The National Institute of Mental Health and the Agency for HealthCare Policy and Research have organized their treatment recommendations into seven categories: (1) antipsychotic medications (generally neuroleptics and atypical, or novel, antipsychotics, (2) additional medications for depression, anxiety or hostility, (3) electroconvulsive therapy, (4) psychological treatments, (5) family interventions, (6) vocational rehabilitation, and (7) assertive community treatment. The earlier schizophrenia is detected and treated, the better the outcome. Studies indicate that patients who receive antipsychotic drugs and other treatments during their first episode are hospitalized less frequently during the following five years and may require less time to fully control symptoms than those who do not seek help as quickly. One study found that intervention with monitoring, low-dose medication, and therapy in patients with very early signs of schizophrenia reduced the diagnosis of full-blown schizophrenia by tenfold. Patients usually endure, however, an average of 10 months of serious symptoms before they receive treatment, and research shows that more than half of individuals with schizophrenia receive inadequate care. In particular, African Americans are less likely to receive good treatment.


General Guidelines of Drug Therapy

Until recently, the mainstay treatments for schizophrenia have been antipsychotic agents, also called neuroleptic drugs. They work by blocking receptors of the neurotransmitter dopamine, which is thought to play a major role in psychotic symptoms. The name neuroleptic derives from the neurologic side effects that they cause [ see below ], which can be very severe. The most disturbing and common side effects of typical antipsychotic drugs are those effects known as extrapyramidal symptoms, which involve the nerves and muscles controlling movement and coordination. In fact, a 1999 analysis reported that fewer than 12% of patients faithfully took these drugs over the course of a year. More recently, so-called atypical, or novel, antipsychotics are proving to be better tolerated and more successful. They appear to benefit both positive and negative symptoms and have significantly fewer severe side effects. Atypical drugs are now recommended by many experts as the first choice for patients with recent-onset schizophrenia, patients on neuroleptics who have severe extrapyramidal side effects, or those who have not responded to traditional neuroleptics. When switching agents, a cross-over period of one to two weeks is recommended.

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Treating an Acute or Initial Phase. For the severe, active phase of schizophrenia, injections of an antipsychotic drug are often given every few hours until the patient is calm. If possible, however, physicians prefer administering a drug orally or at least switching to an oral drug as soon as possible. Generally, higher doses are used to treat acute episodes and lower doses are given during periods of remission. In patients who are being treated for the first time, improvement in psychotic symptoms may be evident within one or two days of treatment, although the full benefit of the drug usually becomes manifest over about six to eight weeks. Thought disturbances tend to abate more gradually.

Relapse and Maintenance. To reduce the risk of relapse, many physicians recommend that drugs be given daily for at least one year. Atypical agents are increasingly being used for those with new-onset psychosis, although the choice of the drug depends on many factors. To avoid side effects and to improve compliance, physicians try to keep dosages (and, therefore, side effects) as low as possible. The drug effects must be monitored carefully by the physician. Side effects and effectiveness vary from individual to individual, and some trial and error adjustments may be necessary when prescribing dosage amounts so that the benefits of treatment outweigh the side effects of the therapy. Depot therapy (long-lasting forms of neuroleptics, usually Haldol or Prolixin, that are administered as monthly injections) have been used with success in people who have difficulty complying with a daily regimen. Even on maintenance therapy, about 30% to 40% of patients relapse within a year of hospital discharge. Adding psychotherapy to the regimen can help reduce this rate.

Atypical Drugs

Atypical, or novel, antipsychotics are producing lower rehospitalization rates than traditional neuroleptics, and many experts now recommend them for patients who are first diagnosed with schizophrenia and for patients who fail to respond to antipsychotics or for those who relapse. They simultaneously affect dopamine receptors and other neurotransmitters responsible for psychotic symptoms; some may improve negative as well as positive symptoms. Evidence further suggests that they have benefits for working memory and mental functioning and may reduce depression, hostility, and even suicide risk. It may take up to six months before they have an effect. Clozapine (Clozaril) was the first atypical antipsychotic. Newer agents include risperidone, olanzapine, ziprasidone, and quetiapine; these drugs have fewer side effects than both clozapine and the typical neuroleptics. Weight gain is the primary concern with these drugs. The individual atypical drugs differ in their effects on weight, with clozapine and olanzapine carrying the higher risk and risperidone and ziprasidone the lowest. A number of atypicals exist; not all are available in the US as of the date of this report. Comparison studies are underway to determine whether one agent is more effective than another. So far, some studies indicate that risperidone may be more effective in reducing psychotic and negative symptoms and be less costly than olanzapine, although olanzapine may improve cognitive impairment. Risperidone and ziprasidone may have a lower risk for weight gain than do clozapine and olanzapine but studies to date have been limited.

Clozapine. Clozapine (Clozaril) was the first atypical agent. Although it has more side effects than more recent drugs, it is still very beneficial and more effective than conventional neuroleptics in reducing symptoms, including those resistant to the older drugs. The drug reduces aggressive behavior and suicidal impulses and may even improve negative symptoms. The effects on symptoms may not be evident for up to nine months, however. It is particularly useful in younger people, although side effects are common, and newer atypical drugs may prove to be better choices. Although clozapine poses only a small risk for tardive dyskinesia (a persistent involuntary movement disorder), it does have other side effects including nasal congestion, drooling, low blood pressure, headache, sleeplessness, and weight gain. There are some serious side effects, including seizures, blood abnormalities, and injury to heart muscle. In up to 1% of cases, agranulocytosis occurs, a potentially life-threatening reduction in certain white blood cells. This effect is most likely to develop within three months of treatment, peaking in the third month; if it hasn't appeared within six months, it most likely will not develop. Older women are at higher risk, and it can be reversed if the drug is withdrawn at once. Of additional concern are a few reports of sudden death from heart muscle injury associated with initial usage of the drug. The drug appears to increase triglyceride levels. People taking clozapine should have both triglyceride and blood glucose levels monitored frequently, especially in people with or at risk for diabetes. The potency of clozapine can be affected by fluctuations in caffeine intake; patients who drink caffeinated beverages should be monitored by a doctor, particularly if their drinking habits change.

Risperidone. Risperidone (Risperdal) is a dopamine receptor blocker that has shown benefits and even superiority in comparison to other antipsychotics. Like clozapine, risperidone may have a beneficial effect on negative symptoms as well as psychosis. Risperidone may also improve verbal memory and the quality of sleep. In general, it is associated with few extrapyramidal effects, although these effects can occur at higher doses. (Research indicates, however, that low doses of risperidone are typically effective and remain so over time.) Common side effects include sleepiness and dizziness.

Olanzapine. Olanzapine (Zyprexa) may be more effective than clozapine as a blocker of serotonin and dopamine. It is associated with a much lower risk for seizures and agranulocytosis. Studies indicate that it is at least as effective for acute symptoms as the typical neuroleptics and that it has a very low risk for causing extrapyramidal symptoms. The drug may also be beneficial for patients who do not respond to neuroleptic drugs. It does not appear to have any significant effect on negative symptoms although it may help cognitive impairment. Like risperidone, olanzapine can cause sleepiness, weight gain, and dizziness. Triglyceride levels may increase significantly in patients who gain weight; such patients should discuss lipid-lowering medications with their physicians. Of some concern are reports of diabetes developing in patients taking olanzapine; more research is needed.

Quetiapine. Quetiapine (Seroquel) is a recently approved drug that shows promise as an effective and safe treatment for schizophrenia. Studies indicate that it is as effective as standard neuroleptics but without the extrapyramidal side effects of those agents. Its most common side effect is sleepiness. It may be particularly beneficial for elderly patients.

Ziprasidone. Ziprasidone (Zoleptil) affects serotonin as well as dopamine receptors and may also improve negative symptoms while causing only limited extrapyramidal side effects. In one comparison study, it produced the least weight gain of all the atypical agents.

Other Atypical Drugs. Amisulpride (Solian), a dopamine blocker, appears to be safe and equal to or even more effective than risperidone in improving both positive and negative symptoms, without posing as high a risk for weight gain.Sertindole (Serdolect), aripiprazole, and iloperidone are other atypical drugs in development or under investigation.

Typical Antipsychotic (or Neuroleptic) Drugs

The standard neuroleptic drug used for schizophrenia is haloperidol (Haldol). Others include chlorpromazine (Thorazine), perphenazine (Trilafon), thioridazine (Mellaril), mesoridazine (Serentil), trifluoperazine (Stelazine), and fluphenazine (Prolixin). Studies have not shown any significant difference in benefits among these drugs. The beneficial impact of these drugs is greatest on psychotic symptoms, particularly hallucinations and delusions in the early and midterm stages of the disorder. They are not very successful in reducing negative symptoms; because of their significant side effects, compliance is often very low.

Side Effects of Neuroleptics. Neuroleptics can have adverse side effects related to many organs and systems in the body. Sleepiness and lethargy commonly occur in the beginning of therapy, but they usually decrease over time. Other side effects include dry mouth, eye problems, allergic reactions, weight gain, and menstrual irregularities in women. Sexual dysfunction resulting from treatments is a common reason for noncompliance, although the drug amantadine may help offset this side effect. A much more serious but rare side effect is the neuroleptic malignant syndrome, in which dangerously high body temperatures occur. Without prompt and expert treatment, this side effect can be fatal in 20% of those who develop it. Sometimes the effects of the drugs mimic schizophrenic symptoms, such as agitation, slow speech, and retarded movement. In response, the physician may be erroneously tempted to increase the dosage. Hyperprolactinemia (high levels of the female hormone prolactin) is common with antipsychotics; this effect can cause menstrual abnormalities and may increase the risk for osteoporosis and possibly breast cancer.

The most disturbing and common side effects of typical antipsychotic drugs are those effects known as extrapyramidal symptoms, which involve the nerves and muscles controlling movement and coordination. Women are at higher risk for these symptoms, and the risk increases with length of therapy and age. So-called high potency drugs (eg, haloperidol and fluphenazine) cause less drowsiness and drops in blood pressure but pose a higher risk for extrapyramidal side effects; low-potency drugs (eg, chlorpromazine, thioridazine) are more sedating, but side effects are not as acute. Nearly every neuroleptic drug can cause extrapyramidal side effects, which occur in up to 70% of patients taking these medications. A condition known as acute dystonia can develop shortly after taking antipsychotic drugs. This syndrome includes abnormal muscle spasms, particularly sustained contortions of the neck, jaw, trunk, and eye muscles. The most serious effect of antipsychotic therapy is tardive dyskinesia , which is often manifest by repetitive and involuntary movements, or tics, most often of the mouth, lips, or of the legs, arms, or trunk. Symptoms range from mild to severe, and sometimes interfere with eating and walking. They can appear months or even years after taking the drugs. After the drug is withdrawn, symptoms can sometimes persist for weeks or months. Some cases of tardive dyskinesia may be permanent although they can go into remission, or remit completely.

Treatment of Extrapyramidal Side Effects. In general, if extrapyramidal side effects occur from neuroleptic drugs, the physician may first try to reduce the dosage or switch to an atypical drug [ see below ].

Extrapyramidal side effects may actually mimic those of Parkinson's disease (caused by too little dopamine), and so physicians may prescribe anti-parkinsonism drugs known as anticholinergics which increase dopamine levels and help to restore balance. Among the anticholinergics most commonly used in the US are trihexyphenidyl (Artane, Trihexy) and benztropine (Congentin). Some of these drugs may also be helpful in managing negative symptoms of schizophrenia. The use of anticholinergics, however, adds to the cost and complicates management: they have their own, sometimes serious, side effects. They commonly cause dryness of the mouth and may cause nausea, blurred vision, increased heart rate, constipation, and urinary retention in men with enlarged prostates. People with glaucoma should use these drugs cautiously. Anticholinergics may even cause significant mental problems, including memory loss, confusion, and hallucinations, which can mimic schizophrenia. They also interact with alcohol and antihistamines. Most experts oppose the routine use of anti-parkinsonism drugs for schizophrenia and recommend them only for patients who cannot be monitored regularly and for those who need very high doses of powerful antipsychotic drugs and are at risk for severe side effect. Experts recommend they be withdrawn after three or four months if possible. If symptoms recur, the drugs can be reinstituted. It should be noted that withdrawal from anticholinergics can cause depression that can exacerbate schizophrenia.

Ondansetron (Zofran), a drug known as a serotonin 3 receptor antagonist, is normally used as an anti-nausea medication but is now under investigation for treating tardive dyskinesia. In one study, it safely improved not only the neuroleptic side effects but also symptoms of psychosis. Side effects include headache, fatigue, constipation, and dry mouth. Vitamin B6 may help relieve these symptoms. Although vitamin E has also been studied, one study found no advantage with vitamin E.

Other Useful Drugs

Antidepressants. Antidepressants are recommended along with antipsychotics to alleviate the depression that is so common in people with schizophrenia. One study indicated that taking antidepressants may even help prevent relapse. In spite of their benefits, less than half of all patients are given these medications. (African Americans are even less likely to receive antidepressants.)

Anti-Anxiety Drugs. Benzodiazepines are drugs normally used to treat anxiety; they have been found to reduce psychotic symptoms, although there are not as effective as standard antipsychotic therapy, and they may have a strong sedative effect. Some physicians use them first during an attack to reduce the need for a higher dose of the more potent antipsychotic drugs. They may be useful in the early stages of a psychotic relapse for preventing a full attack and are sometimes used to treat the restlessness and agitation that can occur with the use of neuroleptics. Severe side effects, including respiratory arrest, very low blood pressure, and loss of consciousness, have been reported in a few people taking antianxiety medication and clozapine but there is no evidence yet of a clear danger associated with the use of these two drugs. In any case, prolonged use of anti-anxiety drugs is generally not recommended in schizophrenia; withdrawal from these agents should be achieved gradually.

Lithium. Lithium, ordinarily used for bipolar disorder, is useful for some patients. It appears to help those with fewer negative symptoms and without a family history of schizophrenia. However, there are no reliable criteria to predict who will benefit.

Antiepileptic Drugs. Drugs ordinarily prescribed for epilepsy, such as carbamazepine (Tegretol), gabapentin, lamotrigine, or others, are occasionally used in combination with neuroleptics or atypical agents for patients who do not respond to standard drugs.