Drug treatment of schizophrenia
A revolution in the treatment of schizophrenia began a half- century
ago, with the introduction of chlorpromazine (Thorazine) in 1952. For
the first time, psychiatrists had a drug that effectively suppressed
the hallucinations and delusions of acute schizophrenia.
Today, those drugs are being supplanted by a second generation of antipsychotic
medications. But the new drugs are only a little better than the old,
and the deeper and more pervasive problems of schizophrenic patients — their “negative” symptoms,
including apathy, social withdrawal, emotional unresponsiveness, and
difficulties with attention and memory — have remained largely
unsolved by pharmacological means.
Experts have come to a general consensus about the medical treatment
of schizophrenia, although the agreement is not perfect and their recommendations
are guidelines rather than commands.
For a patient undergoing a psychotic episode, the first choice is usually
one of the following five drugs, all introduced since 1990 and known
as novel, atypical, or second-generation drugs: risperidone (Risperdal),
olanzapine (Zyprexa), quetiapine (Seroquel), ziprasidone (Geodon), or
aripiprazole (Abilify). Some experts believe all are equally effective
and the choice should depend on side effects; others believe risperidone
or olanzapine is superior.
Clozapine (Clozaril), a sixth second-generation drug, is considered
if the patient has not responded to two other drugs. One of the several
dozen older (“conventional”) drugs, such as chlorpromazine,
thioridazine (Mellaril), or haloperidol (Haldol) may be used if second-generation
drugs fail. Giving a patient more than one antipsychotic drug at a time
is not recommended.
If the response is good, the medication should be continued for at
least six months. If the patient remains free of psychotic symptoms for
a year, a psychiatrist may try withdrawing the drug gradually, while
instructing the patient and the patient’s family about early signs
of relapse. After two relapses within a five-year period, most experts
recommend continuing medication indefinitely.
Other drugs are sometimes used in addition to antipsychotics, especially
antidepressants such as fluoxetine (Prozac) and sertraline (Zoloft),
for depression or obsessive-compulsive symptoms, and mood stabilizers
(lithium or anticonvulsants) for aggression and violence. For agitation,
anxiety, and insomnia, some psychiatrists prescribe a benzodiazepine,
for example, lorazepam (Ativan). Anticonvulsants are also used occasionally
to treat hallucinations and delusions that are not affected by antipsychotic
Some side effects can occur with most of the drugs:
Lethargy and drowsiness — caused by most antipsychotic drugs,
but especially by clozapine (ziprasidone is a possible exception).
Anticholinergic effects (dry mouth, blurred vision, constipation, retention
of urine) — caused especially by clozapine, chlorpromazine, and
Postural hypotension (dizziness on standing up, the result of lowered
blood pressure) — can be caused by most antipsychotic drugs, but
especially by clozapine and by some low-potency first-generation drugs.
All antipsychotic drugs may create a slight risk of heart rhythm abnormalities.
In one study, thioridazine and ziprasidone had the strongest effects
on electrical conduction in the heart.
One set of side effects is produced commonly by first-generation drugs
but only rarely by second-generation drugs. These are the movement disorders:
Acute dystonia — muscle spasms.
Parkinsonism — tremors, stiff posture, diminished and hesitant
arm and leg movements, a shuffling walk, and an immobile, expressionless
Akathisia — restless fidgeting and pacing, which can be agonizing.
Tardive dyskinesia — repetitive involuntary muscle movements
that may include sucking, grimacing, lip-smacking, protrusion of the
tongue, and jerky and writhing movements of the face, neck, and arms.
Another group of side effects is common to most antipsychotic drugs
but especially troublesome for patients taking olanzapine, clozapine,
and to a lesser degree, risperidone and quetiapine. It consists of weight
gain, cholesterol abnormalities, and a possible increased risk of diabetes.
The risk for diabetes is uncertain. One study found that in the 1940s,
before the introduction of antipsychotic drugs, schizophrenic patients
had an even higher rate of diabetes than they have today. But some patients
taking second-generation drugs have developed diabetes at an unusually
The antipsychotic drugs ziprasidone and aripiprazole, do not seem to
cause weight gain and may not raise the risk for diabetes. Nevertheless,
the FDA is being cautious; in 2003 it required warnings in advertising
and on labels for all second-generation drugs. In 2004, several professional
organizations including the American Diabetes Association and the American
Psychiatric Association issued an official statement encouraging physicians
to record the weight, cholesterol levels, and blood sugar of schizophrenic
patients before prescribing an antipsychotic drug to watch for signs
of insulin resistance or diabetes. The statement recommends that physicians
consider switching drugs after a weight gain of more than 5%.
Clozapine seems to be unique in both its drawbacks and its virtues.
It has many side effects, including drowsiness, weight gain, anticholinergic
effects, and a lowered threshold for seizures. It can also produce a
particularly intense withdrawal reaction, which may include a rebound
psychosis. Clozapine’s most serious side effect is agranulocytosis,
a drastic fall in white blood cell count. Agranulocytosis is rare, but
potentially lethal, so patients must have periodic blood tests. For all
these reasons, clozapine is rarely the first choice in treating schizophrenia.
But it appears to work for some patients who do not respond to any other
Schizophrenic patients often relapse because they stop taking the drug
or do not take it consistently. According to one survey, fewer than half
of them follow their prescription faithfully. They may find the side
effects uncomfortable; they may have a poor understanding of the illness;
and they may not sufficiently trust their psychotherapist or prescribing
physician. It may help to make taking the pill part of a daily routine,
with pill boxes and alarms if necessary.
Patients should fully understand the risks of drug treatment and should
be urged to report side effects immediately. (One disadvantage of first-generation
drugs is that more patients refuse treatment because of side effects,
especially movement disorders.) Patients have to know why the medication
is necessary even though they may feel better temporarily without it.
For patients who refuse or forget to take their pills on a regular
basis, one resource is an injection with an effect lasting up to a month.
The older drugs haloperidol and fluphenazine (Prolixin) and the second-generation
drug risperidone are available in this form, which is called depot medication.
The second-generation antipsychotic drugs generated great hopes that have
been only partly fulfilled. All first-generation drugs act by essentially
the same mechanism; the second-generation do not have a single common mechanism
of action, so patients have a better chance of reducing psychotic symptoms
by switching from one to another. Despite this advantage (and the lower
risk of uncomfortable side effects), the second generation drugs are not
always found to be more effective overall.
February 2005 Update
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