Medications for the Treatment of Schizophrenia: Questions and Answers U.S. Department of Health and Human Services National Institute of Mental Health DHHS Publication No. (ADM) 92-1950 Printed 1992 Medications for the Treatment of Schizophrenia: Questions and Answers Prepared by Clinical Treatment Research Branch Deborah Dauphinais, M.D., Editor Division of Clinical and Treatment Research Introduction Schizophrenia, a severe mental disorder characterized by psychotic symptoms (thought disorder, hallucinations, delusions, paranoia) and impairment in job and social functioning, affects more than two million Americans. Current treatment programs for schizophrenia include combinations of medication, psychotherapy, education, and social-vocational rehabilitation. This booklet was prepared in response to inquiries reflecting a growing public need for information on the medications used to treat schizophrenia and related illnesses. In this booklet, meant to serve as a companion to Schizophrenia: Questions and Answers, we have addressed concerns and questions from the public that are frequently directed to us. General Information About Antipsychotic Medications The primary medications used to treat schizophrenia disorders are the antipsychotic medications, also called neuroleptics. Although these medications are not a cure for schizophrenia, they are effective in alleviating or reducing symptoms. Chlorpromazine (Thorazine), the first medication of this kind, became available for use in the United States during the early 1950s. Since its discovery, several other classes of antipsychotic medications have been developed. All of the widely used traditional antipsychotic medications are equally effective in treating schizophrenia; however, some individuals may prefer on medication to another because they experience different side effects. Some patients may respond better or experience fewer side effects with those traditional antipsychotic medications that are available in a long-acting, injectable form. Long-acting, injectable medications may also be helpful to patients who do not take their medication reliably. On the other hand, clozapine (Clozaril), an atypical antipsychotic medication, was first marketed in February 1990 and has been found to be superior to traditional antipsychotic medication for some patients with treatment-resistant schizophrenia. Clozapine appears to cause less muscle stiffness and restlessness (extrapyramidal side effects) than traditional antipsychotic medications and is less likely to produce tardive dyskinesia (TD). However, close monitoring via weekly blood testing is necessary for patients who are treated with clozapine, as described on page 10 of this booklet. The traditional antipsychotic medications are believed to help relieve psychotic symptoms by blocking the binding sites (receptors) for certain chemicals (neurotransmitters) found in the brain. The neurotransmitter dopamine has been the focus of much interest in learning how many of the antipsychotic medications work. Receptors for dopamine and other chemical transmitters in the brain are targets of the antipsychotic medications, different classes of which may affect one receptor type more than another. Specific side effects may result because a particular binding site is effected by a certain medication. One way to classify antipsychotic agents is by the dosage of medication, or the potency (strength) in milligrams, that is typically recommended. Antipsychotic agents are often classified on this basis as high, middle, or low-potency. Table 1 at the back of this booklet lists some common antipsychotic medications and their usual daily dosage. Individual doses of medication taken by patients may vary because of differences among individuals in both the severity of their illness and the rate at which they metabolize (break down) medication. This latter factor is influenced by age, rave, sex, body build, diet, use of cigarettes or alcohol, and other medications being taken. The lowest possible dosage of medication effective in relieving symptoms is usually prescribed. Sometimes symptoms of schizophrenia will flare up, requiring a temporary (weeks to months) increase in medication dosage. After an initial or acute episode of illness has been treated with medication, the doctor usually will taper the dosage very slowly to the lowest possible level necessary to keep the symptoms from returning. In a few circumstances, especially when symptoms are mild, some individuals may not require medication. Others may be able to use very low doses except when symptoms are severe. Because of all these factors, it is important that patients consult with their doctor before making changes in medication dose. Can a Patient Become Addicted to Antipsychotic Medications? Addiction to antipsychotic medication does not occur. However, some individuals who have taken such medications for more than a few weeks experience mild, unpleasant symptoms such as nausea, vomiting, abdominal cramps, diarrhea, or sweating when the medication is abruptly stopped. If it becomes necessary to stop medication, the dosage should be slowly tapered to avoid an increase in psychotic symptoms or the effects mentioned above. How Long Will a Patient Have to Take Antipsychotic Medication? Duration of therapy with antipsychotic medication is highly individual. Most patients with chronic schizophrenia require some type of medication, usually antipsychotic, for most of their lives. However, some individuals, especially those who have insight into the nature of their illness and understand that increased symptoms may be a warning sign for relapse, are able to take a reduced dose or discontinue medication periodically. What Are the Major Side Effects of Antipsychotic Medications? As noted previously, the side effects of antipsychotic medications are a result of their action on chemical receptors. The different classes of antipsychotic medications may affect one receptor more than another, causing different side effects. For example, the lower potency antipsychotic are more likely to produce sedation, dry mouth, episodic low blood pressure, and dizziness, whereas the higher potency agents are more likely to produce drooling and muscle stiffness. Other side effects of antipsychotic medications include constipation, skin rash, sun sensitivity, cholestatic jaundice (slowing of bile flow in the liver), and lowered white blood cell count (agranulocytosis). For al l of the currently available antipsychotic medications except clozapine, the risk of lowered white blood cell count is extremely low. With clozapine, however, the risk is high enough (1% to 2% during the first year) to require weekly blood cell monitoring to ensure early detection of this disorder. Antipsychotic medications are also capable of lowing the seizure threshold. This is an especially critical side effect of clozapine, as patients taking higher doses are at a greater risk for seizure than patients taking lower doses. Additional important side effects (e.g., movement disorders, including muscle stiffness and TD; neuroleptic malignant syndrome; and side effects involving the reproductive system) are discussed separately. Although most patients develop some mild side effects to antipsychotic medications, the risk for developing severe side effects is relatively low overall, and most such side effects can be controlled or tolerated with another medication. What Types of Movement Disorders Are Produced by Antipsychotic Medications? Antipsychotic medications may produce several types of abnormal movements and muscle stiffness. Dystonia is the powerful, involuntary contraction or spasm or a muscle or group of muscle. It may occur in any muscle group and may be dramatic in appearance. Dystonia typically occurs within the first week of treatment, with, or during an increase in dose of, the antipsychotic medications. Akathisia is a feeling of internal restlessness, which may result in continuous leg movements and leaves some patients feeling compelled to pace. Both lowered or stopped, and both can be treated with anticholinergic medications such as benztropine mesylate (Cogentin) and trihexyphenidyl (Artane). Akathisia is also sometimes treated with propanolol (Inderal), amantadine (Symmetrel), or lorazepam (Ativan). Antipsychotic medications can also produce slowed or stiff movements resulting in a condition resembling Parkinson’s disease called pseudoparkinsonism. This condition can occur during the first few weeks of treatment and is characterized by stiffness or rigidity of arms and legs, shuffling when walking, a tremor occurring at rest, and slowed movements of facial muscles causing a lack of facial expression. Pseudoparkinsonism caused by antipsychotic medication may improve with time, is reversible when medication is lowered or stopped, and may be treated with anticholinergic medication. TD is another movement disorder that can result from the use of antipsychotic medications. This syndrome is discussed in the next section. What is TD? TD is a syndrome of abnormal involuntary muscle movements that occurs in some patients who take antipsychotic medications. Research studies show the risk of developing TD to be about 5 percent per year, with 25 to 40 percent of patients developing TD after several years of taking these medications. Certain factors such as being older, being female, and having a diagnosis of affective or organic mental disorder may increase the risk of developing TD. In addition, a high total cumulative dose (the total of all the doses and length of time that medications were taken by a patient) may increase the risk of developing TD. The muscles of the face, especially those of the mouth and tongue, are most frequently involved in TD, although muscles of the neck, trunk, and extremities may also be affected. TD may appear in various forms and degrees of severity, from mild to severe and disabling. The abnormal muscle movements may appear as muscle spasms, twitching, chorea, or athetosis. The movements characteristic of chorea are sudden and brisk, appearing as a flicking or jerking in the trunk, pelvis, arms, and legs, or as a grimace, frown, tic, or smirk in the muscles of the face. Athetosis is a slow twisting or writhing movement of the muscles. Chorea and athetosis may occur alone or together in TD and other neuropsychiatric conditions. Because other neuropsychiatric disorders may be mistaken for TD, a doctor must take a history of the patient to include information about past and present use of antipsychotic medications, neurological and psychiatric symptoms, medical illnesses, and psychiatric and medical illnesses in the family. The doctor should also do a complete physical examination with emphasis on the nervous system. It may be necessary to perform blood tests and a magnetic resonance imaging examination of the brain to rule out other causes of the abnormal movements. Patients who take antipsychotic medications should be examined periodically for TD. Whenever possible, an evaluation for the presence of abnormal movements should be performed before such medication is started. Examination should then be performed after 3 months, 6 months, and at least every 6 months thereafter. Patients who develop TD should be examined every 3 months. In some patients, symptoms of TD may be reversed or reduced when antipsychotic medication is reduced to the lowest dosage possible that will still control psychotic symptoms. Similarly, TD symptoms may lessen or disappear (i.e., be masked) when antipsychotic medication dosages are increased. Some patients experience brief symptoms of TD, known as withdrawal dyskinesia, when antipsychotic medication is stopped or lowered. However, anticholinergic medications, such as trihexyphenidyl (Artane) and benztropine mesylate (Cogentin), which are useful for treating muscle stiffness, may worsen the symptoms of TD. Anxiety and emotional distress may aggravate the symptoms of TD; therefore, antianxiety medications may be helpful to reduce TD symptoms in anxious patients. Recent research studies on medications effective in treating TD suggest that some medications may reduce symptoms in some patients, so any patients identified as having TD should consult their doctor regarding possible treatments. What Is Neuroleptic Malignant Syndrome (NMS)? NMS is a relatively rare but potentially serious side effect of antipsychotic (neuroleptic) medications. It is characterized by muscle rigidity, fever, and dysfunction of the autonomic nervous system (a part of the nervous system that helps regulate blood pressure and body temperature) leading to changes n blood pressure and heart rate, and to increased sweating. Breakdown of muscle tissue can occur in severe cases of NMS, causing high levels of an enzyme creatinine phosphokinase, also called CPK, to accumulate in the bloodstream. Patients who develop severe NMS usually need to be immediately admitted to a medical facility for treatment with intravenous fluids to prevent dehydration, and they may be given muscle-relaxing medications to treat muscle rigidity. Antipsychotic medications should be used very cautiously in patients with a history of NMS. Questions Frequently Asked About the Effect of Antipsychotic Medications of the Reproductive System Will Taking Antipsychotic Medications Affect Sexual Performance? Some men and women who take antipsychotic medications experience a lowering of their sexual drive. Antipsychotic agents may slightly lower blood levels of testosterone, the hormone responsible for maintaining the libido (sex drive) in both men and women. The lower potency antipsychotic medications, such as thioridazine (Mellaril) and chlorpromazine (Thorazine), occasionally cause delayed or retrograde ejaculation in men. During retrograde ejaculation, orgasm is reached without the simultaneous emission of semen; semen is instead propelled backwards into the bladder and eliminated with the next urination (which may appear cloudy as a result). Will Antipsychotic Medications Affect the Menstrual Cycle or the Ability To Have Children? Antipsychotic medications lead to an increased level of the hormone prolactin. High prolactin levels may cause irregularity or lengthening of the menstrual cycle, breast swelling, and lactation (breast milk production) in women. Breast enlargement may also occur in men taking antipsychotic medications ; this is called gynecomastia. These changes are reversible when the dose of antipsychotic medications is reduced or stopped, causing prolactin levels to be lowered or return to normal. Women with schizophrenia, regardless of their medication status, may have a lower level of fertility compared with nonschizophrenic women. Conceiving a child may be more difficult for a woman taking antipsychotic medications because of lowered fertility or menstrual irregularities associated with such medications. Therefore, it is important for women taking these medications to discuss family planning with their doctor and other clinicians. Do Antipsychotic Medications Cause Birth Defects? There are no birth malformations known to be caused by antipsychotic medications . As previously discussed in this booklet, antipsychotic medications are thought to reduce symptoms of schizophrenia by helping to correct chemical imbalances in the brain; it is unknown if the changes in neurochemical levels or their receptors that occur in the brain of a developing fetus exposed to antipsychotic medications will affect the developing nervous system connections or the fetus. Further research is needed in this important area. As all circumstances are not the same and each patient may have different medical and emotional needs, any woman who takes antipsychotic medications (or other medications) and considers becoming pregnant should seek advice from her physician to discuss the risks and benefits for her. What Additional Medications Are Available for Patients Who Do Not Achieve Full Relief of Their Symptoms With Antipsychotic Medications? Some patients receive only partial relief of their symptoms from antipsychotic medications. Research studies suggest that three other medication - lithium, carbamazepine (Tegretol), and some of the benzodiazepine antianxiety medications - may be useful in the treatment of schizophrenic patients when taken in conjunction with traditional antipsychotic medications. Lithium may help to reduce psychotic symptoms further; may increase the length of time between episodes of illness; may reduce excitement; and may lead to improved social functioning, cooperation with treatment, and personal hygiene. Patients do not need to have mood swings to benefit from lithium treatment. Research studies of carbamazepine, an antiseizure medication also used to treat bipolar affective disorder (manic-depressive illness), have found this medication useful in reducing hostile and aggressive behavior in some schizophrenic patients. Benzodiazepines such as lorazepam (Atican) and alprazolam (Xanax), which are primarily used to treat anxiety, have been found to help reduce agitation during acute episodes of schizophrenic illness and may, if given early in the course of an acute episode of schizophrenia, prevent a relapse. Results from research studies of the use of benzodiazepines n patients with chronic schizophrenia show mixed results as to the benefit of these medications for long-term use. Benzodiazepines may help to reduce symptoms of psychosis in very anxious patients, but further research needs to be done into the types and dosages of these medications and the symptoms that may best respond to treatment with benzodiazepines. Antidepressant medications are often helpful in treating depression when it occurs in schizophrenic patients. More recently, clozapine has been used to treat patients with chronic schizophrenia who do not respond well to traditional treatment regimens. Clozapine is more thoroughly discussed in the next section. Many other medications have been studied for their effectiveness in treating schizophrenia, with inconsistent results. Medications not generally considered useful for treatment of schizophrenia include propranolol (Inderal), levodopa, vitamins in high dosages, and valproate (Depakote, Depakene). Electroconvulsive therapy (ECT) was one of the earliest treatments of schizophrenia. Although ECT is not useful for most schizophrenic patients, it may be useful in treating acute symptoms in certain patients who are in severe states of withdrawal (catatonia) or who present with significant affective symptoms such as uncontrolled mania. Clozapine and Other Atypical Antipsychotic Medications As a group, the atypical antipsychotic medications differ from the traditional antipsychotic medications in two ways. First, atypical antipsychotic medications are believed to produce less muscle stiffness and may be less likely to cause TD than the traditional antipsychotic agents. Accordingly, because they are less likely to produce neurological side effects, they do not compound or worsen negative symptoms such as flat affect, lack of motivation, and poverty of thought and speech. Second, they do not cause an increase in the hormone prolactin. Thus, specific endocrine, side effects, such as enlarged breast tissue and menstrual irregularities, occur to a much lesser extent. (See section on Questions Frequently Asked About the Effect of Antipsychotic Medications on the Reproductive System.) Clozapine (Clozaril), the only atypical antipsychotic agent currently marketed in the United States, has been found to be beneficial to some patients who have not responded to treatment with traditional antipsychotic medications or could not tolerate traditional antipsychotic medications because of severe side effects. In a large research study conducted at several medical centers across the United States, it was found that 30 percent of chronic schizophrenic patients who had not responded to treatment with traditional antipsychotic agents improved at least somewhat on clozapine. While there have been a few reports of seriously ill schizophrenic patients making a dramatic recovery from treatment with clozapine, this is a relatively rare event. As previously noted, clozapine can also cause agranulocytosis (low white blood cell count), a serious side effect that can lead to death if not diagnosed and treated immediately. The risk of developing some degree of agranulocytosis on clozapine is between 1 and 2 percent during the first year. If detected and promptly treated, however, this condition is completely reversible. Therefore, patients who take clozapine must have blood tests done every week. Because the high cost of this medication and the weekly blood test requirements have limited its availability, government agencies, consumer groups, and the manufacturer of clozapine have been seeking ways to make this medication more available to patients who may benefit from it. Will Any New Antipsychotic Medications Be Available Soon? Research is ongoing to develop newer, safer antipsychotic medications. Two promising medications, remoxipride (available in Europe under the trade name Roxiam) and risperidone, appear to be as effective as the traditional antipsychotic medications and they may cause less muscle stiffness and other movement disorders. These medications are still being tested in the United States and are not expected to be available here for some time. Questions Frequently Asked About Drugs of Abuse and Their Effects on Schizophrenia Do Street Drugs Cause Schizophrenia? Abusing drugs does not cause schizophrenia, but certain street drugs can produce symptoms similar to acute schizophrenia, such as hallucinations (both visual and auditory), paranoia, delusions disorganized thinking, and excited behavior. Psychostimulant medications (amphetamines and cocaine) and hallucinogenic drugs such as lysergic acid diethylamide (LSD), phencyclidine (PCP), mescaline, and marijuana (especially marijuana high in tetrahydrocannabinol or laced with other drugs) are more likely to produce psychosis that other street drugs. Individuals with a biological vulnerability toward schizophrenia or other psychotic illness may be at greater risk for developing drug-induced psychosis. What Effects Do Drugs of Abuse or Alcohol Have on Patients With Schizophrenia” Drugs of abuse or alcohol may worsen schizophrenia symptoms or lead to a relapse. Therefore, schizophrenic patients who abuse drugs or alcohol may require a higher dose of antipsychotic medication to control their schizophrenic symptoms. Comments Although the antipsychotic medications are not a cure for schizophrenia, they help to relieve the symptoms of illness and prevent the recurrence of those symptoms for many patients. Since the introduction of these medications in the 1950s, many individuals have been able to lead improved lives outside mental institutions. Some of the newer medications under development are as effective as the traditional agents and are likely to produce fewer extrapyramidal side effects. This may result in better medication compliance in patients who experience troubling side effects. Researchers are working to find new medications that are more effective that the traditional antipsychotic agents, especially for the treatment of negative symptoms of schizophrenia, and to find ways to produce the best possible treatment outcome using the currently available medications. Table 1. Antipsychotic medications available in the United States Generic name Trade Name PDR dose range (mg/day)1 Chlorpromazine Thorazine 100-1000 Chlorprothixene Taractan 75-600 Clozapine Clozaril 300-900 Fluphenazine Prolixin, Permitil 1-20 Haloperidol Haldol 1-15 Loxapine Loxatane 60-100 Molindone Moban 15-225 Mesoridazine Serentil 100-400 Perphenazine Trilafon 8-64 Thiothixene Navane 20-60 Thioridazine Mellaril 200-800 Trifluoperazine Stelazine 10-40 Note. - PDR = Physician’s Desk Reference 1 As discussed in this booklet, the daily dosage of medication varies among individuals. The lowest dosage possible to relieve symptoms should be prescribed.