Medications:

Atypical Antipsychotic Drugs

Seven atypical antipsychotic drugs are currently approved in the United States:

• Clozapine (Clozaril)
• Risperidone (Risperdal)
• Olanzapine (Zyprexa)
• Quetiapine (Seroquel)
• Aripiprazole (Abilify)
• Ziprasidone (Geodon)
• Paliperidone (Invega)

Clozapine was the first atypical drug approved (in 1989), and paliperodine the most recent approved (in 2007). Clozapine appears to have more side effects than the other atypical antipsychotics. Most of these drugs come in pill form, but some may come in liquid form or as an injection. In general, it may take up to 6 months before an atypical drug has an effect.

The atypical antipsychotics zotepine (Zoleptil) and amisulpride (Solian) are not approved for use in the United States.

Benefits of Atypical Antipsychotics.

• Affect both dopamine receptors and other neurotransmitters responsible for psychotic symptoms.
• Improve negative and positive symptoms.
• May even improve working memory and mental functioning.
• May reduce depression and hostility.
• May reduce the risk for suicide (clozapine may be particularly helpful for suicide prevention).
• These drugs, particularly the newer atypicals, have fewer extrapyramidal side effects than the typical antipsychotics.

Atypical antipsychotics have some significant limitations and complications, and their benefits compared to each other and to other antipsychotics are not always clear-cut. In-depth comparative studies are needed to determine which specific drugs are more effective and have fewer side effects than others.

Side Effects of Atypical Antipsychotics.

• Nasal congestion or runny nose
• Drooling
• Dizziness
• Headache
• Drowsiness -- although, sometimes the drugs may cause restlessness and insomnia
• Constipation
• Rapid heart beat
• Difficulty urinating
• Skin rash
• Increased body temperature
• Confusion, short-term memory problems, disorientation, and impaired attention

The following are more severe side effects or complications that may occur with these drugs:

• Diabetes
• Weight gain and metabolic problems. The risk is highest for olanzapine, and lowest for aripiprazole and ziprasidone.
• Unhealthy cholesterol levels. Particularly with olanzapine, increased risk for high levels of trigylcerides and total cholesterol.
• Seizures.
• Extreme and very serious increases in body temperature.
• Sudden drop in blood pressure (hypotension).
• A significant drop in white blood cell count (neutropenia), which can be severe, occurs in 1% or more of patients, generally in the first 6 months after starting treatment. Patients should have their white blood count and absolute neutrophil count regularly monitored if they take clozapine.
• Extrapyramidal side effects
• Cataracts and worsening of any existing glaucoma.
• Increased prolactin levels -- prolactin is a hormone associated with infertility and impotence. High levels can cause menstrual abnormalities and may increase the risk for osteoporosis and possibly breast cancer.
• Heart problems, including sudden death.

Diabetes Risk and Atypical Antipsychotics

All atypical antipsychotic drugs carry a “black box” warning on their prescribing labels advising that these drugs can increase the risk of high blood sugar (hyperglycemia) and diabetes. (Olanzapine is more likely to cause high blood sugar levels than other atypical antipsychotic medicines.) The U.S. Food and Drug Administration (FDA) recommends that:

• Patients with an established diagnosis of diabetes who begin atypical antipsychotic treatment should be regularly monitored for worsening of blood sugar control.
• Patients with risk factors for diabetes (obesity, family history of diabetes) should undergo fasting blood sugar testing at the beginning of atypical antipsychotic treatment and periodically during treatment.
• All patients treated with atypical antipsychotics should be monitored for high blood sugar (hyperglycemia) symptoms.
• Patients who develop hyperglycemia symptoms should undergo fasting blood sugar testing.

There may also be an increased background risk of diabetes in patients with schizophrenia. As a precaution, many doctors advise that all patients treated with atypical antipsychotics receive a baseline blood sugar level reading and be monitored for any increases in blood sugar levels during drug treatment. Patients should also have their lipid and cholesterol levels monitored. [For more information, see In-Depth Report #60: Diabetes - type 2.]

Typical Antipsychotic Drugs

The standard typical antipsychotic drug used for schizophrenia is haloperidol (Haldol). Others include:

• Chlorpromazine (Thorazine)
• Perphenazine (Trilafon)
• Thioridazine (Mellaril)
• Mesoridazine (Serentil)
• Trifluoperazine (Stelazine)
• 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, many patient's stop taking the drug.

Depot therapy (long-lasting monthly injections, usually of haloperidol or fluphenazine) has been used with success in people who have difficulty complying with a daily regimen of these drugs. Researchers are studying low-dose regimens to discover if they can be effective and cause fewer side effects.

Side Effects of Typical Antipsychotics. These drugs can have adverse side effects related to many organs and systems in the body. These drugs are also known as neuroleptics, a name that comes from the severe neurological side effects that these medications can cause. Side effects include:

• Extrapyramidal symptoms
• Sleepiness and lethargy -- common in the beginning but usually decreases over time
• Insomnia and agitation -- in some cases
• Dulling of the mind
• Nausea, vomiting, diarrhea, constipation, and heartburn
• Dry mouth and blurred vision
• Allergic reactions
• Sexual dysfunction -- a common reason why patients stop taking the drug; amantadine may help offset this side effect
• Neuroleptic malignant syndrome -- rare, but can be fatal without prompt treatment
• Increased prolactin levels -- prolactin is a hormone associated with infertility and impotence. High levels can cause menstrual abnormalities and may increase the risk for osteoporosis and possibly breast cancer
• A sudden drop in blood pressure (hypotension)
• An increased risk of sudden cardiac death

In general, higher potency drugs cause less drowsiness and drops in blood pressure but pose a higher risk for extrapyramidal side effects. Lower-potency drugs (such as chlorpromazine, thioridazine) are more sedating and have milder side effects.

Extrapyramidal Symptoms

Nearly every drug used to date for schizophrenia can cause extrapyramidal side effects to some degree. These side effects involve the nerves and muscles controlling movement and coordination.

Description of Extrapyramidal Side Effects. These effects resemble some of the symptoms of Parkinson's disease and include the following conditions:

• Tardive dyskinesia is the most serious extrapyramidal side effect. It often manifests itself 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 may appear months or even years after taking the drugs. After the drug is stopped, symptoms can sometimes persist for weeks or months and may be permanent. Some people are more likely to develop these symptoms, including older patients, women, smokers, people with diabetes, and patients with movement disorders.
• Acute dystonia typically develops shortly after taking an antipsychotic drug. This syndrome includes abnormal muscle spasms, particularly sustained contortions of the neck, jaw, trunk, and eye muscles.
• Other extrapyramidal symptoms. Other effects are agitation, slow speech, tremor, and retarded movement. It should be noted that sometimes these symptoms mimic schizophrenia itself. In response, the doctor may be tempted erroneously to increase the dosage.

Treatment of Extrapyramidal Side Effects. In general, if extrapyramidal side effects occur from neuroleptic drugs, the doctor may first try to reduce the dosage or switch to an atypical drug. Other approaches to reduce these symptoms include:

• Anti-parkinsonism drugs known as anticholinergics increase dopamine levels and help to restore balance. Among the anticholinergics sometimes used are trihexyphenidyl (Artane, Trihexy) and benztropine (Cogentin). They are not helpful for tardive dyskinesia, however. Some of these drugs may also help in managing negative symptoms of schizophrenia. The use of these drugs, however, adds to the cost and complicates management. These medicines also have their own, sometimes serious, side effects. Most doctors recommend them only for patients who cannot be monitored regularly, need very high doses of powerful antipsychotic drugs, and are at risk for severe side effects. They should be stopped after 3 or 4 months, if possible. If symptoms recur, the drugs can be reinstituted. Withdrawal from anticholinergics can cause depression that can worsen schizophrenia.
• Benzodiazepines may also alleviate these symptoms.

Supportive Add-On 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, fewer than half of all patients take these medications.

Anti-Anxiety Drugs. Benzodiazepines are drugs normally used to treat anxiety. They also have some modest effect on psychotic symptoms. They may be useful in the early stages of a psychotic relapse for preventing a full attack. They also 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 anti-anxiety medication and clozapine. There is no evidence, however, 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 drugs should occur gradually.

Lithium. Lithium, ordinarily used for bipolar disorder, is useful for some schizophrenic 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.

Anti-Epileptic Drugs. Drugs ordinarily prescribed for epilepsy -- such as carbamazepine (Tegretol), gabapentin (Neurontin), lamotrigine (Lamictal), or others -- are occasionally used in combination with antipsychotic drugs for patients who do not respond to standard drugs.

Estrogen Replacement in Women. Estrogen may be nerve-protective. Some investigators have proposed using estrogen therapy to help with cognitive impairment. However, evidence is weak, and cancer and cardiovascular risks of estrogen therapy must be considered.