of five years, only about one-third of their first-episode psychotic patients have been exposed to antipsychotics, and only about 20% are regularly maintained on the drugs. This is a “continual use” rate similar to the rate for schizophrenia patients from developing countries in the second WHO study, and here are the long-term outcomes for western Lapland’s first-episode psychotic patients: Eighty-six percent are working or back in school at the end of five years, and only fourteen percent are on long-term disability. These outcomes are far better than the norm in Western Europe and the rest of the developed world.

Eli Lilly’s ongoing study of 17,000 schizophrenia outpatients in 37 countries (in all global regions except North America) provides evidence of the second type. Ninety percent of the patients enrolled into the study had been on antipsychotics for some time (with a median duration of illness of seven years,) and thus, as the Lilly investigators assessed their “baseline characteristics,” they were looking at cross-cultural outcomes for patients who had been treated with a paradigm of care that emphasized regular use of the drugs. The medical treatment was much the same for all of the patients enrolled into the study, and Eli Lilly investigators concluded that patients in “developing” and “developed” countries showed a “substantial similarity” in their outcomes, which could be described as fairly poor. Only 19% of the patients entering the Eli Lilly study were employed, and 69% were living in “dependent housing.” The patients were symptomatic much of the time, and many were burdened by drug side effects. “Coupled with the symptom scores, these data demonstrate that patients in this study population are experiencing a significant burden of illness,” the Eli Lilly researchers wrote.

In short, in this Eli Lilly study, the disparity in outcomes between patients in developing and developed countries had disappeared. The patients in the developing countries were no longer enjoying the “exceptionally good social outcome” they had in the earlier WHO studies.

Summing Up the Evidence

I know that this post, given that it contradicts the conventional wisdom that schizophrenia patients need to be on antipsychotics all their lives, will seem “outlandish” to some readers. But I think there is a consistent evidence trail here, and that it does lead to the conclusion that a difference in medication usage in the WHO studies was a primary reason that patients in the developing countries fared better. And if so, that has profound implications for a “best use” model of care today.

Tuesday, May 18, 2010


Mad in America hosts blogs by a diverse group of writers. These posts are designed to serve as a public forum for a discussion—broadly speaking—of psychiatry and its treatments. The opinions expressed are the writers’ own.


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