Anatomy of an Epidemic (16 page)

But what was psychiatry supposed to do with this information? It clearly imperiled the field’s very foundation. Could it really now confess to the public, or even admit to itself, that the very class of drugs said to have “revolutionized” the care of the mentally ill was in fact making patients chronically ill? That antipsychotics made patients—at least in the aggregate—more psychotic over time? Psychiatry desperately needed this discussion to go away. Soon the articles by Chouinard and Jones on “supersensitivity psychosis” were filed away in the “interesting hypothesis” category, and everyone in the field breathed a sigh of relief when Solomon Snyder, who knew as much about dopamine receptors as any scientist in the world, assured everyone in his 1986 book
Drugs and the Brain
that it had all turned out to be a false alarm. “If dopamine receptor sensitivity is greater in patients with tardive dyskinesia, one might wonder whether they would also suffer a corresponding increase in schizophrenia
symptoms. Interestingly, though researchers have looked carefully for any possible exacerbation of schizophrenic symptoms in patients who begin to develop tardive dyskinesia, none has ever been found.”
⁴¹

That moment of crisis within psychiatry, when it briefly worried about supersensitivity psychosis, occurred nearly thirty years ago, and today the notion that antipsychotics increase the likelihood that a person diagnosed with schizophrenia will become chronically ill seems, on the face of it, absurd. Ask psychiatrists at top medical schools, staff at a mental hospital, NIMH officials, leaders of the National Alliance for the Mentally Ill, science writers at major newspapers, or the ordinary person in the street, and everyone will attest that antipsychotics are essential for treating schizophrenia, the very cornerstone of care, and that anyone who touts a different idea is, well, a bit
loony
. Still, we started down this path of research, I’ve invited readers into this loony bin, and so now we need to move up one floor in the Countway Library. The volumes in the basement end in 1986, and now we need to comb the scientific literature since that date, and see what story it has to tell. Was it all a false alarm … or not?

The most efficient way to answer that question is to summarize, one by one, the relevant studies and avenues of research.

In the late 1950s and early 1960s, Vermont State Hospital discharged 269 chronic schizophrenics, most of whom were middle-aged, into the community. Twenty years later, Courtenay Harding interviewed 168 patients from this cohort (those who were still alive), and found that 34 percent were recovered, which 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 general.”
⁴²
This was a startling good long-term outcome for patients who had been seen as hopeless in the 1950s, and those who had recovered, Harding told the
APA Monitor
, had one thing in common: They all “had long since stopped taking medications.”
⁴³
She concluded that it was a
“myth” that schizophrenia patients “must be on medication all their lives,” and that, in fact, “it may be a small percentage who need medication indefinitely.”
⁴⁴

In 1969, the World Health Organization launched an effort to track schizophrenia outcomes in nine countries. At the end of five years, the patients in the three “developing” countries—India, Nigeria, and Colombia—had a “considerably better course and outcome” than patients in the United States and five other “developed countries.” They were much more likely to be asymptomatic during the follow-up period, and even more important, they enjoyed “an exceptionally good social outcome.”

These findings stung the psychiatric community in the United States and Europe, which protested that there must have been a design flaw in the study. Perhaps the patients in India, Nigeria, and Colombia had not really been schizophrenic. In response, WHO launched a ten-country study in 1978, and this time they primarily enrolled patients suffering from a first episode of schizophrenia, all of whom were diagnosed by Western criteria. Once again, the results were much the same. At the end of two years, nearly two-thirds of the patients in the “developing countries” had had good outcomes, and slightly more than one-third had become chronically ill. In the rich countries, only 37 percent of the patients had good outcomes, and 59 percent became chronically ill. “The findings of a better outcome of patients in developing countries was confirmed,” the WHO scientists wrote. “Being in a developed country was a strong predictor of not attaining a complete remission.”
⁴⁵

Although the WHO investigators didn’t identify a reason for the stark disparity in outcomes, they had tracked antipsychotic usage in the second study, having hypothesized that perhaps patients in the poor countries fared better because they more reliably took their medication. However, they found the opposite to be true. Only 16 percent of the patients in the poor countries were regularly maintained on antipsychotics, versus 61 percent of the patients in the rich countries. Moreover, in Agra, India, where patients arguably
fared the best, only 3 percent of the patients were kept on an antipsychotic. Medication usage was highest in Moscow, and that city had the highest percentage of patients who were constantly ill.
⁴⁶

In this cross-cultural study, the best outcomes were clearly associated with low medication use. Later, in 1997, WHO researchers interviewed the patients from the first two studies once again (fifteen to twenty-five years after the initial studies), and they found that those in the poor countries continued to do much better. The “outcome differential” held up for “general clinical state, symptomatology, disability, and social functioning.” In the developing countries, 53 percent of the schizophrenia patients were simply “never psychotic” anymore, and 73 percent were employed.
⁴⁷
Although the WHO investigators didn’t report on medication usage in their follow-up study, the bottom line is clear: In countries where patients hadn’t been regularly maintained on antipsychotics earlier in their illness, the majority had recovered and were doing well fifteen years later.

Tardive dyskinesia and tardive psychosis occur because the dopaminergic pathways to the basal ganglia and limbic system become dysfunctional. But there are
three
dopaminergic pathways, and so it stands to reason that the third one, which transmits messages to the frontal lobes, also becomes dysfunctional over time. If so, researchers could expect to find a global decline in brain function in patients diagnosed with tardive dyskinesia, and from 1979 to 2000, more than two dozen studies found that to be the case. “The relationship appears to be linear,” reported Medical College of Virginia psychiatrist James Wade in 1987. “Individuals with severe forms of the disorder are most impaired cognitively.”
⁴⁸
Researchers determined that tardive dyskinesia was associated with a worsening of the negative symptoms of schizophrenia (emotional disengagement); psychosocial impairment; and a decline in memory, visual retention, and the capacity to learn. People with TD lose their “road map of consciousness,” concluded one investigator.
⁴⁹
Investigators have dubbed this long-term cognitive deterioration tardive
dementia; in 1994, researchers found that three-fourths of medicated schizophrenia patients seventy years and older suffer from a brain pathology associated with Alzheimer’s disease.
⁵⁰

The invention of magnetic resonance imaging technology provided researchers with the opportunity to measure volumes of brain structures in people diagnosed with schizophrenia, and while they hoped to identify abnormalities that might characterize the illness, they ended up documenting instead the effect of antipsychotics on brain volumes. In a series of studies from 1994 to 1998, investigators reported that the drugs caused basal ganglion structures and the thalamus to swell, and the frontal lobes to shrink, with these changes in volumes “dose related.”
⁵¹
Then, in 1998, Raquel Gur at the University of Pennsylvania Medical Center reported that the swelling of the basal ganglia and thalamus was “associated with greater severity of both negative and positive symptoms.”
⁵²

This last study provided a very clear picture of an iatrogenic process. The antipsychotic causes a change in brain volumes, and as this occurs, the patient becomes more psychotic (known as the “positive symptoms” of schizophrenia) and more emotionally disengaged (“negative symptoms”). The MRI studies showed that antipsychotics worsen the very symptoms they are supposed to treat, and that this worsening begins to occur during the first three years that patients are on the drugs.

As part of their investigations of schizophrenia, researchers have sought to develop biological “models” of psychosis, and one way they have done that is to study the brain changes induced by various drugs—amphetamines, angel dust, etc.—that can trigger delusions and hallucinations. They also have developed ways to induce psychotic-like behaviors in rats and other animals. Lesions to the hippocampus can cause such disturbed behaviors; certain genes can be “knocked out” to produce such symptoms. In 2005, Philip
Seeman reported that
all
of these psychotic triggers cause an increase in D
₂
receptors in the brain that have a “HIGH affinity” for dopamine, and by that, he meant that the receptors bound quite easily with the neurotransmitter. These “results imply that there may be many pathways to psychosis, including multiple gene mutations, drug abuse, or brain injury, all of which may converge via D
₂
HIGH to elicit psychotic symptoms,” he wrote.
⁵³

Seeman reasoned that this is why antipsychotics work: They block D
₂
receptors. But in his research, he also found that these drugs, including the newer ones like Zyprexa and Risperdal, double the density of “high affinity” D
₂
receptors. They induce the same abnormality that angel dust does, and thus this research confirms what Lars Martensson observed in 1984: Taking a neuroleptic is like having a “psychosis inducing agent built into the brain.”

In 1989, Nancy Andreasen, a psychiatry professor at the University of Iowa who was editor in chief of the
American Journal of Psychiatry
from 1993 to 2005, began a long-term study of more than five hundred schizophrenia patients. In 2003, she reported that at the time of initial diagnosis, the patients had slightly smaller frontal lobes than normal, and that over the next three years, their frontal lobes continued to shrink. Furthermore, this “progressive reduction in frontal lobe white matter volume” was associated with a worsening of negative symptoms and functional impairment, and thus Andreasen concluded that this shrinkage is evidence that schizophrenia is a “progressive neurodevelopmental disorder,” one which antipsychotics unfortunately fail to arrest. “The medications currently used cannot modify an injurious process occurring in the brain, which is the underlying basis of symptoms.”
⁵⁴

Hers was a picture of antipsychotics as therapeutically ineffective, rather than harmful, and two years later, she fleshed out this picture. Her patients’ cognitive abilities began to “worsen significantly” five years after initial diagnosis, a decline tied to the “progressive brain volume reductions after illness onset.”
⁵⁵
In other words, as her patients’ frontal lobes shrank in size, their ability
to think declined. But other researchers conducting MRI studies had found that the shrinkage of the frontal lobes was
drug-related
, and in a 2008 interview with the
New York Times
, Andreasen conceded that the “more drugs you’ve been given, the more brain tissue you lose.” The shrinkage of the frontal lobes may be part of a disease process, which the drugs then
exacerbate
. “What exactly do these drugs do?” Andreasen said. “They block basal ganglia activity. The prefrontal cortex doesn’t get the input it needs and is being shut down by drugs. That reduces the psychotic symptoms. It also causes the prefrontal cortex to slowly atrophy.”
⁵⁶

Once again, Andreasen’s investigations revealed an iatrogenic process at work. The drugs block dopamine activity in the brain and this leads to brain shrinkage, which in turn correlates with a worsening of negative symptoms and cognitive impairment. This was yet another disturbing finding, and it prompted Yale psychiatrist Thomas McGlashan, who three decades earlier had wondered whether antipsychotics were making patients “more biologically vulnerable to psychosis,” to once again question this entire paradigm of care. He put his troubled thoughts into a scientific context:

His comments appeared in a 2006 issue of the
Schizophrenia Bulletin
, and at that moment it seemed like the late 1970s all over again. The “cure,” it seemed, had once again been proven to be “worse than the disease.”