Medications

At the time of this report, six atypical antipsychotic drugs are approved in the United States.

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

Clozapine was the first atypical drug approved. The other five appear to have fewer side effects than clozapine. In general, it may take up to 6 months before an atypical drug has an effect. Most of these drugs come in pill form, but some may come in liquid form or as an injection.

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

Benefits of Atypical Antipsychotics.

  • They simultaneously affect both dopamine receptors and other neurotransmitters responsible for psychotic symptoms.
  • They improve negative as well as positive symptoms.
  • Some may even improve working memory and mental functioning.
  • They may reduce depression and hostility.
  • They may reduce the risk for suicide. (Clozapine is specifically approved for the prevention of suicide and may be more effective than other drugs in this important area.)
  • These drugs, particularly the newer atypicals, have fewer extrapyramidal side effects than the typical neuroleptics.

These drugs do 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. For example, in one 2002 study, clozapine and olanzapine were more effective than risperidone, but the differences were modest. However, clozapine and olanzapine may have some heart risks that are not as great as other atypicals. Zisprasidone may produce less movement disorders and less weight gain than risperidone.

Studies to date do not report much effect on information processing and concentration, and high doses can dull the mind to the same extent as the older drugs. A 2005 study did indicate that olanzapine prevents loss of gray matter in the brain, unlike the older typical antipsychotic haloperidol. Loss of gray matter has been linked to social, cognitive, and emotional deficits. This study suggests that atypical antipsychotics may halt the brain deterioration that is part of the schizophrenia disease process. More research is needed.

Comparing Atypical Drugs

Drug

Comparative Studies on Effectiveness

Comparative Studies on Adverse Effects

Clozapine (Clozaril)

Superior to risperidone for severe, chronic schizophrenia.

Superior to olanzapine in reducing the risk for suicide.

May be slightly better than others for improving negative symptoms.

Agranulocytosis (1.3% risk). Potentially life-threatening reduction in white blood cells. Occurs within 3 months of taking clozapine. Higher risk in older women. Unlikely to develop after 6 months. Can be reversed if clozapine is withdrawn at once.

Reports of inflammation of the heart, which in rare cases can be fatal.

Highest risk for weight gain of all atypicals. Along with olanzapine has higher risk for diabetes and elevated triglycerides than other atypicals.

Risperidone (Risperdal)

Not as effective as clozapine or olanzapine for chronic, severe schizophrenia, but differences are modest.

More and longer hospitalizations compared to olanzapine.

Monthly injection is available that may cause less symptom fluctuation than the oral form.

Less risk for weight gain and unhealthy cholesterol levels than clozapine and olanzapine. (There is still some risk for weight gain, however. In one study 12% gained weight.) Causes more sexual dysfunction than olanzapine and quetiapine.

Olanzapine (Zyprexa)

Greater improvement in positive, negative, depressive, and cognitive symptoms than quetiapine or risperidone.

Higher risk for unhealthy cholesterol levels, weight gain (27% in one study) and diabetes than other atypicals (except for clozapine).

Quetiapine (Seroquel)

Similar to older antipsychotics in treating positive and negative symptoms. May improve mental performance. May have benefits for elderly patients.

Can cause weight gain, but not as much as clozapine or olanzapine.

Also appears to be free of extrapyramidal side effects and increases in prolactin.

Ziprasidone (Geodon)

May improve negative as well as positive symptoms. May also reduce anxiety.

Appears to have no significant risk for weight gain, high cholesterol levels, or diabetes. May, however, have some adverse effect on heart rate compared to other atypicals. Causes less movement disorders and less effect on prolactin levels than risperidone.

Aripiprazole (Abilify, Abilitat)

Improves positive and negative symptoms.

May have less risk for extrapyramidal and other side effects.

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 (See box: Diabetes Risk and Atypical Antipsychotics)
  • Weight gain
  • Seizures
  • Heat stroke
  • Sudden drop in blood pressure (hypotension)
  • A drop in white blood cell count (neutropenia)
  • Extrapyramidal side effects (See box: Extrapyramidal symptoms)
  • 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

Warning: Because of an increase in death rates for elderly patients with dementia, the FDA has advised that atypicals not be used to treat behavioral disorders in this population. Atypicals are not approved for this indication, but are frequently prescribed on an “off-label” basis.

Diabetes Risk and Atypical Antipsychotics

In 2003, the FDA requested that the strongest warning be added to the product labels of all atypical antipsychotics. This so-called “black box” warning advises that these drugs can increase the risk of high blood sugar (hyperglycemia) and diabetes. The 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. [For more information, see In-Depth Report #60, Diabetes - type 2.]

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)
  • 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 Neuroleptics. Neuroleptics can have adverse side effects related to many organs and systems in the body. The very name neuroleptic comes from the neurological side effects that these drugs cause, which can be very severe. Side effects include:

  • Extrapyramidal symptoms (See box: 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 that patient's 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 the following:

  • Ondansetron (Zofran), an anti-nausea medication, is now under investigation for treating tardive dyskinesia.
  • 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 have no beneficial effect on tardive dyskinesia, however. Some of these drugs may also be helpful in managing negative symptoms of schizophrenia. The use of these drugs, however, adds to the cost, complicates management, and they have their own, sometimes serious, side effects. Most experts 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 effects. They should be stopped after 3 or 4 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.
  • Benzodiazepines may also alleviate these symptoms.
  • Small studies have suggested that certain alternative drugs, including vitamin B6 and melatonin, may help reduce 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, less than half of all patients are given 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 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 drugs should be achieved 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.

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

Omega-3 Fatty Acids. Studies suggest that omega-3 fatty acids found in fish oils have been associated with improvement in patients with schizophrenia. Docosahexaenoic acid and eicosapentaneoic acid (EPA) are the important compounds in these fatty acids. EPA is particularly promising. In a 2002 study, patients taking EPA in addition to their usual medicine reported improvements in treatment-related dyskinesia (involuntary movements) and in schizophrenia symptoms as well.

Stimulants and Other Drugs to Promote Wakefulness. The drugs used for schizophrenia can cause severe and persistent sleepiness. This is a difficult side effect to treat because stimulants may trigger psychosis. Modafinil (Provigil), a drug used for narcolepsy, is being investigated because it has different activities and experts hope it might be safer. Unfortunately, a 2002 case report suggested that this drug, too, may pose a risk for triggering psychosis.

Estrogen Replacement in Women. Estrogen may be nerve-protective. Some investigators are studying whether estrogen therapy will improve symptoms. In a 2002 study, women who wore an estrogen patch plus their regular medication experienced improved symptoms compared to those who had a dummy patch.

Drugs Used to Reduce Weight Gain and Prevent Diabetes. A number of drugs, such as orlistat and metformin, are under investigation to prevent weight gain and diabetes--important side effects of some of the atypicals.

Drugs Used for Alzheimer's Disease. Drugs used for Alzheimer's patients, such as rivastigmine or donepezil, are also being tested for patients with schizophrenia to see if they have any benefits on memory, attention, and planning skills and for reducing medication side effects. To date, studies have reported few or no benefits.

Investigative Therapies for Improving Cognitive Function

Experts are investigating drugs to be used along with antipsychotics or atypicals for improving mental function. Developing such drugs would be an important advance in this disease, particularly as some research suggests that cognitive disturbances play a major role in suicide motivation.

For example, ampakines are drugs that target specific glutamate receptors and some early evidence suggests that they may improve symptoms when used as add-ons to antipsychotic or atypical drugs.

Other investigators are studying the effects of glycine, a common amino acid, which stimulates receptors in the brain that are impaired in schizophrenia. In small studies, large doses of glycine resulted in a small improvement in negative symptoms in some patients. Researchers, however, are more interested in drugs called glycine transport inhibitors, which would elevate glycine levels in the brain, and would therefore have a more potent effect. (Glycine itself is available in health stores, but such products are unlikely to have much effect.)

Herbs and Supplements

Generally, manufacturers of herbal remedies and dietary supplements do not need FDA approval to sell their products. Just like a drug, herbs and supplements can affect the body's chemistry, and therefore have the potential to produce side effects that may be harmful. There have been a number of reported cases of serious and even lethal side effects from herbal products. Always check with your doctor before using any herbal remedies or dietary supplements.

The following are special concerns for people taking natural remedies for schizophrenia:

  • Gingko biloba can increase the risk for bleeding and interact with anti-clotting medications when used at high doses. Commercial gingko preparations have also been reported to contain colchicine, which can be harmful to pregnant women and people with kidney or liver problems.