Schizophrenia

Description

Medications

A number of atypicals are either available or under investigation. Clozapine (Clozaril) was the first atypical antipsychotic. Newer agents include risperidone (Risperdal), olanzapine (Zyprexa), quetiapine (Seroquel), and others. They appear to have fewer side effects than clozapine. Not all are available in the U.S. It may take up to six months before they have an effect.

Benefits of Atypicals. Atypical agents have the following benefits:

• 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.

It is important to note, however, that they have some significant limitations and complications, and their benefits compared to each other and to the antipsychotics are not always clear-cut. In-depth comparative studies are underway to determine which specific agents 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 with other atypicals. Studies to date do not report much effect on information processing and concentration, and in fact high doses can dull the mind to the same extent as the older drugs.

Side Effects. The following are side effects of most atypicals:

• Nasal congestion or runny nose.
• Drooling.
• Dizziness.
• Headache.
• Drowsiness. (In some cases, however, drugs may also cause restlessness and insomnia.)
• Constipation.
• Rapid heart beat.
• Difficulty urinating.
• Skin rash.
• Increased body temperature because of reduced sweating. (On the other hand, some may also cause profuse sweating.)
• Mental effects (confusion, short-term memory problems, disorientation, and impaired attention).

The following are some severe side effects or complications that may occur in with most of these agents:

• Seizures. (Five-percent risk per year with clozapine. Others pose less of a risk.)
• A drop in blood pressure (associated with a few reports of sudden cardiac death with initial usage of the clozapine).
• A higher risk of heat stroke.
• Drop in white blood cells (neutropenia). The risk is highest with clozapine, which requires monitoring, but it may occur with other atypical agents as well.
• Extrapyramidal side effects. It should be noted that risks for these are lower than with standard antipsychotics. (They still occur in about 20% of patients taking most atypicals.)
• An increase in risk for cataracts and worsening of any existing glaucoma.
• An increase in prolactin levels. Prolactin is a hormone that can cause fluid secretions from breasts in women or impotence in men.

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. 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 agents. 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 derives from the neurologic side effects that these drugs cause, which can be very severe. Side effects include the following:

• Extrapyramidal symptoms. These are the most disturbing and common side effects and involve disruption in the nerves and muscles controlling movement and coordination. They are a major reason for noncompliance.
• Sleepiness and lethargy. This commonly occurs in the beginning of therapy but usually decreases over time. (It should be noted that the drugs can also cause insomnia and agitation.)
• Dulling of the mind (but they can also improve thinking and concentration)
• Gastrointestinal side effects (nausea, vomiting, diarrhea, constipation, heartburn).
• Dry mouth and blurred vision.
• Allergic reactions.
• Sexual dysfunction. This side effect is a common reason for noncompliance, although the drug amantadine may help offset this side effect.
• Neuroleptic malignant syndrome. This is a rare side effect, in which dangerously high body temperatures can occur. Without prompt and expert treatment, this condition can be fatal in up to 20% of those who develop it.
• Hyperprolactinemia (high levels of the hormone prolactin). This is common with the use of antipsychotics. This effect can cause menstrual abnormalities and may increase the risk for osteoporosis and possibly breast cancer. This risk is of special concern for adolescents, whose hormonal systems are still developing.
• A sudden drop in blood pressure (hypotension).
• An increased risk of sudden cardiac death.
• Higher potency drugs (e.g., haloperidol and fluphenazine) cause less drowsiness and drops in blood pressure but pose a higher risk for extrapyramidal side effects. Low-potency drugs (e.g., chlorpromazine, thioridazine) are more sedating and have side effects that are not as acute.

Supportive Add-On Agents

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 agents 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 agents 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 Agents 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 agent, 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.

COX-2 Inhibitors. COX-2 inhibitors, which include celecoxib (Celebrex), rofecoxib (Vioxx), and valdecoxib (Bextra), are recent agents that have similar properties to the common nonsteroidal anti-inflammatory drugs (NSAIDs) (such as aspirin and ibuprofen). COX-2 inhibitors suppress certain immune factors and have other effects that might benefit patients with schizophrenia. In support of this, a 2002 study reported that patients who took celecoxib with an atypical experienced improved symptoms. More research is warranted.

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

Agents Used for Alzheimer's Disease. Agents 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 agents to be used along with antipsychotics or atypicals for improving mental function. Developing such agents 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 agents that target specific glutamate receptors and some early evidence suggests that they may improve symptoms when used as add-ons to antipsychotic or atypical agents.

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 agents 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.)

Alternative Treatments

Alternative remedies are often used for chronic illnesses. It should be strongly noted that not all are safe and their effectiveness, if any, cannot be guaranteed.

Gingko Biloba. In small 2001 studies, the herbal remedy gingko biloba was associated with few side effects and improved symptoms when added to a antipsychotic. Although the risks for gingko appear to be low, there is an increased risk for bleeding and interaction with anti-clotting medications at high doses. Commercial gingko preparations have also been reported to contain colchicine, an agent that can be harmful in pregnant women and people with kidney or liver problems.

Vitamin B6. One very small 2001 study suggested that vitamin B6 (pyridoxine) therapy may help to alleviate depression in some schizophrenic patients. A 2002 study reported no effect on psychotic symptoms. Further research is needed.