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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 drugs.

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 thioridazine.

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 face.

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 early age.

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 drug.

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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