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                                                                                COVER STORIES, Page 52

AWAKENINGS

Schizophrenia: A New Drug Brings Patients Back to Life

They are tormented by demons and at times lost to reality. Now,
after years of madness, some schizophrenia patients are being
"awakened" by a costly new drug.

By CLAUDIA WALLIS and JAMES WILLWERTH


    For weeks they had practiced dance steps, shopped for
formals, fretted about hairstyles and what on earth to say to
their partners. Now the Big City band was pumping up the
volume, and the whole ballroom was beginning to shake. Brandon
Fitch, wearing a pinstripe suit and an ear-to-ear grin, shimmied
with a high-stepping blond. Daphne Moss, sporting a floral dress
and white corsage, delighted her dad by letting him cut in. The
usually quiet Kevin Buchberger leaped onto the dance floor and
flat-out boogied for the first time in his life, while Kevin
Namkoong grabbed an electric guitar and jammed with the band.
The prom at Case Western Reserve University had hit full tilt.

    But this was a prom that almost never was. Most of the 175
participants were in their 30s; they had missed the proms of
their youth -- along with other adolescent rites of passage.
Don't ask where they were at 18 or 21. The memories are too
bleak, too fragmented to convey. They had organized this
better-late-than-never prom to celebrate their remarkable
"awakening" to reality after many years of being lost in the
darkness of schizophrenia. The revelers were, in a sense, the
laughing, dancing embodiments of a new wave of drug therapy
that is revolutionizing the way doctors are dealing with this
most devilish of mental illnesses.

    Daphne Moss, 30, can barely reconstruct her 20s, when she
dwelt in a shadowy land of waking nightmares, fiendish voices
and the alarming conviction that her parents were actually
witches. What she can recall clearly is the moment two years
ago when it all came down to one choice: Should she dive
headfirst or feetfirst from the third-floor window ledge of her
room in a Cleveland boarding house? Feetfirst, she decided. It
meant a fractured hip, multiple bruises -- and survival.

    Buchberger, 33, also spent a decade wrestling with inner
demons. He was hounded by a frightening spirit -- a golden beam
of light -- that he believed, had previously haunted an
executed murderer. The spirit never spoke. "It tormented me, but
I never knew what it wanted," he recalls.

    Fitch's memories are just as scary, but in his case the
darkness descended at the tender age of eight. Fitch, now 19,
spent his early years imagining that historical figures such as
Czar Nicholas II lived at his home. He insisted on dressing
formally at all times, in a coat and tie or in historical
costumes, and he avoided the gaze of people pictured on
magazine covers. Watching him boogie the night away at the prom,
his mother recalled the last time she had seen her son near a
dance floor, six years earlier: "We went to a wedding, and he
hid in an alley most of the evening and begged me to take him
home."

    Moss, Buchberger, Fitch and their fellow promgoers were
awakened from their long nightmare of insanity by a remarkable
drug called clozapine (brand name: Clozaril). The dinner dance,
organized with help from psychiatrists and counselors at Case
Western Reserve's affiliated University Hospitals, in
Cleveland, served as a bittersweet celebration of shared loss
and regained hope. "Those of us who are ill travel on a
different road," said prom chairman Fitch in a welcoming address
to his fellow refugees from madness. "We would have liked to
have gone to our senior proms, but fate didn't give us that
chance."

    Until quite recently, medicine didn't offer much of a chance
either. While doctors and drugmakers have made impressive
strides in treating other forms of mental illness, including
depression and anxiety, progress against schizophrenia has been
painfully slow. Fewer than half of America's 2 million to 3
million schizophrenics respond well enough to the standard
treatment with Thorazine (chlorpromazine) and similar drugs to
avoid further hospital visits. Most who do respond remain
somewhat disabled, and about 80% are stuck with serious and
humiliating side effects, including dulled emotions, a clumsy
gait known as the "Thorazine shuffle," a compulsive
foot-tapping restlessness and an irreversible syndrome called
tardive dyskinesia, characterized by twitching and jerky
movements of the facial muscles and tongue.

    Clozapine is not perfect either. In some patients it causes
seizures. A few develop a life-threatening blood defect and must
be immediately taken off the medication. It is also extremely
expensive, costing $4,160 annually for the drug itself and as
much as $9,000 more for doctor-monitored treatment. But for some
it brings miracles. Of 20,000 American schizophrenics who did
not respond well to Thorazine and were given clozapine, more
than half have shown significant improvement: they become less
withdrawn, and the nagging inner voices grow hushed. One patient
in 10 responds to the drug so dramatically that the effect is
like being reborn. "You go from hating the sunshine in the
mornings to loving it," says Daphne Moss, who after two years
of treatment with clozapine is teaching public school part time
and living independently. "In 15 years of practice, I've never
seen anything like it," says Dr. Samuel Risch, a psychiatrist
at Emory University in Atlanta.

    The emergence into sunlight comes gradually. "You don't take
something and wake up the next morning," cautions Dr. Herbert
Y. Meltzer, director of the Biological Psychology Laboratory at
Case Western Reserve's affiliated University Hospitals and one
of the leading U.S. authorities on cloz apine. "You see small,
steady changes." Still, the 10% of patients who experience a
dramatic awakening can be overwhelmed by the bright glare of
reality and by the grief of having lost so much time to mental
illness. To help patients with this "Rip Van Winkle syndrome,"
the Case Western group has learned that each small step forward
with clozapine must be carefully nurtured with psychological
counseling. Without it, the awakened patients can slip back into
mental confusion, and the devilish inner voices may begin
harping again.

    For doctors, patients and anguished families who have coped
for years with schizophrenia, the arrival of a new drug that can
dramatically help even a portion of the victims is cause for
elation. The nation at large should celebrate as well. According
to a 1991 study by the National Institute of Mental Health
(NIMH), mental illness costs the country $129 billion annually,
and schizophrenia alone steals a disproportionate $50 billion
-- roughly equivalent to what the Federal Government spent last
year on all Medicaid grants. Drugs and doctor bills, hospital
beds and police problems add up to $29 billion; lost income and
family crises account for the rest.

    The cost of schizophrenia can be measured on several scales.
By some estimates, fully a quarter of the nation's hospital beds
are occupied by schizophrenia patients. Many are chronic abusers
of drugs and alcohol, the result of desperate attempts to
medicate themselves. The illness can therefore become a one-way
ticket to the bottom of the socioeconomic ladder. A third of
America's homeless are afflicted, as are about 3% of prison
inmates and nearly 6% of those in maximum-security facilities
(compared with 1% of the general population). The disease takes
a mortal toll as well. About 1 in 4 schizophrenics attempts
suicide; 1 in 10 succeeds.

    Schizophrenia typically makes its appearance sometime
between the ages of 15 and 25, a period when the frontal lobes
of the brain are rapidly maturing. Contrary to popular belief,
the disorder has nothing to do with "split personality." The
term schizophrenia (Greek for split mind) was coined in 1908 by
the Swiss psychiatrist Eugen Bleuler and refers to a splitting
of the capacity for thought.

    The onset is insidious. Victims may begin dressing
strangely, sleeping at odd hours, withdrawing from friends and
family, whispering to invisible companions or talking back to
the television set. They become paralyzed by irrational fears or
subject to suspicions that other people are monitoring their
thoughts. Eventually the symptoms can no longer be dismissed as
the moody vagaries of youth.

    Felt from the inside, schizophrenia is terrifying. Here is
how one 22-year-old victim described it: "Sometimes people are
taking away parts of my body and putting them back. Sometimes I
think they are going to kill me." The young man would see huge
rats scurrying about his room, and believed others were reading
his mind. He heard voices he attributed to "just God and Jesus,
but sometimes they sound like my mom and dad."

    For families who have watched a child grow and flower, the
effect is devastating. "At 15 my son returned to the day of his
birth," says a father in Brook Park, Ohio. "He crawled on the
floor, and his mother had to diaper him. He withdrew to his
room and wouldn't come out except to eat. Once, his voices told
him to grab a little girl in a store and undress her. Many times
I saw my wife with bruises. I've learned a lot about
schizophrenia since she died. I think living with my son killed
her."

    What causes such bizarre behavior remains mysterious. For
centuries schizophrenics were believed to be possessed by
devils or even angels. St. Teresa of Avila was probably a
schizophrenic, and so perhaps was the prophet Ezekiel, who, in
addition to his many apocalyptic visions, said he heard a
divine voice command him to sleep on his right side for 390
nights and then switch to his left for 40. Some archaeologists
believe that holes drilled in prehistoric skulls represent
efforts to release the demons of madness. During the Middle
Ages, those who heard voices were frequently burned at the
stake. As recently as the 1950s, psychiatrists blamed the
disorder on parents, specifically a cold, "schizophrenogenic"
mother, though Freud himself had concluded that the illness had
biological roots.

    Freud, of course, was right. Modern research indicates that
the tendency to develop schizophrenia is hereditary. While the
average child has a 1% chance of being stricken, the child of
a schizophrenic parent faces 10 times those odds, and if both
parents are affected, the likelihood jumps to 40%. But genes do
not tell the whole story. Children of parents with schizophrenia
raised by adoptive parents who don't have the illness have a
somewhat reduced risk. In addition, if one identical twin has
the disorder, the odds are just 50% that the other will.
Clearly, environmental factors -- stress and possibly even a
viral infection during infancy or gestation -- also may play a
role in triggering the disease.

    The first useful treatment for schizophrenia was discovered
by accident. A French surgeon serving in Vietnam in the 1950s
noticed that Thorazine, then administered as a sedative, quieted
ravings and hallucinations among soldiers awaiting surgery. That
prompted a Paris psychiatrist to try the drug on schizophrenics.
Thorazine calmed patients and reduced their symptoms. It was
quickly proclaimed a miracle drug. Thorazine and related drugs
such as haloperidol, fluphenazine and thiothixene soon eclipsed
the brutal treatments previously in vogue: lobotomy, primitive
electroshock and artificially induced insulin shock. Over the
next two decades, nearly half a million patients were discharged
from state hospitals in the U.S. and hundreds of thousands more
from hospitals in Europe.

    But the drawbacks soon became apparent. In addition to
producing severe side effects, the drugs leave patients
listless and indifferent. In short, while they alleviate the
so-called positive symptoms of schizophrenia -- the voices and
the delusions -- they do not touch the negative symptoms of
apathy and social withdrawal. Furthermore, they provide this
limited sort of recovery for just 40% of patients; 30% have
flare-ups of madness and must be periodically hospitalized,
while the remaining 30% are considered to be "treatment
resistant" and are largely confined to mental institutions.

    Thorazine works primarily by blocking dopamine, one of the
many biochemical messengers used by the brain. This discovery,
made by Dr. Arvid Carlsson of Sweden in 1967, led doctors to
believe schizophrenia is caused by an excess of dopamine. That
explanation has now been dismissed by many researchers as too
simplistic.

    Clozapine was developed by the Swiss pharmaceutical giant
Sandoz as an alternative that avoids most of Thorazine's side
effects. As a major bonus, it at least partly reduces the
passivity of schizophrenics as well as their more blatant
symptoms. In contrast to the Thorazine family of drugs,
clozapine primarily blocks the neurotransmitter serotonin,
though it also inhibits dopamine transmission to some degree.
The fact that it influences both neurotransmitters may help
explain its greater effectiveness. Still, "nobody completely
understands why clozapine is a superior drug," says Dr. Luis
Ramirez, chief of psychiatry at Cleveland's VA hospitals.

    For all its superiority, the drug almost didn't make it to
the U.S. market. Approved in several European countries in 1969,
it was quickly withdrawn six years later, after Finnish doctors
reported that eight patients taking the drug had died of
agranulocytosis, a sudden loss of infection-fighting white blood
cells. In the U.S., the Food and Drug Administration halted even
preliminary tests. "We assumed it was a dead product," recalls
psychopharmacologist Gilbert Honigfeld, who helped develop the
drug for Sandoz and is now in charge of marketing it in the U.S.
American and European research eventually showed that
agranulocytosis occurred in 1% to 2% of clozapine patients and
that it could be detected and nipped in the bud by conducting
blood tests on a weekly basis.

    In 1989 the FDA approved clozapine for patients who failed
to benefit from Thorazine-type drugs, but required the weekly
blood testing. Then Sandoz, with the agency's approval, added an
unprecedented stipulation: only its representatives could
administer the blood tests. Technicians representing Sandoz
were prepared to travel hundreds of miles to draw a single
patient's blood if necessary. The policy boosted the drug's
price tag to an astonishing $8,944 a year and raised a fire
storm of protest from families, mental-health advocates and
state mental-health-department officials, who argued that local
technicians could perform the blood tests at a much lower cost.
Finally, the controversy was resolved when Sandoz agreed last
summer to sell clozapine without company blood testing.

    Now at $4,160 a year, clozapine still looms beyond the reach
of most who need it. The stiff price has discouraged many state
institutions and agencies, which are responsible for the care
of the vast majority of American schizophrenia patients. While
a few states have embraced the drug -- Minnesota, for example,
has provided clozapine to 1,000 of its 4,300 eligible patients
-- most have not made that commitment. California, for instance,
with 60,000 potentially eligible patients, has treated only
1,300. Veterans hospitals, which treat as many as 9,000 eligible
schizophrenia patients annually, have given clozapine to only
300.

    In addition, many private insurance companies resist paying
for the drug. "The miracle of clozapine has turned into a
mirage," says Laurie Flynn, executive director of the National
Alliance for the Mentally Ill. "You can see it. You can read
about it. But you can't get it." The Flynn family, in
Alexandria, Va., had to pay an extra $6,000 in insurance to
obtain coverage that allowed their daughter Shannon, 24, to use
clozapine. Once seriously ill, the young woman has recovered
sufficiently to graduate from Georgetown University and hold a
part-time job at NIMH.

    Cases like Shannon's indicate that clozapine is a good
investment. In fact, a soon-to-be published study by Case
Western Reserve's Meltzer concludes that cloz apine can save
more than $30,000 a year in medical costs per patient, compared
with Thorazine-type drug treatment, by greatly reducing the
need for hospitalization and other intervention.

    For patients who get the drug, the greatest drawback is the
risk of developing agranulocytosis. So far, six of the 20,000
Americans who have been treated with clozapine have died from
the condition. Although that is considered a low fatality rate,
it is still enough to make mental-health professionals nervous.
They worry that the uncertainty and risks might jump in 1994,
when Sandoz loses its exclusive license to manufacture
clozapine. The appearance of generic versions of the drug may be
a boon for cash-strapped families, but it raises the specter of
fewer controls -- and more deaths.

    The appearance of agranulocytosis -- marked by a drop in
white blood cells -- is always tragic. Some patients, when
informed that they must immediately go off clozapine, beg to
remain on it rather than descend again into madness. Phil, 36,
was awakened by clozapine after 13 years of suffering. Thanks to
the drug, he was able to work part time in a grocery store and
start up a social life. Then agranulocytosis struck, and he had
to be taken off the drug. "He has his voices and moods again,"
his father reports sadly. "We'll just have to wait for something
else to come along."

    Researchers are working furiously to develop that something
else. Janssen Pharmaceutica, a Belgium-based subsidiary of
Johnson & Johnson, is in the lead with risperidone, a drug that
so far appears to be safer than clozapine and works in the same
way. Testing is incomplete, however, and the drug is at least
18 months away from the market. Abbott Labs, Eli Lilly and
others are also developing successors to clozapine.

    Research into brain chemistry is progressing so quickly that
doctors in the frustrating field of schizophrenia finally have
reason to be optimistic. "We can do for schizophrenia what we've
done for so many major illnesses," insists Dr. Samuel Keith,
head of NIMH's National Schizophrenic Plan. "We can dissect and
demystify it. Then we can defeat it."